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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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How hypermobility Ehlers-Danlos Syndrome affects Parasympathetic and Sympathetic (P&S) System?

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DePace NL, Acosta CR, DePace Jr. NL, Kaczmarski K, Goldis M, Colombo J.

What is ehlers danlos hypermobility syndrome?

Hypermobility/Ehlers-Danlos Syndrome (hEDS) defines a spectrum of connective tissue disorders that are caused by defects in the genetic information that is used in humans to produce collagen. 

In both, the collagen is long and flexible, rather than short and stiff.  This results in loose and “leaky” connective tissue.  hEDS may be inherited, usually an autosomal dominant trait, however acquired cases occur frequently. 


What are the characteristics of Hypermobility Ehlers-Danlos Syndrome

To date there is no known cure for hEDS (Hypermobility Ehlers-Danlos Syndrome). However, there are a few characteristics of Hypermobility Ehlers-Danlos Syndrome that are well known (in no particular order): 

1) hEDS affects females significantly more than males;

2) In the young, the additional flexibility seems advantageous due to the lack of significant symptoms;

3) Generally, around the end of development (during later teens or early 20s) symptoms begin to present, and generally active and vivacious teenagers become sickly for no apparent reason with poor and, frequently, debilitating qualities of life.

Another primary characteristic of hEDS patients is that they demonstrate some degree of autonomic dysfunction (a.k.a., dysautonomia).  This may explain the last two characteristics listed above. 

When Dysautonomia Symptoms Appear?

During development, except for a couple of years around ages 8 and 15 when development slows down, the autonomic nervous system (ANS) is very active in development; therefore, dysautonomia symptoms are masked and the symptoms that appear are attributed to current factors with largely unknown histories. 

Once development ends, in the late teens or early twenties, dysautonomia symptoms are unmasked and the effects of a persistently overactive ANS presents.  In general, dysautonomia is the effects of an imbalance between the two autonomic branches:  the Parasympathetic and Sympathetic (P&S), nervous systems. 

What does Research Say About Parasympathetic and Sympathetic (P&S) Activity in Hypermobility Ehlers-Danlos Syndrome Patients?

Here we introduce a clinical cohort and some general characteristics of P&S function in 243 patients, predominantly female.

Younger hEDS patients’ P&S activity is high-normal possibly due to their heightened immune state and their body’s attempt to heal the “leaky” connective tissue.  The initial high-normal S-levels, higher than the P-levels (the opposite is typical), may be why there is persistent inflammation starting in the earlier years, a characteristic of hEDS patients. 

Typically, given that P-activity is more involved in development and pregnancy, P-activity is higher during these years, as in the normal subjects through the 20s and 30s.  Allergies, Mast Cell activation, Arthritis, Small Fiber disorder, etc. all involved S-activity. 

Histaminergic and inflammatory responses are Sympathetic functions.  As the Sympathetics are the reactionary branch, S-activity is normally short-lived. 

Persistent or inflated S-activity, therefore, leads to histaminergic and inflammatory disorders.  In hEDS cases, S-activity is typically inflated by the elevated P-activity and the additional S-activity drives the additional inflammation. 

S-activity is also involved in the pain response.  Amplified S-activity, due to abnormal, excessive P-activity[1], also amplifies the pain response, especially in “Fibromyalgia-like” pain syndromes. 

Since the majority of hEDS patients are female (91.8% of this total population), P-activity (and therefore S-activity) remains higher during childbearing and may be the reason for the persistence of the elevated P&S activity into the middle-age years.  Subsequently, the hEDS patients’ resting P&S activity normalizes, as compared with that of the Normal subjects.  However, the hEDS patients’ resting S-activity remains high compared with resting P-activity.

hEDS is believed to not be life-threatening, except for one form of EDS (the vascular form).  However, based on these sample populations, hEDS may perhaps reduce length of life an average of 10 years; given that they cross the CAN threshold up to 10 years earlier than Normals. 

Again, P-activity is protective.  The more reduced P-activity in the hEDS patients may be the cause of the reduced life span.  It may indicate an immune system that has fatigued earlier or it may be responsible for earlier onset MACE-risk (heat attack, stroke, heart failure, etc.). 

The higher mortality risk is reflected in the CAN with SB > 2.5 condition in the hEDS patients starting around age 60, on average.  CAN with SB > 2.5 is therefore an indicator that therapy should be more aggressive about establishing and maintaining low-normal SB:  0.4 < SB < 1.0; e.g., increasing dosages of Sympatholytics or reducing stress, including Psychosocial stress.  Overall, the P&S data are a better match to the natural history and progression of hEDS.

Many patients present with prior diagnoses of depression and anxiety or psychiatric illness attributed to them, but they know they have something real and abnormal that is not purely psychiatric.  The patients hurt all over and have diffuse pain, which keeps them from functioning properly.  They are often diagnosed as “Fibromyalgia” or “Chronic Pain Syndrome.” 

Many cannot perform any gainful employment.  Certainly, they become anxious and depressed because of their non-functional status.  Dysautonomia features, such as exercise intolerance, orthostatic intolerance (where one cannot stand up without getting brain fog or dizzy), and chronic or persistent fatigue are almost universally present in these patients.  There is a high percentage of females with this problem, but we do also see males in addition, since it is believed that if a person has this disorder, they can transmit it genetically to one or two of their children (autosomal dominant transmission).

It is well known that the P&S is, generally, very active during development.  This level of activity, masking any effects of excessive P&S activity, may explain why symptoms do not present until after development.  It has been postulated that “leaky” connective tissue permitting foreign items to leak-in causes a persistently, heightened immune response. 

This in-turn leads to a persistent state of Parasympathetic Excess (PE), mostly while active as well as for periods of time when younger at rest, as measured as high-normal SB (2.0 < SB < 3.0).  The persistent and prolonged stress on the more exposed and longer Parasympathetics (Vagal) nerves, including Oxidative Stress, tends to cause them to weaken first and fastest. 

The relative PE also forces a relative Sympathetic Excess (SE) which not only multiplies symptoms, but amplifies symptoms, such as Sympathetically-mediated pain and inflammation. 

Unfortunately, there is no cure for P&S imbalance in these patients.  Typically, with many other diseases and disorders, once P&S balance is established, then the nervous system “learns” this new condition and maintains it until some other clinical event occurs.  Unfortunately, in hEDS, the next clinical event, per se (such as the next infection), is only moments away once it leaks into the body. 

Therefore, there is also no real cure for P&S imbalance due to hEDS, only the ability to treat it to maintain P&S balance as much as possible as the systems continues to degrade more rapidly than normal.  Fortunately, once the protocol for the individual patient is determined, it may be implemented immediately should a significant clinical event occur, including pregnancy where patients may need to suspend treatment during that time.

Fatigue, exercise intolerance, shortness of breath, palpitations, and chest pains with which many patients with hEDS present, are often the result of P&S dysfunction. 

This goes hand in hand with the hEDS.  Even the amplified and generalized pain and inflammatory responses (not only in the joints), anxiety, brain-fog, memory and cognitive difficulties, sleep difficulties, GI motility issues, may be secondary to P&S dysfunction caused by hEDS. 

Many patients develop Small Fiber Disease which is an inflammation or dysfunction of unmyelinated small, type C nerve fibers which carry autonomic and sensory, including pain, signals. 

Also, hEDs is associated with Mast Cell hyperactivity which manifests as episodic histaminergic over-production.  Mast Cell may be associated with Celiac disease and food allergies or sensitivities.  Leaky Gut Syndrome may be involved either as a result of histaminergic excess or leaky connective tissue. 

Histaminergic over-production may be associated with persistent or excessive Sympathetic activity secondary to PE.  This may be tested for objectively and serially, with diagnostic test modalities that provide quantitative information.  This, in-turn permits more individualized titration of therapy given the then current state of the patient’s nervous system.

One reason for the lack of understanding and recognition of the P&S dysfunctions underlying hEDS is the fact that virtually all of the data collected from patients are collected while the patient is at rest. 

The ANS, specifically the P&S nervous systems are never at rest. (In fact, it may be argued that they are most active when you are sleeping, resting.)  As a result, the common thread behind the constellation of symptoms associated with hEDS is lost. 

It is well known that the Sympathetic nervous system is the reactionary branch of the ANS and is not supposed to be chronically active.  It is also well known that the Parasympathetic nervous system is the ANS branch that establishes the metabolic threshold around which the Sympathetic branch reacts and then works to quiet the Sympathetic branch.  Under normal resting conditions as one branch is activated the other becomes less active.

This is not the case in most abnormal conditions and is not the case under abnormal dynamic conditions.  There are two significant, dynamic P&S abnormalities (P&S dysfunctions that present when not at rest) that are, apparently, caused by hEDS and serve to exacerbate the symptoms of hEDS. 

One is known as Sympathetic Withdrawal (SW), which is an abnormal alpha-Sympathetic response to head-up postural change (sitting or standing) which leads to poor cardiac and cerebral perfusion which lead to fatigue, exercise intolerance, shortness of breath, palpitations, and chest pains, and anxiety, brain-fog, memory and cognitive difficulties, and sleep difficulties; respectively.  The other is known as Parasympathetic Excess (PE).which is an abnormal Parasympathetic response to a stress (a beta-Sympathetic) response. 

PE not only may exacerbate symptoms caused by SW, but it also amplifies the Sympathetic disorders, including pain and inflammatory responses (including in the joints).  It may also cause, or be the cause of, Mast Cell hyperactivity leading to unexplained rashes and Mast Cell Activation Syndrome (MCAS), and Small Fiber disorder.

PE may be a primary disorder caused by hEDS.  It is well known that the Parasympathetics control and coordinate immune responses, including providing the “memory” for the immune system.  Since hEDS enables foreign substances to “leak-in” to the body all of the time, the immune system is always on constant, heightened “alert” and thereby forces the Parasympathetics to remain overactive. 

Dynamically, PE forces the Sympathetic response to also be excessive (Sympathetic Excess or SE), secondarily.  Unfortunately, since most clinical office measurements are Sympathetically-based (HR, BP, etc.), only the SE is recognized (high HR and high BP), and therefore treated. 

However, this results in more PE because the complimentary Sympathetic activity is reduced enabling the increase in PE.  This often leads to unresponsive or labile patients which are often misinterpreted.  In these patients, when PE is recognized as a primary autonomic dysfunction, and treated as such, the secondary SE is often relieved organically, in time, and then the Sympathetically-based symptoms are often relieved organically, in time, assuming no end-organ effects.

A final thought for now.  Since the human body will assimilate foreign, ingested, collagen (i.e., from bones, shellfish shells and other animal connective tissue) perhaps this is a basis for some relief of hEDS.  The (normal) animal collagen may help to “plug the leaks” caused by the abnormal native collagen.  Many patients empirically find relief of symptoms with intake of collagen products.

As mentioned before, there is no genetic testing or lab testing that is diagnostic of hEDS.  That is not to say that we will not in the future hone down on a specific gene loci or other biomarkers that may be supportive of hypermobile Ehlers-Danlos Syndrome.  However, to date, there are none. 

Franklin Cardiovascular uses a scoring system developed by the EDS Society.  For now, it is possible to re-establish P&S balance and thereby help to restore an improved quality of life that permits a productive lifestyle, with less pain and better sleep.  This is just the beginning of a research effort that must include many more patients from many more sources as hEDS awareness continues to grow.

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What is Joint Hypermobility Spectrum Disorder?

Joint Hypermobility Syndrome or Joint Hypermobility Spectrum Disorder

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The joint hypermobility syndrome, also abbreviated JHS and the hypermobility spectrum disorder, also known as HSD are new terminology often used to describe the most common hereditary disorder of connective tissue diseases.  Connective tissue diseases include joint hypermobility syndrome, or the hypermobility spectrum disorder, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, Stickler syndrome.  Connective tissue disease disorders do not generally include lupus, rheumatoid arthritis, Sjogren’s disease, scleroderma, mixed connective tissue disease, vasculitis and other related rheumatologic diseases, although these diseases can give pain throughout the body and joints and muscles. They are usually not associated with connective tissue disorders unless there are two separate disease entities existing.

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Ehlers Danlos Syndrome

Do I have Hypermobile Ehlers-Danlos Syndrome Type III?

Ehlers-Danlos Syndrome Type III or Joint Hypermobility Syndrome

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Do I have Hypermobile type Ehlers-Danlos syndrome or hEDS, or am I just simply hypermobile and have diffuse pain all over?

I hurt all over.  These are questions that I am often asked from patients that come to our Ehlers-Danlos Syndrome doctors at Franklin Cardiovascular Associates.

There are several types of Ehlers-Danlos Syndrome.

We will discuss the various types subsequently.

However, the most common type that we see in clinical practice is the type known as Hypermobile Ehlers-Danlos Syndrome Type III.

This is also known as the hypermobile type of Ehlers-Danlos Syndrome (hEDS).  It has also been referred as benign joint hypermobility, or joint hypermobility syndrome (JHS).

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