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Autonomic Dysfunction : For Patients

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Q: What is the Autonomic Nervous System (ANS)?

A:  The body’s nervous system consists of the Central Nervous System (CNS) and the Peripheral Nervous System (PNS)The Autonomic Nervous System (ANS), which is a division of the PNS, influences and modifies the function of our internal organs.  The ANS acts as the control system, and functions without our knowledge; it functions unconsciously or involuntarily.  It regulates the body functions we do not think about, such as heart rate, blood pressure, blood vessel tone and size, breathing, urination, sexual function, sweating, and pupil reaction to light.

 

Q: What are the branches of the ANS?

A:  The ANS is composed of two parts, which together control and coordinate all the systems of the body.  They are the Parasympathetic Nervous System (PNS) and the Sympathetic Nervous System (SNS).

The Parasympathetic Nervous System is commonly referred to as the “Rest and Digest” Nervous System.  It is responsible for conserving energy and establishing metabolic baselines.  In many situations, it acts like the brakes of your car.  It is the “Protective” Nervous System.  The Sympathetic Nervous System is commonly referred to as the “Fight or Flight” Nervous System.  In many situations, it acts as the accelerator of your car.  It is the “Reactionary” Nervous System.  The ANS is one of the main human systems responsible for our capability and adaptability.  The interplay between the Parasympathetic and Sympathetic branches underlies these abilities.

Collectively, the Parasympathetic and Sympathetic Nervous Systems are the regulatory branches of the nervous system.  Anatomically and physiologically, they exist in both the Central and Peripheral portions of the nervous system.  Together, the PNS and SNS control bodily functions.  To properly affect this control in two components, the PNS and SNS need to be in balance.  The specific PNS-and-SNS balance required varies from individual to individual and is influenced by a person’s genetics.  It also varies with age, lifestyle, environment, and medical history.  Autonomic Dysfunction, commonly referred to as, “Dysautonomia”, results when there is an imbalance between the Parasympathetic and Sympathetic Nervous Systems.

 

Q:  What is Autonomic Nervous System Dysfunction?

A:  Autonomic Nervous System Dysfunction, also called, “Dysautonomia”, occurs when the nerves of the Autonomic Nervous System are damaged.  Another term for “Dysautonomia” is “autonomic neuropathy.  It can range from life-threatening to only minor problems.  It can affect the entire autonomic nervous system or parts of it.

Since the ANS controls actions such as heartbeat, involuntary breathing, or blood vessel size; any dysregulation can cause serious problems, especially with blood pressure or heart rhythm.  Basically, any organ system in the body, including sexual function and urinary function, may be adversely affected when there is a dysfunction of the Autonomic Nervous System.  The nerves that reach the organs are described as small type C fibers.  They are oftentimes damaged by other disease entities such as diabetes, Parkinson’s, amyloid, or autoimmune processes.  Occasionally, toxic substances, such as alcohol, or infectious agents, such as viruses or bacteria, can cause damage to the Autonomic Nervous System.  Simple aging can cause degeneration of the nerve fibers of the Autonomic Nervous System.  Some individuals have accelerated aging of their nerve fibers.

Some types of Autonomic Nervous System dysfunction are temporary, and recover over time.  Identification and treatment is therefore important.  Other types of Autonomic Nervous System dysfunction cannot recover completely, but can recover only partially or we can potentially delay continued deterioration of the nerve fibers with several measures.

When Autonomic Nervous System dysfunction is secondary to a disease entity, the autonomics will most likely improve when the underlying disease gets treated and improved.

When no cause of Autonomic Nervous System dysfunction is identified, we call this “idiopathic”.  In many instances, treatment can improve the symptoms and abnormalities.

When there is no cure, treatment can usually improve quality of life.

In treating patients with these illnesses, the goal is generally to get more good days than bad days.

 

Q:  What common disorders involve Parasympathetic and Sympathetic Nervous System Dysfunction?

A:  There are many disorders involving PNS and SNS dysfunction.  These include anxiety; chronic fatigue; fibromyalgia; persistent headaches; and various forms of fainting or pre-fainting (involving lightheadedness or dizziness), which we respectively term, “syncope” and “near syncope”.  Digestive problems, such as gastroparesis, gastroesophageal reflux disease (GERD), and irritable bowel syndrome, are also affected by PNS and SNS dysfunction.  Most importantly, a large percentage of patients in the world have what is termed, “orthostatic dysfunction”, commonly manifested as “orthostatic intolerance”.  This form of lightheadedness or dizziness is arguably the most debilitating symptom of ANS dysfunction or autonomic neuropathy.  Usually, orthostatic dysfunction occurs when people are in the upright position, standing, or walking and develop evidence of lack of cerebral perfusion, which is blood flow to the brain.  It can cause visual effects, such as black spots.

Up to 97% of the time, this orthostatic intolerance syndrome is associated with chronic fatigue syndrome (CFS), which is defined as six months of significant exhaustion associated with unrefreshing sleep, daytime somnolence, swollen lymph nodes, sore throat, depression, and an inability to function.  It is felt that many of these disorders, including migraines, and neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s dementia, and fibromyalgia, may be the result of Autonomic Dysfunction.

 

Q:  What are the main chemical messengers, or neurotransmitters, used to communicate within the Autonomic Nervous System?

A:  The main chemical messengers, or neurotransmitters, are Acetylcholine (Ach) and Norepinephrine (Ne).  The nerve fibers that secrete Ach are cholinergic fibers, whereas the fibers that secrete Ne are called adrenergic fibers.  Generally, Ach has parasympathetic inhibitory effects and Ne has sympathetic or stimulating effects.

Occasionally, Ach has sympathetic effects, such as stimulating sweating or piloerection, where the hair stands up on end.

Simple measures and pharmacological drugs can relieve symptoms of autonomic dysfunction.  Some of these medications work like or through Ne or Ach, and other drugs oppose Ne or Ach.

ANS testing may give us guidance of how to treat a certain disorder by evaluating whether we believe sympathetic dominance or parasympathetic dominance is responsible.

 

Q:  How do I know I have ANS dysfunction?  What symptoms are indicators?

A:  Below is a questionnaire of 25 items, which we use in our clinical practice.  The more positive items answered, the higher the possibility an individual will test positive for ANS dysfunction.

AUTONOMIC QUESTIONNAIRE

CIRCLE WHICH SYMPTOMS YOU HAVE:

 

1

Lightheaded

2

Fainting and near fainting

3

Fatigue

4

Brain Fog or

Mental cloudiness

5

Difficulty findings words

6

Short term memory loss

7

Sensory: hypersensitive to light, sound, motion, touch

8

Pins and needs in arms/legs

9

Numbness in hands and feet

10

Coat hanger pain in neck and shoulders

11

Migraine

Headache

12

Tension headaches

13

Nausea, vomiting

14

Difficulty standing

15

Chest pain, palpitations

16

Short of breath

17

Hypermobility joints-

Joints pop out

18

Depression, anxiety

19

Sweat too much

20

Sweat too little

21

Salivate too little,

Dry mouth

22

Cold hands or feet

23

Dimmed vision

24

Dimmed hearing or ringing in ears

25

Does hot or cold weather bother you

We also list the commonly-used medicines a person may have been on for treatment.

A doctor’s evaluation is important.  Blood-pressure and heart-rate responses to lying, sitting, and standing need to be taken continuously up to three to five minutes.  Orthostatic Hypotension Syndrome is characterized by a drop in systolic blood pressure of more than 20 millimeters of mercury or a drop in diastolic blood pressure of more than 10 millimeters of mercury.  A rise in heart rate greater than 30 beats per minute within 3 minutes of standing suggests Postural Orthostatic Tachycardia Syndrome (POTS).

Questions that are also important include:  Does one feel full prematurely after eating?  Do they feel their stomach empties slowly or that they get nauseous or have to vomit quite easily?  This may represent gastroparesis.  While one is thought to be a purely gastrointestinal disorder, this may reflect abnormalities in the Autonomic Nervous System and also may be a clue that an individual has Autonomic Nervous System Dysfunction.

Another question to ask is:  Do I have erectile dysfunction?

Also, urinary tract questions need to be considered, such as:  Does one pass urine involuntarily, such as urinary incontinence, or have difficulty emptying urine, such as urinary retention?  While structural abnormalities may be the etiology, oftentimes, Autonomic Dysfunction may be the problem.

There are lab tests that may be useful in assessing if an individual has autonomic dysfunction.  Norepinephrine levels are often drawn while one is lying and standing.  Also, cortisol levels to rule out Addison’s disease, an adrenal disorder, oftentimes are measured.  A 24-hour urine for prostaglandins and metabolites of histamine are done to rule out mast cell activation syndrome, which may have autonomic dysfunction components associated with it.  Also, blood tryptase levels are drawn for individuals suspected of having mast cell activation syndrome.

There are many tests that can also assess for autonomic dysfunction, which can be done in a doctor’s office or in an outpatient laboratory setting.  One is a tilt test, which is a special type of evaluation in which a person is exposed to passive tilt at 45 or 60 degrees and the feet are unsupported.  Blood-pressure and heart-rate monitoring are done, and certain maneuvers are performed to see how their vital signs respond.  Computer printouts and waveforms are also analyzed.  There are also tests which require respiration and EKG heart rate monitoring in which cardiorespiratory testing can be employed to test individual’s heart rate responses to certain maneuvers such as a Valsalva maneuver (bearing down as though someone was moving their bowels), a standup or orthostatic posture assumption, or a passive tilt.  Also, deep breathing is a maneuver used to assess for vagal autonomic function.  There are also machines which can test for one’s sweating function.  This may be important, and an abnormal test may indicate peripheral autonomic nervous system dysfunction.

Individual’s autonomic nervous system dysfunction may also have peripheral somatic neuropathy of the other small type C fibers that are in the peripheral nervous system but are not autonomic but rather sensory.  Patients can lose sensation or have tingling or pins and needles sensation (paresthesia) in the hands and feet.  They can also experience burning or pain in various neuropathies that involve somatic nerves and not autonomic nerves.  Also, muscles may become weak if somatic nerves are affected.  There are various tests that can test for these types of somatic nervous system disorders which is a part of the peripheral nervous system separate from the autonomic nervous system, another part of the peripheral nervous system.  That is beyond the scope of this question and answer session, however.  Usually, a neurologist can address the workup of various types of peripheral neuropathies which are non-autonomic but somatic.  They are very commonly found in diabetics as is diabetic autonomic neuropathy.  Oftentimes, an individual can have both peripheral autonomic neuropathy and peripheral somatic neuropathy coexisting.  In patients who present with neuropathy symptoms, burning and tingling in their hands and feet, we oftentimes will test them and also find they have concomitant autonomic nervous system dysfunction.  Remember, both types of small fibers known as type C nerve fibers are affected and get disease in these types of peripheral nervous system disorders.

 

Q:  What causes fainting (syncope) or near fainting (presyncope)?

A:  Fainting, or syncope, occurs when there is a self-limited loss of consciousness caused by lack of blood flow and oxygen delivery to the brain, due to reduced cerebral blood flow.  Presyncope is near-loss of consciousness by the same mechanism.  Blood loss and dehydration are common causes which precipitate syncope or presyncope.

Syncope can be caused by cardiac abnormalities or abnormalities of the vessels within the lungs or abnormalities within the large blood vessel which leads to the heart (the aorta).  When structural cardiovascular diseases are excluded, most causes of syncope are usually benign.  An electrical abnormality in the heart or a cardiac arrhythmia is extremely important to exclude as this oftentimes can be life threatening.

The most common cause of syncope is neural reflex known as vasovagal syncope (VVS).  This is a neural reflex and it can be situational to cough, post-micturition after urination, status post emotional upset, or as a reaction to pain.  Also, extreme heat can precipitate this.\

Other causes of syncope occur only on assuming the upright position, either immediately or in a delayed fashion.  Vasovagal syncope can occur while sitting or standing for a prolonged periods of time but usually not immediately, whereas, orthostatic forms of syncope on assuming the upright position usually occur more immediately.  It is rate for an individual to have syncope while lying down.  The orthostatic causes of syncope are due to a considerable drop in the blood pressure that can be induced by drugs or other disorders that affect the autonomic nervous system.  Such disorders include diabetes, viruses, Parkinson’s disease, amyloidosis, and rarely other forms of autonomic central nervous system abnormalities such as multiple system atrophy (MSA).  There is also a disorder known as primary autonomic dysfunction with pure autonomic failure which affects the peripheral nervous autonomic system.  Parkinson’s, although it is a central nervous system disease, affects the peripheral autonomic nerves.

A cardiologist and a neurologist are often required to identify the cause of syncope if one is not clearly evident.  A cardiac arrhythmia and structural heart disease must be ruled out before addressing non-cardiac causes of syncope.  Cardiologists will use Holter monitors, long-term monitors up to 30 days, and even implantable loop recorders for years to search for arrhythmias which may be causing fainting episodes.  Echocardiograms, which are ultrasounds of the heart, stress tests, and even more advanced cardiac testing including electrophysiology assessment in a laboratory oftentimes can be required to exclude arrhythmias.

When a cardiac cause of syncope is excluded, but one is not sure if the patient is having a syncopal episode due to a vasovagal or an orthostatic issue, a tilt test is oftentimes indicated to differentiate between the two entities.  There are some other noninvasive tests which can be done in the office and use standing responses without tilt testing which may also be helpful such as cardiorespiratory testing with heart rate variability.  You should seek out a trained physician, preferably a neurologist, cardiologist, or occasionally an endocrinologist who may have specialized training in using these various forms of equipment.  As mentioned, sweat testing can identify if there is a peripheral autonomic nervous system disorder present, but cannot differentiate the types in an individual.

 

Q:  What is vasovagal syncope (VVS)?

A:  Vasovagal syncope (VVS) is also known as the “simple fainting spell”.  This is a neutrally-mediated type of syncope.  Vasovagal syncope involves a temporary loss of consciousness by a neurological reflex due to sudden dilatation of blood vessels of the legs and/or a slow heart rate.

Vasovagal syncope is also known as neurocardiogenic syncope.

Vasovagal syncope is usually benign and may be recurrent.  It also may be chronic.  It can go into crescendo phases of flare-ups.  Usually, it is caused by blood pooling in the legs due to sudden vasodilatation of the venous blood vessels.  Vasovagal syncope can be precipitated by emotional stress or prolonged upright posture, or even prolonged sitting.  It is oftentimes situational and can be caused by cough, heat, urination, pain, and alcohol.  A tilt test may be necessary to confirm that the syncope is reflexed by showing first a progressive early drop in blood pressure, gradual in onset without symptoms with the passive or head-up tilt test procedure.  This is later followed by a rapid drop in blood pressure and finally a slow heart rate.  Oftentimes, nausea, excessive fatigue, and sweating precede episodes of vasovagal syncope.  These are warning symptoms and allow the patient to preemptively lie down.

A tilt test is often used when one cannot differentiate vasovagal syncope from an orthostatic type of syncope, such as orthostatic hypotension.

Warning symptoms, when they occur, are often helpful in having a patient lie down to avoid an overt fainting episode.  These symptoms consist of lightheadedness, ringing in the ears, visual disturbances, sweating, and nausea.

As mentioned, symptoms of vasovagal syncope may occur sporadically and may not occur for long periods of time.  One out of three individuals will experience an episode of vasovagal syncope during their lifetime.  Some may not have recurrence.  Individuals who have recurrent episodes at times can go into a crescendo, or a frequently and disabling time period when they have very frequent episodes of vasovagal syncope.  These patients oftentimes require intensive pharmacology to attempt to put these reflex syncope episodes in remission.

Pacemaker therapy is rarely warranted and is usually discouraged in patients with frequent vasovagal syncope.  It may be helpful in older individuals over the age of 40 when documented periods of heart standstill or very slow heart rates are recorded, oftentimes with Holter monitors or loop recorders.

Treatment for vasovagal syncope is oftentimes supportive.  An individual should avoid circumstances that precipitate fainting episodes such as a crowded room or drinking alcohol in a hot environment.  Medications may also be helpful in treating episodes, especially when there are flare-ups.  We have found that anticholinergic therapy in individuals who test in our autonomic lab for high vagal tone may be useful.  In the past, individuals have used anticholinergics such as disopyramide (Norpace) (which is actually an antiarrhythmic drug).  Some physicians have used scopolamine (another anticholinergic).  We oftentimes use a tricyclic agent known as nortriptyline, which has strong anticholinergic mechanisms.  SSRIs and SNRIs, which are antidepressants, oftentimes have some anticholinergic effect and often are useful in people who have high anxiety syndromes or are very tense.  It is useful to hydrate and use salt loading frequently in patients who have frequent vasovagal syncope.  Compression stockings are often useful in addition.  In terms of pharmacological treatment, we have found that midodrine is often helpful and should be taken three to four times a day, usually starting at a 2.5 mg low dose and titrating upwards.  Also useful are mineralocorticoids such as fludrocortisone, which retain water within the blood vessel system.  Beta blockers, once thought to be very effective, have now been found not to be extremely effective.  They may be beneficial in patients older than 40 years of age, but in our experience, they have limited efficacy.  Selective serotonin reuptake inhibitors, or SSRIs, and selective norepinephrine reuptake inhibitors, or SNRIs, have been shown to be useful in some patients, especially those who have high anxiety or very high vagal tone.

Midodrine has been shown to be the most effective agent in patients who have flare-ups.  It is usually well tolerated but not recommended in patients with hypertension or heart failure.  It is actually an adrenergic agonist or potential vasoconstrictor that constricts the veins in the lower extremities.  It was approved by the Food and Drug Administration in 1996 for treatment of dysautonomia and orthostatic hypotension.  Midodrine is a prodrug which forms an active metabolite desglymidodrine, which is an alpha receptor agonist.  It does not stimulate heart rate.  Because it does not cross into the central nervous system, it does not cause any central effects.  Individuals who take midodrine, however, do complain of piloerection or goose bumps, sometimes paresthesias and tingling, especially over the scalp, occasionally men will have symptoms attributed to urinary frequency, and occasional headache can occur.  We have found in our experience that titrating very low doses up slowly make it much easier for people to tolerate this medication.  Midodrine is a very inexpensive and very effective agent in all types of autonomic nervous system dysfunction whether they are vasovagal or orthostatic such as orthostatic hypotension and postural orthostatic tachycardia syndrome.  The key is to start the medication very slowly at a low dose and slowly titrate it upward and give the patient time so that they can adapt to some of the minor side effects.

A new pharmacologic agent, Ivabradine (Corlanor) is a new sodium potassium If blocking agent which affects the sinus node and the heart rate.  It slows the heart rate down.  As vasovagal syncope may involve an increase in heart rate prior to when the blood pressure drops further and there is a decrease.  This medication may initially blunt the initial heart rate rise in the early part of the reflex.  It has been shown to be effective.  It was thought at one time that beta blockers would do this also.  There are some instances they are helpful also, especially occasionally in individuals over 40.  More research is being done on both of these agents, but we have found Corlanor to be very effective in various types of fainting disorders and even in treating patients with postural orthostatic tachycardia syndrome who have presyncope and not actual syncope.

 

Q:  What is orthostatic intolerance (OI)?

A:  Orthostatic intolerance affects millions of Americans at all ages.  It is a condition when the body changes in position, for example, assumes the upright position, a triggering of dizziness, lightheadedness, nausea, sweating, fainting, or near fainting may occur.  Lying down improves symptoms.  It is often related to improper regulation of the ANS.

Brain fog is also known as brain fatigue and can be caused by prolonged standing in a patient with orthostatic intolerance.  This is due to an abnormality of cerebral blood flow where not enough blood is delivered and oxygen demand is not met in the brain tissue.  Brain fog can cause:  a) a lack of focus; b) poor memory recall; and c) reduce mental acuity, and is often associated with lightheadedness and near syncope.  It is also associated with significant fatigue.  After episodes of brain fog and orthostatic intolerance, individuals have to lie down and often have debilitating fatigue for hours and days.

Orthostatic intolerance is due to predominantly three mechanisms:  1) Withdrawal of the sympathetic nervous system input into the legs assuming the upright position.  2) A more advanced form is actual orthostatic hypotension where the blood pressure drops more than 20 millimeters systolic or 10 millimeters diastolic and this can cause dramatic effects including syncope.  3) Postural orthostatic tachycardia can also cause orthostatic intolerance.  This is because there is a significant increase in the sympathetic nervous system outpouring on standing and the heart rate response becomes very rapid and impairs blood flow to the brain.

Regardless of the disease entity associated with orthostatic intolerance, the mechanism is a failure of delivery of enough blood to the brain to the cerebral vessels and brain fog, fatigue, visual acuity issues, memory issues, and lack of focus become very important.  It is a very disabling problem and requires medical attention.

One needs to understand the pathophysiology of upright posture to understand why orthostatic intolerance occurs.  Normally, when a person stands, about one-half quart of blood leaves their chest and goes into their lower abdomen, buttocks, and legs.  Also, 10-15% of the plasma volume leaks out of blood vessels and goes into interstitial tissues.  To compensate for this, there is an increased heart rate of 10 to 20 beats a minute, a negligible change in systolic blood pressure, and a 5 millimeter increase in diastolic blood pressure.  People with orthostatic intolerance have abnormal compensatory mechanisms for this one-half liter of blood which goes from the chest into the lower extremities.  This causes a lack of appropriate blood flow to the brain and, hence, the symptoms of brain fog.

 

Q:  What is the treatment for orthostatic intolerance?

A:  Simple measures such as elevating the head of the bed may help patients who have orthostatic intolerance.  We also encourage our patients to drink six to eight glasses of fluid a day, or more if possible.  Adding sodium to the diet is also helpful.  Usually we have our cardiac patients restrict sodium for blood pressure or heart failure reasons.  However, adding sodium in people who are not hypertensive or have heart failure may be beneficial.  Gentle isometric exercise to build muscle tone is also helpful.  Wearing compression stockings is a very important non-pharmacological measure.  We start with compression stockings below the knees at 20 millimeters, but they do leave indentations and oftentimes need to do them up to the waist.  Also, changing positions slowly is important.  Medicines such as midodrine in low doses have also been effective in people who are quite symptomatic from orthostatic intolerance.  Frequent, small meals may also be helpful.  Avoiding alcohol or heat may be helpful.  Patients have learned countermeasures such as crossing their legs and tensing their leg muscles or whole body to relieve symptoms of orthostatic intolerance.

Drinking water rapidly does improve symptoms of orthostatic intolerance.  It was initially thought that this was due to increasing volume, however, drinking fluids rapidly also increases sympathetic activity by a reflex mechanism.  Also, in addition to gentle isometric exercises, water aerobics and water jogging may be useful.  We often have people with orthostatic intolerance use a recumbent bike initially before embarking on more upright exercises and adapting in that way.  Some people do postural training measures where they stand erect against a wall or other surface for longer periods of time.  We have found that using an inversion table and just the opposite, having the head down and legs up for prolonged periods of time may also be helpful in relieving ongoing symptoms of orthostatic intolerance with patients.

 

Q:  What is postural orthostatic tachycardia syndrome (POTS)?

A:  POTS is a condition where there is an excessive increase in heart rate in the upright position, usually seen within 10 minutes of standing.  An increase in heart rate of greater than 30 beats per minute in adults and 40 beats per minute in children is usually required.  There is no drop in blood pressure.  There usually has to be accompanying symptoms, such as those due to orthostatic intolerance, which are occurring for more than six months, to make this diagnosis.  These are symptoms of chest discomfort, lightheadedness, tachycardia, anxiety, palpitations, exercise intolerance, extreme fatigue, headache, brain fog, mental clouding, blurred vision, tunnel vision, tremulousness, and nausea.  Headaches and fatigue are often non-positional.  Symptoms are relieved with lying down.  It is difficult to make a diagnosis of POTS without having orthostatic intolerance symptoms lasting more than six months despite the heart rate rising with standing position, as described above.

POTS can affect children, teenagers, and adults.  It is five times more common in women than in men, and usually affects women in their childbearing years.  It is more common than expected and it is estimated to affect 1 to 3 million people in the United States.  Interestingly, 30% of people with POTS also have reflux or vasovagal syncope, which is a neural-mediated type of syncope.  Patients with POTS do not have syncopal episodes, but have pre-fainting or presyncope.  However, if 30% of them do have a vasovagal syndrome, they can have fainting and that needs to be determined.

POTS is seen oftentimes in patients with Ehlers-Danlos syndrome, which is a hypermobility type disorder.  Oftentimes, an orthopedic physician or a rheumatologist can diagnose these hypermobility syndromes which run in families.  Also, POTs is seen in patients who have a high incidence of irritable bowel syndrome.

Symptoms can be mild to severe and the spectrum at times can lead people to severe exhaustion and disability.  One in four people may not be able to work.  Almost all patients with POTs have some degree of fatigue.

Patients with POTs on standing have a marked decrease in their stroke volume or the amount of blood ejected from the heart.  Normally, when people stand, they initially have a small drop in the stroke volume or blood that is ejected from the heart, but in POTs this is exaggerated and there is an extremely small amount of blood ejected from the heart and the heart becomes very small in size.  This causes an overcompensation of the sympathetic nervous system where it becomes extremely revved up or hyperactive.  With this hyperactivity of the sympathetic nervous system, the heart rate becomes extremely high on standing.  There is no drop in blood pressure.  Therefore, this is a hypersympathetic state.

POTs is a heterogeneous type of disorder. There are several different types of POTs and oftentimes we do not test to find out what type of POTs syndrome a patient is in because there can be overlaps.  Initially, it was said that there can be a type of POTs that involves denervation of the sympathetic nerves to the lower extremities which prevents blood from going from the leg up to the heart.  There are other types of POTs which involve chronic hyperadrenergic activity where norepinephrine levels increase on standing.  Other types of POTs patients are chronically hypovolemic or have a low blood volume and nuclear testing can confirm that, although we rarely have to do that.  Other types of POTs are associated with mast cell disorders where histamine is released into the blood system and hives, anaphylaxis, and flushing can occur.  There is also a genetic type where there is a norepinephrine reuptake transporter defect which is very rarely seen.  Regardless of the type of POTs, usually the treatment requires a multifaceted approach including volume resuscitation, salt intake, pharmacology and counter-maneuvers.

 

Q:  What is the treatment of POTS?

A:  As mentioned previously, fluid hydration is an important treatment for POTs patients.  Compression stockings are also useful.  Drinking fluids, especially a bottle of water rapidly with rapid fluid ingestion and salt tablets immediately before arising in the morning is also beneficial.

Patients with POTs can be quite disabled.  Because of this, pharmacology may be necessary.  Volume expansion with fludrocortisone has been effective in many patients with POTs who have a hypovolemic-type syndrome.  Plasma volume is expanded through enhanced kidney sodium retention.  However, one can lose potassium and become hypokalemic or have a low potassium and this should be monitored.  Also, edema occasionally is seen with fludrocortisone.  Low doses of beta blocker such as propranolol 10 to 20 mg by mouth several times a day have also been shown to be effective in keeping the heart rate from rising.  Clonidine, which is a blood pressure medicine, but also acts centrally in the brain to prevent increases from sympathetic nervous system activation, also can be used and we often give it at night as it can make patients drowsy.  This also blunts the heart rate response.

Vasoconstrictor therapy with midodrine we have found to be extremely effective and especially with fluid loading in patients with POTs.  It is an alpha agonist which constricts the vein blood vessels in the lower extremities and promotes blood flow upward to the brain.

Increasing vagal tone with pyridostigmine 30 to 60 mg by mouth several times a day is also important.  Pyridostigmine is a peripheral acetylcholinesterase inhibitor and by increasing the AcH it prevents the heart rate response to standing in patients with POTs.  It is very effective in combination with low-dose beta blockers.  However, it can cause diarrhea and is usually better tolerated in people who have significant constipation and not diarrhea-predominant irritable bowel syndrome if they have POTs.

We have used Ivabradine to treat the inappropriate sinus tachycardia that occurs with POTs with great success.  We have found it to be more successful than beta blockers.  It does not affect blood pressure.  As mentioned, it blocks the If channels of the sodium potassium membrane.  It is a proven treatment of angina pectoris and heart failure in patients, but has been used off label in dysautonomia, especially in patients with vasovagal syncope and with patients with POTs.  We prefer this medicine over beta blockers, but it is expensive and it needs to be precertified.

Occasionally, we stimulate the central nervous system because of significant brain fog which occurs with patients with POTs and Modafinil is used.  However, this may aggravate blood pressure and arrhythmias and needs to be watched carefully if one prescribes it.  Usually, this medication is used for patients who are refractory to conventional treatment for sleep apnea.  It does have alert-producing properties.  We do not like to use this drug unless it is an extremely last resort in a patient who is very disabled and we attempt to use some of the measures we have discussed previously.

Exercise training has been found to be highly receptive improving symptoms in POTs and many POTs patients go into remissions at various times for prolonged periods of time.  Also, females have exacerbations of POTs in premenstrual cycle.  We oftentimes, when fluid load will increase fluids, give midodrine specifically during this time of the month for females who have symptomatic POTs.

 

Q:  What is orthostatic hypotension?

A:  Orthostatic hypotension is sometimes called neurogenic orthostatic hypotension if there is no identifying cause such as dehydration, blood loss, or medications.  Idiopathic or neurogenic orthostatic hypotension is defined as a blood pressure drop greater than 20 millimeters systolic or 10 millimeters diastolic within 3 minutes on one standing from a lying or sitting position.  Usually, this drop in blood pressure occurs earlier.  If someone is severely hypertensive, we may increase the systolic blood pressure drop to be 30 millimeters rather than 20.  There are delayed forms of orthostatic hypotension, but these patients are not very symptomatic for the most part, in our experience.

Orthostatic hypotension occurs with increasing frequency as one ages.  It is estimated to have a prevalence greater than 20% in individuals over the age of 60.  It is also a very strong adverse prognostic factor for cardiovascular events such as heart attacks and strokes.

Orthostatic hypotension can be a primary disorder.  It could also be associated with other neurological disorders such as dementia and with Lewy bodies and Parkinson’s disease.  There is a pure autonomic failure type of the peripheral nervous system which was identified back in the 1920s.  A severe, very aggressive form of autonomic dysfunction known as multiple system atrophy can also occur, but is rarely seen.

The mechanism for orthostatic hypotension is that on standing the stroke volume goes down in normal amounts as it does in a normal individual.  However, there is a failure of the compensatory sympathetic nervous system to go up and it remains level.  This causes a drop in blood pressure without an increase in heart rate since the sympathetic nervous system has not been activated appropriately in a compensatory fashion.  In POTs, the situation is the reverse.  The heart rate goes up because of too much sympathetic reactivity and the blood pressure does not drop.  In orthostatic hypotension, the heart rate does not go up because there is a lack of sympathetic activation and the blood pressure goes down because without compensatory sympathetic activation of any type, one cannot get blood from the veins up to the upper extremities and brain.

Oftentimes, people who faint with orthostatic hypotension are difficult to differentiate from individuals with vasovagal syncope as the drop in blood pressure can occur sporadically.  In these instances, a tilt test may be useful.  In a hemodynamic head-up tilt test, there is usually a sudden drop in blood pressure and heart rate with vasovagal syncope during the examination in a laboratory; whereas, patients with orthostatic hypotension will have an early and progressive decline in blood pressure without a drop in heart rate.

Orthostatic hypotension is a very disabling disorder and oftentimes requires hospitalization as patients fall and can have trauma as they get older.  It is usually important to exclude causes of orthostatic hypotension such as anemia, blood loss, dehydration, and medicine use, which can be easily reversed before concluding that a person has an autonomic or idiopathic type of orthostatic hypotension disorder.

 

Q:  What is treatment for orthostatic hypotension?

A:  In addition to conventional treatment of orthostatic intolerance, which involves hydration or reversing dehydration, increasing salt, bolus of water ingestion, and waist-high garments are often required.  However, pharmacology is usually required as a system worsens.  Midodrine is a mainstay of treatment started at a low dose, however, can cause supine hypertension and in elderly men urinary retention especially.  One should not lie down for several hours after taking midodrine.  If a person is extremely hypertensive, oftentimes we will lower their blood pressure with pharmacological therapy which does not induce orthostasis prior to giving it.  However, there is an alternative in people who are hypertensive, namely, pyridostigmine.  This is an acetylcholinesterase inhibitor that prolongs the effects of acetylcholine and increases sympathetic tone.  It can cause diarrhea, nausea, vomiting, and excessive salivation, but does not cause blood pressure elevations when lying down and, therefore, is a rather safe medicine to give in patients who have underlying hypertension if one does not want to give midodrine.  Initial reports in studies in 2004 showed its efficacy in treating orthostatic hypotension.  Florinef is occasionally given, but again can cause blood pressure elevations when lying down, headaches, low potassium, and swelling of the legs.  One has to follow the potassium closely on an individual on Florinef.  We prefer salt tablets and fluid loading orally.

Recently, a pharmacological agent, Northera, or droxidopa, has been approved for treatment of orthostatic hypotension.  It is the synthetic amino acid precursor which acts as a prodrug to the neural transmitter norepinephrine.  Unlike norepinephrine, however, it does cross the blood-brain barrier and converts norepinephrine in the brain.  It has few side effects except for maybe mild headache, nausea, some hypertension, some dizziness, and fatigue.  We have found it extremely effective in treating this disorder and even more efficacious than midodrine without the worries of significant supine hypertension, although Northera can increase the blood pressure while lying down.  Northera induces a peripheral venous constriction which maintains blood flow to the brain.  It is extremely expensive and requires special precertification and the cost is thousands of dollars a month if one does not have proper insurance, although Compassionate Care can be obtained.

Some people have attempted to use a caffeine and ergotamine combination as they use in migraines for treatment of orthostatic hypotension, although we have not found this to be very effective.

There are other medications which have been used off label to treat orthostatic hypotension which you may want to consult with a specialist in autonomics regarding their use as some cannot be obtained in the United States.  Others require subcutaneous use and have significant side effects.

 

Q:  What is sympathetic withdrawal?

A:  Back in 1980, Williams and coworkers described episodes of low blood pressure associated with sympathetic withdrawal.  We have observed sympathetic withdrawal in patients with orthostatic intolerance symptoms without having rises in heart rate consistent with POTs or drops in blood pressure consistent with orthostatic hypotension.  We have monitored these patients with heart rate variability and cardiorespiratory testing, a form of testing that can identify if an individual’s compensatory increase in sympathetics on rising from a sitting to standing position occur too slowly or are inadequate.  This prevents the leg veins from getting their blood squeezed from increasing sympathetic tone and propelling blood to the brain.  Sympathetic withdrawal can cause brain fog and orthostatic intolerance-type symptoms.  Occasionally, they have small drops in blood pressures, but do not have the appropriate stand response, which is a 5 millimeter rise in diastolic blood pressure and usually no change in systolic blood pressure.  Also, the heart rate usually increased by less than 10 beats per minute in individual’s sympathetic withdrawal.

The treatment of sympathetic withdrawal is the same as that for any orthostatic intolerant symptomatic patient, usually fluids, salt, compression stockings, and occasionally midodrine is needed.  Rarely is Florinef needed.  Also, rarely is combination therapy of mineralocorticoids or alpha agonists such as midodrine indicated as we occasionally have to do in patients with orthostatic hypotension or POTs syndrome.  It appears that sympathetic withdrawal is a mild form of autonomic dysfunction, although patients can have syncopal episodes when their blood volume is down, such as times of dehydration or hypovolemia.  It is important to recognize since patients are told to well hydrate, consume enough salt, and use compression stockings as needed.

 

Q:  What is multiple system atrophy (MSA)?

A:  MSA is a progressive disease which involves degeneration of the nervous system, usually involving the autonomic nervous system (ANS) and areas of the central nervous systems (CNS) such as the cerebellum or basal ganglia/striatonigral pathways.  When involving the cerebellum, gait issues are evident.  Ocular movement disorders may also occur.  The striatonigral pathways produce Parkinson-like symptoms.  These involve tremor, rigidity, slow movement, and irregular, jerky, postural and intention tremors.  Speech can be affected in both types of MSA as can swallowing.

MSA usually presents itself with an individual in their 50s.  The autonomic dysfunction, which occurs later, encompasses urinary incontinence and retention, erectile dysfunction in men, and orthostatic hypotension, which is usually more than 30 millimeters on standing.

It may be difficult to differentiate true Parkinson’s disease from MSA.  Usually, patients with Parkinson’s disease respond to the medicine levodopa and patients with MSA do not respond.

 

Q:  How do I get checked for MSA?

A:  A good board-certified neurologist should be sought out first.  Also, a good clinical evaluation and brain imaging are helpful.  Magnetic resonance imaging (MRI) may suggest a patient has MSA, and not Parkinson’s disease, by showing atrophy of certain parts of the brain, known as the putamen and the cerebellum.  This, however, is not conclusive.  Positron-emission tomography (PET) may be suggestive of MSA if metabolism of glucose is low in the affected areas of the brain.  Most imaging techniques, however, are still experimental.

Usually, MSA occurs at a younger age and progresses more rapidly than does Parkinson’s disease, which it can mimic.  Some investigators measure supine and standing norepinephrine levels.  ANS testing and sweat testing may be useful.  In MSA, pseudomotor testing for sweating may be normal.  This is because MSA is a central autonomic failure and not peripheral.

There are specialized university centers, which have expertise in the diagnosis of MSA.  Your neurologist or autonomic specialist may refer you to one for further testing, especially some of the new state-of-the-art imaging techniques which are helping to narrow the diagnosis down more.

 

Q:  What autonomic findings can you see in Parkinson’s disease?

A:  Autonomic dysfunction is a peripheral type in Parkinson’s disease, whereas in MSA, it is an essential type.  Similar autonomic dysfunction features are seen in Parkinson’s disease as in MSA, but they are more severe in MSA.  Also, MSA patients do not respond to levodopa, a drug used to improve symptoms in Parkinson’s disease.

Symptoms in Parkinson’s disease which reflect autonomic dysfunction include orthostatic hypotension, which is a significant drop in blood pressure on standing, urinary symptoms such as urgency and incontinence due to diminished bladder capacity, diaphoresis, constipation, sexual dysfunction, and swallowing difficulties.

It should be noted that Parkinsonian patients are usually older in age than patients who develop MSA also.  Treatment of orthostatic hypotension in Parkinson’s disease along with other autonomic dysfunction symptoms is similar to the treatment of other disorders which cause orthostatic hypotension or idiopathic orthostatic hypotension.

 

Q:  What is Ehlers-Danlos syndrome?  What autonomic dysfunction is associated with it?

A:  Ehlers-Danlos syndrome is a group of disorders that affects the connective tissue or the supportive tissue in the body that is found in skin, bones, blood vessels, and virtually every organ.  Usually, individuals with Ehlers-Danlos syndrome have very loose joints, but they could have life-threatening complications, especially from the vascular standpoint.  There are six types of Ehlers-Danlos syndromes that have been described.  There is the classical type, hypermobility type, vascular type, kyphoscoliosis type, the arthrochalasia type, and the dermatosparaxis type.  There are different genetic causes and patterns of inheritance that are noted.  The skin is oftentimes affected, it can be lax or very hypermobile.  Usually large joints can become hypermobile with most forms of Ehlers-Danlos syndrome.  The hypermobility type has the most excessive movement of joints.  Many of these joints become dislocated or pop out.  Patients will complain of their hips, knees, elbows, and even jaw dislocating oftentimes.  Even the cervical spine can dislocate.  Patients get quite accustomed to putting their joints back in position themselves.

Many patients with Ehlers-Danlos syndrome have a velvety-type skin that is highly stretchable or elastic.  Some types of Ehlers-Danlos syndrome have poor wound healing which leave scars that create the so-called cigarette paper-type scars.  Life-threatening rupture of blood vessels can occur in the vascular type of Ehlers-Danlos syndrome.

Autonomic dysfunction is often found in the hypermobility type Ehlers-Danlos syndromes.

Typical signs include fast heartbeat or tachycardia, low blood pressure, gastrointestinal motility problems, bladder problems, and sweating regulation abnormalities.  Orthostatic intolerance is common in many patients.  Some patients have orthostatic hypotension and many have postural orthostatic tachycardia syndrome.  Some patients also have vasovagal syncope.  There is no good series of patients that has gone over the percentage of abnormalities of the various autonomic dysfunction states.  In our experience, we have found overlap between reflex and vagal-dominant autonomic dysfunction and postural orthostatic abnormalities.

Some patients with Ehlers-Danlos syndromes excrete an excessive amount of histamine which can cause low blood pressure and tachycardia.  Mast cell activation syndromes have been noted in high frequency in some of these patients in studies.  It has been postulated that high circulating levels of histamine may be a mechanism for contributing to cardiovascular dysfunction in patients with Ehlers-Danlos syndrome.

Interestingly, mitral valve prolapse, a disorder of the mitral valve with excessive motion of the valve, has been shown to be associated with excessive catecholamine and orthostatic intolerance syndromes.  Literature suggests that it is not very common in patients with Ehlers-Danlos syndrome, but in our experience it has been seen in more than 10% of patients (the literature suggests 6%).  While screening for mitral valve prolapse in Ehlers-Danlos syndrome is not indicated, if auscultatory features reveal a murmur or a click, or a patient has significant palpitations or chest pain, we do consider echocardiographic evaluation. This is especially true if the electrocardiogram is abnormal.

A poor man’s stand test can often be done to identify orthostatic hypotension or POTs.  Usually, this should be done for 5 minutes and even preferably up to 10 minutes.  Usually, changes are seen within 3 to 5 minutes, however.  The patient should rest supine for 5 minutes before testing.

Treatment of autonomic dysfunction in Ehlers-Danlos syndrome is not different than treatment for the various categories of orthostatic disorders and reflex disorders.  We do, however, attempt to stay away from stimulants such as methylphenidate and dextroamphetamine, especially because there is some incidence of vascular abnormalities in some of these patients.

Understandably, many of these patients have significant disability, require neck braces, knee braces, and whole body braces at times because of significant subluxation.  Anxiety and depression levels can be quite high.  Selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors are helpful in these patients, especially with orthostatic intolerance and in the setting of coexisting pain and the anxiety and depressive symptoms.

I often tell individuals who have autonomic symptoms to be checked for Ehlers-Danlos syndrome (EDS), especially the hypermobile type, by an experienced rheumatologist or orthopedic physician if they have abnormalities of their joints with subluxation, dislocation, and have extreme flexibility or double-jointed features.

 

Q:  What are mitochondrial disorders?

A:  Mitochondrial disorders were initially described as genetic disorders that involve ocular and neurological abnormalities from birth.  However, it recently has been noted that the mitochondria can become diseased with the aging process and develop acquired myocardial dysfunction disorders.

First, we have to understand what the mitochondria are.  The mitochondria are small components known as organelles of most cells in the body, the most notable exception being red blood cells.  Mitochondria are the power factories of the body.  They produce the energy molecule adenosine tri-phosphate (ATP).  The production of energy or ATP is somewhat complex and critical to good health, wellbeing, and life itself.  There are several biochemical cycles in the body which help produce the ATP.  One cycle is known as the Krebs or citric acid cycle.  The other is the electron transport chain.  There are cofactors and enzymes in these biochemical pathways that are crucial for production of the energy molecule ATP.  There is also the pyruvate dehydrogenase complex that is a substrate for the transition reaction going into the Krebs cycle.  While these types of biochemical terms appear to be quite formidable, what they basically state is that nature has a way of transforming things that we consume such as sugars, fats, and proteins into the energy molecule going through these pathways.  Most of the reactions take place in the mitochondria which are the power factories of the cells.

As one ages, the mitochondria become smaller in size and less in number.  With certain illnesses, mitochondrial number and size can drop dramatically.  For example, in chronic fatigue syndrome and fibromyalgia, some researchers have noted very small and decreased numbers of mitochondria.

When mitochondria are diseased or decreased in number, they produce less energy or ATP.  Also, mitochondria are very important in extinguishing free radicals which are actually produced by the mitochondria themselves.

As mitochondria become dysfunctional such as in aging or with chronic disease, all body parts and organs are affected.  Persistent oxidative stress also destroys mitochondria.  Chronic diseases are noted to occur and this includes slowing of the immune system.  Slowing of the immune system could also promote tumorigenesis.

Mitochondrial dysfunction affects many organs and may cause chronic fatigue, fibromyalgia, and migraines.  It has also been associated with many neurodegenerative disorders such as Friedreich’s ataxia, brain ischemia, and spinal cord injury.  It also has been linked to Parkinson’s disease and various dementias.  Mitochondrial dysfunction may be linked to myocardial infarction, atherosclerosis, and diabetes complications.  In the liver, one can see abnormalities of liver function and even steatosis, or fatty liver.  In the kidneys, one can see glomerulonephritis, ischemic injury, and potentially even renal stones.  This is because the mitochondria when they are damaged and diseased produce reactive oxygen species which, if there are not enough antioxidants in the human being’s environment, can go unopposed to cause more tissue damage.

The biochemical reactions involved with mitochondrial dysfunction are beyond the scope of this question and answer section.  However, when mitochondrial damaged ATP production is diminished, energy is diminished, and fatigue is a major factor.  The immune system is compromised and inflammation becomes more widespread in the body.  The autonomic nervous system is very susceptible to injury when mitochondrial dysfunction occurs as the neurons are very plentiful in this area.

One measure of treating mitochondrial dysfunction is to promote a strong antioxidant atmosphere.  Another is an anti-inflammatory milieu.  A third would be increased nitric oxide, especially for anti-atherosclerotic effects.  Many of our patients with autonomic dysfunction do respond to a cocktail of antioxidants which we feel are helpful in mitochondrial dysfunction based on the fact that some of these substances are actually seen in the chemical pathways of the Krebs and electron transport chain. Specifically, these are alpha-lipoic acid and coenzyme Q10.  Other cofactors such as B vitamins, manganese, and magnesium are important.  The nitric oxide pathway is also important to preserve and we feel that using precursors to nitric oxide such as L-citrulline, L-arginine, and even beet root extract, in which inorganic nitrates go to nitric oxide, may be useful.  We also believe in using omega-3 to strength myelin sheaths and to act as an anti-inflammatory molecule.  An interesting point is that atherosclerosis requires oxidation of LDL molecules to be incorporated into plaque and artery walls and many of the compounds in the Franklin Cardiovascular cocktail have antioxidant effects and may retard oxidation of LDL particles.

In our empiric experience, the following cocktail regimen has been given to patients in whole or in part as an adjunct to treat certain diseases which may have a basis of mitochondrial dysfunction.  There are other such cocktails that one can research in the medical literature that have been proposed to be beneficial also.  We encourage individuals to research the medical literature to see what supplements in addition to a healthy diet (we prefer the Mediterranean diet), a healthy exercise program (we prefer 150 minutes a week minimally for exercise), and a stress reduction program (we prefer exercise or meditation for stress reduction) would be useful in conjunction with a supplement program that has anti-inflammatory, antioxidant, and nitric oxide boosting potential.  Many of our patients on this program have noted a significant increase in energy and diminishing of autonomic dysfunction symptoms when on these regimens while others have not.

 

Q:  Are there different degrees of abnormality or gradation to autonomic dysfunction?

A:  Autonomic dysfunction can be mild, moderate, or severe.  It is really a continuum.  There is no dichotomy.  The most advanced form is known as Cardiac Autonomic Neuropathy (CAN).  CAN is a serious medical condition because the heart rate is unstable and there are problems with essential and peripheral vascular control.  CAN has been linked to greater risks of sudden cardiac death and mortality, heart attack, and silent ischemia.  Patients with CAN may be diabetics and have silent ischemia but many patients do not have diabetes.  Basically, CAN should be suspected if an individual has orthostatic hypotension, resting tachycardia, neurocardiogenic syncope, exercise intolerance, postural orthostatic tachycardia, or silent myocardial ischemia.  Heart rate variability (HRV) testing is considered one of the earliest and first signs and symptoms to suggest CAN.  Testing can be done in a laboratory or even in a doctor’s office by looking at changes and beat-to-beat heart rate intervals to see if a person has evidence of CAN.  If CAN is detected, we will recommend a full noninvasive cardiac workup, even in patients who are asymptomatic, if they have not had one.

As noted, autonomic dysfunction occurs when the autonomic nerves are damaged. CAN appears to be a rather advanced stage of autonomic dysfunction.  We believe that there are measures that can be instituted when patients have autonomic dysfunction prior to developing CAN.  Oftentimes, the patient does have a sinus tachycardia at rest because they have low vagal tone and the vagal function or parasympathetic function is greatly impaired.  Testing with Valsalva maneuvers, deep breathing, and standing and tilt response can yield calculations and reflect if a person has cardiac autonomic neuropathy or not.

A less advanced but still significant form of autonomic nervous system dysfunction is advanced autonomic nervous system dysfunction.  This is a stage that is below CAN.  If it is associated with diabetes, we term this Diabetic Autonomic Neuropathy (DAN).  In diabetic autonomic neuropathy, patients may also have resting heart rates that are high.  Usually, the same testing that is done to detect CAN is done to detect advanced autonomic neuropathy or diabetic autonomic neuropathy, namely, heart rate variable intervals with different maneuvers.  Many patients with diabetic autonomic neuropathy also will have peripheral neuropathy which is common in diabetics.  It is hoped that by detecting patients in advanced autonomic dysfunction stages, we can institute treatment, especially with antioxidant therapy and try to balance the autonomic nervous system with other measures to prevent progression to cardiac autonomic neuropathy.  Aggressive risk factor modification as in cardiac autonomic neuropathy is also important, that is, controlling cholesterol, blood pressure, and blood sugar if the patient is diabetic.  Also, if one smokes, they should stop smoking.  If they drink alcohol excessively, they should stop drinking alcohol entirely in these instances.  Exercising daily maintains a good healthy condition.  Drinking plenty of fluids, exercising regularly, and avoiding stress may also be important in treating autonomic dysfunction.

Mild autonomic neuropathy oftentimes can be diagnosed also with assessing heart rate variable intervals based on the electrocardiogram changes and heart rate with response to the maneuvers of Valsalva, which is bearing against a closed glottis maneuver as though you were bearing down, and deep breathing responses along with standing or tilt responses.  With mild autonomic neuropathy, one sees abnormalities mainly just with deep breathing or with Valsalva or both.  There are calculations and a format we rely on called time domain variables in which we do three different measurements with individuals when assessing heart rate variability.  If they have one out of three abnormalities, autonomic neuropathy is usually mild, two out of three abnormalities is usually moderate or advanced, and three abnormalities suggests they may have CAN.  Again, risk factor reduction is most important along with antioxidant therapy approaches as outlined above.

 

Q:  Why are diabetics more susceptible to neuropathies, including peripheral sensory neuropathies and peripheral autonomic neuropathies?

A:  When a diabetic develops neuropathy, they are more at risk of heart disease than a diabetic who does not have neuropathy.

Any person can develop neuropathy of the sensory nerves, which can result in a burning sensation, tingling sensation, or pain in the extremities.  However, neuropathy is more common in diabetics.  The reason why neuropathy is more common in diabetics has not been fully elucidated.

In regards to diabetic autonomic neuropathy (DAN), this is a serious complication.  It can lead to cardiac autonomic neuropathy (CAN), which is a more severe form of nerve dysfunction.  Both DAN and CAN in diabetics leave patients at a higher risk of having cardiac events, such as heart attacks and sudden cardiac death.  We are very aggressive in diagnosing this and treating these patients.

Clinical manifestations of DAN (and also CAN) include an increase in heart rate or resting tachycardia with exercise intolerance.  Many times, these patients have orthostatic hypotension and have silent myocardial ischemia, which is lack of blood supply to the heart without chest pain.  They may also have motility problems with their esophagus or gastroparesis in which stomach contents cannot pass through the stomach into the intestines at a quick enough rate.  This leaves the patient with nausea, vomiting, and early satiety.  Constipation or diarrhea can be a manifestation of DAN, as can actual incontinence of stool.  Oftentimes, the bladder becomes neurogenic, which we call, “diabetic cystopathy”.  Erectile dysfunction and retrograde ejaculation can occur in men, and women can have sexual dysfunction with loss of vaginal lubrication.  There is also lack of sweating and heat intolerance, which can be associated along with dry skin in diabetics and even non-diabetics who develop advanced neuropathy.  Gallbladder enlargement and contraction of the gallbladder has also been described in patients with DAN.

Microvascular or small vessel skin flows under the control of autonomic nervous system is regulated both by the essential and peripheral parts of the autonomic nervous system.  In diabetics, the contraction of the small blood vessels is disordered and microvascular insufficiency is probably the cause of diabetic neuropathy.  Therefore, it is believed that a blood flow phenomenon, especially with diabetics who are susceptible to this, could be the potential cause of diabetic neuropathy.  Microvascular blood flow can be accurately measured noninvasively in a laboratory utilizing various Doppler techniques.  It is important that diabetics have a good blood flow, especially to the skin, since dry skin, loss of sweating, and development of fissures and cracks can lead to infections with microorganisms which can cause cellulitis and eventually even gangrene of the extremities. Therefore, foot care is extremely important.  Interestingly, autonomic neuropathy can also lead to increased activity of osteoclasts, which are cells which can cause reduction in bone density and osteoporosis.

As mentioned, heart rate response to various maneuvers can be important to determine dysfunction of the autonomic nervous system.  A heart rate response in deep breathing is the most important function of parasympathetic activity, although the sympathetic nervous system may affect this.  In short term, standing and the parasympathetics play the initial important role where parasympathetics are withdrawn and then the sympathetics take effect.  Heart rate response in Valsalva maneuver is influenced by both parasympathetic and sympathetic activity.  To assess sympathetic responses, measurements of blood pressure or response to standing and blood pressure response to sustained hand grip are used oftentimes.

A physician trained in autonomics can do simple noninvasive tests in the office to determine if there are abnormalities potentially in the autonomic nervous system and to what gradation.  Patients should be off all medications when these tests are performed and this includes even over-the-counter medications.

There is a danger with diabetic autonomic neuropathy in that there can be inability to get warning signals of when the blood sugar drops, that is when hypoglycemia occurs.  This is an extremely important problem also.

 

Q:  In what areas has targeting the autonomic nervous system with therapy been most supported by research data and applied clinically?

A:  An area of heart failure, a manipulation of the autonomic nervous system has been a tremendous breakthrough.  Major advances in heart failure management have been achieved over the past three decades by targeting two main pathways activated in heart failure, namely, the renin angiotensin-aldosterone system and the sympathetic nervous system.

It appears that heart failure progresses when the sympathetic nervous system is activated and this sympathetic activation causes myocardial dysfunction and fibrosis.  In fact, the current pharmacotherapies are drugs used to treat heart failure and target the autonomic nervous system.  For example, beta blockers and renin angiotensin system inhibitors reduce morbidity and mortality by targeting aspects of the autonomic nervous system, specifically those that involve the sympathetic nervous system.  Even recently in animal studies, renal sympathetic denervation, which is a non-pharmacological measure, has been shown to protect failing hearts.  There is a recent article in the Journal of the American College of Cardiology by Dr. Polhemus and coworkers out of New Orleans that explains how aspects of manipulating the autonomic nervous system, particularly the sympathetics, are most effective in treating heart failure patients.

For several decades, it has been evident that by blunting the effects of the sympathetic nervous system by various means whether using beta blockers, in some cases angiotensin receptor blockers, or what we term as ACE inhibitors, heart failure patients can get improvement in their heart function and extend their life expectancy.  There is recent data that there are other measures that will modulate the autonomic nervous system in a beneficial way.  Recent data has looked at enhancing the parasympathetic nervous system in heart patients to afford them a protection from such things as sudden cardiac death and cardiac events.

“Modulation of the autonomic nervous system is a treatment for heart failure but has been limited mostly to pharmacological therapies.”  (Reference Journal of American College of Cardiology, volume 20, #17, 2017, p. 2148, Renal sympathetic denervation protects the failing heart by inhibition of neprilysin activities in the kidneys, by Polhemus and coworkers.)  Therefore, it is well proven that blunting the sympathetic nervous system, or modulating it, can improve the most advanced forms of heart disease, that is, those patients with heart failure.

Autonomic dysfunction, however, can affect other organs besides the heart.  It can affect the blood vessels, the brain, the kidneys, the GI tract, the urinary tract, the lungs, and so on.  It is because of this modulating of the autonomic nervous system is not only beneficial in our opinion, it can also be beneficially influenced by offering the autonomic nervous system and significant ongoing research is evolving in this area.

We tend to treat autonomic dysfunction pharmacologically when we are able to, to correct excesses of what we believe are due to parasympathetic or sympathetic problems or deficiencies of parasympathetic or sympathetic problems.  An example of this is the use of midodrine to increase sympathetic tone to the lower vessels in the legs to treat many syncope and orthostatic symptoms.  We also believe some cases of chronic fatigue, depression, fibromyalgia, and migraine are benefitted by anticholinergic treatment (for example, tricyclics, such as nortriptyline) if a low sympathetic/vagal ratio or high vagal dominance is suspected.

In summary, therefore, tremendous evidence with heart failure and modulating the autonomic nervous system by pharmacology which blocks the sympathetic activation has shown the most evidence-based data to date, but data forthcoming with other organ systems is becoming more supportive that the heart is not the only organ benefited by modulating the autonomic nervous system.

 

Q:  How does one diagnose Ehlers-Danlos syndrome?

A:  Ehlers-Danlos syndrome should be suspected or diagnosed when several of the following are noted:

  1. Pains in multiple locations which are very refractory to treatment. These can be continuous or intermittent. They may involve migraines, joint aches, abdominal discomforts, significant shoulder and intrascapular discomfort, and so forth.
  2. Hypermobility usually occurs in childhood but is currently present. Usually a patient describes being very flexible in their joints, even sometimes double-jointed. Oftentimes, they can do gymnastics much better than their peers.  For example, extending the thumb all the way back to the wrist or putting one foot behind one’s head.  Also, side splits and being able to touch the palms of your hands to the floor are features of hypermobility.
  3. The skin oftentimes stretches. Stretch marks may be seen. The skin is quite fragile.  There could be easy bruisability.  There could be scars on the skin.  The skin may be thin.  There could be delayed healing depending on the type of Ehlers-Danlos syndrome that is present.  Oftentimes, one can stretch the skin.
  4. Oftentimes, bleeding from the gums or nose or heavy menstrual cycles in women is associated with Ehlers-Danlos syndrome.
  5. Fatigue during the day and fatigue on waking. Oftentimes, patients get bouts of drowsiness. Oftentimes, they cannot lift up their arms or legs because they feel very heavy.
  6. Hypersensitivity to sounds, lights, hearing, smells, or touch.
  7. Fatigue in vision or the vision becomes blurred, tunnel vision, or the image becomes split.
  8. Becoming short of breath with minimal exertion.
  9. Attention difficulties, difficulty concentrating, anxiety, difficulty getting oriented, and decreased memory.
  10. Unable to stand for prolonged periods of time, which we call orthostatic intolerance. This may cause tachycardia, excessive sweating, low blood pressure, chills, and cold extremities, especially hands and feet. Oftentimes, the patient has to lie down.  These are manifestations of autonomic dysfunction.
  11. Motor abnormalities which involve clumsiness or difficulty walking, hitting into objects, not being able to walk a straight line, frequent dislocations or subluxations, joints popping out, especially hips, knees, elbows, fingers, jaw, and ankles. Also, patients may have involuntary dystonic motions and may actually have episodes of falling.

 

There are several types of Ehlers-Danlos syndrome.  The one we most often see is the hypermobility type.  Usually we can get a family history of several relatives who have features of hypermobility in the family.  Another type of Ehlers-Danlos syndrome involves the blood vessels and there is a risk of blood vessel rupture.  This is a rare form, but should be screened for in some patients because fatalities from aneurysm rupture have occurred in these patients.  We rarely see this type of Ehlers-Danlos syndrome.   Another type involves poor wound healing.  The most common type that we see associated with autonomic dysfunction is the hypermobility type.  Oftentimes, there is a history dating back to childhood and early teens and patients have excelled in gymnasium classes because of their hypermobility and flexibility, especially in gymnastics.

Many times patients with Ehlers-Danlos syndrome are treated for presumed psychiatric disorders.  They do not necessarily do well with antidepressants.  A proper diagnosis is needed to treat these patients effectively and not treat them simply as functional or pure psychiatric disorders.  Each person has unique features that a trained physician should treat.

The true incidence of Ehlers-Danlos syndrome is not known, but it is more frequent than expected.  If a patient has very flexible joints, dislocation and subluxation of joints, poor wound healing, orthostatic intolerance, and many of the features as discussed above, they should be evaluated for this as a possibility.  It is usually a hereditary disease, but gene testing has not been found useful in the hypermobility form.  Sporadic mutations, however, have been found.  It can cause cognitive impairment as noted.  Oftentimes, it is erroneously diagnosed as a mental illness.

Below is a questionnaire we use in our clinical practice for new patients to complete.

Questionnaire on Hypermobility Syndromes (EDS and Related Disorders):

  1. Do you develop pain in joints that is continuous or intermittent that is difficult to relieve and causes discomfort, and also possible abdominal discomfort or migraines?
  2. Do you have significant fatigue during the day or on awakening?
  3. Do your limbs feel like lead and become heavy at times?
  4. Do you get bouts of drowsiness or sleepiness?
  5. Do you have difficulty standing up for long periods of time?
  6. Do you have profuse sweating?
  7. Do you get chills or cold extremities?
  8. Do you believe that you have a drop in blood pressure periodically?
  9. Do you bruise easy? Do you have bleeding from your gums, mouth, nose, or heavy periods?
  10. Are you hypersensitive to sound, smells, sudden positional changes, flickering lights, or any cutaneous stimulation?
  11. Do you have problems with blurred vision or does the image ever split? Does your vision at times feel as though it gets tired?
  12. Do you get shortness of breath on minimal exertion?
  13. Do you have memory deficits?
  14. Do you get brain fog, orientation difficulties, difficulty concentrating, or have attention deficit problems?
  15. Do you have clumsiness when you walk? Do you fall?
  16. Do you get frequent sprains, dislocate, or sublux your joints, such as your ankles, knees, jaw, or any other joints? Please list joints that are affected.
  17. Have you suffered numerous miscarriages (if female)?
  18. Do you have urological problems such as losing urine or retaining urine?
  19. Do you get sleep disturbances?
  20. Do you get pneumothoraces?
  21. Have you ever had swelling of the legs or lymphedema?
  22. Have you ever had a history of arterial aneurysms?
  23. Do you have excessive elasticity or stretchability of your skin?
  24. Do you have easy bruisability?
  25. Do you have scars that formed oftentimes on your skin?
  26. Do you have stretch marks before pregnancy or do you get stretch marks easily?
  27. Do you have delayed healing?
  28. Do you have thin skin?
  29. Do you have transparent skin?

 

Q:  What is the Beighton score?  Is it useful in diagnosing Ehlers-Danlos syndrome?

A:  The Beighton scoring system is a system that we use to evaluate if a patient has significant hypermobility in various areas of the body.  In and of itself, whether the score is high or low does not necessarily rule in or rule out Ehlers-Danlos syndrome.  There must be other symptoms and signs that are present in addition.  In brief, the Beighton score is calculated as follows:

  1. One point while standing forward and bending so you can place your palms on the ground without bending your knees.
  2. One point for each elbow that bends backwards.
  3. One point for each knee that bends backwards.
  4. One point for each thumb that touches the forearm when bent backwards.
  5. One point for each of the little fingers that bend backwards beyond 90 degrees.

Unfortunately, the Beighton does not take into account significant joints that are affected with hypermobility such as the jaw (temporomandibular syndrome), the shoulders, midthoracic spine, hips, ankles, feet, and very importantly the cervical spine, which can be quite a significant problem in some patients.

However, significant hypermobility, especially if it occurred even at one time but then went into remission, is important to note.  Of course, other clinical characteristics such as orthostatic intolerance, inability to stand, elasticity of the skin and poor wound healing, shortness of breath, palpitations, chronic pain syndrome refractory to treatment, migraines, and other features and other clinical aspects do go along with the syndrome.

A good trained rheumatologist/orthopedic physician is usually the best equipped to give an accurate diagnosis.  Genetic testing may be useful in some instances; however, there is significant controversy on this issue since hypermobility types generally do not test positive even though a family history is present.

 

Q:  What is the rationale for using antioxidants such as L-carnitine, coenzyme Q10, and lipoic acid in the treatment of autonomic dysfunction patients?  Also, how is enhancing nitric oxide potentially useful?

A:  Enhancing nitric oxide production is an easier question to answer.  Increasing nitric oxide increases the function and health of the inner lining of the endothelial cells that line all the blood vessels.  By increasing blood flow to nerves, especially autonomic fibers, one could easily see how the nerve fibers are kept healthy.  This may be one reason why diabetics develop autonomic nervous system dysfunction early.  Diabetics oftentimes have impaired circulatory flow to nerve fibers, or impaired endothelial function.  It is hoped that by enhancing nitric oxide production with precursors such as L-arginine, L-citrulline, or even beet root extract, blood flow will be enhanced to nerve fibers of the autonomic nervous systems.  Also, nitric oxide is known as the anti-atherosclerotic molecule and is believed to be useful in delaying or preventing atherosclerosis from occurring by virtue of its many beneficial effects on the blood vessel.

In terms of antioxidants, the question becomes more difficult.  There have been many studies with antioxidants such as vitamin C and vitamin E evaluating them for the prevention of heart disease outcomes and they have been negative.  However, certain antioxidants such as coenzyme Q10 and alpha-lipoic acid appear to recycle vitamin C and vitamin E in the body.  There has been some published data, especially in Germany, that alpha-lipoic acid is helpful in improving autonomic dysfunction.

The biological feasibility whereby Autonomic Dysfunction becomes manifest involves a mechanism at the cellular level where the mitochondria malfunction and oxidative stress becomes a dominant feature.  The mitochondria are the powerhouses of the cells.  They are found in almost every cell in the body except the red blood cell.  It is believed that dysfunction of the mitochondria can cause many disease entities.  Many of them are inherited.  The first mitochondrial disease was described by Luft and his colleagues in 1962 when a 35-year-old female presented with muscle weakness, excessive sweating, heat intolerance, drinking too much water, urinating too much, and had a basal metabolic rate of 180% of normal, which is very high.  This patient had an abnormality in the production of energy, or ATP, which is the energy molecule produced by the mitochondria through a series of reactions involving electrons in addition (the electron transport chain, an important part of ATP production).

The authors Pecznik and Neustadt in Mitochondrial Dysfunction of Molecular Pathways of Disease published in Experimental and Molecular Pathology in 2007 lists the following as required conditions in which mitochondrial dysfunction has been implicated and also referenced them with key articles:

  1. Diabetes.
  2. Huntington’s disease.
  3. Cancer, including hepatitis C and virus-associated hepatocarcinogenesis.
  4. Alzheimer’s disease.
  5. Parkinson’s disease.
  6. Bipolar disorder.
  7. Schizophrenia.
  8. Aging and senescence.
  9. Anxiety disorders.
  10. Non-alcoholic steatohepatitis.
  11. Cardiovascular disease including atherosclerosis.
  12. Sarcopenia.
  13. Exercise intolerance.
  14. Fatigue, including chronic fatigue syndrome, fibromyalgia, and myofascial pain.

Mitochondria synthesize ATP, which is the energy molecule of the body.  This requires three steps:

  1. The citric acid cycle or TCA cycle breaks down pyruvate.
  2. The electron transport chain uses energy from the electrons to pump hydrogen ions into the membranes.
  3. ATP synthesis takes place in complexes with coenzymes located on them.

While this is complicated, it is not hard to understand that the rationale is that we can consume supplements that potentially have the same chemical formula that are involved.

Coenzyme Q10, which is derived from vitamin B5; NAD+, which contains niacin (vitamin B3); FAD+, which contains riboflavin, which is vitamin B2; lipoic acid; thiamine thiophosphate (TPP), which as the name indicates, contains thiamine; and vitamin B1 are all cofactors important in the generation of ATP energy molecules.

Also in the TCA cycle, there are coenzymes that are required such as cysteine, iron, niacin, magnesium, manganese, thiamine, riboflavin, pantothenic acid, and lipoic acid.  Next to pantothenic acid, one would put vitamin B5 (which coenzyme Q10 is derived from).

It is believed that many of these cofactors and coenzymes aid in sequestering of antioxidants.  We often advocate supplements containing these cofactors to many patients.

Many metabolic abnormalities can cause mitochondrial dysfunction.  As vitamins, minerals, and other metabolites act as cofactors necessary for mitochondrial function, these are very important.  Enzymes as pathways for heme (iron) synthesis and are important in GME.  Deficiencies of any component of the TCA cycle or electron transport chain can lead to the production of free radicals which can damage DNA in the body.  This is important.  This is one rationale for giving antioxidants, as listed above.

 

Q:  Is chronic fatigue syndrome related to autonomic dysfunction?

A:  There is no question that chronic fatigue syndrome is interrelated with autonomic dysfunction.  Chronic fatigue syndrome is also known as systemic exertion intolerance disease (SEID), or myalgic encephalomyelitis (ME).  It is a debilitating disease with multiple causes and etiologies most of which are unknown or idiopathic.  It also has overlap with many illnesses, especially fibromyalgia.

Many definitions have been offered for chronic fatigue syndrome.  Criteria by Fukuda have been the most commonly used.  Generally, it consists of the presence of prolonged fatigue for six or more months, not substantially alleviated by rest.  Also, concurrent occurrence of at least four or more of the following:  1) recently impaired memory or concentration; 2) sore throat; 3) tender cervical or axillary lymph nodes; 4) muscle pain; 5) multijoint pain without joint swelling or redness; 6) headaches of new type pattern or severity; 7) unrefreshing sleep; and 8) discomfort post effort lasting more than 24 hours.

In fact, post-effort fatigue is a hallmark characteristic of the disorder.

The prevalence is unknown.

Initially thought to be a psychiatric disease, chronic fatigue is now being appreciated more as an immunological or neurological disorder.

Some investigators have found chronic fatigue and orthostatic intolerance in up to 97% of people.  Orthostatic intolerance causes brain fog.  Patients with orthostatic intolerance cannot stand for long periods of time because they get significant fatigue and tiredness and have to lie down.  Presyncope (near fainting) is common.

There appears to be a relationship between chronic fatigue syndrome and the autonomic nervous system.  There is also a relationship between immunological dysregulation.  Some have found feedback of the hypothalamus-pituitary axis to be enhanced in patients with chronic fatigue.  Others have found abnormal cortisol levels in people with chronic fatigue.  There are many studies which show immune system abnormalities.  There are deficiencies in killer immunological cells which destroy infectious agents.  There are also increased levels of certain cytotoxic T cells that are found.  There are many altered immune responses in people with chronic fatigue syndromes and there are many articles on various levels of elevated inflammatory proteins called cytokine in these people.

Also, sleep disturbances are common in chronic fatigue syndrome.  It is felt that some of these sleep disturbances involve abnormalities of the sympathetic and parasympathetic function.  Sleep apnea has been reported to be increased in people with chronic fatigue syndrome.  Exercise studies have shown patients to be extremely intolerant.  If one repeats a treadmill study consecutively with a patient with chronic fatigue-type syndrome, they will see a marked decrease in their exercise tolerance.  Some studies have shown increased lactate production as reflecting a reduction of mitochondria in oxygen-transport capacity is demonstrated.  There is also a greater reduction in EMG activity during physical exercise which suggests an inability to recruit normal amounts of muscles.

While many believe that CFS is caused by a flu-like illness or infectious agent, the actual agent has not been discovered.  Some researchers believe it was the Epstein-Barr virus that was initially the culprit.  Some have found herpesvirus type 6 to be activated in people with chronic fatigue syndrome.  A causal role for both of these viruses has not been proven.  Some patients have shown abnormalities in lymphocyte pathways, which suggests viral infection.  Antiviral pathways have been activated in chronic fatigue syndrome and this is all strong evidence that chronic fatigue can be triggered by acute infections.

We believe that any type of a trigger event which increases oxidative stress and causes strain on the mitochondrial function can potentially trigger chronic fatigue.  This can be an emotional upset, trauma, an infectious agent, a concussion, and so forth.

Oxidative stress is imbalance between antioxidant and oxidants in the body.  However, data suggests that oxidative stress is increased significantly in patients with chronic fatigue.  Whether this is the cause or effect is not certain.  There is increased response of antioxidant enzyme activities which may be a compensatory measure in response to chronic fatigue and oxidative stress.  Increase in cytokine levels cause the formation of nitric oxide that combines with superoxide to form a potent buffer agent.

Many treatments have been tried for chronic fatigue therapy including immunotherapy, antiviral, antidepressant, steroidal therapy, anticholinergic, CNS stimulants, hormones, diets, and supplements.  Of the supplements, oral NADH shows improvement in symptoms in some patients.  Randomized trials showed that compounds with L-carnitine showed significant improvement in fatigue and cognitive function associated with treatment.  Essential fatty acids have not been shown to be effective.  Non-pharmacological measures have had mixed results such as cognitive behavior therapy.  Some randomized studies have shown cognitive behavior for therapy to be effective.  Graded aerobic exercise has shown positive effects on physical conditioning in patients with chronic fatigue syndrome.  However, aggressive programs actually cause more harm than good.  There has been a theory that prolonged rest may be helpful also.

Chronic fatigue syndrome is a complex illness with multifactorial causes and symptoms.  It is very disabling and can even prevent people from doing household chores.  Its true prevalence is not known, but is certainly not insignificant.  It is a primary disorder of young to middle-aged people and therefore strikes individuals in the prime of their life.

We have attempted to address the autonomic dysfunction associated with chronic fatigue syndrome, especially those with orthostatic intolerance syndromes.  We have performed autonomic testing and even addressed abnormalities in the autonomic nervous system with specific therapies addressed at either cholinergic or adrenergic mechanisms.  We have found beneficial empiric results in these patients, especially when combined with a cocktail of antioxidants and nitric oxide-producing substances.  The difficulty in treating chronic fatigue syndrome is that it is not a homogenous disorder.  It involves dysregulation of several organ systems including the immune system, central nervous system, autonomic nervous system, and circulatory system.  There has also been overlap of chronic fatigue syndrome with fibromyalgia-type symptoms since chronic pain and unrefreshing sleep are seen in both disorders.  Also, there is overlap of collagen vascular disease since disorders such as lupus have chronic fatigue as a major symptom.

Many therapies have been tried in chronic fatigue syndrome.  There is no uniform therapy that works and each individual has to be treated in the context of the circumstances surrounding their illness and their symptom complex.  However, when orthostatic intolerance is present, that is, patients have difficulty standing for prolonged periods of time, get exhausted easily with standing or walking, and do have brain fog and cognitive disorders on assuming an upright position and feel better lying down, we have found that autonomic testing and treatment of dysautonomia has been useful.  One must be very patient in treating this disorder and have significant understanding that patients will have good days and bad days and may have remissions and relapses.  Addressing sleep disorders is also very important.

If you believe you have symptoms consistent with chronic fatigue syndrome, we suggest you see a physician that has familiarity with this disorder.  Other disorders that may predispose to fatigue should be excluded such as depression, anxiety, and other psychiatric illnesses, inflammatory infectious diseases, collagen vascular diseases, and chronic viral illnesses.

When one asks what causes chronic fatigue syndrome, the answer is we do not know for sure.  There could be viruses, a weakened immune system, stress, and hormone imbalances.  However, we do find that autonomic dysfunction is significantly associated with it.  Many believe, as we do, that there is an injury to the mitochondria due to oxidative stress that causes problems with antioxidant and oxidant balance.  We believe chronic fatigue syndrome may be just a chronic mitochondrial disorder that is triggered by various agents and subsequently causes abnormalities in immune system, hormone system, and so forth.  There may be a genetic predisposition.

There is no one blood test that can diagnose chronic fatigue syndrome.  While it is estimated that up to 2.5 million Americans may be affected with it, the true incidence is not known.  One needs to rule out mononucleosis, multiple sclerosis, other neurodegenerative diseases, Lyme disease, lupus, hypothyroidism, fibromyalgia, and depressive disorders as mentioned above.  Drugs can cause chronic fatigue such as alcohol, antihistamines, gabapentin, Lyrica, and some psychotropics.  Looking at one’s medication list may be important as omission of medicines may be helpful in some instances.  Some patients will respond paradoxically to SSRIs or antidepressants and not do well.

Unfortunately, the disability caused by chronic fatigue syndrome and the decreased quality of life are significant.  Further research is ongoing in this area.

 

Q:  Is chronic fatigue related to autonomic dysfunction?  Are migraine headaches related to autonomic dysfunction?

A:  Two common causes of pain and disability are fibromyalgia and migraine syndrome.  They also may have similar mechanisms.  Fibromyalgia is a chronic pain disorder with unknown etiology.  Basically, patients with fibromyalgia have chronic pain, fatigue, and tenderness to touch.  It is probably the most common medical cause of chronic pain in the United States and affects up to 4% of people, mostly women.  Symptoms consist of chronic pain in muscles, joints, and bones, although it is not, per se, a muscle disorder or bone disorder.  Fatigue is common as is unrefreshing sleep.  These symptoms obviously overlap with the definition of chronic fatigue syndrome.  Tenderness to light touch throughout the body is noted and there are many trigger points that are painful.  Patients with chronic fatigue and fibromyalgia oftentimes have depression, anxiety, abdominal pain, dry eyes, cognitive difficulty, concentration difficulty, dry mouth, bladder symptoms, pelvic pain, heart palpitations, paresthesias, chemical sensitivities, weight gain, multiple allergies, and sleep disorders.  Many of these symptoms overlap with autonomic dysfunction symptoms.  Fibromyalgia is a generalized pain syndrome also.

It is believed that fibromyalgia is also associated with dysfunction of the mitochondria and increased oxidative stress.  Whether this is a cause or effect needs to be investigated.  Certainly, we attempt to identify any autonomic dysfunction abnormalities associated with patients who have fibromyalgia and treat those as best as we can empirically or with appropriate data.  Also, antioxidant therapy in a cocktail is very important with nitric oxide boosting agents and antioxidants, specifically coenzyme Q10 and alpha-lipoic acid.

Trigger point injections may be helpful.  There is no uniform treatment that is effective for fibromyalgia.

Fibromyalgia is considered to be a disorder of pain regulation classified under the term of central sensitization.  It shares features with several other pain disorders that are more central rather than peripheral such as migraine, tension headaches, temporomandibular joint disease, and irritable bowel syndrome.  Because of the overlap of chronic fatigue and fibromyalgia, oftentimes there is difficulty differentiating the two.  Indeed, orthostatic intolerance, which is an autonomic dysfunction abnormality, is found in many patients with chronic fatigue.

Treatment of chronic fatigue is difficult.  Treatment is individualized and is multifaceted.  Pharmacological measures may be effective.  Exercise may also be effective.  Medications that have been shown to be effective include amitriptyline or nortriptyline, duloxetine, milnacipran, or pregabalin.  Low doses of drugs should be started and titrated up closely.  We like to use a low dose of tricyclic agents at bedtime, especially if patients have evidence of high vagal tone on testing.  We usually start with 10 mg of nortriptyline and notice a response in six weeks.  We use this in conjunction with an antioxidant/nitric oxide boosting mechanism.  Some use cyclobenzaprine as an alternative to nortriptyline.

Prognosis varies with fibromyalgia.  Each case is individual.

One should consult with a rheumatologist if orthostatic intolerance and autonomic dysfunction symptoms are present, or see a physician trained in this area such as a neurologist or cardiologist.

In regards to exercise, low impact aerobic activity such as biking, swimming, or water aerobics may be successful.  Usually, the intensity should be low in the beginning.  If one starts out with high intensity exercise activities, the symptoms of fibromyalgia will worsen just as they can with chronic fatigue syndrome.

Migraine headache is another chronic pain disorder that has central mechanisms and has been associated with autonomic dysfunction abnormalities.  Migraine headaches usually involve pulsatile headaches and oftentimes nausea.  It is a very disabling disorder.  Common symptoms of migraine are eye pain, sensitivity to light, nausea, vomiting, and severe pain on one side of the body.  We have found many people with migraines have high vagal tone and also respond to anticholinergic therapy.  There are many approaches to treating migraine.  If one finds there is a high adrenergic tone involved, beta blockers, calcium blockers, and ACE inhibitors such as Lisinopril or losartan have been shown to be effective.  If one sees high cholinergic features on testing, anticholinergic therapy with nortriptyline may be beneficial.  Studies have shown that clinical/laboratory detection of autonomic dysfunction is common among patients with migraines, both with and without symptoms of orthostatic intolerance.  Many patients have positive head upright tilt test, clinical autonomic reflex testing, and quantitative pseudomotor axon reflex testing for sweating.  Also, punch skin biopsies for morphometric evaluation of small fiber nerve density has shown to be important and suggests autonomic system dysfunction playing a role.

If one suffers from migraine headaches, they should seek the attention of a headache clinic that specializes in this disorder or a neurology practice that has significant experience with this.  One should also consider exploring autonomic issues, especially if they have orthostatic intolerance, although autonomic dysfunction is found to be significant in patients without orthostatic intolerance as shown in a study by Stillman, Zhou, and Fouad-Terazi in the Journal of Neurology, 2014.

In children migraine equivalents, recurrent abdominal pain and cyclical vomiting are symptoms that are found in studies of autonomic nervous system dysfunction.  The degree of nausea and vomiting can also influence the route of administration of medicines.  There is no question there is dysregulation of the autonomic nervous system, some patients having hypofunction, some hyperfunction, or imbalance of sympathetic and parasympathetic symptoms in migraine patients.  There is no uniform autonomic system finding, and therefore each individual must be tested separately.  Treatment, especially pharmacology, may be dictated by whether there are abnormalities with adrenergic or parasympathetic aspects of the autonomic nervous system as there is a large variety of medications used for treating migraine headaches and oftentimes cocktails in combinations are employed.  We also believe antioxidant therapy and nitric oxide boosting therapy is important as oxidative stress and mitochondrial dysfunction have been linked with migraine headaches.

 

Q: Why is ANSAR’s Parasympathetic and Sympathetic (P&S) monitoring different from other autonomic nervous system (ANS) monitors? 

A: The ANS is made up of the P&S nervous systems.  The ANS is similar to your car, in that it has brakes (the Parasympathetics) and an accelerator (the Sympathetics).  Knowing that your car does not work is not enough information to know how to repair it.  Knowing that the brakes are jammed or the fuel line is clogged is more information and leads to better therapy and improved outcomes, less guess work.  ANS monitoring provides information only about the total ANS, P&S combined, like only knowing my car does not work.  Only knowing total ANS activity forces assumption and approximation.  P&S monitoring provides more and specific information that leads to better therapy planning and improved outcomes.

 

Q: Is Tilt-Table Testing required?

A: Some believe that tilt-table testing is required to monitor the ANS, and once it was the only test available.  It is, however, a measure of total ANS activity (see question #1).  Tilt-testing may still be required in some cases.  Both tests have their limitations, and your physician knows them both.

Q: Most physicians say that the ANS is not treatable, is this true?

A: Most treatments affect only one or the other branch of the ANS:  Parasympathetic or Sympathetic.  Until rather recently, there was not enough information regarding the two branches to know how treatments may affect them, and when treatments were attempted, too often the results were not what was expected.  So physicians did treat the symptoms and hoped for some relief.  However, this lead to multiple medications and often times did not fully restore quality of life.

 

Q: Why is Autonomic Dysfunction so difficult to diagnose and treat?

A: The function of the ANS is to control the organs and thereby all bodily functions.  The ANS is mostly “hidden” behind the organs.  If an organ starts to be dysfunctional, the P&S systems work to keep it functioning properly, even if they themselves are dysfunctional.  So symptoms do not present yet.  It is not until the P&S systems (one or both) begin to fail that the organ dysfunction and associated symptoms present and you do not feel well.  P&S monitoring may detect impending autonomic failure before symptoms and it is often used to maintain wellness either (1) in patients who have been made well after an illness or (2) in patients that have a chronic condition (like hypertension or diabetes) that do not feel poorly, but are at risk.

 

Q: What is the goal of P&S monitoring and therapy?

A: The goal is balance.  Balance between the P&S branches is known as Sympathovagal Balance.  Regardless of age, history, lifestyle, or genetics, a balanced ANS minimizes health risks, promotes wellness, reduces hospitalizations and re-hospitalizations, and may (ultimately) reduce medications.

 

Q: Why do other physicians tell me that my tests results are normal, yet P&S monitoring shows abnormalities?

A: Most tests test you at rest.  The P&S systems support both dynamic as well as resting functions.  The earlier autonomic dysfunctions affect your dynamic states.  Dynamic autonomic dysfunctions are not revealed during tests at rest.  It is not until much later in a diseases process that the resting autonomic states are affected.  The P&S (ANSAR) test report will show both resting and dynamic results.  The resting results often support what other physicians find.  The dynamic results often show the more information needed to help improve wellness.

 

Q: Why does P&S therapy take so long to treat autonomic dysfunction?

A: First of all, P&S therapy has to be low dose.  It is like a pendulum; you have to make small adjustments otherwise other problems may be created from the therapy.  Secondly, the P&S systems have memory (like the rest of your nervous system, including your brain) of your entire history and must be retrained to operate in a more normal and balanced manner.  Think of a habit you want to break.  That takes time to retrain yourself.  Normalizing P&S function is like that.  The longer you had the habit, the longer you had the autonomic dysfunction, the longer it takes to normalize.