My Dearest Doctor,
I hope this card finds you happy and healthy! My name is MS, and you had been treating me for Neurocardiogenic Syncope and advanced Autonomic Dysfunction. My saddest regret about moving to FL was not having you for my doctor.

I want to thank you with all my heart for your kind professionalism and sympathetic care. You have such compassion for my well-being and I can’t find the words to express my gratitude. You advised me to file for SSI and stuck with me when I applied for student loan forgiveness. Had you not done those compassionate things for me and not become frustrated when Nelnet kept sending the forms back to you I don’t know how I could ever make it. Now I should be able to fin a place to live on the SSI income. Your medical care and compassion changed my life! You truly have.

My late fiancé used to call you my Angel Dr. He was so grateful when you took me on as a patient and I feel certain that he is smiling down on both of us from Heaven.

I wish you, your family and your staff everything wonderful life has to offer.

With Great fondness,
MB

PS – If you ever come to Florida, you’re always welcome!

The P&S (Autonomic) Nervous Systems

Question 1:  What is the Autonomic Nervous System (ANS)?

Answer:  Anatomically, the body’s nervous system consists of two parts:  1) the Central Nervous System (CNS, inside the skull and spine) and 2) Peripheral Nervous System (PNS, outside the skull and spine).  Functionally (physiologically), the body’s nervous system consists of three parts:  1) the sensory nervous system (taking input from the world around us through the eyes, ears, nose, tongue, skin, etc.), 2) the motor nervous system (the nerves that control all of our muscles so that we may respond to the input from the world around us; sometimes known as the voluntary nervous system), and 3) the Autonomic Nervous System (ANS, the nerves that take input from inside of us and controls everything inside of us; virtually every cell in our bodies and sometimes known as the involuntary nervous system).  It influences and modifies the function of all of our internal organs.  The ANS, with its two branches, acts as the control system and functions without our knowledge.  That is to say it functions unconsciously or involuntarily.  It regulates the body functions we do not think about such as the heart rate, blood pressure, breathing, digestion, urination, sexual function, sweating, eye blink, and pupil reaction to light.

Question 2:  What are the two branches of the ANS?

Answer:  The ANS is composed of two parts.  These two parts control all of the systems of the body and coordinate them.  They are the Parasympathetic Nervous System (P) and the Sympathetic Nervous System (S).

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 on 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 P&S nervous systems are one of the main human systems responsible for our capability and adaptability.  The interplay between the P&S branches underlies this ability.

Collectively, the P&S 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 P&S Nervous Systems control bodily functions.  To properly affect this control in two components, P&S, need to be in balance.  The specific P&S balance required varies from individual to individual, time to time, activity to activity, and is affected by a person’s genetics.  It also varies with age, lifestyle, environment, and medical history.  P&S dysfunctions result when there is an imbalance between the P&S Nervous Systems.

Question 3:  What are the main chemical messengers, or neurotransmitters, used to communicate within the Autonomic Nervous System and between the ANS and the rest of the body?

Answer:  The main chemical messengers or neurotransmitters are Acetylcholine (Ach) and Norepinephrine (NE).  The nerve fibers that secrete Ach are called cholinergic fibers, whereas the fibers that secrete NE are called adrenergic fibers.  Generally, Ach has Parasympathetic effects and NE has Sympathetic effects.  Note, Parasympathetic effects are typically thought of as inhibitory (slowing things down, or decreasing them) and Sympathetic effects are thought of as excitatory (speeding things up, or increasing them), things like heart rate and blood pressure (the so called “push-pull” effect); however, that is mainly for the heart.  This is generally true also for the brain:

Question 4:  Only two chemical messengers, or neurotransmitters, effect the whole body?

Answer:  Yes, only two.  This is so that the whole body may have a totally coordinated response to a single (important) stimulus.  Think about it.  If you are scared and need to run away or fight, many different systems of the body need to act in concert so that you have a chance of running away or fighting.  Just standing-up engages several different systems doing several different things all together, as coordinated by the Sympathetic Nervous System:  the vasculature needs to constrict in the periphery to move more blood to the heart to help the heart get blood to the brain, which means the core vasculature must dilate and heart rate and blood pressure must increase for a few seconds, breathing must increase for a few seconds, the fluid systems in the Central Nervous System must compensate for the pressure changes, and even though they have constricted, the peripheral vasculature need to supply more blood to the leg muscles so they may work to support standing.  This additional work also requires additional “fuel” so insulin must be released from the Pancreas to open the muscle cells to receive more glucose (sugar) and the glucose and nutrients stored in the Liver must be released to supply the muscle cells.

Simple pharmacological drugs can relieve symptoms of P&S dysfunction, some of which work like or through NE or Ach, or some which oppose NE or Ach.  P&S testing may give us guidance of how to treat a certain disorder by evaluating which is P&S branch is responsible:  for example, whether there is an S-dominance or a P-dominance.

Question 5:  How do the two chemical messengers, or neurotransmitters, effect the brain?

Answer:  More Parasympathetic activity in the brain and we become more sleepy and with even more, we begin to become depressed (depression is too much Parasympathetic activity, and is the start of many of the psychological symptoms of today, including Anxiety, ADD/ADHD, Bipolar Disorders, Manic-Depression, Major Depressive Disorders, Obsessive Compulsive Disorders, etc.).

• Less Parasympathetic activity in the brain and we become less sleepy or less depressed.
• More Sympathetic activity in the brain and we become more awake and with even more, we begin to become hyper-aroused and may experience Anxiety (including palpitations), ADD/ADHD, Obsessive Compulsive Disorders, etc. It is hard to focus and learn because that is more a Parasympathetic mediated function.
  • Note, the reason why both too much Parasympathetic and too much Sympathetic activity may both lead to Anxiety, ADD/ADHD, and OCD, etc., is because these symptoms are caused by too much Sympathetic activity (Sympathetic Excess, or SE). SE may happen both on its own (where SE is a primary response) or may be forced due to a Parasympathetic Excess (where SE is a secondary response).  Therefore, the symptoms of SE are possible in both situations.
• Less Sympathetic activity in the brain and we become less awake less aroused.

Question 6:  The answer to Question 3 describes the “push-pull” effect of the P&S systems on the heart, but that does not seem to be the case in the brain, what other systems of the body are under the influence of both P&S with the “push-pull” effects?

Answer:  The diameter of the iris of your eye opens with Sympathetic activation to let in more light (e.g., to run or fight) and the opposite happens with Parasympathetic activation to let in less light.

• Thyroid gland: S-activity increases Thyroid activity and SE causes Hyperthyroidism, and P-activity decreases Thyroid activity and PE causes Hypothyroidism.
• Insulin release from the Pancreas is increased with S-activity and decreased with P-activity.
• Liver function: glucose and nutrients are released from the Liver with S-activity and stored in the Liver with P-activity (note P-activity controls digestion, see Question 12, and the storage of the glucose and nutrients from digestion is part of this operation.)
• Kidneys:  S-activity decreases volume to prevent excessive blood loss if injured while fleeing or fighting, and P-activity increases volume to ensure all cells of the body are properly perfused (receive proper amounts of blood).
• Bladder: S-activity increases sphincter tone to prevent emptying.  SE causes a persistent “full-feeling.”  P-activity decreases sphincter tone to urge emptying.  PE causes the feeling of needing to empty often.
• Estrogen and testosterone increases with S-activity and decreases with P-activity. Too much testosterone, due to SE leads to rage.  Too little P-activity is associated with too little estrogenor too little testosterone and is associated with peri-menopause or impotence, respectively.

Question 7:  What systems of the body are not under the influence of both P&S systems and their “push-pull” effects?

Answer:  Hormones are typically controlled by only one autonomic branch:  more or less adrenaline or cortisol is from more or less S-activity.  More or less growth hormone is from more or less P-activity.

• Tearing (lacrimcal gland activity) and Salivation is increased or decreased with increases or decreases in P-activity. Sörgrens Disease (dry eyes and dry mouth) is caused by too little P-activity.
• While breathing is controlled by both P&S branches, ventilation (diaphragm) movement is controlled by P-activity and the diameter of the Bronchi are controlled by S-activity.
• The entire Gastrointestinal tract is controlled uniquely by P-activity. More P-activity increases motility, including gastric empting and bowel motility and vice versa.  PE leads to GERD due to excessive gastric motility and diahhrea with or without IBS.  Too little P-activity leads to gastroparesis and constipation with or without IBS.  As a corollary, the Splanchic system is also uniquely controlled by P-activity.  To collect the nutrients from digestion when P-activity increases to facilitate digestion, P-activity opens the Splanchic system and vice versa.  PE can lead to hypovolemia.
• The vasculature throughout the body is uniquely controlled by S-activity. More S-activity constricts the vasculature (increasing blood pressure) and vice versa.  As a corollary, the Angiotensin-Renin system is also controlled by S-activity to also help control fluid volume within the body.  Increased S-activity increases Angiotensin-Renin activity, thereby increasing volume and causing  Decreased S-activity decreases Angiotensin-Renin activity, thereby decreasing volume.  SE, over stimulates Angiotensin-Renin activity and leads to hypertension.  S-insufficiency does not stimulate enough Angiotensin-Renin activity and leads to hypotension.
• Different aspects of sex function are controlled by only one or the other P&S systems. P-activation leads to vaginal lubrication and erection, and S-activation leads to orgasm and ejaculation.  S-insufficiency is associated with impotence and SE is associated with pre-mature ejaculation.
• Sweat glands are uniquely controlled by S-activity. Increased S-activity increases sweating to reduce core temperature.  Decreased S-activity decreases sweating to conserve core temperature.  Occasionally, Ach has S-effects as well, such as stimulating sweating or piloerection, where the hair stands up on end.

Dysfunction of the P&S Nervous Systems

Question 8:  What is P&S or Autonomic Dysfunction?

Answer:  Autonomic Dysfunction also called dysautonomia occurs when the nerves of the Autonomic Nervous System are damaged or not working normally.  Oftentimes, this is called autonomic neuropathy or, as mentioned, dysautonomia.  It can range from life-threatening to only a minor problem.  It can affect the entire autonomic nervous system or only parts of it.

Regardless of the cause, autonomic dysfunction is a result of a persistent imbalance between the P&S nervous systems.  Again, the P&S nerves control actions such as heartbeat, involuntary breathing, or blood vessel size, and blood delivery to all parts of the body; especially the brain.  As a result, any dysregulation can cause serious problems, especially with blood pressure or heart rhythm.  In the case of blood flow to the brain, P&S dysfunction may cause lightheadedness or dizziness, which may be debilitating, or it may cause cognitive difficulties or “brain fog.”  Also, sexual function could be adversely affected, as can digestive, bowel, or urinary function.  Basically any organ system in the body may be adversely affected when there is a dysfunction of the P&S Nervous Systems.

Question 9:  What may cause P&S or Autonomic Dysfunction?

Answer:  The P&S nerves that control and coordinate the organs are small, type-C fibers, and are typically more fragile than other nerves.  As a result they are more sensitive to insult and attack.  They are oftentimes damaged by other disease entities such as diabetes, Parkinson’s, amyloid, or autoimmune processes.  Occasionally, toxic substances or conditions such as alcohol, high blood acid levels such as from too much sugar in the blood, or infectious agents such as viruses or bacteria can cause damage to the P&S nerves.  Further, nerves have some of the highest cellular metabolic rates in the body and as a result are very sensitive to low oxygen or nutrient levels which may be damaging.  Simple aging can cause degeneration of the P&S nerve fibers.  Some individuals have accelerated aging of their nerve fibers, typically due to persistent imbalances between the P&S systems caused by disease, injury, adverse lifestyle, poor genetics, etc.

Question 10:  What is the typical P&S or Autonomic Dysfunction?

Answer:  Again, all P&S dysfunctions are imbalances, and actually there are two general types of imbalances:  a resting imbalance and a dynamic or challenge imbalance.  The typical imbalance is a resting imbalance and is due to the fact that the P-nervous system (the majority of which, outside the central nervous system, is the Vagus Nerve) is a longer and a more exposed portion of the ANS, and therefore more vulnerable to insult or attack.  The balance then suffers and the P-nervous system declines faster than the S-nervous system.  Ultimately this is like the “brakes” failing faster than the “accelerator” on your car.  The problem is that once the “brakes” inside you fail, they cannot be replaced.  This progression includes 1) Peripheral Autonomic Neuropathy (PAN, or Peripheral Autonomic Dysfunction[1]), 2) Advanced Autonomic Dysfunction (AAD, indicating increased morbidity risk – the risk of more secondary symptoms) or Diabetic Autonomic Neuropathy (DAN⁴¹, which is ADD with the complications of abnormal insulin and blood glucose levels due to diabetes), and finally 3) Cardiovascular Autonomic Neuropathy (CAN, indicating increased mortality risk – the risk of sudden death or other major adverse cardiac event, aka. MACE).

[1] At this stage “neuropathy” is a misnomer and has led to the misperception that P&S imbalance cannot be treated.  As a result many people have suffered unnecessarily.  “Neuropathy” implies “dead nerves.”  The nerves are not dead, just damaged and they can be healed and their function normalized for their age.  This is why “Dysfunction” is the preferred term.

Some types of P&S dysfunctions are temporary, and may recover over time; such as functional CAN (CAN that is reversed with therapy, as opposed to structural CAN that is not reversed with therapy).  Identification and treatment is therefore important.  Some types of P&S dysfunction cannot recover completely, but can recover only partially.  Ultimately, all we can do is delay continued deterioration of P&S nerve fibers (in effect delay the aging effect) with several measures, including the Franklin Cardiovascular Mind-Body Wellness Program.

Question 11:  What are dynamic P&S or Autonomic Dysfunctions?

Answer:  The clinical P&S (or ANSAR) test includes three dynamic challenges that simulate common, daily activities:  Deep Breathing challenge (which stimulates the P-nervous system), Valsalva challenge (which stimulates the S-nervous system), and the postural change or stand challenge (which stimulates both the P&S systems and tests the coordination between the P&S systems).  Dynamic balances by definition requires one branch to be significantly higher than the other, but there are limits; both lower and upper limits to how much higher (see insert below).

Dynamic imbalances contribute significantly to Quality of Life (QoL) dysfunctions, as well as PAN and AAD (or DAN).  Even though the primary issue in CAN is minimizing the risk of MACE, once CAN is minimized by normalizing P&S balance (Sympathovagal Balance), normalizing remaining dynamic imbalances may help to improve QoL.  Oftentimes, when P&S dysfunction is secondary to a disease entity, the autonomics will improve when the underlying disease gets treated and improved.  When no cause of P&S dysfunction is identified, we call this idiopathic.  In many instances, treatment can improve the symptoms and abnormalities.  There may be no cure, but treatment often improves QoL.  In these cases, the goal of therapy, including lifestyle changes (such as those in the Franklin Cardiovascular Mind-Body Wellness Program) is to have more better days than bad days oftentimes in treating patients with these illnesses.

Question 12:  What common disorders involve P&S Nervous System Dysfunction?

Answer:  There are many disorders involving P&S Nervous System dysfunction.  These include anxiety, chronic fatigue, fibromyalgia, persistent headache, 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 P&S Nervous System 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 proper cerebral perfusion, which is blood flow to the brain.  It can cause visual effects such as black spots.

Up to 90% 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, oftentimes, unrefreshing sleep, daytime somnolence, swollen lymph nodes, sore throat, depression, and an inability to function.  It is felt that many of these disorders including Anxiety, migraines and neurodegenerative diseases such as Parkinson’s disease, and Alzheimer’s dementia may be the result of P&S dysfunction.

Question 13:  How do I know I have ANS dysfunction?

Answer:  First, note that “if you can feel it, it is not autonomic dysfunction.”  In other words, “pins and needles,” pain (the other small type C fibers), weakness, numbness, etc., are sensory (somatic) and motor dysfunctions, not autonomic dysfunctions.  Typically, by the time these sensory and motor dysfunctions present, P&S dysfunction has already presented.  For example, P&S dysfunction first causes vascular disorder which causes poor perfusion of the tissues in that area (like hands and feet or legs), including the other nerves in that area, which is what leads to the sensory and motor dysfunction.

Diabetes is a sign of P&S dysfunction.  According to the American Diabetes Association by the time a patient is diagnosed with type 2 Diabetes, they have had the disease for 5 to 7 years, and the early stages of autonomic decline already began (see Figure 201).

Lightheadedness or dizziness is a common first symptom of P&S dysfunction, as is fatigue, malaise, exercise intolerance, but there are a number of other potential reasons for these symptoms as well.  Lightheadedness or dizziness may include postural orthoastatic tachycardia syndrome (POTS) or Syncope, with or without fainting.  P&S Monitoring helps to identify P&S dysfunction as a reason for these symptoms.  Compromise of the QoL functions are also indicators, including:  stomach (GI) upset, sleep disorders, bowel and bladder dysfunction, and sex dysfunction.  Also, difficult to control blood pressure, blood sugar (even without diabetes), and hormones (e.g., estrogen and thyroid) are signs of P&S dysfunction, as are unexplained seizures or palpitations, excessive sweating or no sweating, and frequent headache or migraine.  Depression, Anxiety, PTSD, Ehlers-Danlos syndrome, are conditions that typically involve P&S dysfunction.

Question 14:  What symptoms are indicators of Autonomic Dysfunction?

Answer:  As indicated in the answer to Question 13, early symptoms are difficult to detect, and by the time symptoms present it is later in the progression of autonomic decline.  The reason for this is that the P&S nervous systems are “hidden” behind the organs.  In fact, the job of the P&S nervous systems is to maintain normal organ function, as long as possible, even if they themselves are abnormal or dysfunctional.  Symptoms are caused by the organs.  So by the time the organs become symptomatic the P&S nervous systems may have been dysfunctional for a while.

In addition to the symptoms listed in the answer to Question 13, other questions to ask is include:  1) “Do I have erectile dysfunction?” 2) Urinary tract questions such as “Does one pass urine involuntarily such as urinary incontinence.” or 3) “Does one have difficulty emptying urine such as urinary retention.”   While structural abnormalities may be the etiology, oftentimes, autonomic dysfunction may be the problem.

In our practice we use the 25 point “Simplified Autonomic Questionnaire,” above, to help determine if P&S monitoring is to be considered.  The more positive items answered the higher the possibility an individual will test positive for P&S dysfunction.

Question 15:  Are there different degrees of abnormality or gradation to autonomic dysfunction?

Answer:  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.

Tests of the P&S Nervous Systems and for Autonomic (P&S) Dysfunction

Question 16:  Are there lab tests to determine the presence of Autonomic Dysfunction?

Answer:  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.  Cortisol levels are drawn to rule out Addison’s disease, an adrenal disorder.  Oftentimes, a 24-hour urine for prostaglandins and metabolites of histamine are assessed to rule out a mast cell activation syndrome which may have autonomic dysfunction components associated with it.  Also, blood Tryptase levels are drawn for individuals suspected of mast cell activation syndrome.

There are many tests which can also assess for autonomic dysfunction that 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° 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.

Question 17:  What tests are available to determine if I have P&S or autonomic dysfunction?

Answer:  Over the years several non-invasive tests have been developed to assess the P&S nervous systems, including:  tilt-table testing, heart rate variability, beat-to-beat blood pressure, Quantitative Sudomotor Axon Reflex test (Q-SART), and a simplified version of Q-SART:  Q-Sweat.  However, the one we most prefer is P&S Monitoring which is most able to quantify the P&S branches, simultaneously and without assumption or approximation.  We prefer it because “simultaneously and without assumption or approximation” is unique to P&S Monitoring [8].

Question 18:  Why is P&S Monitoring, or autonomic testing in general, not well understood?

Answer:  There are various tests that can test for types of disorders of somatic nervous system (a part of the peripheral nervous system separate from the autonomic nervous system).  Usually, a neurologist can address the workup of various types of peripheral neuropathies which are non-autonomic but somatic.  Unfortunately, because of the difficulty measuring the P&S nervous systems (because they are “hidden”), there was very little data on them until relatively recent, and the data we had was on total (the sum of P&S) autonomic function, which was not specific enough.

Where it is more well known was (and is) in the diabetes world.  Autonomic (Diabetic Autonomic Neuropathy) as well as somtosenory neuropathies are very commonly found in diabetics.  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.

Question 19:  Why may P&S Monitoring discover and document things most other physicians or tests cannot?

Answer:  The P&S nervous systems are dynamic systems.  Except for stress tests (on treadmills), most other tests are administered while you are at rest (sitting or laying on the exam table).  To that end, most patients come to us after having seen several physicians, who by that time, all say that the patient is “normal.”  Yet the patient is still complaining of symptoms.  When we test a patient, we also test them at rest, but we test them dynamically (in response to challenges) as well.  This is what makes the test more complicated both for the physician and the patient.  However this dynamic feature is important, because most often that is where the patients’ disorders are found and documented.  So we show patients both the fact that often they are normal at rest (they should be a number of doctors have worked on them a number of years to get them and keep them that way!), but abnormal in response to challenges.  Furthermore, these abnormalities are also treatable and in treating them they may be relieved.

Question 20:  Why is P&S Monitoring a complex test, both for the patient and the physician?

Answer:  As stated in the Answer to Question17, the P&S nervous systems are dynamic systems, and as such require more testing to document.  In addition, A doctor’s evaluation is important.  Blood pressure and heart rate responses to different stresses, sitting and standing need to be taken and require up to five minutes to document.  A weak blood pressure response (increase) to Valsalva (the stress response) or too great a blood pressure response (decrease) to Deep Breathing (the relaxation response) may cause lightheadedness and other symptoms (including “brain fog” and anxiety-depression syndromes).  A drop in systolic blood pressure of more than 20 millimeters of mercury or a 10 millimeter of mercury drop in diastolic upon standing may be seen in Orthostatic Hypotension.  This is another potential cause of lightheadedness and other symptoms, as are it related diseases:  Orthostatic Intolerance and Orthostatic Hypertension.  Another is Postural Orthostatic Tachycardia syndrome (POTS), which is characterized by a rise in heart rate greater than 30 beats per minute within 3 minutes of standing.  Syncope, including Vasovagal Syncope, is another fairly common disorder that requires a dynamic test to elucidate.  These are yet another potential causes of lightheadedness and other symptoms.  None of these abnormal, responses common to P&S dysfunction may be detected at rest.

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

Lightheadedness (“Dizziness”) Due to Autonomic Dysfunction

Question 21:  What Autonomic dysfunctions underlie lightheadedness?

Answer:  As mentioned in Question 12, lightheadedness (also characterized as “dizziness”[2]) is a common (first) symptom of P&S (autonomic) dysfunction.  The postural change (stand) portion of the P&S Monitoring test helps to differentiate the underlying cause of lightheadedness.  There are three possible, abnormal, P&S results:  Sympathetic Withdrawal (SW), Sympathetic Excess (SE), and Parasympathetic Excess (PE).

• SW is associated with orthostatic dysfunctions, e.: Orthostatic Intolerance, Orthostatic Hypotension, Orthostatic Hypertension, and Postural Orthostatic Tachycardia Syndrome (POTS).
  • PE may mask SW, especially if there is a decrease blood pressure response to stand.
• SE is associated with (pre-)Syncope, e., Neurogenic Syncope, Vasovagal Syncope, Cardiogenic Syncope, of Neurocardiogenic Syncope (yes, patients may have both a neurological and cardiological dysfunction that both may cause Syncope).
  • PE with SE is associated with (pre-)Vasovagal Syncope.

[2] Physicians differentiate lightheadedness from dizziness by associating dizziness specifically to Vestibular disorders and lightheadedness to non-Vestibular causes of “dizziness.”  Patients, especially the elderly, frequently have both Vestibular and at least one non-Vestibular cause of lightheadedness or dizziness.

Question 22:  Why is Sympathetic Withdrawal associated with Orthostatic Dysfunction.

Answer:  In 1980, Williams and coworkers described episodes of low blood pressure associated with Sympathetic Withdrawal (SW).  Normally upon standing the (alpha-) Sympathetic nervous system increases activity to cause vasoconstriction in the legs to help move blood to the abdomen to help the heart pump blood to the brain upon standing or assuming an upright (head-up) posture.  This is a compensatory mechanism, compensating for the effects of gravity upon standing.  Sympathetic Withdrawal (SW) is the failing of the increase due to autonomic dysfunction (possibly due to disease, aging, or injury), where the Sympathetics do not respond properly and due to the lack of vasoconstriction, blood pressure may not increase sufficiently, or may decrease, and Orthostatic dysfunction may result.

Note, SW is more information and may be used to indicate preliminary forms of Orthostatic dysfunction prior to symptoms or the demonstration of full clinical symptoms.  This may help to prevent full clinical symptoms or enable earlier treatment helping to promote prevention and wellness.

We have observed SW 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.  SW 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 mmHg 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 with SW.

Question 23:  Is SW treatable?

Answer:  The treatment of SW is the same as that for any orthostatic intolerant symptomatic patient (see “Lightheadedness (“Dizziness”) Due to Autonomic Dysfunction”), 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 OH or POTS syndrome.  It appears that SW 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.

Question 24:  What causes fainting (syncope) or near fainting (pre-syncope)?

Answer:  Fainting or syncope occurs when there is self-limited loss of consciousness caused by lack of blood flow and oxygen delivery to the brain resulting in reduced cerebral perfusion.  Pre-syncope is near loss of consciousness by the same mechanism.  Blood loss and dehydration are common causes which precipitate syncope or pre-syncope.  Sympathetic Excess upon standing is associated with (pre-)Syncope and is believed to be the result of the brain using the Sympathetic Nervous System to signal for more blood (by increasing heart rate or blood pressure, thereby increasing cardiac output, expecting to drive more blood to the brain).

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).  An electrical abnormality in the heart or a cardiac arrhythmia is extremely important to exclude as this oftentimes can be life threatening.  When cardiovascular diseases (structural or electrical) are excluded, most causes of syncope are usually benign, albeit potentially debilitating.  The remaining causes of syncope are neural.

Note, the most commonly diagnosed form of Syncope is Neurocardiogenic Syncope, meaning both of neural and cardiac origins.  While both may cause Syncope at the same time in a patient, this is more often a guess due to the fact that most autonomic measures cannot differentiate P&S without assumption or approximation.  The most common cause of syncope is due to an abnormal neural reflex known as vasovagal syncope (VVS).  This neural (Vagal) reflex can be situational to cough, post-micturitional (after urination), status post-emotional (like seeing blood or like the excitement experienced after one’s football team scores a touchdown) or post-prandial (after a large meal), or as a reaction to pain or extreme heat.

Question 25:  Do all forms of syncope occur only while standing?

Answer:  Some forms of syncope occur only on assuming the upright position, either immediately or in a delayed fashion.  Vasovagal syncope may occur sitting or standing for a prolonged periods of time but usually not immediately.

Question 26:  What is the difference between Syncope and Orthostatic Dysfunction, including POTS?

Answer:  As mentioned in the answer to Question 20, some forms of syncope (i.e., Vasovagal Syncope) whereas, orthostatic forms of syncope may occur sitting or standing, whereas Orthostatic Dysfunctions occur only on assuming the upright position and 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 P&S (aka., cardiorespiratory) testing.  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.

Question 27:  What is Vasovagal Syncope (VVS)?

Answer:  Vasovagal syncope is also known as the “simple fainting spell.”  This is a neurally 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 or both.  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, emotion, a large meal, pain, and alcohol.  A tilt test may be necessary to differentiate vasovagal syncope from an orthostatic type of fainting such as orthostatic hypotension.  A tilt-test may also be needed 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.

Question 28:  There are warning signs to Vasovagal Syncope (VVS)?

Answer:  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.

Question 29:  What is therapy for Vasovagal Syncope (VVS)?

Answer:  Pacemaker therapy is rarely warranted and is usually discouraged in patients with frequent vasovagal syncope.  However, it may be helpful in older individuals over the age of 40 when documented periods of asystole (a pause in the heart rate) or very slow heart rates are recorded, oftentimes with Holter monitors or loop recorders.

Treatment for vasovagal syncope is typically 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 (to treat the Vagal or Parasympathetic component) in individuals who test in our autonomic lab for high vagal tone may be useful.  In the past, individuals have used anticholinergics such as Norpace (which is actually an antiarrhythmic drug).  Some people 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, especially with low blood pressures.  Compression stockings are often useful in addition.  In terms of pharmacological treatment, Mineralocorticoids such as Fludrocortisone are also useful.  These retain water within the blood vessel system, building or maintaining blood volume to help properly perfuse the brain.  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.

We have found that Midodrine is often helpful and may be taken up to three to four times a day, usually starting at a 2.5 mg low dose and titrating upwards.  In fact, Midodrine has been shown to be the most effective agent in patients who have flare-ups.

Question 30:  If Midodrine is so useful for VVS, why is it not use more often and by more physicians?

Answer:  While Midodrine is usually well tolerated, it is not recommended in patients with hypertension or heart failure.  It is also contra-indicated for people with supine hypertension or high resting blood pressure.  Midodrine is an adrenergic agonist, a potent 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, and if a pure autonomic dysfunction, may not need the higher doses.  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 channel blocking agent which affects the sinus node and thereby 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.  While more research is being done on this agent, we have found Corlanor to be very effective in various types of fainting disorders and even in treating patients with POTS who have presyncope and not actual syncope.

Question 31:  What is Orthostatic Intolerance (OI)?

Answer:  Orthostatic intolerance affects millions of Americans at all ages.  It is a condition that is triggered when the body changes position (for example, assumes an upright posture), dizziness, lightheadedness, nausea, sweating, fainting, or near fainting may occur.  Lying down improves symptoms.  It is often related to improper regulation of the ANS; typically the alpha-Sympathetic nerves that innervate the peripheral vasculature.  These alpha-Sympathetic nerves do not communicate properly to the blood vessels, which do not constrict upon standing, causing blood to pool in the legs and making it hard for the heart to properly pump blood to the brain.

“Brain fog,” (aka., 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 d) is often associated with lightheadedness and near syncope.  It is also associated with significant levels of (physiologic) fatigue.  After episodes of brain fog and orthostatic intolerance, individuals have to lie down and often have debilitating fatigue for hours and possibly days.

Orthostatic intolerance is predominantly due to three mechanisms:  1) Withdrawal of the (alpha-) Sympathetic nervous system input into the legs while 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.

Question 32:  Why do some people have Orthostatic Intolerance (OI) only occasionally and in others it is debilitating?

Answer:  In some people OI may be masked by elevated or high blood pressure.  This may be a compensatory mechanism, where the body sets the resting pressure high enough to sustain the drop and still provide enough blood to the brain.  It others, their hearts are strong enough to compensate, but it may only be short lived.  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 a transient increased heart rate of 10 to 20 beats a minute (over about the first 30 seconds after assuming an upright position), 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.

Question 33:  What is the treatment for orthostatic intolerance?

Answer:  Simple measures such as elevating the feet of the bed may help patients who have orthostatic intolerance.  We also encourage our patients to drink six to eight glasses of water 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.

Question 34:  What is Postural Orthostatic Tachycardia Syndrome (POTS)?

Answer:  POTS is a condition where there is an excessive increase in heart rate in the upright position usually seen soon after standing within 10 minutes.  A 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 that 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 that are lasting more than six months despite the heart rate rising with standing position as described above.

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.

Question 35:  Who may Postural Orthostatic Tachycardia Syndrome (POTS) effect?

Answer:  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 (See Question 22).  Patients with POTS do not have syncopal episodes, but have pre-fainting or pre-syncope.  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.

Question 36:  What are the symptoms of Postural Orthostatic Tachycardia Syndrome (POTS)?

Answer:  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 over-compensation of the Sympathetic nervous system where it becomes extremely hyperactive (“revved up”).  With this Sympathetic hyperactivity, heart rate becomes extremely high on standing.  There is no drop in blood pressure.  Therefore, this is characterized by a hyper-Sympathetic 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 dysfunction or 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 hyper-adrenergic activity where Norepinephrine levels increase on standing.  Other types of POTS patients are chronically hypovolemic or have a low blood volume.  Hypovolemia may be confirmed by nuclear testing, 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.  Histamine may have induced a form of hypovolemia.  There is also a genetic type where there is a Norepinephrine reuptake transporter defect which is very rarely seen.

Question 37:  What is the treatment of POTS?

Answer:  Regardless of the type of POTS, usually the treatment requires fluid hydration to increase blood volume, and drink the water very rapidly along with taking salt tablets.  Doing this immediately before arising in the morning is very beneficial.  Compression stockings are also useful.

Exercise training has been found to be highly beneficial, 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 the premenstrual cycle.  Oftentimes, we will increase fluids and give Midodrine specifically during this time of the month for females who have symptomatic POTS.

Patients with POTS can be quite disabled.  Because of this, pharmacology may be necessary:

• Fludrocortisone: a volume expander.  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.
• Propranolol: 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: is a blood pressure medicine, which 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.
• Midodrine: a vasoconstrictor.  We have found vasoconstrictor therapy with Midodrine to be extremely effective, especially with fluid loading in patients with POTS.  Midodrine is an alpha-Sympathetic agonist which constricts the venous blood vessels in the lower extremities and promotes blood flow to the brain.
• Pyridostigmine: 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.
• Ivabradine: 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 ion 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 pre-certified.
• Modafinil: Occasionally, we stimulate the central nervous system with Modafinil to treat the significant brain fog which occurs with patients with POTS.  However, this may aggravate blood pressure and arrhythmias and needs to be watched carefully if prescribed.  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.

Question 38:  What is Orthostatic Hypotension (OH)?

Answer:  Orthostatic Hypotension is sometimes called Neurogenic Orthostatic Hypotension (NOH) if there is no identifying cause such as dehydration, blood loss, or medications.  Idiopathic or NOH is defined as a blood pressure drop greater than 20 millimeters systolic or 10 millimeters diastolic within 3 minutes of 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 OH, but these patients are not very symptomatic for the most part, in our experience.

OH occurs with increasing frequency as one ages or suffers from prolonged or chronic diseases (the aging and disease effects correlate with the progression of autonomic decline).  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 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.

Question 39:  What are the symptoms of Orthostatic Hypotension (OH)?

Answer:  The mechanism for OH 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 increase and it remains level or decreases.  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 OH, 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 OH 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 OH will have an early and progressive decline in blood pressure without a drop in heart rate.

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

Question 40:  What is treatment for Orthostatic Hypotension?

Answer:  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, Midodrine is contraindicated in patients with supine hypertension and in elderly men, especially, Midodrine may cause urinary retention.  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.
• Pyridostigmine: is an alternative to Midodrine in people who are hypertensive.  Pyridostigmine is an acetylcholinesterase inhibitor that prolongs the effects of acetylcholine and increases Sympathetic tone.  However, 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 supine hypertension or resting hypertension, and one does not want to give Midodrine.  Initial reports in studies in 2004 showed its efficacy in treating OH.
• 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.
• Northera: recently Northera, or Droxidopa, has been approved for treatment of OH.  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.  However, 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.

Diseases that Result from Dysfunction of the P&S (Autonomic) Nervous Systems

Question 41:  What is Multiple System Atrophy (MSA).

Answer:  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, especially early.  Usually, patients with Parkinson’s disease respond to the medicine Levodopa and patients with MSA do not respond.  In general, patients with MSA loose Sympathetic innervation of the heart, whereas, those with Parkinson’s do not.

Question 42:  How do I get checked for MSA?

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

Usually, MSA occurs at a younger age and progresses more rapidly than 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 sweat testing 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.

Question 43:  What autonomic findings can you see in Parkinson’s disease?

Answer:  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.

Question 44:  What is Ehlers-Danlos syndrome?

Answer:  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 1) classical type, 2) hypermobility type, 3) vascular type, 4) kyphoscoliosis type, the 5) arthrochalasia type, and the 6) dermatosparaxis type.  Different genetic causes and patterns of inheritance are noted.  The skin is oftentimes affected, it can be lax or also 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, largely due to poor peripheral circulation, in part, due to P&S dysfunction.  This leaves scars that are the so-called cigarette paper-type scars.  Life-threatening rupture of blood vessels can occur in the vascular type of Ehlers-Danlos syndrome.  P&S dysfunction is often found in the hypermobility type Ehlers-Danlos syndromes.

Question 45:  What symptoms are associated with Ehlers-Danlos syndrome?

Answer:  Typical symptoms include fast heartbeat or tachycardia, low blood pressure, gastrointestinal (GI) motility problems, bladder problems, and sweating regulation abnormalities.  Postural change abnormalities are common in patients, including:  Orthostatic intolerance, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome, or Vasovagal Syncope.

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, causing inflammation and abnormal blood volume changes, 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 (stethoscope) 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.

Question 46:  What autonomic dysfunction is associated with Ehlers-Danlos syndrome?

Answer:  The typical symptoms of fast heartbeat or tachycardia, low blood pressure, gastrointestinal (GI) motility problems, bladder problems, and sweating regulation abnormalities are associated with autonomic dysfunction (both branches, P&S).  Postural change abnormalities (including:  Orthostatic intolerance, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome (POTS), or Vasovagal Syncope) are also associated with P&S dysfunction.  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.

To test for P&S dysfunction and differentiate the specific postual change abnormality for the individual patient (e.g., Orthostatic Hypotension or POTS), a stand test may be ordered.  Usually, this should be done for at least 5 minutes or up to 10 minutes.  Usually, changes are seen within 3 to 5 minutes, however, some take longer.  The patient should rest supine for 5 minutes before testing to establish a baseline.  Heart rate, blood pressure and P&S measurements are taken during the two postual positions of the stand test.

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

Question 47:  What therapies are typical for Ehlers-Danlos syndrome?

Answer:  P&S dysfunction is treated to address the autonomic imbalances that may underlie the cardiovascular, GI, bladder, sweating and lightheadedness (due to postural change abnormalities) symptoms.  Treatment of P&S dysfunction in Ehlers-Danlos syndrome is not different than treatment for the various categories of orthostatic disorders and reflex disorders.  The underlying P&S imbalances often exacerbate the pain associated with Ehlers-Danlos syndrome and lead to anxiety and depressive symptoms.  As a result, we 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 disabilities, and require neck braces, knee braces, and whole body braces at times because of significant subluxation (joint dislocations).  Anxiety and depression levels can be quite high.  Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are helpful in these patients, especially with orthostatic intolerance and in the setting of coexisting pain and the anxiety and depressive symptoms.

Question 48:  Why are diabetics more susceptible to neuropathies including peripheral sensory neuropathies and peripheral autonomic neuropathies?

Answer:  When a diabetic develops neuropathy, they are more at risk of heart disease than a diabetic who does not have neuropathy.  However, the odds of a diabetic developing neuropathy is very high, and the heart disease is a result of the associated increases in morbidity (the stage known as diabetic autonomic neuropathy, or DAN) and mortality risks (the stage known as cardiovascular autonomic neuropathy, or CAN), significantly affecting QoL and longevity, respectively.

Regardless of diabetes, any person can develop neuropathy of the sensory nerves which can leave one with a burning sensation, tingling sensation, and pain in the extremities.  However, it is more common in diabetics.  The reason that neuropathy is more common in diabetics has not been fully elucidated.  However, it is believed to significantly involved the effects of sugar acidosis due to excess sugars remaining in the blood stream turning the blood more acid.  The more acid the blood the more likely it is to damage tissues, especially the highly fragile P&S nerves.  Once the P&S nerves are compromised, blood flow becomes compromised.  Compromised blood flow means less blood to the periphery, meaning less oxygen delivered to the periphery.  So now, not only are the nerves being damaged by the acid in the blood, there is less oxygen being delivered to support the remaining function.  Less oxygen also means a slowing of the repair processes, which are slow enough naturally in nerves.

Question 49:  What are DAN and CAN?

Answer:  DAN is diabetic autonomic neuropathy.  It is an indication of increased morbidity risk.  It is the diabetic form of Advanced Autonomic Dysfunction (AAD), including the insulin and blood glucose issues.  DAN is a serious complication of diabetes.  It often leads to cardiovascular autonomic neuropathy (CAN).  CAN is an indication of increased mortality risk.  CAN is a more severe form of P&S nerve dysfunction than DAN.  Both CAN and DAN in diabetics leave patients at a higher risk of having cardiac events such as heart attacks and sudden cardiac death.  CAN may be characterized as very high risk.  In fact, if a person is found to demonstrate CAN, and they have not recently had a cardiac work-up, then the cardiac work-up is highly recommended as soon as possible.  We are very aggressive in diagnosing CAN and treating these patients.

Question 50:  How might I know that I may have DAN or CAN?

Answer:  DAN and CAN are painless since it effects the nerves that would let you sense the associated pain or discomfort.  So it is difficult to know without P&S testing.  This is why P&S testing is recommended shortly after diagnosis.  Many people associated the fatigue and malaise with “getting older and slowing down.”  This may not be the case.  Clinical manifestations of DAN and CAN include Orthostatic dysfunction.  Many times, these patients have Orthostatic Hypotension.  They experience an increase in heart rate, or resting tachycardia, with exercise intolerance.  This is a result of the imbalance between the P&S nervous systems, in which P-activity declines faster than S-activity.  A lack of P-activity means that the body including the heart is not properly protected.  A common effect of CAN is silent myocardial ischemia (a lack of blood supply to the heart without chest pain due to a lack of the nerves that enable you to feel the heart attack).

The lack of P-activity may cause GI motility problems, including gastroparesis (a disorder of the stomach in which the weak Parasympathetics do not move the stomach contents 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 and we have called this a diabetic cystopathy.  Erectile dysfunction and retrograde ejaculation can occur in men.  Women may 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 who develop advanced neuropathy as can any person actually who develops advanced neuropathy.  Gallbladder enlargement and contraction of gallbladder has also been described in patients with diabetic autonomic neuropathy.

Question 51:  What are the clinical manifestations of DAN or CAN?

Answer:  Microvascular or small vessel blood flow is under the control of the Autonomic Nervous System (ANS) and is regulated both by the central and peripheral parts of the ANS.  In diabetics, the contraction of the small blood vessels is disordered and microvascular insufficiency results.  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.  This is why 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 ANS.  A heart rate response in deep breathing is an important function of P-activity.  Lightheadedness due to Sympathetic Withdrawal is a common, early, clinical manifestation leading to Orthostatic dysfunction.  Heart rate responses to Valsalva maneuver and stand are influenced by both P&S activity.  To assess S-responses, measurements of blood pressure, HR and P&S activity, and sometimes to sustained hand grip, are used.

The danger with DAN,and especially CAN, is that there may be the inability to get warning signals of when the blood sugar drops, that is when hypoglycemia occurs.  This is an extremely important problem which easily indices silent heart attacks.  A physician trained in autonomic assessment can do simple noninvasive tests in the office to determine if there are abnormalities in the P&S nervous systems and to what severity.

Question 52:  In what areas has targeting the autonomic nervous system with therapy been most supported by research data and applied clinically?

Answer:  Historically, Diabetes is arguably the area that has been most supported by research, the results of which are mentioned in Question 48 through Question 51.  Heart failure is another area that has been well targeted.  A manipulation of the ANS has been a tremendous breakthrough in Heart Failure.  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.  This Sympathetic activation causes myocardial dysfunction and fibrosis.  In fact, the current pharmacotherapies are drugs used to treat Heart Failure by targeting the ANS.  For example, beta blockers and Renin Angiotensin System inhibitors reduce morbidity and mortality by targeting aspects of the ANS, 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 ANS, particularly the Sympathetics, are most effective in treating heart failure patients:  “Modulation of the Autonomic Nervous System is a treatment for Heart Failure, but has been limited mostly to pharmacological therapies” [3].  This is the culmination of research that has 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.

For several decades, it has been evident that by blunting the effects of the Sympathetic nervous system by various means [21] whether using beta blockers, or in some cases Angiotensin receptor blockers (what we term as ACE inhibitors), Heart Failure patients improve their heart function and extend their life expectancy.  There is recent data that there are other methods that will modulate the ANS in a beneficial way.  Recent data has looked at enhancing the Parasympathetic nervous system activity in heart patients to afford them a protection from such things as sudden cardiac death and cardiac events.

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.  Modulation of the P&S nervous systems is not only beneficial, in our opinion, but it can also be beneficially influenced by the significant ongoing research that 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 P&S problems or deficiencies.  An example of this is the use of Midodrine to promote, we believe, relief in some cases of Depression, Chronic Fatigue, Fibromyalgia and Migraine, as examples.  However, we also note that pharmacological therapies are often insufficient, leaving gaps.  In these cases, we also recommend lifestyle and supplement therapy to support the pharmacological therapy and sometimes to “fill the gaps.”  The lifestyle and supplement recommendations are contained in the Franklin Cardiovascular Mind-Body Wellness Program.

In summary, therefore, tremendous evidence with Diabetes and Heart Failure and modulating the P&S 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 ANS.

[3] Polhemus DJ, Trivedi RK, Gao J, Li Z, Scarborough AL, Goodchild TT, Varner KJ, Xia H, Smart FW, Kapusta DR, Lefer DJ.  Renal Sympathetic Denervation Protects the Failing Heart Via Inhibition of Neprilysin Activity in the Kidney.  J Am Coll Cardiol. 2017 Oct 24;70(17):2139-2153. doi: 10.1016/j.jacc.2017.08.056.

Mitochondria and Ditochondrial Disorders

Question 53:  What are mitochondria?

Answer:  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, well being, 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.

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 (P&S) nervous system is very susceptible to injury when mitochondrial dysfunction occurs as the neurons (nerve cells) are some of the highest consumers of energy in the body.

Question 54:  What are mitochondrial disorders?

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

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 of the energy molecule of the body known as ATP (Adensine Tri-Phosphate).  Fewer ATPs means we have less fuel (energy) to support our nerve, heart and muscle activities, which causes us to fatigue and tire much more easily.  Also, mitochondria are very important in extinguishing free radicals which are actually produced by the mitochondria themselves.  (See the “Energy Production” section of this book, and note that the few free radicals that normal Mitochondrial function does produce are used by the immune system to attack and destroy invading bacteria and viruses.)

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 (cancer).

Question 55:  How does mitochondrial disorder affect me?

Answer:  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 free radicals and reactive oxygen species which, if there are not enough antioxidants in the body, can go unopposed to cause more tissue damage.

Question 56:  How is mitochondrial disorder treated?

Answer:  One method of treating mitochondrial dysfunction is to promote a strong antioxidant atmosphere (milieu) throughout the body.  Another is to promote an anti-inflammatory milieu throughout the body.  A third would be increased nitric oxide throughout the body, especially for anti-atherosclerotic effects.  These are some of the goals of the Franklin Cardiovascular Mind-Body Wellness Program.  Many of our patients with autonomic dysfunction do respond to this 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 substances include Alpha-Lipoic Acid and Coenzyme Q-10.  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, are very helpful.  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 the plaque of atherosclerotic lesions of the artery walls and many of the compounds in the Franklin Cardiovascular cocktail have antioxidant effects which retard oxidation of LDL particles.

In our empiric experience, the Mind Body 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 and lifestyle modifications are best for them.  Typical lifestyle modifications include 1) a healthy diet (we prefer the Mediterranean diet), 2) a healthy exercise program (we prefer 150 minutes a week minimally for exercise), and 3) a stress reduction program (we prefer exercise or meditation for stress reduction).  Typical supplement programs include anti-inflammatories, antioxidants, and nitric oxide boosting compounds.  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.

Ehlers-Danlos Syndrome (EDS) and Autonomic Dysfunction

Parasympathetic and Sympathetic Monitoring Identifies Earliest Signs of Autonomic Neuropathy (NuroSci)

Long-Covid Syndrome: A Multi-Organ Disorder

Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients (NeuroSci)

Long COVID and the Autonomic Nervous System (NeuroSci)

Long COVID Syndrome for Patients

Long-COVID Syndrome Article by Dr. DePace – January 2022

General Information Brochure on Orthostatic Intolerance and its Treatment (with August 2021 Addendum)

Coronavirus Induces Oxidative Stress Leading to Autonomic Dysfunction Often With Delayed Symptom Onset

COVID Leads to Oxidative Stress and Parasympathetic and Sympathetic (P&S) Dysfunction

Hypermobility Ehlers-Danlos Syndrome and the Parasympathetic and Sympathetic Nervous Systems

Improved Patient Outcomes by Normalizing Sympathovagal Balance: Midodrine and Parasympathetic and Sympathetic Monitoring

Do I Have Mast Cell Activation Syndrome (MCAS)?

COVID-19 Involves Oxidative Stress and Inflammation:
Antioxidants Are Possibly Therapeutic and Preventative

COVID-19 (Coronavirus) and Exercise, Diet, and Antioxidants

Biological Aging and Anti-Aging Mechanisms

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

Maintaining Antioxidant Balance

Autoimmune Autonomic Ganglionopathy and Autoimmune Autonomic Neuropathy

Autoimmune and Postural Orthostatic Tachycardia Syndrome (POTS)

Chronic Fatigue Syndrome, Mitochondrial Dysfunction and Parasympathetic Excess: A Summary Review

Gastroparesis Part 3, Dumping Syndrome

Gastroparesis Part 2, Treatment

Gastroparesis Part 1,  Diagnosis, Etiology, and Testing

The Brain-Gut Connection

Vasovagal Syncope and Chronic Vagal Excess

Nitric Oxide in Promoting Healthy Autonomic Function

Overactive Sympathetic Nervous System

What is Orthostatic Intolerance?

Do I Have Postural Orthostatic Tachycardia Syndrome (POTS)?

What is Joint Hypermobility Spectrum Disorder?

What is Hypermobile Ehlers-Danlos Syndrome?

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

The Six-Prong Lifestyle

Overview of the Autonomic Nervous System

Dizzy? It Could be Your Nerves (NJ.com article about the book: Clinical Autonomic Dysfunction)

Interview with Dr. DePace on KYW News Radio (MP3)

Click Here to  Download the Autonomic Questionnaire

Click Here to  Download the Dysautonomia Drugs Questionnaire

Click Here to  Download the Compass 31 Questionnaire

Click Here to  Download the Cultural Competency Form

Click Here to  Download the EDS Questionnaire

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