what are dysautonomias? - ndrf

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What areDysautonomias?

Dysautonomias areconditions wherealtered activity of the“automatic” nervoussystem (the autonomicnervous system) isharmful to health.

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In Dysautonomias,What Goes Wrong?Probably the most common type of dysautonomia is acondition where altered autonomic nervous systemfunction worsens another disease process that happens tobe going on at the same time. For instance, when aperson shovels snow, the exercise and cold exposurewhile standing up activate the sympathetic nervoussystem, and this increases the blood pressure, pulse rate,and the force of the heartbeat, which are appropriateresponses. More blood is delivered to the heart muscle,which uses up oxygen because of the increased work ofthe heart. But if the person has severe coronary arterydisease, where the blood vessels that are supposed todeliver blood to the heart muscle are narrowed, the bloodsupply does not increase to meet the increased demandfor oxygen. This imbalance can lead to a heart attack orfatal abnormal heart rhythm. In other words, in thissituation, the increased sympathetic nervous systemoutflow would be appropriate, but the person ends upsuffering anyway, because of the worsening of anindependent disease.

In other forms of dysautonomia, the problem is fromabnormal function of the autonomic nervous systemitself. This is the form of dysautonomia that most of therest of this book is about.

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Altered “automatic” nervous systemfunction can worsen another disease or canitself harm health. In this book,“dysautonomias” refer to disorders of theautonomic nervous system itself.

For a variety of reasons, we know much more about whatgoes wrong with the sympathetic nervous system thanwith other parts of the autonomic nervous system indysautonomias.

In general, there are two ways dysautonomias can resultfrom abnormal function of the sympathetic nervoussystem. The first is when the system is activated to takeover when another system fails. We call thiscompensatory activation. The second is when there is aprimary abnormality of the system.

Finally, there are two general ways the function of thesympathetic nervous system can be abnormal. The first isby underactivity of the system, and the second isoveractivity of the system. Both underactivity andoveractivity of the sympathetic nervous system can bepersistent and long-term or can be occasional and short-termæ in other words, chronic or episodic.

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Altered Autonomic Nervous System Function

Worsening ofanother disease

Harmful change inautonomic

nervous systemfunction

Compensatoryactivation

Abnormalautonomic

nervous systemfunction

Too active Too inactive

Acute Chronic Acute Chronic

There are four types of dysautonomia,depending on whether there is too much ortoo little activity and whether the conditionis new or has been going on a long time.

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The “Mind-Body”Issue

It is worthwhile to discuss here the issue of the “mindversus body” as a primary cause of disease, becausedysautonomias are, possibly more than any otherailments, mind-body disorders.

Dysautonomias are mind-body disorders.

This is a difficult subject for both doctors and patients.The problem is the old notion that the body and mind areseparate and distinct in a person, and so diseases must beeither physical or mental. If the disorder were physical, itwould be “real,” something imposed on the individual,while if it were mental, and “in your head,” it would notbe real, but something created in and by the individual.

Mind Thoughts Mental Illness

Body Imposed Challenges Physical Illness

Traditional separation of mental fromphysical illness.

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Distinctions between the “body” and the“mind,” the physical and mental, problemsimposed on the individual and those in themind of the individual, are unhelpful intrying to understand dysautonomias.

These notions date from the teachings of the Renaissancephilosopher, Descartes. They are outdated by now andalso inappropriate and unhelpful in trying to understanddisorders of the autonomic nervous system.

Here is why. Remember in the first chapter you learnedabout the “inner world” and the “outer world”? The minddeals with both worlds, simultaneously, continuously,and dynamically in life. Conversely, both worlds affectthe mind, and each individual filters and colorsperceptions of the inner and outer world. For instance,there is no such thing as a person exercising without“central command,” to tense and relax specific muscles.At the same time, and as part of the same process, thebrain automatically directs changes in blood flow to themuscles. The exercising muscle and changes in bloodflow lead to information—feedback—to the brain abouthow things are going both outside and inside the body.

The autonomic nervous system operates atthe border of the mind and body.

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Now here is the key: The autonomic nervoussystem operates exactly at the border of themind and body. The brain uses and dependson the autonomic nervous system for theinternal adjustments that accompany everymotion a person performs and every emotiona person feels.

You already know this, if you think about it. When youjog, for instance, the blood flow to the skin and muscleincreases, the heart pumps more blood, you sweat, andyou move more air. These are automatic features of theexperience of exercising. Can you imagine exercisingand not noticing these things?

It’s also true that virtually every emotion a person feelsincludes changes in the same body functions. Forinstance, when you are enraged, the blood flow to theskin and muscle increases, the heart pumps more blood,you sweat, and you move more air.

From the point of view of the bodily changes, it wouldmatter little whether these changes resulted from thephysical experience of exercise or the mental experienceof rage. Both situations involve alterations in the activityof components of the autonomic nervous system. Both

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Mind

AutonomicNervousSystem

Inner World

SomaticNervousSystem

Outer World

A systems approach to the mind-body issue.

situations involve changes in the inner and outer worlds.And if your autonomic nervous system were tomalfunction, your reactions to either situation would notbe regulated correctly, in either situation you could feelsick, look sick, and be sick!

A “systems” approach helps to understanddysautonomias. According to the systems approach, themind simultaneously directs changes in the somaticnervous system and the autonomic nervous system, based

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on perceptions about what is going on in the inner worldand the outer world.

Note that the autonomic nervous system affects both theinner world and outer worlds. For instance, if a personlooked pale, because the blood quite literally had drainedfrom the face, and was sweaty, trembling, and mumblingincoherently, other people would likely react to thesesigns of distress and ask, “Are you OK?”And it is wellknown that strong emotions, probably via adrenalinerelease, can energize an individual. In fact, one of theentries under weightlifting in the Guiness Book ofRecords referred to a 123-pound mother who summonedthe strength to lift the front end of a 3,600-pound carafter a jack had collapsed and the car had fallen on herchild!

Analogously, the somatic nervous system can affect theinner world. For instance, you can voluntarily increaseyour blood pressure any time you want, by clenching atight fist, or dunking your hand in cold water.

How would a systems approach help to understand adysautonomia? A malfunction at almost any part of thesystem could lead to an alteration in activity of theautonomic nervous system. For instance, if there were nofeedback to the brain about the state of the blood pressure(part of the inner world), then there would be an inabilityto keep the blood pressure within bounds, by changingthe activity of the autonomic nervous system. If therewere no feedback about the extent of physical exercise,there would also be an inability to adjust the blood

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pressure and blood flows appropriately. Of course, ifthere were a failure of the autonomic nervous systemitself, this would also interfere with regulation of theinner world, but there would also be difficulty in dealingwith the outer world, manifested by problems likeexercise intolerance or an inability to tolerate standingfor a prolonged period (orthostatic intolerance). Finally,if the person had a psychiatric disorder such aspanic/anxiety, then the inappropriate emotionalexperience of fear would be linked to both autonomicnervous system and somatic nervous system changes.

A clinician’s ability to treat a dysautonomia successfullywould also benefit from a systems approach. Treatmentsat any of several steps might help, but the best place inthe system to insert a treatment would be the step closestto where the problem is.

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When in Life doDysautonomias

Occur?Different types of dysautonomia occur indifferent stages of life.

Dysautonomias can occur at any age.

In infants and children, dysautonomia oftenreflects a genetic change, called a mutation.A mutation is like a “typo” in the geneticencyclopedia.

One type of mutation that runs in the family of people ofeast European Jewish extraction causes familialdysautonomia. Another mutation that producesdysautonomias in children causes a type ofphenylketonuria (PKU). Another causes “kinky hairdisease” (Menkes disease). In general, dysautonomiasfrom genetic mutations are rare. In adults, dysautonomia

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Infancy/ChildhoodSensory and Autonomic Neuropathy (SAN)

Familial Dysautonomia (a form of SAN)Menkes Disease

Childhood/AdulthoodPostural Tachycardia Syndrome (POTS)

Neurocardiogenic Syncope (NCS)Hypernoradrenergic Hypertension

Autoimmune Autonomic FailureAcute Baroreflex Failure

Adulthood/ElderlyDiabetic Autonomic Neuropathy

ChemotherapyParkinson’s Disease

AmyloidosisMultiple Myeloma

Multiple System Atrophy (MSA)Shy-Drager Syndrome (a form of MSA)

Pure Autonomic Failure (PAF)

Different forms of dysautonomia happen atdifferent ages. Here are some examples.

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usually reflects a functional change in a generally intactautonomic nervous system.

Examples are neurocardiogenic syncope (where theperson has frequent episodes of fainting or near-fainting),postural tachycardia syndrome (where the person cannottolerate standing up for long periods and has a rapidpulse rate during standing), and hypernoradrenergichypertension (where overactivity of the sympatheticnervous system causes a form of high blood pressure).Less commonly, there is a loss of nerve terminals, suchas caused by a toxic substance, viral infection, or thebody attacking itself (autoimmune autonomic failure).Rarely, dysautonomia in adults reflects a geneticmutation, the one-in-a-million “typo” in the geneticencyclopedia, or a polymorphism, which is geneticchange that is more common than a mutation.

In the elderly, dysautonomia usually reflects adegeneration of the autonomic nervous system, often inassocation with other evidence of degeneration of thebrain. Examples are multiple system atrophy andParkinson’s disease.

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How AreDysautonomias

Classified?Since dysautonomias can be somewhatmysterious and controversial, doctors candisagree about the diagnostic classificationof dysautonomias. In this section we followthe diagram about types of dysautonomiafrom a few pages ago.

Doctors can disagree about how to classifydysautonomias.

As you read about the dysautonomias, keep in mind thatthe particular labels that are given for many of theseconditions are “best guesses;” many labels refer toessentially the same set of symptoms; even with the samelabel, different people can have very different symptoms;and actual mechanisms for many of these conditions arenot well understood. Further research will lead todiscoveries about the causes of these conditions, andnew, definitive names for the conditions.

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The primary concern for the patient anddoctor should be symptom management,which will provide relief and better qualityof life.

Changes in autonomic nervous system function canadversely affect health by worsening another disease.One example of this is the activation of the sympatheticnervous system during exercise in the cold, such asduring shoveling snow. Both cold exposure and exerciseincrease activity of the sympathetic nervous system.Under normal circumstances this helps the person, bypreserving and generating body heat and by deliveringmore blood to the muscles. The blood pressure and pulserate increase, the work of the heart increases, and theblood flow to the heart muscle by the coronary arteriesnormally increases. But if the person has severe coronaryartery disease, where the coronary arteries feeding theheart are narrowed, then when the work of the heartincreases, due to activation of the sympathetic nervoussystem, the blood flow in the coronary arteries does notincrease. This imbalance between the limited delivery ofoxygen by the blood and the increased demand foroxygen can produce chest pain or pressure, heart attacks,or fatal abnormalities in heart rhythm. In other words,what would in other situations be a normal, helpfulincrease in sympathetic nervous system activity ends upworsening the health of the patient, in this case byturning “silent” coronary artery disease into a killer.

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Changes in autonomic nervous system function can alsobe harmful, when activity of the system changes tocompensate for abnormal functioning of a different bodysystem. For instance, in heart failure, the heart fails todeliver an appropriate amount of blood to body organs.As compensation to improve the pump function of theheart, the sympathetic nervous system is activated. At thesame time that this can improve the pump function of theheart, the activation of the sympathetic nervous systemalso increases the risk of fatal abnormal heart rhythms,increases the work of the heart, and promotes overgrowthof heart muscle, which can stiffen the heart walls andworsen the heart failure.

When doctors think about dysautonomias, they usuallydon’t think about altered function of the autonomicnervous system worsening another disease, or aboutharmful effects of compensatory activation when anothersystem fails. Instead, doctors think about abnormalfunction of the autonomic nervous system itself.

In general, there are four types of abnormal function ofthe autonomic nervous system. There may be acuteoveractivity, chronic overactivity, acute underactivity,and chronic underactivity. The next chapters describethese disorders.

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In WhatConditions is the

AutonomicNervous System

Underactive?Different parts of the autonomic nervoussystem are underactive in differentdisorders.

When the parasympathetic nervous system isunderactive, the person has constipation, retention ofurine in the bladder, a tendency to fast pulse rate,decreased salivation, and in men impotence. Severaldrugs can cause this combination of problems, butsometimes they result from failure of some part of theparasympathetic nervous system. Whether the problem isin the brain, in the nerve traffic from the brain, in theganglia that act like transfer stations on the nervoussystem highway, in the nerve terminals preventingrelease of the chemical messenger, acetylcholine, or inthe receptors for acetylcholine in the tissue, the effects interms of the way the patient feels and looks are about the

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Parasympathetic nervous systemunderactivity produces constipation, urinaryproblems, fast pulse rate, decreased spit, or(in men) an inability to have an erection.

same. In other words, many different mechanisms canresult in the same symptoms.

The parasympathetic nervous system is underactive inseveral types of dysautonomia, including Parkinson’sdisease with autonomic failure, pure autonomic failure,and multiple system atrophy. All these types ofdysautonomia also feature underactivity of thesympathetic nervous system too, and they are discussedlater in separate sections. Parasympathetic functions tendto decrease also with normal aging.

When the sympathetic nervous system is underactive, theperson has a fall in blood pressure if the patient standsup, which is called orthostatic hypotension. Sympatheticfailure produces a tendency to slow pulse rate and in meninability to ejaculate. Several drugs can cause thiscombination of problems, but sometimes they result fromfailure of some part of the sympathetic nervous system.

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A fall in blood pressure when the patientstands (orthostatic hypotension) is animportant sign of failure of the sympatheticnervous system.

As for underactivity of the parasympathetic nervoussystem, whether the problem is in the brain, in the nervetraffic from the brain, in the ganglia, in the nerveterminals preventing release of the chemical messenger,norepinephrine, or in the receptors for norepinephrine inthe tissue, the effects in terms of the way the patient feelsand looks are about the same.

Sweating and blood pressure are“automatic” functions controlled bydifferent chemicals.

Since acetylcholine is the main chemical messenger usedby the sympathetic nervous system for sweating, whilenorepinephrine is the main chemical messenger used bythe sympathetic nerve system to tighten blood vessels andmaintain blood pressure during standing, a patient with aspecific problem in the production, release, or receptorsfor norepinephrine could have orthostatic hypotensionand yet sweat normally.

The sympathetic nervous system is underactive in severaltypes of dysautonomia, including Parkinson’s diseasewith autonomic failure, pure autonomic failure, and

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multiple system atrophy. Acute sympathetic failure alsoappears to play a key role in fainting.

When the adrenomedullary hormonal system isunderactive, the effects on the body are much moresubtle than when the parasympathetic nervous system orthe sympathetic nervous system is underactive. This isprobably because the adrenomedullary hormonal systemis activated in relatively unusual emergency situations.When you are at rest, your adrenal glands release verylittle epinephrine into the bloodstream.

Epinephrine (adrenaline) is one of the body’s mainhormones for regulating blood levels of glucose, one ofthe body’s main fuels. Failure of the adrenomedullaryhormonal system can cause a tendency to low glucoselevels, a condition called hypoglycemia. This can be amajor problem in patients who have diabetes and takeinjections of insulin, because failure of theadrenomedullary hormonal system in these patients canresult in susceptibility to severe hypoglycemia reactionsto the insulin.

Failure of the adrenomedullary hormonalsystem can cause a tendency to low glucoselevels (hypoglycemia).

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What isOrthostatic

Hypotension?Normally, when you stand up, you don’t notice much thatis different. Nevertheless, there are quite a few automatic,largely unconscious, reflexive changes directed by thebrain that are required for tolerating the act of simplystanding up. When the reflexes fail, the patient can’ttolerate simply standing up. If the blood pressure falls bymore than 20 millimeters of mercury between lying flatand standing up, this is called orthostatic hypotension.

Inability to tolerate standing up, or orthostaticintolerance, is a symptom, a complaint about somethingabnormal a person notices that provides subjectiveevidence of a disease. A fall in blood pressure when aperson stands up, or orthostatic hypotension, is a sign,something a doctor can observe or measure that providesobjective evidence of a disease. Neither orthostaticintolerance nor orthostatic hypotension is a diagnosis,which is a decision about the cause of a specific case ofdisease.

Orthostatic hypotension: a 20 point orlarger fall in blood pressure when a personstands up from lying down.

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When a person stands up, this sets into motion animportant reflex called the baroreflex. The baroreflexhelps to maintain the blood pressure. When a personstands up, the force of gravity tends to pool blood in thelegs and lower abdomen. This decreases the return ofblood to the heart in the veins. The heart ejects lessblood. Baroreceptors are tiny distortion receptors in thewalls of large vessels and in the heart muscle. When theheart ejects less blood, information changes in nervestraveling from the baroreceptors to the brain. The brainresponds by directing an increase in the activity of thesympathetic nervous system. The sympathetic nervesrelease norepinephrine, and the norepinephrine activatesreceptors on cells in the blood vessel walls. This tightensthe blood vessels, and so the total resistance to bloodflow in the body increases. In other words, the totalperipheral resistance increases. Even though the totalamount of blood ejected by the heart per minute (cardiacoutput) has decreased, the average blood pressurenormally is maintained, due to the increase in totalperipheral resistance.

You might understand the baroreflex better by thinkingabout the water pressure in a garden hose. The pressure isdetermined by how much the faucet is turned on and howmuch the nozzle is tightened. If you turned down thefaucet, the pressure in the hose would decrease, and lesswater would come out the nozzle. If you wanted to keepthe pressure in the hose the same, you could tighten thenozzle.

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Pressure0

FaucetOnFull

FaucetOn

Part

TightenNozzle

FaucetOnFull

A B

There are two ways to control the pressurein a garden hose: the faucet and the nozzle.There are two ways to control bloodpressure: cardiac output and totalperipheral resistance.

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B r a i n

B a r o r e c e p t o r s

B l o o d P r e s s u r e

S ym p a t h e t i cN e r v o u s S y s t em

S t a n d i n g Up

D e c r e a s e d S t r e t c h o fB l o o d V e s s e l s

D e c r e a s e d I n p u t f r omB a r o r e c e p t o r s

I n c r e a s e d T i g h t e n i n g o fB l o o d V e s s e l s

D e c r e a s e d R e s t r a i n t o ft h e S ym p a t h e t i c S y s t e m

B r a i n

B a r o r e c e p t o r s

B l o o d P r e s s u r e

S ym p a t h e t i cN e r v o u s S y s t em

S t a n d i n g Up

D e c r e a s e d S t r e t c h o fB l o o d V e s s e l s

D e c r e a s e d I n p u t f r omB a r o r e c e p t o r s

I n c r e a s e d T i g h t e n i n g o fB l o o d V e s s e l s

D e c r e a s e d R e s t r a i n t o ft h e S ym p a t h e t i c S y s t e m

The baroreflex and sympathetic nervoussystem must both work, for a person totolerate standing up.

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Baroreflexes control the amount of tightening of theblood vessels. When a person stands up, the bloodvessels tighten reflexively, helping maintain the bloodpressure, and the main system responsible for tighteningthe vascular nozzle is the sympathetic nervous system.This explains why failure of the sympathetic nervoussystem always causes orthostatic hypotension.

In sympathetic nervous system failure, thepatient can’t tighten the “nozzle.”

Doctors may have different opinions about the amount oforthostatic hypotension that is clinically significant.Normally the systolic pressure falls slightly duringstanding up, because the heart is ejecting less blood, andnormally the diastolic pressure does not fall at all,because of the reflexive constriction of blood vessels inthe body as a whole. In general, if the systolic bloodpressure (the peak pressure when the heart beats)decreases by more than 20 millimeters of mercury andthe diastolic pressure decreases by more than 5millimeters of mercury, then the patient has orthostatichypotension.

Orthostatic hypotension is a key sign of sympatheticneurocirculatory failure. Any of several diseases canproduce orthostatic hypotension from sympatheticneurocirculatory failure.

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?

Sympathetic Neurocirculatory Failure

Sympathetic Denervation?

Central Neurodegeneration?

No YesNo Yes

Anti-Nicotinic Receptor Ab?

Yes No

AutoimmuneAutonomic Failure

Parkinson's MSAPAF

DLBD?

Yes No

Sympathetic neurocirculatory failure hasmany potential causes.

These include pure autonomic failure (PAF), multiplesystem atrophy (MSA), Parkinson’s disease, diffuse Lewybody disease (DLBD), and autoimmune autonomic

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failure. In these diseases, orthostatic hypotension occurspersistently and consistently.

There are other disorders where the patients cannottolerate prolonged standing, even though they do nothave persistent, consistent orthostatic hypotension. Theseorthostatic intolerance syndromes are discussed later.

Remember that neither orthostatic intolerance nororthostatic hypotension is a disease. One is a symptom(or set of symptoms) that a person has when standing.The other is a sign that a doctor can measure.

Many factors besides sympathetic neurocirculatoryfailure can cause orthostatic hypotension. Prolonged bedrest for virtually any reason can do this. Indeed, in theAmerican space program, a study of normal volunteers inperfect health found that after prolonged bed rest with thehead slightly down, these healthy people often developedorthostatic hypotension. It should not be surprising thatelderly, bedridden patients also routinely have orthostatichypotension. Orthostatic hypotension can also result fromconditions that cause depletion of blood volume, such asheavy menstrual periods or gastrointestinal hemorrhagefrom a bleeding ulcer.

There are many causes of orthostatichypotension, besides sympathetic nervoussystem failure.

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Always Sometimes

PAF Parkinson's

MSA

NeurocardiogenicSyncope(Fainting)

BaroreflexFailure

Failure of the sympathetic nervous system toregulate blood pressure occurs in bothpersistent diseases and occasional episodes.

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What isOrthostatic

Intolerance?A major main way dysautonomias causeproblems is by producing orthostaticintolerance. Remember that orthostaticintolerance is based on symptoms, such asdizziness or lightheadedness while standing.Orthostatic intolerance is not a sign,because it isn’t something an observer canmeasure objectively. And it isn’t a disease(although there are many diseases thatproduce orthostatic intolerance). The factthat there are many possible causes oforthostatic intolerance poses a challenge toany doctor trying to come up with adiagnosis to explain orthostatic intolerancein a particular patient.

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Patients with orthostatic intolerance can’ttolerate prolonged standing.

Chronic Fatigue

NeurocardiogenicSyncopePOTS

About 60% of patients with Chronic FatigueSyndrome have Chronic OrthostaticIntolerance, with Postural TachycardiaSyndrome (POTS), NeurocardiogenicSyncope, or both.

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?

Chronic Orthostatic Intolerance

No Syncope Syncope

Tachycardia? Tachycardia?

No Yes Yes No

Neurocardiogenic SyncopePOTS

Tilt Table Test

No


Yes

Orthostatic Hypotension?Abnormal Valsalva Blood Pressure?

One approach in the diagnosis of chronicorthostatic intolerance is based on whetherthe patient has a fall in blood pressureduring standing (orthostatic hypotension).

Patients with Chronic Fatigue Syndrome often haveorthostatic intolerance. The orthostatic intolerance canbe associated with postural tachycardia syndrome(POTS), neurocardiogenic syncope, or both.

A starting point in identifying a cause of orthostaticintolerance is to determine whether the patient has failureof the sympathetic nervous system to regulate the heartand blood vessels correctly. We call this sympatheticneurocirculatory failure. In dysautonomias that produce

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?

Chronic Orthostatic Intolerance

No Syncope Syncope

Tachycardia? Tachycardia?

No Yes Yes No

Neurocardiogenic SyncopePOTS

No


Yes

Orthostatic Hypotension?Abnormal Valsalva Blood Pressure?

Tilt Table Test

Doctors often do tilt table testing in patientswho cannot tolerate standing (orthostaticintolerance) and do not have a fall in bloodpressure during standing (orthostatichypotension).

chronic sympathetic neurocirculatory failure, the patientalways has a fall in blood pressure during standing, ororthostatic hypotension.

In other forms of chronic orthostatic intolerance, theperson does not have sympathetic neurocirculatoryfailure, and the blood pressure does not fall consistentlywhen the person stands up (although the person can havedelayed orthostatic hypotension after many minutes ofstanding). Instead, the person feels dizzy or lightheaded

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during standing, even while the blood pressure ismaintained. Orthostatic hypotension can produceorthostatic intolerance, but orthostatic intolerance canoccur without orthostatic hypotension.

In the evaluation of a patient with chronic orthostaticintolerance, where the patient does not have evidence ofsympathetic neurocirculatory failure, doctors oftenprescribe a tilt table test. The chapter about testing fordysautonomias discusses the tilt table test. In general,there are two types of positive tilt table test result. If thepatient has an excessive, progressively more severeincrease in pulse rate during the tilting, then this wouldbe consistent with postural tachycardia syndrome, orPOTS. If the patient has a decrease in the level ofconsciousness and finally loses consciousness (syncope),then this would be consistent with neurocardiogenicsyncope. The loss of consciousness is virtually alwaysassociated with a fall in blood pressure, or neurallymediated hypotension. A tilt table test can also yieldresults consistent with both POTS and neurocardiogenicsyncope, such as when the patient has a large increase inpulse rate, followed by a sudden fall in pulse rate back tonormal, neurally mediated hypotension, and syncope.

Once a diagnosis of POTS is made, the workup maycontinue, to determine if the rapid pulse is part of aprimary problem or is part of a compensation. Thesection about POTS discusses this workup.

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In patients with neurocardiogenic syncope, thesympathetic nervous system can fail to work correctlyonly once in a while, in episodes, and in these episodes aperson can feel faint or actually lose consciousness. Acommon form of dysautonomia where the sympatheticnervous system fails episodically is in fainting, whichalso has been called neurally mediated syncope,neurocardiogenic syncope, or the common faint. It isimportant to recognize that between episodes of fainting,patients with repeated episodes of neurocardiogenicsyncope often do not feel well. In fact, they can complainof the same non-specific symptoms that patients withPOTS describe, such as fatigue, heat intolerance,headache, exercise intolerance, and orthostaticintolerance.

The sympathetic nervous system fails whenpeople faint.

Much less commonly, orthostatic intolerance reflectsfailure of the baroreflex. In this situation, the sympatheticnervous system is not activated appropriately in responseto a decrease in blood pressure or in response to adecrease in venous return to the heart. Seeminglyparadoxically, baroreflex failure does not necessarilycause orthostatic hypotension, but it does always causelarge swings in blood pressure, both high and low,because of the inability of the baroreflex to keep theblood pressure within limits.

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DecreasedCatecholamineEffects in the

Heart

IncreasedCatecholamineEffects in theHeart (POTS)

NeurocardiogenicSyncope(Fainting)

BaroreflexFailure

Baro. Failure

PrimarySecondary

NET Defic.

DehydrationDec. Blood Volume

Dec. Renin System

Panic

Hyperdyn. Circ.

Medication

Extravasation

Hyperinnervation

Adrenomedullary

Neuropathic POTSAdrenocortical

Etc.

Etc.

Orthostatic intolerance can be associatedwith increased or decreased effects ofadrenaline-like chemicals in the heart.

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Pure AutonomicFailureThis and the following sections describe several specificdysautonomias. The description is not meant to beexhaustive, and individual patients can have symptoms orsigns that overlap.

Pure Autonomic Failure (PAF)� Mid-aged or elderly of either sex andany race� Chronic, persistent fall in blood pressureduring standing up� No signs of brain disease� Not inherited or infectious� Can go one for many years

Pure autonomic failure (PAF) features persistent falls inblood pressure when the patient stands—orthostatichypotension—in the absence of signs of central nervoussystem disease and in the absence of other known causesof orthostatic hypotension. The orthostatic hypotensionresults from sympathetic neurocirculatory failure.

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Pure autonomic failure, while chronic and causingdisability, is not thought to be lethal.

Patients report progressively worsening dizzinessstanding up or after a large meal. Often they havedecreased sweating. Because of severe orthostatichypotension, pure autonomic failure patients often learnto sit or stand with their legs twisted pretzel-like, sincethis decreases pooling of blood in the legs. In men,impotence can be an early symptom.

In patients with pure autonomic failure, blood pressureresponses to the Valsalva maneuver show the abnormalpattern that indicates sympathetic neurocirculatoryfailure. The Valsalva maneuver is discussed in thechapter about tests for dysautonomias.

The sympathetic neurocirculatory failure and orthostatichypotension in pure autonomic failure typically resultfrom loss of sympathetic nerve terminals.

Drug tests can confirm a diagnosis of pure autonomicfailure. Because of the loss of sympathetic nerveterminals, drugs that release norepinephrine fromsympathetic nerves, such as yohimbine, amphetamine,and ephedrine, produce relatively small increases inblood pressure. In contrast, drugs that directly stimulatenorepinephrine receptors, such as midodrine andphenylephrine (Neo-Synephrine™) constrict bloodvessels and increase blood pressure.

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Because of the phenomenon of “denervationsupersensitivity,” where receptors for norepinephrineincrease and other adaptive processes probably occur thatexaggerate constriction of blood vessels, patients withpure autonomic failure can have surprisingly largeincreases in blood pressure in response to the receptor-stimulating drugs.

As a result of loss of sympathetic nerve terminals, plasmanorepinephrine levels typically are low in PAF, evenwith the patient lying down, and the levels fail to increasewhen the patient stands. In response to the above drugs,plasma norepinephrine levels fail to change as much asexpected.

Another way to identify PAF is from sympatheticneuroimaging. In this type of test, the patient receives aninjection of a radioactive drug that gets taken up bysympathetic nerve terminals. The sympathetic nerves inorgans such as the heart become radioactive, and thenerves can be visualized by scans that detect where theradioactivity is, in a manner similar to commonly usedclinical tests such as bone scans or brain scans. Since inPAF the sympathetic nerve terminals usually are absentin the organs, scanning after injection of one of thesedrugs fails to visualize the sympathetic innervation.Sympathetic neuroimaging tests such as fluorodopaminePET scanning of the chest usually produce remarkablygraphic results in PAF, with a failure to visualize theheart walls at all.

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No one knows what causes pure autonomic failure. It isnot inherited, and no known environmental toxin causesit.

Treatment of pure autonomic failure is directed mainly atthe orthostatic hypotension, which virtually always issevere and disabling. Fludrocortisone, a high salt diet,and potassium supplementation are the mainstays oftreatment. Clinicians usually recommend elevation of thehead of the bed. Body stockings may or may not help.The patient should not take large meals, because this maycause the blood pressure to decrease. Drugs that releasenorepinephrine from sympathetic nerves, such asephedrine, Ritalin™, or yohimbine, may not work,because of the lack of nerve terminals, whereas drugsthat artificially stimulate receptors for norepinephrine,such as midodrine, can be very effective.

-- 98 --

Blood FlowPET Scan

Sympathetic NervePET Scan

Heart MuscleLiver

Liver

Patients with Pure Autonomic Failuretypically have a loss of sympathetic nervesin the heart muscle.

-- 99 --

Multiple SystemAtrophy

Multiple system atrophy (“MSA”) is a disease thatinvolves progressive degeneration of multiple portions ofthe nervous system, including portions that regulate theautonomic nervous system. Several unconscious“vegetative” functions fail, such as digestion, urination,speech and swallowing mechanisms, and cardiovascularreflexes. Unlike pure autonomic failure, MSA isunfortunately a disease that is progressive and eventuallylethal. On average, patients survive for about a half dozenyears after the diagnosis is made. MSA differs frommultiple sclerosis, which is characterized clinically byremissions and exacerbations and by relatively fewchanges in functions of the autonomic nervous system.

Multiple System Atrophy (MSA)� Mid-aged or elderly of either sex andany race� Not inherited or infectious� Chronic, persistent autonomic failure� Signs of brain disease, such as slurredspeech, rigidity, tremor, poor coordination� Relentless progression over years

-- 100 --

No one knows what causes MSA. It is not inherited, andno known environmental toxin causes it. According toone view, MSA results from a form of auto-immuneprocess, where the patient’s immune system attacks anddestroys particular brain cells.

MSA has different forms, which result in somewhatdifferent symptoms and signs. In the parkinsonian formof MSA (MSAP) the patient has symptoms and signs ofParkinson’s disease, such as shakiness of the hands(tremor) that is most prominent at rest and decreases withintentional movements, muscular rigidity, and slowinitiation of movement. Unlike in Parkinson’s disease,these problems usually do not respond well to treatmentwith Sinemet™, the most commonly used drug forParkinson’s disease.

In the cerebellar form of MSA (MSAC) the patient hassymptoms and signs of failure of the cerebellum, whichis a part of the brain that plays an important role incoordinated movements, coherent speech, balance, andaccurate gait. If the patient has a tremor, it worsens withintentional movements. The typical patient also hasslurred speech and a wide-based, “drunken sailor” typegait.

In the mixed form of MSA (MSAM) the patient has amixture of parkinsonian and cerebellar symptoms andsigns.

MSA always involves one or more symptoms or signs offailure of the autonomic nervous system. Failure of the

-- 101 --

parasympathetic nervous system produces urinaryretention and incontinence, constipation, erectileimpotence, and decreased salivation. Failure of thesympathetic nervous system produces a fall in bloodpressure when the patient stands up (orthostatichypotension) or after a meal (post-prandial hypotension),resulting in symptoms such as dizziness, weakness, orfaintness upon standing or after eating.

MSA with failure of sympathetic reflexes (sympatheticneurocirculatory failure) is also known as the Shy-Drager syndrome. The most clear sign of sympatheticneurocirculatory failure is orthostatic hypotension.

MSA with a fall in blood pressure standingis also called the Shy-Drager syndrome.

Some investigators have equated MSA with the Shy-Drager syndrome. Others have considered MSA as anumbrella diagnosis that includes the Shy-Dragersyndrome when orthostatic hypotension figuresprominently in the clinical presentation but also includesforms where signs of cerebellar atrophy or ofParkinson’s disease stand out. A recent proposal hasrecommended discarding using the Shy-Drager syndromeas a diagnosis.

Based on clinical findings and results of autonomicfunction testing, we have proposed a somewhat differentclassification scheme that distinguishes MSA withpredominantly parasympathetic or other brainstem

-- 102 --

degeneration from MSA with predominantly sympatheticdegeneration, so that the Shy-Drager syndrome issynonymous with MSA and sympathetic neurocirculatoryfailure.

Symptoms and signs of parasympathetic degenerationinclude constipation and decreased urinary bladder tone,resulting in urinary incontinence, frequency, urgency,and the need for self-catheterization. Symptoms andsigns of other brainstem degeneration include particularabnormalities in eye movements (“progressivesupranuclear palsy”), slurred speech, dyscoordinatedswallowing, abnormal breathing, and repeated aspiration,where swallowed food goes into the airway. Theseproblems can occur in patients with MSA who do nothave orthostatic hypotension or other evidence of failureof the sympathetic nervous system.

In MSA, it is thought that the autonomic failure reflectsloss of the ability to regulate sympathetic andparasympathetic nerve traffic to the nerve terminals, butthe terminals themselves are intact. This appears to be amajor difference between MSA and the usual form ofpure autonomic failure, where the autonomic failureincludes a loss of sympathetic nerve terminals. Becauseof the presence of intact sympathetic nerve terminals,patients with MSA have increases in blood pressure whenthey receive drugs such as yohimbine that releasenorepinephrine from sympathetic nerve terminals andhave decreases in blood pressure when they receive drugssuch as trimethaphan that decrease release ofnorepinephrine from sympathetic nerve terminals.

-- 103 --

The fact that trimethaphan, which works by blockingtransmission of autonomic nerve impulses in the ganglia,decreases blood pressure in patients with MSA means thatin MSA the problem is not so much decreased autonomicnerve traffic as failure of the brain to regulate that trafficappropriately.

The widely used dietary supplement or herbal remedy,ma huang, is ephedrine, which releases norepinephrinefrom sympathetic nerve terminals. Since patients withMSA and sympathetic neurocirculatory failure haveintact sympathetic nerve terminals, and they also havefailure of the brain to regulate sympathetic nerve trafficappropriately via baroreflexes, taking ma huang canevoke a dangerous increase in blood pressure in thesepatients.

Patients with MSA appear to have approximately normalsympathetic nerve traffic to intact sympathetic nerveterminals when they are lying down, and so while theyare lying down they usually have normal plasma levelsnorepinephrine, the chemical messenger of thesympathetic nervous system. The patients often have afailure to increase sympathetic nerve traffic when theystand up, and so they have a failure to increase plasmanorepinephrine levels normally when they stand up. Incontrast, patients with pure autonomic failure, who havea loss of sympathetic nerve terminals, usually have lowplasma norepinephrine levels even when they are lyingdown.

-- 104 --

Another way to distinguish MSA from pure autonomicfailure is from sympathetic neuroimaging. In this type oftest, the patient receives an injection of a radioactive drugthat gets taken up by sympathetic nerve terminals. Thesympathetic nerves in organs such as the heart becomeradioactive, and the nerves can be visualized by scansthat detect where the radioactivity is, in a manner similarto commonly used clinical tests such as bone scans orbrain scans. Since in MSA the sympathetic nerveterminals are present in the organs, scanning afterinjection of one of these drugs visualizes the sympatheticinnervation. In contrast, in pure autonomic failure (andin Parkinson’s disease, discussed elsewhere), where thesympathetic nerve terminals typically are lost,sympathetic neuroimaging fails to visualize thesympathetic innervation of the heart.

The parkinsonian form of MSA can bedifficult to distinguish from Parkinson’sdisease.

Distinguishing the parkinsonian form of MSA (MSAP)from Parkinson’s disease with autonomic failure can bea difficult diagnostic challenge. As mentioned above, oneway to distinguish these diseases is from sympatheticneuroimaging, since patients with MSA have normalsympathetic innervation of the heart, and patients with

-- 105 --

Blood FlowPET Scan

Sympathetic NervePET Scan (Normal)

Heart Muscle

Liver

LiverHeart Muscle

MSA patients have normal sympatheticnerves in the heart muscle.

-- 106 --

Parkinson’s disease and orthostatic hypotension have aloss of sympathetic innervation of the heart.

Treatment of MSA is directed at the symptoms and signs,such as orthostatic hypotension, and does not prevent ordelay the progressive deterioration of the nervous system.

Because of steadily worsening difficulty withcoordination of speech and swallowing mechanisms,patients with MSA have a high risk of aspiration,aspiration pneumonia, bloodstream infection, or suddendeath from stopped breathing.

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Parkinson’s Diseasewith Orthostatic

HypotensionOrthostatic hypotension, a fall in blood pressure whenthe patient stands up, occurs fairly commonly inParkinson’s disease. Neurologists have presumed that theorthostatic hypotension results from treatment withlevodopa, or else the patient doesn’t really haveParkinson’s disease but has a different disease, such as“striatonigral degeneration” or multiple system atrophy.

Parkinson’s Disease with OrthostaticHypotension

� Elderly of either sex and any race� Signs of Parkinson’s disease, such asslow movements, rigidity, tremor� Movement problem improves withSinemet™ (DOPA+carbidopa)� Chronic, persistent fall in blood pressurestanding� Can be inherited� Slow progression over years

-- 108 --

Evidence is accumulating that all patients withParkinson’s disease and orthostatic hypotension—evenpatients off levodopa or never treated withlevodopa—have failure of regulation of the heart andblood vessels by the sympathetic nervous system. In otherwords, in Parkinson’s disease, orthostatic hypotensionreflects sympathetic neurocirculatory failure and istherefore a form of dysautonomia.

Patients with Parkinson’s disease and a fallin blood pressure when they stand up have aform of dysautonomia.

In patients with Parkinson’s disease and orthostatichypotension, the sympathetic neurocirculatory failureappears to result from loss of sympathetic nerveterminals in the body as a whole. Because of thesympathetic denervation, there is a decreased amount ofnorepinephrine available for release in response tostanding up, and failure to release an adequate amount ofnorepinephrine explains the orthostatic hypotension inParkinson’s disease.

Many patients with Parkinson’s disease whodo not have a fall in blood pressure whenthey stand up still have a loss of sympatheticnerves in the heart.

-- 109 --

Blood FlowPET Scan

Sympathetic NervePET Scan

Heart MuscleLiver

Liver

Patients with Parkinson’s disease often havea loss of sympathetic nerves in the heartmuscle.

Surprisingly, most patients with Parkinson’s disease whodo not have orthostatic hypotension nevertheless have

-- 110 --

neuroimaging evidence for a loss of sympathetic nervesupply in the heart. Parkinson’s disease therefore appearsto be not only a disease of control of movement but alsois a dysautonomia, because of the loss of sympatheticnerve terminals.

Pure autonomic failure also features orthostatichypotension from loss of sympathetic nerve terminals.Some elderly patients with pure autonomic failure havesubtle signs of parkinsonism, such as a mask-like facialexpression and a type of stiffness of muscles. Pureautonomic failure can be difficult to distinguish fromearly or mild Parkinson’s disease in these patients.

The long-term outlook in Parkinson’s disease withorthostatic hypotension from sympatheticneurocirculatory failure seems about the same as inParkinson’s disease without orthostatic hypotension. Theorthostatic hypotension does not appear to worsen withlevodopa treatment, although the blood pressure bothwhile lying down and when standing up can decrease.

The functional significance of loss of sympatheticinnervation of the heart in Parkinson’s disease remainsunknown. One would presume that this would cause orcontribute to an inability to tolerate exercise.

Treatments used for Parkinson’s disease with orthostatichypotension from sympathetic neurocirculatory failureinclude Florinef™ and a high salt diet, midodrine,frequent small meals and avoidance of large meals, andelevation of the head of the bed on blocks at night.

-- 111 --

Treatments that depend on release of norepinephrinefrom sympathetic nerve terminals, such as ephedrine, d-amphetamine, methylphenidate, and yohimbine, may notwork, because of the loss of the nerve terminals.

Patients with Parkinson’s disease also often complain ofconstipation and urinary retention, urgency, andincontinence. These might reflect a form of failure of theparasympathetic nervous system; however, whether thisis the case remains poorly understood. Failure of theparasympathetic nervous system supply to the heartappears to cause the constant pulse rate seen in mostpatients with Parkinson’s disease and orthostatichypotension; however, whether this reflects a loss ofparasympathetic nerve terminals or a problem inregulating parasympathetic nerve traffic to intactterminals remains unknown.

-- 112 --

PosturalTachycardiaSyndrome (POTS)Patients with the postural tachycardia syndrome(postural orthostatic tachycardia syndrome, POTS) havean excessive increase in pulse rate during standing.

POTS patients have too rapid a pulse ratewhen they stand, and usually several othernon-specific problems.

That being said, it should be pointed out at the beginningof this discussion that different research groups havedifferent views about the classification ofdysautonomias, and especially about POTS and chronicorthostatic intolerance. Just having a fast pulse rate whilestanding would not necessarily be harmful and cannot bea syndrome, which always involves more than a singlesymptom or sign.

POTS is associated with a variety of other symptomsthat, when thought of individually, are not specific forany particular disease process. These include inability totolerate prolonged standing, a tendency to faint, chestpain, cool, sweaty extremities, migraine-like headache,pain in the back of the neck or shoulders, heat

-- 113 --

Bilat. Adrenomed. Hyperplas.

Renin System

Baroreflex Failure

Neuropathic POTS

Extravasation

Dehydration

a-Hypoadrenergic State

Postural Tachycardia Syndrome

PrimarySecondary

Low Central Blood Volume?

No Yes

Blood Loss

SNS Outflow��

Hyperdynamic Circ. Syndr.

Cardiac Hyperinnervation

NET Deficiency

Adrenocortical Activity��

Venous PoolingHyperthyroidism

Medication

��

POTS has many potential causes.

intolerance, chronic fatigue, exercise intolerance,shortness of breath on exertion, and panic/anxiety. Atleast some of these symptoms are thought to reflectincreased effects of the catecholamines, norepinephrine(noradrenaline) or epinephrine (adrenaline), in the heart,from overactivity of the sympathetic nervous system oradrenomedullary hormonal system, or both.

-- 114 --

Most cases occur in relatively young (14-45 years old)women (female:male ratio about 5:1).

Postural Tachycardia Syndrome (POTS)� Mainly young adult women� Too rapid pulse rate during standing� Several non-specific associatedproblems (inability to tolerate prolongedstanding, fatigue, faintness, chest pain, heart“flip-flops,” heat intolerance, exerciseintolerance, tendency to panic)� Variable outlook, can improve� Not life-threatening

Some investigators view POTS as synonymous withchronic orthostatic intolerance. As discussed later, thecondition has features also suggestive of hyperdynamiccirculation syndrome or “neurasthenia.” The many termsthat have been used probably reflect different emphasesby different research groups and large gaps in knowledgeabout the underlying mechanisms in individual patients.

The orthostatic tachycardia usually occurs withoutorthostatic hypotension. The finding of orthostatichypotension does not exclude a diagnosis of POTS,however, and delayed orthostatic hypotension can occurin this condition.

-- 115 --

POTS is a syndrome, not a single disease,and can have any of several causes.

Most postural tachycardia is secondary to identifiableproblems, such as side effects of medications ordehydration from chronic illness. When the cause is notreadily identified, and the patient has other complaintsdiscussed below, then the patient is thought to havepostural tachycardia syndrome, or POTS.

The occurrence of a rapid pulse rate when a personstands is necessary but is not sufficient to diagnosePOTS. The key word in postural tachycardia syndrome isthe word, “syndrome.” A syndrome is a set of symptomsthat occur together. Patients with POTS not only have arapid pulse rate when they stand up, they also haveseveral other symptoms, such as orthostatic intolerance,chronic fatigue, heat intolerance, exercise intolerance,headache, chest pain, palpitations, neuropsychologicalcomplaints such as disturbed sleep, anxiety, ordepression, and disability.

Trying to identify a specific cause in a particular patientwith POTS can be a great challenge to clinicians. Thereare probably as many causes of a fast pulse rate as thereare of a fever, and all the symptoms of POTS are notspecific for any single disease.

Researchers have thought that usually in POTS,sympathetic nerve traffic to the heart is increased as a

-- 116 --

compensation. The compensation could be for a decreasein the amount of blood returning to the heart or adecrease in the total peripheral resistance to blood flowwhen the patient stands up. Either situation could alterinformation from the baroreceptors to the brain, leadingto a reflexive increase in sympathetic nervous systemactivity directed by the brain.

Low Blood Volume

There are many causes for a decrease in the amount ofblood returning to the heart when a patient is standing.The possibility of blood volume depletion or excessivepooling of blood in the legs during standing up has drawnparticular attention. Indeed, low blood volume was notedin the first case report of POTS, and the response, at leastin the short run, to infused normal saline can bedramatic.

Low blood volume in turn can result from blood loss,from failure of the bone marrow to make an adequatenumber of red blood cells, or from failure of hormonesystems such as the renin-angiotensin-aldosteronesystem. In addition, blood volume can fall while a personstands, due to leakage of fluid out of the blood vesselsinto the tissues (extravasation). Finally, an “effective”low blood volume can occur, when the blood poolsexcessively in the veins after a person stands, such asbecause of a lack of muscular “tone” in the vein walls.

-- 117 --

Delayed orthostatic hypotension in POTS is also thoughtto result from a progressive, exaggerated decline in bloodvolume during prolonged standing, from leakage of fluidinto the tissues through blood vessel walls(extravasation). Consistent with excessive blood poolingin the legs or lower abdomen during orthostasis, inflationof a military antishock trousers (MAST) suit reducessubstantially the increase in heart rate in response toorthostasis in patients with POTS.

Neuropathic POTS

In partial dysautonomia, or neuropathic POTS, there isthought to be a patchy loss of sympathetic innervation,such as in the legs. When the patient stands up, the bloodpools in the veins of the legs, and less blood returns tothe heart, or else the arterioles fail to constrict, and thetotal resistance to blood flow decreases. In response toeither or both of these abnormalities, the sympatheticnervous system supply to the heart would be stimulatedreflexively.

There are other possible causes of decreased totalperipheral resistance that might reflexively increasesympathetic nervous system traffic to the heart. Forinstance, any of several drugs block receptors fornorepinephrine in blood vessel walls, and other drugsdirectly relax blood vessel walls.

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DEHYDRATIONor

BLOOD LOSS

HEARTNE

HR, SV

NE

Brain

Baroreceptors

NORMAL

HEART

Norepinephrine

Heart Rate

Sympathetic Nerves

NE

SNS

Baroreceptors

Norepinephrine

Heart Rate

Norepinephrine Norepinephrine

TotalPeripheralResistance

Sympathetic Nerves

Brain

StrokeVolume

Aldosterone

Angiotensin II

StrokeVolume

Aldosterone

Angiotensin IITotal

PeripheralResistance

Dehydration, blood loss, or other causes ofdecreased blood volume can produce acondition that looks like POTS.

-- 119 --

RENIN-ANGI OTENSIN-ALD OSTERONE

SYSTEMDEFI CIENCY

VR

HEARTNE

HR, SV

NE

Brain

Baroreceptors

NORMAL

HEART

Norepinephrine

Heart Rate

Sympathetic Nerves

NE

SNS

Baroreceptors

Norepinephrine

Heart Rate




Sympathetic Nerves

Brain

StrokeVolume

Aldosterone

Angiotensin II

StrokeVolume

Aldosterone

Angiotensin II

POTS can result from failure of a key systemregulating salt balance and blood volume inthe body, called the renin-angiotensin-aldosterone system.

-- 120 --

NEUROPATHICPOTS

VR

HEARTNE

HR, SV

NE

Brain

Baroreceptors

NORMAL

HEART

Norepinephrine

Heart RateStroke Volume

Sympathetic Nerves

NE

SNS

Baroreceptors

Norepinephrine





Sympathetic Nerves

Brain

In “neuropathic POTS,” sympathetic nervesto the heart are thought to be overactive, asa compensation for loss of sympatheticnerves elsewhere.

-- 121 --


NOREPINEPHRINETRANSPORTERDEFI CIENCY

HEARTNE

HR, SV

NE

Brain

Baroreceptors

NORMAL

HEART

Norepinephrine


Sympathetic Nerves

NE

SNS

Baroreceptors

Norepinephrine




Sympathetic Nerves

Brain

Rarely, POTS can result from failure toinactivate norepinephrine, a key chemicalmessenger of nerves in the heart.

-- 122 --

In rare patients, POTS results from deficiency of the cellmembrane norepinephrine transporter, or NET.

Hyperadrenergic OrthostaticIntolerance

In hyperadrenergic orthostatic intolerance, the problemis thought to be a primary abnormality in the functioningor regulation of the autonomic nervous system itself.

For instance, in acute baroreflex failure, the brain doesnot respond appropriately to information from thecardiovascular system, and the sympathetic nervoussystem is activated inappropriately. In acute baroreflexfailure, orthostatic intolerance is associated with largeswings in blood pressure, because of the inability of thebaroreflexes to keep the blood pressure in check, withepisodes of extreme high blood pressure and fast pulserate. Because of this failure, relatively minor stimuli canproduce large increases in the activity of the sympatheticnervous system.

Another cause of hyperadrenergic orthostatic intoleranceis decreased function of the cell membranenorepinephrine transporter, also called NET deficiency.The cell membrane norepinephrine transporter plays akey role in inactivating norepinephrine. Normally, mostof the norepinephrine released from sympathetic nerveterminals is “recycled,” by being taken back up into thenerve terminals. When the transporter is underactive,more norepinephrine is delivered to its receptors in the

-- 123 --

heart and blood vessel walls for a given amount ofnorepinephrine release, producing an exaggeratedincrease in pulse rate and blood pressure in situationswhere the sympathetic nervous system is activated.

In a related syndrome, called the hyperdynamiccirculation syndrome, the patients have a fast pulse rateall the time, variable high blood pressure, increased heartrate responses to the drug, isoproterenol, and increasedplasma norepinephrine and epinephrine levels at rest andduring provocative maneuvers. ß-Adrenoceptor blockerssuch as Inderal™ or benzodiazepines such as Valium™improve the syndrome. It is unclear whether patients withthis syndrome have an increased frequency of laterdevelopment of established hypertension. Episodes offast pulse rate and increased blood pressure can beassociated with blotchy flushing of the face, neck, andupper chest.

“Neurasthenia” a term introduced in the late 1860s.refers to a syndrome initially described in Civil Warsoldiers. Also called neurocirculatory asthenia, thesyndrome consists of a large number of symptoms,including breathlessness, palpitations, chest pain,dizziness, shortness of breath on exertion, fatigue,excessive sweating, trembling, flushing, dry mouth,numbness and tingling feelings, irritability, and exerciseintolerance.

Most modern research about neurocirculatory astheniahas been conducted in Russia. Western cardiovascularresearchers rarely use this term. The symptoms resemble

-- 124 --

those in POTS, and as in POTS, the multiplicity ofsymptoms contrasts with a relative lack of signs, whichall are non-specific—relatively fast pulse rate, relativelyrapid breathing, facial and neck flushing, slight tremor,sweaty palms, a “functional” heart murmur, andhyperactive kneejerk reflexes, with generally normalresting blood pressure. Just as in POTS or thehyperdynamic circulation syndrome, in neurastheniainjections of adrenaline can evoke these symptoms. ß-Adrenoceptor blockers often normalize thecardiovascular findings without affecting the othersymptoms and signs. Drugs such as caffeine can evokefast pulse rate, increased ventilation, tremor, andsweatiness in patients with neurocirculatory asthenia.

In another related condition, inappropriate sinustachycardia, the heart rate is increased to 100 beats perminute or more, even under resting conditions.Radiofrequency ablation of the sinus node, the heart’spacemaker area, is considered for patients withinappropriate sinus tachycardia who are resistant totreatment with medications.

-- 125 --

ACUTEBAROREFL EX

FA ILURE

HEARTNE

HR, SV

NE

Brain

Baroreceptors

NORMAL

HEART

Norepinephrine


Sympathetic Nerves

NE

SNS

Baroreceptors

Norepinephrine





Sympathetic Nerves

Brain

Failure of the baroreflex can produce acondition that looks like POTS.

-- 126 --

HYPERDYNAMICCIRCULATIONSYNDROME

VR

HEART

NE

HR, SV

NE

Brain

Baroreceptors

NORMAL

HEART

Norepinephrine


Sympathetic Nerves

NE

SNS

Baroreceptors

Norepinephrine





Sympathetic Nerves

Brain

The hyperdynamic circulation syndrome cancause POTS.

-- 127 --

As discussed below, the POTS syndromes differ fromneurocardiogenic syncope (neurally mediated syncope),in that patients with neurocardiogenic syncope haveinhibition, rather than stimulation, of the sympatheticnervous system, at least during acute episodes.Patients with POTS often have increased plasma levels ofnorepinephrine, the chemical messenger of thesympathetic nervous system, especially when they arestanding up. Indeed, according to one suggestion, criteriafor diagnosing chronic orthostatic intolerance include anupright plasma norepinephrine level of 600 pg/ml ormore; however, whether increased sympathetic nervousoutflows constitute a primary abnormality orcompensatory response usually is unknown in anindividual patient.

In general, one would predict that if the orthostatictachycardia were primary, then treating it would help thepatient, but if the orthostatic tachycardia weresecondary, then treating the problem would not help thepatient. Keeping this principle in mind can help tounderstand how one patient may feel better fromtreatment with a beta-blocker, which forces the pulse rateto go down, while another may not feel better at all, eventhough the pulse rate has decreased to the same extent.

Treatment of POTS should be tailored to theindividual patient.

The first step in management of chronic orthostaticintolerance is to search carefully for common, reversible

-- 128 --

causes, such as diabetes, weight loss, prolonged bed rest,debilitating diseases, and medications.

Medical treatments for POTS generally have attempted toincrease blood volume, such as using Florinef™ andliberal salt and water intake, injections of erythropoietin,or infusions of saline intravenously; block fast pulserates, such as using ß-adrenoceptor blockers or sinusnode ablation; decrease exaggerated norepinephrinerelease, such as using clonidine, a-methylDOPA, ormoxonidine; or enhance vasoconstriction, such as usingmidodrine, ergotamine, or octreotide. Other treatmentsinclude venous compression hose, calf muscle resistancetraining, exercise training, or even insertion of apacemaker.

Often these treatments, while helpful, do not bring thepatients back to a sense of normal health. Over the courseof months or even years, the patients can improve, or elsethey learn to cope with a chronic, debilitating, but notlife-threatening disorder.

-- 129 --

NeurocardiogenicSyncope

Syncope is sudden loss of consciousnessassociated with loss of muscle tone andthe regaining of consciousness within afew minutes.

Syncope is sudden loss of consciousness(you black out) that is associated with lossof muscle tone (you go limp) and reversesrapidly (you wake up within minutes.)

Neurocardiogenic syncope, which is also calledvasovagal syncope, vasodepressor syncope, neurallymediated syncope, and the common faint, is by far themost common cause of sudden loss of consciousness inthe general population.

In neurocardiogenic presyncope, the patient feels like heor she will faint but does not actually lose consciousness.

Most patients with frequent episodes ofneurocardiogenic syncope recognize early signs of

-- 130 --

fainting coming on and are usually able to abort theepisode before syncope actually occurs.

Neurocardiogenic syncope is most common in youngadult women and in children.

Neurocardiogenic syncope is fainting.Neurocardiogenic presyncope is near-fainting but without actual loss ofconsciousness.

In mid-aged or elderly adults, syncope is more likely tobe a sign of a heart problem (abnormal heart rhythm,abnormal conduction of electrical impulses in the heart,or heart valve problem) or orthostatic hypotension. Inpatients where neurocardiogenic syncope is a frequentproblem, even between episodes the patients often feelunwell, with an inability to tolerate prolonged standing,chronic fatigue, headache, and chest pain.

Neurocardiogenic syncope can resemble POTS. Bothdisorders mainly involve young adult women, (althoughin children neurocardiogenic syncope may be morecommon than POTS), and both are associated withinability to tolerate prolonged standing, chronic fatigue,headache, and chest pain (although POTS may morecommonly involve symptoms about multiple bodysystems). In both conditions the patients have a tendencyto near-fainting or fainting spells, especially whilestanding. Neurocardiogenic syncope does appear to differ

-- 131 --

from POTS, in that neurocardiogenic syncope does notfeature a fast pulse rate.

Neurocardiogenic Syncope� Mainly young adult women or children� Normal pulse rate during standing� Can be associated with several non-specific associated problems (inability totolerate prolonged standing, heatintolerance, fatigue, chest pain, heart “flip-flops,” exercise intolerance)� Variable outlook, can improve� Not life-threatening

Tilt-table testing can provoke a sudden fall in bloodpressure, called neurally mediated hypotension, inpatients with POTS or neurocardiogenic syncope.Regardless of the diagnosis, acute neurally mediatedsyncope may have the same mechanism. According toone proposal, the mechanism is from marked decreases insympathetic nervous system outflow to the skeletalmuscle in the limbs and probably several body organs,combined with increases in adrenomedullary hormonalsystem outflow and therefore high plasma adrenaline(epinephrine) levels.

The combination of loss of sympathetic vasoconstrictortone and epinephrine (adrenaline)-induced relaxation of

-- 132 --

blood vessels in skeletal muscle could decrease vascularresistance in skeletal muscle and in the body as a whole.It has been suggested that this combination explains thedecreased total peripheral resistance, without acompensatory increase in the ejection of blood by theheart, the cardiac output. This combination characterizesneurocardiogenic syncope. Because of the fall in totalperipheral resistance, without an increase in cardiacoutput, the blood pressure falls. The patient feels faint(presyncope) or actually loses consciousness (syncope).

Although physiological and hormonal changes thataccompany neurocardiogenic syncope have receivedconsiderable research attention, studies so far have failedto identify predisposing factors. A decrease in the rate ofsympathetic nerve traffic to the heart, or a restraint onrelease of norepinephrine from sympathetic nerveterminals in the heart, might cause a tendency to faint, bypreventing compensatory increases in the force and rateof the heartbeat in response to a fall in total peripheralresistance; however, no published study so far has testedthis idea.

Reports about a high frequency of neurocardiogenicsyncope and neurally mediated hypotension duringprovocative tilt table testing have supported the view thatchronic fatigue syndrome often includes and may resultfrom a form of dysautonomia.

The usual treatments for neurocardiogenic syncope arethe same as for POTS: Florinef™ and liberal salt andwater intake; ß-adrenoceptor blockers; midodrine; calf

-- 133 --

muscle resistance training; exercise training; or insertionof a pacemaker.

Consistent with the notion that decreased sympatheticnerve traffic or decreased norepinephrine releasepredisposes to neurocardiogenic syncope, some patientsnote improvement with sympathomimetic amines such asd-amphetamine or methylphenidate (Ritalin™).

As in POTS, in neurocardiogenic syncope, there does notseem to be much risk of chronic cardiovascular disease.

-- 134 --

NEUROCARDIOGE NICSYNCOPE

VR

HEART

NE

HR, SV

NE

Brain

Baroreceptors

NORMAL

HEART

Norepinephrine


Sympathetic Nerves

NE

SNS

Baroreceptors

Norepinephrine





Sympathetic Nerves

Brain

Epinephrine

Neurocardiogenic syncope involves anunusual pattern where before the acuteepisode, epinephrine (adrenaline) levels arehigh, and yet the sympathetic nervoussystem shuts down.

what are dysautonomias? - ndrf

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