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Dysautonomias: Clinical disorders of the autonomic nervous system

Article in Annals of Internal Medicine · December 2002

DOI: 10.7326/0003-4819-137-9-200211050-00011 · Source: PubMed

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 NIH Conference
Dysautonomias: Clinical Disorders of the Autonomic Nervous System
Moderator: David S. Goldstein, MD, PhD; Discussants: David Robertson, MD; Murray Esler, MD; Stephen E. Straus, MD;
and Graeme Eisenhofer, PhD

The term dysautonomia refers to a change in autonomic nervous sympathetic neurotransmitter norepinephrine to its receptors in
system function that adversely affects health. The changes range the heart. Increased sympathetic nerve traffic to the heart and
from transient, occasional episodes of neurally mediated hypoten- kidneys seems to occur as essential hypertension develops. Acute
sion to progressive neurodegenerative diseases; from disorders in panic can evoke coronary spasm that is associated with sympa-
which altered autonomic function plays a primary pathophysio- thoneural and adrenomedullary excitation. In congestive heart fail-
logic role to disorders in which it worsens an independent patho- ure, compensatory cardiac sympathetic activation may chronically
logic state; and from mechanistically straightforward to mysterious worsen myocardial function, which rationalizes treatment with
and controversial entities. In chronic autonomic failure (pure au- ␤-adrenoceptor blockers. A high frequency of positive results on
tonomic failure, multiple system atrophy, or autonomic failure in tilt-table testing has confirmed an association between the chronic
Parkinson disease), orthostatic hypotension reflects sympathetic fatigue syndrome and orthostatic intolerance; however, treatment
neurocirculatory failure from sympathetic denervation or deranged with the salt-retaining steroid fludrocortisone, which is usually
reflexive regulation of sympathetic outflows. Chronic orthostatic beneficial in primary chronic autonomic failure, does not seem to
intolerance associated with postural tachycardia can arise from be beneficial in the chronic fatigue syndrome. Dysautonomias are
cardiac sympathetic activation after “patchy” autonomic impair- an important subject in clinical neurocardiology.
ment or blood volume depletion or, as highlighted in this discus- Ann Intern Med. 2002;137:753-763. www.annals.org
sion, from a primary abnormality that augments delivery of the For author affiliations, see end of text.

Drs. David S. Goldstein and Graeme Eisenhofer ganglia outside the central nervous system, whereas nerves
(Clinical Neurocardiology Section, National Institute of projecting to skeletal muscle arise from the anterior horns
Neurological Disorders and Stroke [NINDS], National In- of the spinal cord. Langley introduced the term parasym-
stitutes of Health [NIH], Bethesda, Maryland): The no- pathetic nervous system to denote the cranial and sacral por-
tion that the sympathetic nervous system coordinates body tions of the autonomic nervous system, in contrast with
functions probably originated with the second-century the sympathetic nervous system, which originates from
Greek physician Galen, who taught that nerves were hol- thoracolumbar ganglia.
low tubes distributing “animal spirits” in the body, thereby Langley did not include the adrenal medulla in the
fostering concerted action, or “sympathy,” of the organs. autonomic nervous system. In the 1920s, Walter Cannon
In 1552, Bartolomeo Eustachius first depicted the sympa- considered the sympathetic nerves and adrenal medulla as a
thetic nerves and the adrenal glands. Winslow reintroduced functional unit—the “sympathico-adrenal” system (1).
the sympathetic nervous system in 1732 to describe the The parasympathetic nerves would subserve vegetative,
chains of ganglia and nerves connected to the thoracic and energy-producing processes, such as digestion, during peri-
lumbar spinal cord. ods of quiescence and the sympathico-adrenal system en-
The functions of these structures remained unknown ergy-consuming processes during emergencies. The two
until the 19th century, when Bernard and others first re- systems would antagonize each other in maintaining “ho-
ported the effects of sympathetic nerve stimulation. In meostasis,” a word Cannon invented.
1895, Oliver and Schäfer described the potent cardiovas- The concept of altered autonomic function as patho-
cular stimulatory effects of adrenal extracts. Soon after- physiologic is relatively new in clinical medicine, possibly
ward—almost exactly a century ago—Abel and Takamine dating from reports by Bradbury and Eggleston in the
identified epinephrine (“adrenaline” in British and Euro- 1920s that demonstrated a neurogenic cause for postural
pean countries) as the active principle of the adrenal gland. hypotension (2). Humans absolutely require a functionally
Also in the late 19th century, Langley coined the term intact sympathetic nervous system to tolerate the “non-
autonomic nervous system to denote the portion of the ner- emergency” behavior of simply standing up. This explains
vous system largely responsible for involuntary, uncon- why orthostatic intolerance constitutes a cardinal clinical
scious functions of internal organs, in contrast with the manifestation of sympathetic neurocirculatory failure.
portion responsible for voluntary, conscious, externally ob- In more general terms, dysautonomia refers to a con-
servable functions of skeletal muscle. Supporting this dis- dition in which altered autonomic function adversely af-
tinction, nerves projecting to internal organs arise from fects health (Figure 1). These conditions range from tran-

An edited summary of a Clinical Staff Conference held on 31 May 2000 at the National Institutes of Health, Bethesda, Maryland.
Authors who wish to cite a section of the conference and specifically indicate its author may use this example for the form of the reference:
Robertson D. Autonomic function in chronic orthostatic intolerance. In: Goldstein DS, moderator. Dysautonomias: clinical disorders of the autonomic nervous system. Ann Intern Med. 2002;137:
756-7.

© 2002 American College of Physicians–American Society of Internal Medicine 753

NIH Conference Dysautonomias

Figure 1. Dysautonomias featuring altered sympathetic and norepinephrine in antecubital venous plasma. These
noradrenergic function. include the efficiency of neuronal reuptake of released nor-
epinephrine, modulation of norepinephrine release by ␣2-
adrenoceptors on sympathetic nerve terminals, local blood
flow, and, as discussed later, clearance of norepinephrine
from the circulation.
Norepinephrine is released into the bloodstream at the
same time as it is removed from the bloodstream. Esler first
applied the tracer dilution principle to estimate the rate of
entry of norepinephrine into the bloodstream—the so-
called norepinephrine spillover (3). Because of the rele-
vance of this principle to presentations in this report, we
discuss the underlying concepts here.
Because organs remove circulating norepinephrine as
it passes through them, when a tracer amount of 3H-nor-
epinephrine is infused, the concentration of 3H-norepi-
nephrine in arterial plasma exceeds that in local venous
plasma. There is less specific activity of 3H-norepinephrine
(the amount of 3H-norepinephrine per unit of total nor-
epinephrine) in the vein than in the artery because unla-
beled endogenous norepinephrine enters the bloodstream
in the organ. By quantifying the amount of dilution of the
tracer, one can estimate the norepinephrine spillover from
the organ.
Human plasma contains not only the catecholamines
norepinephrine and epinephrine (with trace amounts of
free [unconjugated] dopamine) but also two other cat-
echols. Measurements of the other catechols can greatly
enhance the interpretation of plasma norepinephrine levels
in terms of sympathetic function (Figure 2). One catechol,
3,4-L-dihydroxyphenylalanine (levodopa or L-dopa), is the
precursor of the catecholamines and the immediate prod-
uct of the rate-limiting step in catecholamine biosynthesis.
The regional rate of L-dopa spillover (usually estimated
In dysautonomias, altered function of the autonomic nervous system
from the arteriovenous increment in plasma L-dopa levels,
adversely affects health. multiplied by the plasma flow) provides an index of nor-
epinephrine synthesis in sympathetic nerves (4, 5).
sient episodes in otherwise healthy people to progressive Another catechol, dihydroxyphenylglycol (DHPG), is
neurodegenerative diseases; from conditions in which al- the main neuronal metabolite of norepinephrine (6). This
tered autonomic function plays a primary pathophysiologic catechol is produced by the action of monoamine oxidase
role to those in which it worsens an independent patho- on norepinephrine in the sympathetic axoplasm. Axoplas-
logic state; and from mechanistically straightforward to mic norepinephrine has two sources—leakage from storage
mysterious and controversial entities. vesicles and reuptake after exocytotic release. The neuronal
Norepinephrine (“noradrenaline” in British and Euro- uptake process is called uptake-1. Entry of DHPG into the
pean countries) is the main chemical messenger of the bloodstream reflects both loss of norepinephrine from ves-
sympathetic nervous system. The messenger of the para- icles by leakage and reuptake of norepinephrine by up-
sympathetic nervous system is acetylcholine. For thermo- take-1. Under resting conditions, most DHPG production
regulatory sweating, sympathetic nerves release acetylcho- is from the former mechanism. Local DHPG spillover
line as the main effector. (usually estimated from the arteriovenous increment in
Modern clinical chemical methods can measure nor- plasma DHPG levels, multiplied by the blood flow) has
epinephrine in human plasma (normal concentration is been used as an index of norepinephrine turnover in sym-
about 1.5 nmol/L). One might think that the plasma nor- pathetic nerves (6, 7). Thus, simultaneous assessments of
epinephrine concentration would provide a means to assess norepinephrine, L-dopa, and DHPG spillovers provide in-
sympathetic “activity”; however, several processes deter- formation about related but different aspects of sympa-
mine the relationship between sympathetic nerve traffic thetic noradrenergic function.
754 5 November 2002 Annals of Internal Medicine Volume 137 • Number 9 www.annals.org
 Dysautonomias NIH Conference

CHRONIC AUTONOMIC FAILURE Figure 2. Sources of plasma levels of catechols.

Dr. David S. Goldstein (Clinical Neurocardiology
Section, NINDS, NIH, Bethesda, Maryland): Orthostatic
hypotension has been defined as a decrease in systolic pres-
sure of at least 20 mm Hg or a decrease in diastolic pres-
sure of at least 10 mm Hg within 3 minutes of standing or
head-up tilt (8). Orthostatic hypotension usually results
from depletion of blood or extracellular fluid volume or
from a prolonged bedridden state and only uncommonly
results from autonomic failure. Conversely, however, or-
thostatic hypotension constitutes a key manifestation of
sympathetic neurocirculatory failure (9).
Most chronic autonomic failure occurs as a conse-
quence of disease processes (for example, diabetes, amy-
loidosis, or multiple myeloma), toxic agents (for example,
alcohol), or medications (for example, antidepressant, an-
tipsychotic, antihypertensive, or antineoplastic drugs).
Sometimes, autonomic failure dominates the clinical pre-
sentation and has no clear cause; this is called primary
chronic autonomic failure.
Primary chronic autonomic failure in adults has been
classified in terms of three clinicopathologic states (8, 10).
Pure autonomic failure features orthostatic hypotension
without symptoms or signs of central neurodegeneration.
Multiple system atrophy, which includes a combination of
autonomic failure and progressive central neurodegenera-
tion, has been divided into parkinsonian, cerebellar, and
mixed forms. Finally, autonomic failure can occur in asso-
ciation with Parkinson disease.
Multiple system atrophy can include parkinsonian fea-
tures; thus, because patients with Parkinson disease can
have autonomic failure, distinguishing the two conditions
Norepinephrine (NE), dihydroxyphenylglycol (DHPG), and endogenous
can pose a difficult diagnostic challenge. Patients with Par- L-dopa are produced intraneuronally after uptake of tyrosine. Note that
kinson disease usually respond to carbidopa-levodopa, hypofunction of the membrane norepinephrine transporter, responsible
whereas patients with multiple system atrophy usually do for neuronal uptake of catecholamines via the uptake-1 process, should
result in augmented responses of plasma norepinephrine levels and at-
so to only a limited extent (8). This distinction does not tenuated responses of plasma DHPG levels during sympathetic stimula-
always suffice, for two reasons. First, some neurologists tion. MAO ⫽ monoamine oxidase.
may be reluctant to prescribe carbidopa-levodopa for a pa-
tient with Parkinson disease who already has orthostatic Patients with multiple system atrophy of any subtype
hypotension because such treatment might worsen the or- generally have intact cardiac sympathetic innervation and a
thostatic hypotension. Second, some patients with multiple large decrease in blood pressure in response to ganglion
system atrophy improve when taking carbidopa-levodopa. blockade with trimethaphan (15). In contrast, patients
Recent neuroimaging techniques applied to the heart with Parkinson disease and autonomic failure have no de-
have clearly distinguished these two forms of chronic au- tectable 123I-MIBG– derived (16 –20) or 6-[18F]fluorodo-
tonomic failure. Cardiac sympathetic nerves take up 123I- pamine– derived (21, 22) radioactivity in the left ventricu-
metaiodobenzylguanidine (123I-MIBG) and 6-[18F]fluoro- lar myocardium and a small or normal decrease in blood
dopamine, which radiolabel the vesicles in the terminals pressure in response to trimethaphan (Goldstein DS. Un-
(11, 12). This allows visualization of the sympathetic in- published observations). Such patients also have markedly
nervation of the heart by scintigraphy or single-photon decreased or absent cardiac spillovers of norepinephrine,
emission computed tomography after injection of 123I- L-dopa, and DHPG, which provides neurochemical confir-
MIBG (13) and by positron emission tomography (PET) mation of a loss of sympathetic terminal innervation in the
after injection of 6-[18F]fluorodopamine (14). This visual- heart.
ization is independent of adrenoceptor binding; rather, it These differences point to a preganglionic lesion in
depends on active transport of the radioactive drug by the multiple system atrophy and postganglionic lesion in Par-
uptake-1 process, followed by vesicular sequestration. kinson disease with autonomic failure. Separating sympa-
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NIH Conference Dysautonomias

Figure 3. Regulation of sympathetic outflows to the heart and other parts of the body in orthostatic intolerance syndromes.

Thick lines represent increased activity, thin lines represent normal activity, and dashed lines represent decreased activity.

thetic denervation from deranged nerve traffic to intact stand for more than 1 or 2 minutes. Orthostatic intoler-
terminals might be clinically important not only for diag- ance, which generally occurs in much younger patients,
nosis but also for treatment and predicting side effects of rarely features rapid orthostatic hypotension, but delayed
drugs. Patients with orthostatic hypotension from sympa- orthostatic hypotension can occur.
thetic denervation might not benefit from a sympathomi- Orthostatic intolerance is common (23). Although
metic amine or ␣2-adrenoceptor blocker because the pres- formal studies about prevalence have not been done, we
sor effects of these drugs depend on releasable estimate that 500 000 Americans have this problem. In
norepinephrine stores; however, such patients might bene- elderly persons, orthostatic intolerance can be a manifesta-
fit from midodrine, an orally acting ␣-adrenoceptor ago- tion of cerebral hypoperfusion from carotid disease; how-
nist, or L-threo-3,4-dihydroxyphenylserine, which is con- ever, most patients with orthostatic intolerance are young
verted to norepinephrine by L-aromatic amino acid women between the ages of 15 and 45 years. They report
decarboxylase, an enzyme found in many types of paren- dizziness, visual changes, head and neck discomfort, poor
chymal cells. A patient with orthostatic hypotension from concentration while standing, fatigue while standing (as
dysregulation of sympathetic outflows might be at in- well as at other times), palpitations, tremor, anxiety, pre-
creased risk for acute hypertension from herbal remedies, syncope, and, in some cases, syncope.
such as ma-huang and yohimbe bark, which release nor- In neuropathic postural tachycardia syndrome (Figure
epinephrine. 3), orthostatic intolerance seems to be associated with a
Future research about chronic autonomic failure “patchy” dysautonomia, which results in orthostatic pool-
should focus more on the pathogenic mechanisms of cen- ing of blood in the splanchnic and dependent circulations
tral and peripheral neurodegeneration and less on treat- and activation of the remaining cardiac sympathetic sys-
ments of the orthostatic hypotension. tem, causing tachycardia on standing (24). Orthostatic in-
tolerance is also associated with deficient functioning of the
AUTONOMIC FUNCTION IN CHRONIC ORTHOSTATIC renin–angiotensin–aldosterone system (25), acute baro-
INTOLERANCE reflex failure (26), and excessive extravasation during or-
Dr. David Robertson (Clinical Research Center, thostasis.
Vanderbilt University School of Medicine, Nashville, Ten- Some patients have orthostatic intolerance associated
nessee): Orthostatic hypotension and orthostatic intoler- with a primary abnormality of sympathetic nervous func-
ance are not synonymous. Patients with orthostatic hypo- tion, which results in augmented delivery of the sympa-
tension, a clinical sign, typically have a rapid decrease in thetic neurotransmitter norepinephrine to its receptors
blood pressure exceeding 20/10 mm Hg and often cannot during orthostasis. We present the case of a family with
756 5 November 2002 Annals of Internal Medicine Volume 137 • Number 9 www.annals.org
 Dysautonomias NIH Conference

orthostatic intolerance for which we could identify a spe- membrane norepinephrine transporter can produce ortho-
cific cause (27). static tachycardia by amplifying delivery of norepinephrine
The index patient was a 33-year-old woman who had to its receptors in the heart. We are studying the frequency
15 years of exertional dyspnea and tachycardia on standing. of the proline-for-alanine substitution in other patients
She had typical orthostatic symptoms and occasional syn- with orthostatic intolerance. We predict that mutations or
cope. A pacemaker had been implanted, and the symptoms polymorphisms of other monoamine transporters will also
partially improved. The patient had been treated with have clinically important manifestations.
␤-adrenoceptor blockers, clonidine, and fludrocortisone.
In normal patients, peroneal muscle sympathetic activ-
ity approximately doubles during orthostatic stress, with an
approximate doubling of the plasma norepinephrine con- AUTONOMIC FUNCTION IN ESSENTIAL HYPERTENSION,
centration (28 –31). In this patient, there may have been PANIC DISORDER, AND CONGESTIVE HEART FAILURE
only an attenuated increase in sympathetic nerve traffic Dr. Murray Esler (Baker Medical Research Institute,
while standing; however, the plasma norepinephrine level Prahran, Victoria, Australia): Three conditions associated
increased by more than threefold. with altered autonomic function that adversely affects
To explore this dissociation, we evaluated plasma nor- health are neurogenic essential hypertension, psychogenic
epinephrine spillover and clearance by using the tracer ischemic heart disease, and congestive heart failure. In
dilution technique described earlier. We found reduced some patients with essential hypertension, chronic sympa-
systemic norepinephrine clearance during various interven- thetic nervous activation may be a primary causal mecha-
tions. nism. In panic disorder, acute episodes can evoke sympa-
We also measured the plasma level of DHPG, which, thetic neuronal and adrenomedullary activation and
as noted earlier, is the intraneuronal metabolite of norepi- precipitate coronary artery spasm. In heart failure, chroni-
nephrine. In the supine posture, the plasma DHPG level cally elevated cardiac sympathetic tone probably contrib-
was higher than the norepinephrine level (a normal find- utes to progressive deterioration of the myocardium and
ing), but with sustained upright posture, the plasma nor- may serve as a target for therapy.
epinephrine level increased by threefold, whereas the
DHPG level increased minimally. This neurochemical pat- Neurogenic Essential Hypertension
tern seemed unusual in this patient. Because increments in Approximately 40% of patients with untreated essen-
plasma DHPG levels during sympathetic stimulation de- tial hypertension have chronically increased cardiac and
pend largely on neuronal reuptake of released norepineph- renal spillover of norepinephrine and increased rates of ef-
rine, we hypothesized that the patient had deficient func- ferent sympathetic nerve firing in the outflow to the skel-
tion of the cell membrane norepinephrine transporter, etal muscle vasculature (27, 33, 34). These alterations are
which is responsible for inactivation of norepinephrine by most evident in relatively young patients. The sympathetic
uptake-1. Tyramine is a substrate for the norepinephrine activation originates within the central nervous system and
transporter, and the pressor effect of tyramine depends on seems to be driven by noradrenergic projections from the
neuronal uptake of the sympathomimetic amine and dis-
brainstem to the forebrain (35).
placement of norepinephrine from storage vesicles in sym-
Chronic sympathetic nervous activation contributes to
pathetic nerves. During tyramine infusion, we found that
hypertension by stimulating the heart and elevating cardiac
the patient had a blunted pressor response compared with
output in the early phases; by neurally mediated vasocon-
other patients with orthostatic intolerance and normal per-
sons. striction; and, in the kidney, by augmenting renin secre-
The DNA sequence and polypeptide structure of the tion and tubular reabsorption of sodium (27, 33, 34, 36,
plasma membrane norepinephrine transporter protein are 37). The renal sympathetic activation may be of particular
known (32). In our patient, we found a previously un- importance for the development of the hypertension. In-
known polymorphism of the gene encoding this protein, terestingly, the three most commonly used nonpharmaco-
which predicted a proline substitution for alanine at posi- logic therapies to reduce blood pressure (calorie restriction,
tion 457 (27). Expression of the wild-type norepinephrine weight loss, and exercise training) tend to inhibit sympa-
transporter in a cell line in vitro led to uptake of 3H- thetic nervous system outflows (27).
norepinephrine from the medium, whereas cells expressing A combination of high plasma norepinephrine levels
the transporter with the proline-for-alanine substitution with augmented pressor responses to yohimbine (38) or
did not. Mixture of the two cell lines led to partial inhib- augmented depressor responses to clonidine (39) identifies
itory effects, suggesting a dominant negative interaction. patients in whom increased sympathetic nervous system
The pattern of altered upright plasma norepinephrine, outflows contribute to high blood pressure—termed hy-
DHPG, and heart rate cosegregated with the norepineph- pernoradrenergic hypertension. A reasonable hypothesis for
rine transporter mutation in this large family. future testing is that laboratory profiling predicts long-term
These findings indicate that deficiency of the plasma responses to different classes of antihypertensive agents.
www.annals.org 5 November 2002 Annals of Internal Medicine Volume 137 • Number 9 757
NIH Conference Dysautonomias

Figure 4. Peroneal sympathetic nerve traffic during a panic epinephrine (45).

attack. In most patients who experience panic disorder, epi-
nephrine is released into the cardiac venous drainage, even
when an attack is not occurring (45). Presumably, the car-
diac sympathetic nerves extract epinephrine from the cir-
culation during panic-induced surges of epinephrine secre-
tion, and, subsequently, some of the epinephrine is released
as a result of ongoing cardiac sympathetic nerve traffic. The
rate of cardiac epinephrine spillover, measured by using the
tracer dilution approach during concurrent administration
of 3H-norepinephrine and 3H-epinephrine, averages about
20% of the norepinephrine spillover.
Some patients with panic disorder describe severe,
crushing precordial chest pain that resembles angina pec-
toris. Electrocardiographic changes can indicate myocardial
ischemia in these patients (44). Coronary angiography is
also sometimes done when a patient has no evident coro-
nary atherosclerosis but has coronary artery spasm during a
panic attack that can be reversed with nitroglycerin.
Patients with mitral valve prolapse can report “auto-
nomic” symptoms, such as chest pain and palpitations,
associated with panic or anxiety (46, 47). In general, such
patients have normal values for indices of sympathetic
function, at rest and during orthostasis (48, 49).

Congestive Heart Failure

Congestive heart failure is a third condition in which
increased sympathetic nervous system outflows adversely
affect clinical outcome. According to an older concept that
was derived from the finding of myocardial norepinephrine
During a panic attack, the amplitude of bursts of sympathetic nerve
firing recorded by microneurography increases markedly. depletion by Chidsey and colleagues (50), the failing heart
is sympathetically denervated. This provided a rationale for
the long-term use of adrenergic agonists as cardiac ino-
Panic Disorder tropes in patients with heart failure—a form of therapy
Distress, by increasing sympathetic and adrenomedul- that subsequently proved unhelpful if not outright danger-
lary outflows, can trigger morbid or even mortal cardiovas- ous.
cular events. For instance, there is unequivocal evidence of Clinical and empirical research initiated by Swedish
increased cardiac risk in people caught in natural disasters, cardiologists contradicted this concept. Patients with heart
such as earthquakes (40). In acute mental stress responses, failure from dilated cardiomyopathy who were treated with
sympathetic nervous system activation preferentially targets ␤-adrenoceptor blockers had long-term improvement, not
the heart (41), providing a straightforward mechanism for worsening, of their condition (51). Use of ␤-adrenoceptor
precipitation of myocardial infarction or ventricular ar- blockers in the treatment of heart failure from other causes
rhythmias in the presence of fixed coronary artery stenosis. has slowly and progressively increased, and a new concept
Definitive proof does not exist, however, for a psycho- of the neurobiology of heart failure has emerged (52).
somatic contribution to the long-term development of It is by now clear that in cardiac failure, despite the
ischemic heart disease. There is accumulating support for presence of low myocardial tissue concentrations of norepi-
increased cardiac risk in panic disorder (42) and depressive nephrine, cardiac norepinephrine spillover is markedly in-
illness (43), but the bases for the increased risk remain creased—in some cases by 50-fold (53, 54). In healthy
unknown. persons, such a high rate of norepinephrine release occurs
Occasionally, patients have a spontaneous episode of only at near-maximal aerobic exercise. Moreover, an in-
panic while being monitored during cardiac catheterization crease in cardiac sympathoneural outflow, as indicated by
(44). This allows assessment of neurophysiologic and cardiac norepinephrine spillover, characterizes early heart
neurocirculatory aspects of the attack. During a panic at- failure at a stage when more generalized sympathetic stim-
tack, the amplitude of bursts of sympathetic nerve firing ulation does not occur (55).
recorded by microneurography increases markedly (Figure Prospective studies have shown that the extent of sym-
4), accompanied by increased adrenomedullary secretion of pathetic stimulation of the failing heart potently and inde-
758 5 November 2002 Annals of Internal Medicine Volume 137 • Number 9 www.annals.org
 Dysautonomias NIH Conference

pendently predicts early death (56). This could reflect (71, 72). The latest estimates in four U.S. cities indicate
more recruitment of cardiac sympathetic outflow in pa- 200 to 250 cases per 100 000 persons.
tients with worse heart failure, acceleration of cardiac de- Hypothesized causes for CFS abound. For many years,
compensation as a result of increased sympathetic outflows, researchers considered CFS infectious but obtained no
or both. The increases in sympathetic outflow are compen- proof (73). Others viewed CFS as an immunologic disor-
satory because cardiac transplantation normalizes total- der. Although cumulative data suggest some immune dif-
body and regional norepinephrine spillovers (57). Never- ferences between patients with CSF and control patients,
theless, chronic increases in cardiac sympathoneural the literature does not support a primary immune dysfunc-
outflow might worsen the heart failure by augmenting car- tion (74). Many patients with CFS are highly inactive and
diac hypertrophy, for example (58), which would decrease have decreased exercise tolerance, suggesting physical de-
myocardial compliance and diminish cardiac baroreceptor conditioning. A substantial number have difficulty sleeping
restraint of sympathetic nervous system outflows, and by (75), depression, or anxiety, indicating an affective compo-
promoting apoptosis of myocardial cells (59). If these nent (76). Several studies implicate a neuroendocrine dis-
events occurred simultaneously, the likelihood of one or order (77).
more positive feedback loops could increase, inducing a Finally, data first reported by Rowe and colleagues
downward clinical spiral. (78, 79) suggested a form of dysautonomia in patients with
These concepts rationalize treatment with ␤-adreno- CFS (78 – 81). When evaluated by prolonged head-up tilt-
ceptor blockers or other drugs affecting sympathetic neu- ing at a 70-degree angle, more than 60% of patients with
roeffector function (60). Cautious use of ␤-blockade seems CFS have abnormal blood pressure or pulse rate responses,
beneficial in patients with heart failure related to ischemic with sudden hypotension or severe bradycardia or tachy-
or idiopathic dilated cardiomyopathy. The novel drug cardia, which is accompanied by a decreased level of con-
carvedilol, which features ␤-adrenoceptor blockade, ␣1- sciousness—a phenomenon termed neurally mediated hy-
adrenoceptor blockade, and antioxidant properties, seems potension.
especially promising (61, 62). Large-scale clinical trials By contrast, patients with neurally mediated hypoten-
with other ␤-adrenoceptor blockers are under way. Results sion, whether manifested clinically as postural tachycardia
of attempts to improve clinical status or survival in patients or neurocardiogenic syncope, often report chronic fatigue.
with heart failure by blocking ␣1-adrenoceptors using pra- For many years, it has been thought that a combination of
zosin have been disappointing (63); the benefit of inhibit- a left ventricular hypercontractile state with decreased car-
ing catecholamine synthesis using ␣-methyl-p-tyrosine (64) diac filling precipitates neurocardiogenic syncope via “col-
or of inhibiting sympathetic outflow using clonidine (65, lapse firing” of cardiac or central venous baroreceptors (82,
66) remains uncertain. 83). Recent studies have not supported aspects of this
hypothesis because syncope usually is attended by a precip-
itous decrease in sympathetic nervous system outflow with-
DYSAUTONOMIA AND THE CHRONIC FATIGUE out clear preceding ventricular hypovolemia or hypercon-
SYNDROME tractility (84, 85).
Dr. Stephen E. Straus (National Center for Comple- Most patients with orthostatic intolerance due to sym-
mentary and Alternative Medicine, NIH, Bethesda, Mary- pathetic neurocirculatory failure benefit from treatment
land): The chronic fatigue syndrome (CFS) is characterized with the sodium-retaining steroid fludrocortisone com-
by new, unexplained fatigue that lasts for at least 6 months, bined with a high-salt diet. In preliminary, uncontrolled
is not relieved by rest, and has no clear cause (67– 69). The studies, many patients with CFS also seemed to benefit
syndrome is associated with four or more new symptoms, from this combination (79). In a recent placebo-controlled
such as memory or concentration problems, sore throat, clinical trial of this therapeutic approach (86), 100 patients
tender lymphadenopathy, myalgia, arthralgia, headache, with CFS who had positive results on tilt-table testing took
unrefreshing sleep, and postexertional malaise. The cogni- escalating doses of placebo or fludrocortisone for 9 weeks.
tive problems and fatigue are the most disconcerting as- Symptoms improved in 10% of the placebo recipients and
pects for patients. in 14% of patients receiving fludrocortisone—a statistically
Chronic fatigue syndrome is a sporadic illness with nonsignificant difference. The ability to tolerate tilt also
occasional, poorly understood geographic clusters (70). did not improve, and there was no correlation between the
Despite substantial work, there is no evidence for conta- tilt-table test measures and any of the self-rating categories.
gion or seasonal or geographic differences. Women are af- Thus, CFS is a fairly common, incompletely under-
fected two to three times as often as men. The syndrome stood disorder that overlaps clinically with dysautonomias.
seems to be less prevalent in minority groups, but this The basis for the relationship between the two types of
finding may reflect ascertainment biases. Young, middle- conditions continues to elude us. Treatment with fludro-
aged persons are most often affected. Depending on the cortisone does not seem to improve orthostatic intolerance
definition of CFS used and the epidemiologic tool, 10 to in patients with CFS. Other possibly effective treatments
1000 per 100 000 persons in the United States have CFS include the orally active ␣-adrenoceptor agonist midodrine
www.annals.org 5 November 2002 Annals of Internal Medicine Volume 137 • Number 9 759
NIH Conference Dysautonomias

and ␤-adrenoceptor blockers (87). Whether effective treat- to provoke me” (88). This proved to be one of the most
ment of orthostatic intolerance actually improves the sense ironic statements in medical history, for on 16 October
of chronic fatigue in patients with CFS remains unknown. 1793, incensed at remarks criticizing him at a meeting of
the board of governors of St. George’s Hospital, he left the
room, collapsed, and dropped dead. At autopsy, his body
DYSAUTONOMIAS AND NEUROCARDIOLOGY demonstrated severe coronary arteriosclerosis.
Controversy surrounding the “type A coronary prone
Dr. David S. Goldstein (Clinical Neurocardiology
behavior pattern” (89) probably stunted the growth of neu-
Section, NINDS, NIH, Bethesda, Maryland): Clinical
rocardiology as a medical discipline. The roles of personal-
neurocardiology deals with interrelationships between dys-
ity and distress in the development of atherosclerosis re-
function in the nervous and cardiovascular systems. Topics
main contentious. As used here, “neurocardiology”
in clinical neurocardiology include normal and abnormal
includes both well-accepted clinical entities, such as auto-
neural and neuroendocrine regulation of the cardiovascular
nomic failure and stroke-induced myocardial necrosis, and
system, diseases that feature concurrent neural and cardio-
persistently mysterious conditions, such as chronic ortho-
vascular pathology, effects of cardiovascular pathologic
static intolerance, neurocardiogenic syncope, and CFS.
states on nervous system function, and diseases of embyro-
Research in clinical neurocardiology is mainly patient
logic development and senescence of neurocirculatory reg-
oriented. Several disorders under the umbrella of “dysau-
ulation. Because of the key roles played by the autonomic
tonomia” have no cellular or animal model. For some,
nervous system in neurocirculatory regulation, dysautono-
neuroendocrine, autonomic, physiologic, and psychologi-
mias constitute a major portion of clinical neurocardiology
cal alterations seem bound inextricably, and traditional
research and practice.
borders among “mind,” “brain,” and “body” blur (90).
The ideas that the brain affects the heart and that
We predict further use of the neurochemical, neuro-
emotion-related alterations in cardiovascular function
imaging, and molecular genetic techniques highlighted
might cause or contribute to disease are not new. In fact, in
here to discover bases for predispositions to hypofunctional
William Harvey’s 17th book, Exercitatio Anatomica de
dysautonomias, such as CFS and neurocardiogenic syn-
Motu Cordis et Sanguinis in Animalibus (in English, “On
cope, and to hyperfunctional dysautonomias, such as the
the Motion of the Heart and Blood in Animals”), the same
postural tachycardia syndrome, hypernoradrenergic hyper-
landmark book that introduced the concept of the circula-
tension, and melancholic depression (91). Progress in this
tion of the blood, Harvey also noted links among emo-
field will depend on interdisciplinary collaboration and de-
tions, the brain, the heart, and disease:
velopment of theoretical frameworks for understanding the
For every affection of the mind that is attended with integrative functions of homeostatic systems.
either pain or pleasure, hope or fear, is the cause of an This report has not covered dysautonomias compre-
agitation whose influence extends to the heart, and hensively. Familial dysautonomia, baroreflex failure, adre-
there induces change from the natural constitution, in nomedullary hyperplasia, “autonomic epilepsy,” reflex
the temperature, the pulse and the rest, which impair- sympathetic dystrophy, stroke-induced myocardial necro-
ing all nutrition in its source and abating the powers at sis, and diabetic autonomic neuropathy received no atten-
large, it is no wonder that various forms of incurable tion. Instead, we have attempted to sketch a large spectrum
disease in the extremities and in the trunk are the con- with a few hues. Interested readers should consult more
sequence, inasmuch as in such circumstances the whole comprehensive recent reviews (92, 93).
body labours under the effects of vitiated nutrition and
a want of native heat. From National Institute of Neurological Disorders and Stroke, Bethesda,
Maryland; Vanderbilt University School of Medicine, Nashville, Tennes-
The death of Dr. John Hunter, the noted 18th- see; Baker Medical Research Institute, Prahran, Victoria, Australia; and
National Center for Complementary and Alternative Medicine, National
century Scottish surgeon, is probably the earliest, best-doc- Institutes of Health, Bethesda, Maryland.
umented, and most ironic illustration of emotion worsen-
ing a cardiovascular pathologic state. By all accounts, Acknowledgments: The authors thank Courtney Holmes, CMT, and
Hunter was notorious for impatience, defensive argument, Sandra Brentzel, RN, Clinical Neurocardiology Section, National Insti-
and irrational outbursts— epitomizing what today might tute of Neurological Diseases and Stroke, Bethesda, Maryland; Dr. Si-
be called a hostile “type A” personality. In 1785, he began mon Bruce, formerly of the National Institute of Child Health and
to experience angina pectoris, a syndrome his friend Wil- Development, Bethesda, Maryland; Dr. Jacques Lenders, University of
liam Heberden had only recently described. Despite having Nijmegen, the Netherlands; Drs. Italo Biaggioni, Nancy Flattern, John
Shannon, and Randy Blakely, Vanderbilt University School of Medicine,
autopsied one of Heberden’s patients with angina, Hunter
Nashville, Tennessee; Dr. Jens Jordan, Berlin, Germany; Dr. Giris Jacob,
either never recognized or never admitted his own condi- Haifa, Israel; and Drs. Hugh Calkins and Peter Rowe, Johns Hopkins
tion for what it was. He did recognize the relationship School of Medicine, Baltimore, Maryland. They also thank the nursing,
between emotional upset and his symptoms when he technical, and support staff of the Vanderbilt Autonomic Dysfunction
claimed, “My life is at the mercy of any rogue who chooses Center and of the National Institute of Allergy and Infectious Diseases,
760 5 November 2002 Annals of Internal Medicine Volume 137 • Number 9 www.annals.org
 Dysautonomias NIH Conference
National Heart, Lung, and Blood Institute, National Institutes of Neu- clinical and experimental studies with radiolabeled MIBG. J Nucl Med. 2000;
rological Diseases and Stroke and the staff of the National Institutes of 41:71-7. [PMID: 10647607]
Health Positron Emission Tomography Department. 19. Yoshita M, Hayashi M, Hirai S. [Iodine 123-labeled meta-iodobenzylgua-
nidine myocardial scintigraphy in the cases of idiopathic Parkinson’s disease,
Requests for Single Reprints: David S. Goldstein, MD, PhD, Clinical multiple system atrophy, and progressive supranuclear palsy]. Rinsho
Shinkeigaku. 1997;37:476-82. [PMID: 9366173]
Neurocardiology Section, National Institutes of Neurological Diseases
and Stroke, National Institutes of Health, Building 10 Room 6N252, 10 20. Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H. (123)I-metaiodo-
benzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neuro-
Center Drive MSC-1620, Bethesda, MD 20892-1620.
surg Psychiatry. 1999;67:189-94. [PMID: 10406987]
21. Goldstein DS, Holmes C, Cannon RO 3rd, Eisenhofer G, Kopin IJ. Sym-
Current author addresses are available at www.annals.org. pathetic cardioneuropathy in dysautonomias. N Engl J Med. 1997;336:696-702.
[PMID: 9041100]
22. Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO 3rd.
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Then he felt so bad that he agreed to a visit from a doctor with the condition that he
(the doctor) wouldn’t examine him, nor ask questions about his pains, nor attempt to
give him anything to drink. “Only to talk, he said.

The electee could not have matched his desires more. His name was Hercules
Gastelbondo, and he was an old man blessed with happiness; he was huge and
placid with a shining dome of total baldness and the patience of a drowned man,
and that alone would relieve the illnesses of others. His skepticism and scientific
courage were famous on the whole coast. He prescribed chocolate cream and melted
cheese for bile distress, advised love-making during digestive lethargy as a good
palliative for a long life, smoked endless carter’s cigarettes done up in brown
wrapping paper, and prescribed them for the sick against every type of malady of
the body. The patients said that he never cured them fully, but that he entertained
them with his flowery words. He exploded in plebeian laughter.

“The other doctors may kill as many sick people as me,” he said. “But with me, they
die happier.”

Gabriel Garcı́a Márquez

El General en Su Laberinto (The General in His Labyrinth)
Barcelona: Plaza & Janés; 1998;219-20
Submitted by:
Leonard M. Rubin, MD
Chestnut Hill, MA 02467

Submissions from readers are welcomed. If the quotation is published, the sender’s name will be
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www.annals.org 5 November 2002 Annals of Internal Medicine Volume 137 • Number 9 763
 Current Author Addresses: Drs. Goldstein and Eisenhofer: Clinical Dr. Murray Esler: Baker Medical Research Institute, Commercial Road,
Neurocardiology Section, National Institute of Neurological Disorders 3181 Prahran, Victoria, Australia.
and Stroke, National Institutes of Health, Building 10, Room 6N252, Dr. Stephen Straus: National Center for Complementary and Alternative
10 Center Drive MSC-1620, Bethesda, MD 20892-1620. Medicine, NIH, Building 31 Room 5B37, 31 Center Drive, MSC-2182,
Dr. David Robertson: Director, Center for Space Physiology and Med- Bethesda, MD 20892-2182.
icine, Vanderbilt University School of Medicine, Nashville, TN 37232-
2195.

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