Download Aaem minimonograph #48: Autonomic nervous system

ABSTRACT: The autonomic nervous system maintains internal homeostasis by regulating cardiovascular, thermoregulatory, gastrointestinal, genitourinary, exocrine, and pupillary function. Testing and quantifying autonomic
nervous system function is an important but difficult area of clinical neurophysiology. Tests of parasympathetic cardiovagal regulation include heart
rate analysis during standing (the 30:15 ratio), heart rate variation with deep
breathing, and the Valsalva ratio. Tests of sympathetic adrenergic vascular
regulation include blood pressure analysis while standing, the Valsalva
maneuver, sustained handgrip, mental stress, and cold water immersion.
Tests of sympathetic cholinergic sudomotor function include the sympathetic
skin response, quantitative sudomotor axon reflex test, sweat box testing,
and quantification of sweat imprints. Pupil function is tested pharmacologically and with pupillographic techniques. Tests of gastrointestinal and
genitourinary function do not satisfactorily isolate autonomic regulation from
their other functions. The available tests have various sensitivities and ease
of administration. They are typically administered in a battery of multiple tests, which improves sensitivity and reliability, and allows probing of
various autonomic functions. © 1997 American Association of Electrodiagnostic
Medicine. Published by John Wiley & Sons, Inc. Muscle Nerve 20: 919–937, 1997
Key words: autonomic function; head-up tilt-table testing; 30:15 ratio; Valsalva ratio; sinus arrhythmia; sympathetic skin response; quantitative sudomotor axon reflex; thermoregulatory sweat test; sweat imprint test
AAEM MINIMONOGRAPH #48:
AUTONOMIC NERVOUS
SYSTEM TESTING
JOHN M. RAVITS, MD
Neurology Section, Virginia Mason Medical Center, Seattle, Washington 98111, USA
Received 29 January 1997; accepted 20 February 1997
The autonomic nervous system is a complex neural
network maintaining internal physiologic homeostasis, especially cardiovascular, thermoregulatory, gastrointestinal (GI), genitourinary (GU), exocrine,
and pupillary. Disordered function is manifested by
such problems as orthostatic hypotension, heat intolerance, abnormal sweating, constipation, diarrhea, incontinence, sexual dysfunction, dry eyes, dry
mouth, loss of visual accommodation, and pupillary
irregularities. Autonomic failure is paramount in
multiple system atrophy (which also causes cognitive, cerebellar, extrapyamidal, and pyamidal failure) and in pure or progressive autonomic failure
(which does not cause other neurologic failure). Autonomic failure may accompany diseases of the central nervous system (CNS) such as Parkinson’s disease and other neurodegenerative diseases, trauma,
Correspondence to: American Association of Electrodiagnostic Medicine,
21 Second Street, S.W., Suite 103, Rochester, MN 55902, USA
CCC 0148-639X/97/080919-19
© 1997 American Association of Electrodiagnostic Medicine. Published
by John Wiley & Sons, Inc.
AAEM Minimonograph #48
vascular diseases, neoplastic diseases, metabolic diseases such as Wernicke’s and cobalamin deficiency,
multiple sclerosis, and various medications. It occurs
in many neuropathies such as diabetes, Guillain–
Barré syndrome, Lyme disease, human immunodeficiency virus infection, leprosy, acute idiopathic dysautonomia, amyloidosis, porphyria, uremia,
alcoholism, and familial neuropathies such as Riley–
Day syndrome, Fabry’s disease, and familial amyloidosis. It occurs in diseases of the presynaptic neuromuscular junction such as botulism and myasthenic
syndrome.48,59
The autonomic nervous system is divided into
two opposing systems, the sympathetic and parasympathetic.84 The sympathetic nervous system exits from
the thoracolumbar regions of the spinal cord and
synapses at prevertebral and paravertebral ganglia.
Preganglionic fibers are myelinated, relatively short,
and cholinergic; postganglionic fibers are unmyelinated, long, and primarily adrenergic, except for the
innervation of the sweat glands, which are cholinergic. The parasympathetic nervous system travels with the
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third, seventh, ninth, and tenth cranial nerves and
the sacral spinal roots. Preganglionic axons are myelinated and have long peripheral projections to
cholinergic synapses in ganglia located close to the
end-organs; postganglionic axons are short and cholinergic. Afferent conduction originates in receptors in
the viscera and conducts, along somatic and autonomic nerves to initiate local, segmental, or rostral
reflexes. The central autonomic network6 is a complex
network in the CNS integrating and regulating autonomic function.
Testing autonomic function is an important area
in clinical neurophysiology. A variety of tests measure autonomic function (Table 1).49,60 These tests
are reviewed in this report.
TESTS OF CARDIAC AND VASCULAR
AUTONOMIC REGULATION
Sympathetic and parasympathetic fibers innervate the atria, ventricles,
coronary arteries, and resistance vessels of the peripheral circulation. Sympathetic activity increases
heart rate, increases myocardial contractility, dilates
coronary vessels, and constricts resistance vessels;
parasympathetic activity does the converse except it
has little influence on peripheral vasculature. Afferent activity originates in arterial baroreceptors located in the carotid sinus, aortic arch and various
thoracic arteries, cardiac mechanoreceptors, and
pulmonary stretch receptors. Regulation is by a
negative-feedback system. Increasing activity of the
afferent pathway results in decreasing activity of the
sympathetic efferent pathway and/or increasing activity of the parasympathetic efferent pathway and
vice versa. For example, increases of blood pressure
and cardiac output increase the activity of the afferent pathway, which reflexly inhibits sympathetic activity or activates parasympathetic activity or both.
Conversely, decreases in blood pressure and cardiac
output decrease afferent activity, which reflexly allows excitatory compensatory responses.
Anatomy and Physiology.
Recording Heart Rate and Blood Pressure. Since
heart rate reflexes occur within seconds of a perturbation, beat-to-beat heart rate analysis is necessary,
and this comes from analysis of electrocardiograms
(ECGs). While an ECG is usually recorded on commercial ECG machines, it is easily recorded on standard electromyographic (EMG) equipment. ECG
signals have low-frequency content, so the filters of
the amplifiers must be low; low-frequency (high
pass) filters of 1–5 Hz and high-frequency (low pass)
filters of 500 Hz are sufficient. Slow oscilloscope
sweep rates or continuous printing is needed to rec-
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ord the 1–2 min epochs required for most tests.
Many modern electromyographs do not have continuous printers, and signals must be collected before printing. Computerized programs for signal
analysis of ECG are present in some systems. Standard limb or precordial placement of the recording
electrodes are used. Some laboratories place the active electrode over the midline posteriorly between
the points of the scapulae and the reference over the
left midaxillary line. Heart rate is inversely related to
R-R interval (interval between QRS complexes) and
is easily calculated from it; heart rate (R-R/min)
equals paper or sweep speed of the recording system
(mm/s) multiplied by a correction factor 60 (s/min)
divided by the R-R interval (mm/R-R interval). All
tests presuppose the patient is in normal sinus
rhythm. If premature beats occur, both that R-R interval and the subsequent one (which may have a compensatory pause) must be excluded from analysis.
Blood pressure is usually recorded by a standard
inflatable sphygmomanometer. The level of measurement must be maintained at the level of the
heart in all postures to avoid hydrostatic pressure
effects of the column.98 Beat-to-beat blood pressure
measurements formerly required invasive intraarterial recording, but modern photoplethysmographic
(Finipres) devices generate waveforms similar to intraarterial recordings and allow noninvasive recording.39,67,81,99 There is some dispute over the concordance of Finipres determinations with direct
intraarterial blood pressure determinations,44 but it
is reliable if sufficient attention is paid to cuff application and temperature standardization.
Cardiovascular Responses to Standing and 30:15
Ratio. Indications. Studying blood pressure changes
to standing is indicated in testing the integrity of the
sympathetic adrenergic function. Studying heart rate
changes to standing (30:15 ratio) is indicated in testing the integrity of parasympathetic cholinergic (cardiovagal) function. The tests are indicated in progressive autonomic failure syndromes, orthostatic
intolerance including syncope, postural tachycardia
syndrome, and other diseases where autonomic cardiovascular regulation may be altered.
Normal Responses. In addition to gravitational
changes from upright posture, standing induces an
exercise reflex and mechanical squeeze on both
venous capacitance and arterial resistance vessels.13,23,102 The immediate effect is squeezing capacitance vessels by postural muscles, which displaces blood toward the heart, and increases, not
decreases, venous return and cardiac output. Similarly, the postural muscles squeeze resistance vessels,
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August 1997
which increases blood pressure. These changes
stimulate the baroreceptors, and there ensues a pronounced neurally mediated reflex, which decreases
sympathetic outflow, releases vasoconstrictor tone,
decreases total peripheral resistance by up to 40%,
and drops blood pressure by up to 20 mmHg; these
changes last 6–8 s. The heart rate increases immediately upon standing and continues to rise for the
next several seconds, whereupon it slows to a maximal extent by 20 s.23 The initial cardiac acceleration
upon standing is an exercise reflex which withdraws
parasympathetic tone, and subsequent changes are
baroreflex-mediated changes which enhance sympathetic tone. Pharmacologic testing suggests most of
the heart rate changes are parasympathetic withdrawal. The subsequent steady-state is controlled not
only by autonomic reflexes but also by humoral
mechanisms, capillary-fluid-shift mechanisms, and
renal-body-fluid control mechanisms.
Protocol. Examination of postural blood pressure and heart rate is the most fundamental and
simple test of autonomic regulation. Measurements
should be obtained after the patient has been resting
and inactive, preferably for 20 min, since responses
are different after a few minutes than after 20 min of
supine rest. The blood pressure and heart rate are
recorded at baseline and then serially for 1–3 min
after postural standing. The ECG allows determination of the 30:15 ratio, which is the ratio of the longest R-R (slowest heart rate) occurring about 30 beats
after standing, divided by the shortest R-R (fastest
heart rate), which occurs about 15 beats after standing.23,24
Normal Values. Orthostatic hypotension is a reduction of systolic blood pressure of at least 20
mmHg or diastolic blood pressure of at least 10
mmHg within 3 min of standing.18 But other norms
allow greater changes: more than 30 mmHg systolic,
20 mmHg diastolic or 20 mmHg.60 Orthostatic tachycardia is a sustained increase of heart rate of more
than 25 beats per minute (bpm) or a resting tachycardia of greater than 110 bpm with further increases of greater than 20 bpm or to greater than
140 bpm. The 30:15 ratio as originally defined is
normally greater than 1.04 and abnormal if less than
1.0.23 More precise age-related norms are: 10–29
years, >1.17; 30–49 years, >1.09; 50–65 years,
>1.03.100
Clinical Comments. The advantages of the tests
are that they are simple, direct, easily accessible,
quantitative, and clinically relevant. The disadvantage is that the underlying physiology is complex and
interpretation must be cautious, results may lack reproducibility, and autonomic failure must be ad-
AAEM Minimonograph #48
vanced before abnormality is detected (poor sensitivity). The hallmark of orthostatic hypotension from
autonomic failure is the absence of compensatory
tachycardia. This indicates failure of both the cardiac and vascular reflexes. A rare syndrome called
orthostatic tachycardia is characterized by normal or
minimally decreased blood pressure but dramatic increases in heart rate upon standing; this may represent focal or multifocal autonomic failure.38,79,80
The diagnosis of either orthostatic hypotension or
tachycardia is only tenable after medical conditions
are excluded. These conditions include hypovolemia
such as dehydration, diuresis, hemorrhage, or vomiting; medications such as alpha and beta antagonists, venodilators, peripheral dopa agonists; metabolic dysfunction such as adrenal insufficiency,
hypothyroidism, and thiamin deficiency; septic
shock; and prolonged bed rest with physical deconditioning. (Baroreflex failure is an uncommon problem caused by disruption of the reflexes regulating
blood pressure. It is manifested by volatile or labile
hypertension, tachycardia, palpitations, headache,
inappropriate diaphoresis, pallor and flushing, and
resembles pheochromocytoma. The disrupted
baroreflexes are caused by such problems as previous transsection of the glossopharyngeal nerve, neck
irradiation, and resected bilateral carotid body tumors.56,73)
Indications. Studying
the responses to tilt-table testing is indicated in testing the integrity of the autonomic cardiovascular reflexes (early responses occurring in 30–60 s) and
also the integrity of neurocardiogenic reflexes (late
responses occurring in 30–60 min. The autonomic
cardiovascular reflexes (early responses) are similar
but not identical to standing; blood pressure is regulated by sympathetic adrenergic function, and heart
rate is regulated by parasympathetic cholinergic
(cardiovagal) function. The test is indicated in progressive autonomic failure syndromes, orthostatic intolerance including syncope, postural tachycardia
syndrome, and other diseases where autonomic cardiovascular regulation may be altered. Most laboratories assess autonomic cardiovascular responses either to standing or tilting on a table but not both.
The neurocardiogenic reflexes (late responses) are
the focus in cardiology laboratories, and testing
them is indicated in recurrent unexplained syncope
in able to establish a diagnosis of neurocardiogenic
syncope.1,40,74
Normal Responses. The responses to tilt-table testing differ from active standing because the exercise
reflex and the mechanical squeeze on the capaci-
Head-Up Tilt-Table Testing.
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921
tance and resistance vessels are less.32,74,102 Upon
changing from a recumbent to upright position on a
tilt-table, there is a 25–30% shift of venous blood
from the central to the peripheral compartment;
50% of the change occurs within seconds. This results in decreased cardiac filling pressures, and the
stroke volume is decreased by up to 40%. This decreases afferent activity from the sensory baroreceptors, and the heart rate rises, first from withdrawing
parasympathetic activity and then from increasing of
sympathetic activity. The sympathetic activity increases vascular tone and total peripheral vascular
resistance. Overall, the cardiac output only drops
20%, and blood pressure is largely maintained.
Blood pressure and heart rate are subsequently
maintained during prolonged periods of upright
posture.
Protocol. ECG is monitored continuously and
blood pressure either is measured serially with a standard sphygmomanometer at 1 min and every 3 min
thereafter, or measured continuously if a continuous
monitoring device is available. The test is performed
after a standard period of supine rest, since the responses are different following 1 min than 20 min of
preceding rest. In autonomic laboratories, after
baseline ECG and blood pressures are established,
the patient is positioned at an incline of 80° from the
horizontal on a tilt-table with a foot board for weight
bearing and monitored for a period of 3–5 min. In
cardiology laboratories, the patient is positioned at
an incline of 60° and monitored for about 45–60
min. Some laboratories use different degrees of tilt
and different durations. Infusion of isoproterenol, a
beta adrenergic agonist that increases ventricular
contraction and may activate depressor reflexes, has
been used in the past to increase the diagnostic yield
of the test,2 but is no longer recommended.40
Normal Values. Orthostatic hypotension is a reduction of systolic blood pressure of at least 20
mmHg or diastolic blood pressure of at least 10
mmHg within 3 min.18 In cardiology laboratories investigating unexplained syncope, a positive response
is syncope or presyncope associated with a significant
drop of blood pressure (usually greater than 30
mmHg systolic or 20 mmHg mean arterial pressure)
or bradycardia.40,74
Clinical Comments. In autonomic laboratories,
the advantages of tilt-table testing are that it is
simple, more easily standardized than standing since
less physiologically complex, and quantitative. It is
helpful in achieving upright posture in patients with
motor difficulties such as Parkinson’s disease and
multiple system atrophy. The disadvantages are that
the underlying physiology is artificial compared to
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standing, and special equipment and space are
needed. In cardiology laboratories, tilt-table testing
evaluates neurocardiogenic syncope and its treatment. Neurocardiogenic (vasovagal, vasodepressor) syncope, often known as simple faint, is characterized by
hypotension accompanied by paradoxical bradycardia. It is called neurocardiogenic to emphasize that
autonomic reflexes are present (and overactive, in
contradistinction to autonomic failure where they
are failing and there is little or no compensatory
tachycardia with hypotension) and to distinguish it
from cardiogenic syncope.1 Neurocardiogenic syncope may occur spontaneously or reflexly from
stress, fear, micturition, defecation, phlebotomy,
coughing, or sneezing. The mechanism involves the
Bezold–Jarisch reflex. This reflex originates in the
cardiac mechanoreceptors which are sensitive to
ventricular wall tension—increased wall tension such
as from a vigorous contraction gives rise to increased
afferent activity, which activates parasympathetic reflexes and withdraws sympathetic ones to cause bradycardia, vasodilation, and hypotension. Tilt-table
testing has shown neurocardiogenic syncope is the
cause of 50–75% of patients with recurrent unexplained syncope,40,74 67% of patients with recurrent
unexplained seizurelike episodes unresponsive to
anticonvulsants,32 and 71% of patients with recurrent vertigo associated with syncope or near syncope.33
Heart Rate Variation with Respiration (Sinus Arrhythmia; R-R Interval Analysis. Indications. Studying
heart rate variation with respirations is indicated in
testing the integrity of the parasympathetic cholinergic (cardiovagal) function. The test is indicated in
progressive autonomic failure syndromes, orthostatic intolerance including syncope, postural tachycardia syndrome, and other diseases where autonomic
cardiovascular regulation may be affected, including
peripheral neuropathies.
Normal Responses. The variation of heart rate
with respiration, often known as sinus arrhythmia, is
generated by autonomic reflexes. In 1973, Wheeler
and Watkins quantified it to measure autonomic innervation of the heart,100 and the test has been refined subsequently.10,11,20,22 Inspiration increases
heart rate, and expiration decreases it (see Fig. 1).
The variation is primarily mediated by the vagus innervation of the heart. Transection or freezing of the
vagus nerve in animals and parasympathetic blockade (with agents such as atropine) abolish sinus arrhythmia, while sympathetic blockade (with beta
blockers) has little effect. Pulmonary stretch receptors as well as cardiac mechanoreceptors and possi-
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August 1997
FIGURE 1. Heart rate variation (sinus arrhythmia) with six per minute deep respiration in normal subject (closed triangles) and 53-year-old
patient with multiple system atrophy (MSA) (open circles). The mean maximal to minimal heart rate variations are 20 and 4 beats per
minute, respectively.
bly baroreceptors contribute to regulating the heart
rate variation. Sinus arrhythmia is influenced by several important factors.10,11,22,53,68,101 It decreases
with age; it increases with slower respiratory rates
and reaches a maximal around 5 or 6 respirations
per minute; it decreases with hyperventilation and
hypocapnia; it decreases with increasing resting
heart rate; it also decreases in cardiac failure, pulmonary disease, and CNS depression.
Protocol. A variety of protocols for quantifying
sinus arrhythmia has been established.10,11,20,49,68
While some protocols quantify sinus arrhythmia with
the patient breathing normally or after a single deep
breath, most require deep breathing at 5 or 6
breaths per minute, a rate which maximizes variation
and allows sensitive quantification. In quantifying
heart rate variation, calculations can be performed
on the R-R intervals or on the heart rate. Multiple
numeric calculations have been performed20,22,35,65,87:
maximal-to-minimal differences, maximal-tominimal ratios, maximal-to-minimal variation expressed as a percent of the mean, means with standard deviations, mean consecutive differences, mean
circular resultants, and so on. The mean variation
over several respiratory cycles [also called the inspiratory (I) to expiratory (E) difference] and the E to
I ratio are the simplest and most commonly used
calculations.49
A simple protocol is to have the patient supine
with the head elevated to 30°. The patient breathes
deeply at six respirations per minute, allowing 5 s for
inspiration and 5 s for expiration. Care should be
taken lest the patient hyperventilate—hypocapnia
AAEM Minimonograph #48
reduces variation. The maximal and minimal heart
rates within each respiratory cycle and the mean
variation are determined. The E to I ratio or index
can be calculated as the sum of the six longest R-R
intervals of each of the six respirations divided by the
sum of the six shortest R-R intervals. Alternatively, it
may be calculated as the average of the six ratios of
the longest R-R interval and shortest R-R interval
within each of the six respirations. The E to I ratio
can be performed as a single deep respiration (5 s
inspiration and 5 s expiration).85
Normal Values. Normal values by age for 6 per
minute deep breathing expressed as average (or
mean) maximal-to-minimal variation in bpm are:
10–40 years, >18 bpm; 41–50 years, >16 bpm; 51–60
years, >12 bpm; 61–70 years, >8 bpm.49,53 Normal
values by age for single deep breaths expressed as E
to I ratio (lower 95th percentile) are: 16–20 years,
>1.23; 21–25 years, >1.20; 26–30 years, >1.18; 31–35
years, >1.16; 36–40 years, >1.14; 41–45 years, >1.12;
46–50 years, >1.11; 51–55 years, >1.09; 56–60 years,
>1.08; 61–65 years, >1.07; 66–70 years, >1.06; 71–75
years, >1.06; 76–80 years, >1.05.85
Clinical Comments. The main advantages to using heart rate variation with respiration are that it is
sensitive, reproducible, quantitative, simple, fast,
and readily obtained on most electrophysiologic
equipment; it has become one of the most utilized
autonomic function tests. The main disadvantages
are that it is influenced by numerous variables, many
different protocols exist, and several different methods of quantification exist. In patients with autonomic failure syndromes such as multiple system
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923
atrophy and progressive autonomic failure, abnormalities are detected in 80–85% of patients.17,72 In
diabetics, abnormalities are detected in up to 67% of
patients—the diagnostic yield increasing as patients
progress from asymptomatic through symptomatic
polyneuropathy to symptomatic autonomic neuropathy.9–11,54,100 Abnormalities have been reported in
39% of uremic patients,97 about 67% of patients with
peripheral neuropathy and clinical dysautonomia,82
28% of patients with distal small fiber neuropathy,88
in patients with hereditary neuropathies,12 in patients with amyotrophic lateral sclerosis,69 and in extrapyramidal and cerebellar disorders.75
Valsalva Maneuver and Valsalva Ratio. Indications.
Studying blood pressure changes during the Valsalva
maneuver is indicated in testing the integrity of sympathetic adrenergic cardiovascular function. Testing
heart rate changes during the Valsalva maneuver
(Valsalva ratio) is indicated in testing the integrity of
parasympathetic cholinergic (cardiovagal) function.
These tests are indicated in progressive autonomic
failure syndromes, orthostatic intolerance including
syncope, postural tachycardia syndrome, and other
diseases where autonomic cardiovascular regulation
may be affected, including peripheral neuropathies.
Normal Responses. The Valsalva maneuver consists of respiratory strain which increases intrathoracic and intraabdominal pressures and alters hemodynamic and cardiac functions.7,8,64 The Valsalva
maneuver is recorded by invasive monitoring of the
intraarterial blood pressure. Levin monitored the
heart rate alone without monitoring blood pressure
during the Valsalva maneuver and calculated a ratio
of the fastest heart rate to the slowest as a way of
noninvasively quantifying the procedure.46 Newer
photoplethysmographic monitoring devices are able
to record beat-to-beat blood pressures noninvasively
as well as heart rates, thus allowing easier evaluation
of the maneuver.7,76
The Valsalva maneuver has four phases (see Fig.
2A). Phase I occurs at the onset of strain—there is a
transient, few-second-long increase of the blood
pressure caused by increased intrathoracic pressure
and mechanical squeeze of the great vessels. There
are no neurally mediated changes in heart rate.
Phase II occurs with continued straining. It has two
subphases.76 In early phase II, venous return decreases, which results in decreasing stroke volume,
cardiac output, and blood pressure. In about 4 s, late
phase II, blood pressure recovers back toward baseline levels. This recovery stems from increased peripheral vascular resistance from sympathetically mediated vasoconstriction. This is blocked by alpha
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FIGURE 2. (A) Valsalva response in control subject. (B) Valsalva
response in patient with autonomic failure from primary amyloidosis; note the pronounced fall in mean arterial pressure in phase
II, absence of bradycardia, and absence of overshoot of blood
pressure in phase IV. Arrows indicate onset and cessation of the
Valsalva maneuver. Reproduced with permission from Ref. 60
(McLeod JG, Tuck RR: Disorders of the autonomic nervous system: Part 2. Investigation and treatment. Ann Neurol 1987;21:
519–529).
adrenergic blockade with phentolamine. Throughout phase II, heart rate increases steadily. The increased heart rate results initially from vagal withdrawal. This is evidenced by the fact it is abolished by
muscarinic blockade with atropine, and subsequently by increased sympathetic activity, as evidenced by the fact it is abolished by beta blockade
with propranolol. Since selective adrenergic blockade has its most specific impact on the blood pressure rise in late phase II, this is a sensitive index of
sympathetic adrenergic function. Phase III is the opposite of phase I—it occurs with release of the strain,
which results in a transient, few-second-long blood
pressure decrease caused by mechanical displacement of blood to the pulmonary vascular bed, which
had been previously under increased intrathoracic
pressure. There are no neurally mediated reflex
changes in heart rate. Phase IV occurs with further
cessation of the strain. The blood pressure slowly
increases and heart rate decreases. Since the blood
pressure rises to above and the heart rate falls to
below baseline levels, it is often called the ‘‘overshoot.’’ This generally occurs about 15–20 s after the
MUSCLE & NERVE
August 1997
strain has been released and may last for 1 min or
longer. The mechanism is increasing venous return,
increasing stroke volume, and increasing cardiac
output, which return the blood pressure and heart
rate back toward baseline. The Valsalva ratio (see Fig.
3) is the ratio of the maximal heart rate in phase II
to the minimal heart rate in phase IV. This may be
calculated easily as the ratio of the longest R-R interval during phase IV to the shortest of phase II. The
most important factors that affect the Valsalva ratio
are age, position of the patient, expiratory pressure,
duration of the strain, and medications.3,8,49 These
must be standardized in test protocols and normative values.
Protocol. A number of protocols for determining
the Valsalva ratio have been used.3,8,49 The patient is
supine or with head slightly elevated to about 30°.
Most labs have the patient strain against 40 mmHg
applied for 15 s by blowing into a mouthpiece attached to a sphygmomanometer. The system should
have a slow leak to ensure the patient strains continuously and not falsely maintain pressure by glottic
closure of the airway or tongue closure of the mouthpiece. Following cessation of the Valsalva strain, the
patient relaxes and breathes at a normal comfortable
rate. The ECG is monitored during the strain and
30–45 s following its release. The maximal heart rate
of phase II actually occurs about 1 s following cessation of the strain, and that is generally taken as the
maximal heart rate. The minimal heart rate occurs
about 15–20 s after releasing the strain. The ratio of
the maximal-to-minimal heart rate is determined as a
FIGURE 3. R-R intervals during the Valsalva maneuver. During
phase II, the period of strain, R-R intervals decrease (heart rates
increase) and during phase IV, after the strain is released, R-R
intervals increase (heart rates decrease) beyond baseline to form
the ‘‘overshoot.’’ The ‘‘Valsalva ratio’’ is the ratio of the maximal
to the minimal R-R interval.
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simple ratio. After a brief rest, the maneuver is repeated until three ratios are determined. The largest
ratio of the three is the most meaningful, since this
represents the best performance of the autonomic
function. Beat-to-beat blood pressure monitoring
with photoplethysmographic recordings adds sensitivity, since the heart rate ratios alone may be normal
but not corresponding blood pressure changes, especially in early and mild sympathetic adrenergic
failure.76
Normal Values. Some laboratories regard a Valsalva ratio of less than 1.2 as abnormal, 1.2–1.45 as
borderline, and greater than 1.45 as normal.3,46
Since the Valsalva ratio decreases with age, however,
age specific norms are more precise: 10–40 years,
>1.5; 41–50 years, >1.45; 51–60 years, >1.45; 61–70
years, >1.35.49,53 If photoplethysmographic recordings of the blood pressure are available, blood pressure drops of greater than 20 mmHg during early
phase II in conjunction with either absent phase IV
or absent late phase II are considered abnormal (see
Fig. 2B).7,8,49
Clinical Comments. The main advantages of the
Valsalva ratio are that it is sensitive, reproducible,
quantitative, simple, fast, and readily obtained on
most electrophysiologic equipment. It has become
one of the most utilized autonomic function tests.
The main disadvantage is that without photoplethysmographic recordings of beat-to-beat blood pressure, the compensatory heart rate is being recorded
instead of the true stimulus, blood pressure, and this
can lead to occasional spurious results. For example,
exaggerated drops of blood pressure during early
phase II from sympathetic adrenergic failure produce an exaggerated tachycardia, which can normalize the ratio to the otherwise abnormal bradycardia
in phase IV. Or, lack of overshoot in phase IV can
lessen the bradycardia and decrease the Valsalva ratio.7 Another disadvantage is that the test may be
difficult for debilitated patients. In patients with autonomic failure syndromes such as multiple system
atrophy and progressive autonomic failure, abnormalities are detected in over 90% of patients, but the
clinical subtypes are not distinguishable.17,72 In diabetics, abnormalities are detected in up to 67% of
patients—the diagnostic yield increasing greatly as
patients progress from asymptomatic through symptomatic polyneuropathy to symptomatic autonomic
neuropathy.9,10,68
Miscellaneous Tests. Blood Pressure Response to Sustained Handgrip. Sustained muscle contraction
causes blood pressure and heart rate to increase.
The mechanism involves the exercise reflex, which
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925
withdraws parasympathetic activity and increases
sympathetic activity. The blood pressure changes are
regulated by sympathetic adrenergic vascular function, and the heart rate changes are regulated by
parasympathetic cholinergic (cardiovagal) function.
The test requires the patient to apply and maintain
grip at 30% maximal activity for up to 5 min if possible, although 3 min may be adequate. The diastolic
blood pressure should rise more than 15 mmHg;
11–15 mmHg rise is borderline.25 The rise is relatively independent of age30 and absent in diabetic
and uremic neuropathy. There is less experience
with this test, and it has not been widely studied.
Blood Pressure Response to Mental Stress. Mental
stresses such as arithmetic, sudden noise, and emotional pressure cause sympathetic outflow to increase
and with it blood pressure and heart rate. It has been
used as a measure of sympathetic efferent function
that has the advantage of not requiring direct afferent stimulation, but the test lacks sensitivity.55
Blood Pressure Response to Cold Water Immersion
(Cold Pressor Test). This is an older test of autonomic function.36 The patient submerges a hand in
ice water, and subsequently there is a rise of blood
pressure. The afferent limb of the reflex is somatic,
and the efferent limb is sympathetic. The problems
with the test are that it is difficult for many patients
to maintain the hand in ice water for the requisite
period of time, and the test lacks sensitivity, since
many normal subjects do not have a significant rise
of blood pressure.
Skin Vasomotor Testing. Skin blood flow can be
measured by using laser Doppler velocimetry. Maneuvers which cause vasoconstriction include inspiratory gasp, standing, and Valsalva. The response
largely, but not solely, depends on postganglionic
sympathetic cutaneous adrenergic function. The
problems with skin vasomotor testing are marked
fluctuations and noisiness of the baseline and large
coefficients of variation.52
Plasma Catecholamine Levels and Infusion Tests.
Since upright posture induces vasopressor responses
which are sympathetic and adrenergic, plasma norepinephrine levels nearly double. In a preganglionic
sympathetic disorder such as multisystem atrophy,
resting supine norepinephrine levels are normal but
fail to rise when standing because of the lack of preganglionic drive. In postganglionic sympathetic disorders such as progressive autonomic failure, resting
supine norepinephrine levels are low and fail to rise
when standing.71,103 Since metabolic clearance of
norepinephrine varies, sensitivity of the test may improve using indices of norepinephrine biosynthesis.61 Various infusions such as norepinephrine, tyra-
926
AAEM Minimonograph #48
mine, isoproterenol, phenylephrine, edrophonium,
vasopressin, and angiotensin have been studied to
evaluate autonomic responses, including afferent
baroreflex sensitivity.70
Newer Techniques.77 Newer techniques attempt
to assess the cardiac parameters directly controlled
by autonomic regulation instead of indirect parameters such as blood pressure, which are assessed by
the tests currently available. Blood pressure is the
product of total peripheral resistance and cardiac
output, which in turn is the product of heart rate
and stroke volume. The standard method of measuring cardiac output is invasive, using thermodilution
techniques. Newer methods are noninvasive and include Doppler echocardiographic techniques, pulse
contour analysis, and impedance cardiography. Another line of investigation has been spectral analysis
of heart periods, using sophisticated signal analysis
methods such as Fourier transformations. Highfrequency components may be indicative of parasympathetic activity, and low-frequency components may
be mixed sympathetic and parasympathetic.28 Wide
ranges of normal values probably limit the clinical
value of spectral analysis of heart periods, and the
usefulness of these techniques in a clinical setting is
undemonstrated.47
TESTS OF THERMOREGULATORY FUNCTION
Thermoregulation is
controlled by the sympathetic nervous system, with
the parasympathetic system playing a minor role.
Sympathetic sudomotor fibers, the only sympathetic
postganglionic fibers that are cholinergic, innervate
sweat glands to regulate evaporative heat loss. Sympathetic vasomotor fibers cause vasoconstriction of cutaneous vasculature comprised of abundant arteriovenous anastamoses in the dermis, which shunts
blood flow away from the surface to reduce convective heat loss. The control of pilomotor function is
rudimentary in humans; contraction reduces surface
area, which limits convective heat loss. Afferent activity arises from thermosensitive neurons located
within the hypothalamus skin, abdominal viscera,
spinal cord, and brain stem. Thermoregulation is
controlled in the hypothalamus, where a set-point is
established by a balance between the activities of the
thermosensitive neurons. When body temperature
goes below set point, heat is generated by shivering,
and heat loss is minimized by cutaneous vasoconstriction and piloerection. When body temperature
exceeds set-point, heat is dissipated by heat loss
through sweating, cutaneous vasoconstriction, and
release of piloerection.
Anatomy and Physiology.
MUSCLE & NERVE
August 1997
Sympathetic Skin Responses (Peripheral Autonomic
Surface Potential). Indications. The sympathetic
skin response (SSR) test is indicated in assessing the
integrity of peripheral sympathetic cholinergic (sudomotor) function. It is indicated in progressive autonomic failure syndromes, diseases where thermoregulation may be affected, peripheral neuropathies
where autonomic or other small fiber involvement is
suspected, distal small fiber neuropathies, and possibly in diseases with sympathetically maintained
pain.
Normal Responses. Electrodermal activity reflects
sympathetic cholinergic sudomotor function which
induce changes in resistance of skin to electric conduction.34,37,45,93 The changes are regulated by activity in the sweat glands of the dermis and may be
generated by presecretory rather than secretory activity. Electrodermal activity is brought out either directly or reflexly; a direct response is recorded by stimulating a peripheral nerve or sympathetic trunk,
which evokes a time-locked potential. Because of the
difficulty achieving the high threshold for activation
of the unmyelinated C fibers and the unavoidable
simultaneous activation of pain fibers, direct responses are not studied in a clinical setting. A reflex is
brought out indirectly by a wide variety of stimuli
which perturb the sympathetic nervous system and
bring out the potential—they do not directly evoke
it. Many modalities of stimulation suffice to elicit the
potential reflexly: commonly, for example, electric
depolarization of a sensory nerve in the digit which
startles the subject. Other elciting stimuli include
startling auditory sound or deep inspiratory gasps.
The morphology of the potentials are mono-, bi-, or
triphasic and are variable from stimulus to stimulus
(see Fig. 4). Potentials are symmetric in homologous
body regions. The potentials in the hands have
larger amplitudes and shorter latencies than those in
the feet. The latency is about 1.5 in the hand and
about 2 s in the foot following an eliciting stimulation. The major contributor to latency is the efferent
conduction along the sudomotor pathways, which
are small unmyelinated C fibers. Since conduction
along these fibers is all or none, latencies are not
generally meaningful. Amplitudes are difficult to define because of the variable morphology of the potential, but an increasing number of studies indicate
usefulness of this parameter.
Protocol. The SSR can be easily recorded on
most standard EMG equipment. The potential has
low-frequency content and the amplifiers of the recording equipment, especially the low-frequency
(high pass) filter, must be set as low as possible, such
as 0.1 or 0.5 Hz. Increasing the low-frequency (high
AAEM Minimonograph #48
FIGURE 4. The sympathetic skin response from hands (channels
1 and 2) and feet (channels 3 and 4). The potentials have larger
amplitudes and shorter latencies in hands than feet and are symmetrical in homologous regions.
pass) filter from 0.1 Hz to 1.0 Hz may begin to filter
and thereby attenuate the potential. Some equipment can record direct current, which is best except
for drift of the baseline. A high-frequency (low pass)
filter of 500 or 1000 Hz is sufficient. The gain should
be set to record a potential which is 500 µV to 3 mV
peak-to-peak amplitude, and the sweep is set to record 5 s after the stimulus. Recordings are obtained
simultaneously from the hands and feet. The active
electrodes are placed in the palm or sole and the
reference over the dorsum of the respective body
part. All skin surfaces are cleaned but not abraded.
Temperatures are standardized to over 30°C, preferably over 32°C. Standard disk electrodes are employed, although silver/silver chloride electrodes are
better. Electrolyte gels (not pastes) are used. As
noted, many modalities of stimulation suffice, but
commonly electric depolarization of a sensory nerve
in the digit (either contralateral or ipsilateral to the
recording site) is used. Two common pitfalls lead to
an erroneous conclusion that the potentials are absent: inadequate stimulation and habituation. Both can
be guarded against by having the stimuli intense
(slightly noxious such as to cause startle or blinking),
irregular, and infrequent. Patients can be asked to
MUSCLE & NERVE
August 1997
927
indicate when the stimuli are strong but tolerable.
The stimuli are delivered randomly, looking for a
blink or slight withdrawal to indicate a startle showing the stimulus is sufficiently strong. Several diligent attempts should be made to record the potential before deciding it is absent. Other eliciting
stimuli include startling sound or deep inspiratory
gasps. The best potentials are chosen for measurement, since they represent the ‘‘best’’ sudomotor
response. Averaging should not be performed, since
the latency and morphology vary from one recording to the next and this may cause phase cancellation.
Normal Values. The SSR is age dependent. It is
normally present in both hands and both feet in
subjects under the age of 60 years, but only 50% of
feet and 73% of hands in subjects older than 60
years.19 As discussed above, the SSR is controlled by
conduction along unmyelinated fibers, and latency
measurement is not useful. Initially regarded as an
all-or-none phenomenon, now as techniques are refined, amplitude criteria are defined. According to
Hoeldtke,37 latency in hands is 1.6 ± 0.1 s, amplitude
in hands is 1.3 ± 0.2 mV, latency in feet is 2.1 ± 0.1 s,
and amplitude in feet is 0.8 ± 0.1 mV. According to
Knezevic,45 latency in hands is 1.5 ± 0.1 s, amplitude
in hands is 0.5 ± 0.1 mV, latency in feet is 2.1 ± 0.2 s,
and amplitude in feet 0.1 ± 0.04 mV. According to
Drory,19 mean latency in hands is 1.5 s, mean amplitude in hands is 0.450 mV, mean latency in feet is 1.9
s, and mean amplitude in feet is 0.15 mV.
Clinical Comments. The main advantages of the
SSR are that it is sensitive, reproducible, semiquantitative, simple, fast, and readily obtained on most
electrophysiologic equipment. The main disadvantages are that it is only semiquantitative, may be difficult to elicit or be habituated and thereby be mistaken as abnormal, and it involves neural pathways
beyond the postganglionic sudomotor ones. In patients with autonomic failure syndromes such as multiple system atrophy and progressive autonomic failure, abnormalities are detected in 88% of patients,
but there is no usefulness in distinguishing between
the clinical subtypes.72 In diabetics, abnormalities
are detected in up to 66–83% of patients—the diagnostic yield increasing as patients progress from
asymptomatic through symptomatic polyneuropathy
to symptomatic autonomic neuropathy.63,86 Abnormalities have been reported in 67% of uremic patients,97 50% of patients with peripheral neuropathy,
85% of patients with neuropathy and clinical dysautonomia,82,83 58% of alcoholic neuropathies,94 and
10% of patients with distal small fiber neuropathy.21
The SSR is comparable in its sensitivity to the quan-
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AAEM Minimonograph #48
titative sudomotor axon reflex test (QSART) (discussed below) for the detection of autonomic dysfunction, and there is concordance. 57 In tests
comparing the SSR with tests of cardiovascular reflexes, they were nearly comparable, with the cardiovascular reflexes being slightly more sensitive than
SSR to dysfunction.57 Not all investigators, however,
advocate the value of this test in assessing sudomotor
function.78
Quantitative Sudomotor Axon Reflex Test. Indications. The QSART is indicated in assessing the integrity of peripheral sympathetic cholinergic (sudomotor) function. It is indicated in progressive
autonomic failure syndromes, other diseases where
thermoregulation may be affected, peripheral neuropathies where autonomic or other small fiber involvement is suspected, distal small fiber neuropathies, and in sympathetically maintained pain states.
Normal Responses. Sweat gland function can be
assessed by direct activation from intradermal injection of methacholine, which activates muscarinic receptors; sweat output is measured by weighing filter
paper.4 Alternatively, sweat gland function can be
assessed by indirect activation from axon reflexes.
Axon reflexes are generated when acetylcholine activates nicotinic receptors in the sudomotor fiber terminal, sending impulses antidromically to branch
points and then orthodromically back to remote
neurosecretory synapses. In this way, the sudomotor
axon is stimulated chemically, not electrically, by
acetylcholine iontophoresis. The QSART quantifies
postganglionic sympathetic sudomotor function by
measuring dynamic sweat output in response to activation from axon reflexes. Several regions of the
body may be sampled to obtain topography.49,51
Protocol. QSART requires a multicompartmental
sweat capsule and a sudorometer (see Fig. 5). The different compartments of the sweat capsule allow for
both stimulation and pickup of the sweating response. Stimulation requires a constant current generator which applies a current over one of the compartments to iontophorese acetylcholine onto the
skin. The acetylcholine is iontophoresed at 2 mA for
5 min. Since this also stimulates sweat glands directly, the site of evaluation of the subsequent sweating responses is remote from the site of stimulation
in a different compartment. Measurement requires a
sudorometer, which measures humidity. Low-humidity
nitrogen gas is piped through the sudorometer to
measure baseline or input humidity. The gas passes
into the sweat compartment of the sweat capsule
through an intake port and then exits the compartment through a different port. The gas passing over
MUSCLE & NERVE
August 1997
Table 1. Tests of autonomic function.*
Test
Stimulus
Afferent
Efferent
Orthostatic BP
Upright posture
Baroreceptors &
CN IX & X
Sympathetic
(adrenergic)
Orthostatic HR
& 30:15 ratio
Upright posture
Baroreceptors &
CN IX & X
Heart rate
variation with
respiration
Respiration
CN X
Parasympathetic
(cardiovagal)
(cholinergic)
Parasympathetic
(cardiovagal)
(cholinergic)
Valsalva ratio
Strain
Baroreceptors &
CN IX & X
Valsalva
maneuver
Strain
Baroreceptors &
CN IX & X
BP to sustained
handgrip
Isometric
exercise
Muscle afferents
BP to mental
stress
Cold pressor
test
Arithmetic
None
Hand immersed
in cold
Skin vasomotor
testing
Various
Pain &
temperature
pathways
Various
Normal
response
Sensitivity†
Ease†
2, 3
4
Clinically
relevant
2, 3
4
Clinically
relevant
4
4
Single best
cardiovagal
test
3
4
3
3
Second best
cardiovagal
test
Needs special
equipment to
monitor beat
to beat BP
Sympathetic
(adrenergic)
Vasoconstriction,
BP
maintained
HR increases
initially, then
decreases
HR increases
with
inspiration,
decreases
with expiration
HR increases
initially, then
decreases
BP increases
phases I, IIL,
& IV; BP
decreases
phases IIB &
III
Vasoconstriction,
BP increases
2
3
Sympathetic
(adrenergic)
Sympathetic
(adrenergic)
Vasoconstriction,
BP increases
Vasoconstriction,
BP increases
2
2
2
2
Sympathetic
(adrenergic)
Cutaneous
vasoconstruction
2
2
Vasoconstriction,
levels
increase
Skin potential
2
3
3
3
Parasympathetic
(cardiovagal)
(cholinergic)
Sympathetic
(adrenergic)
Plasma
Supine &
catecholamines Standing
Baroreceptors &
CN IX & X
Sympathetic
(adrenergic)
Skin
sympathetic
response
Usually electric
stimulation
Somatosensory
& others
Sympathetic
(cholinergic)
QSART
Axon (by ACh
iontophoresis)
Sudomotor axon
(antidromic)
Sympathetic
(cholinergic)
Local sweating
3
2, 3
Thermoregulatory Rise in core
sweat test
body
temperature
Various
Sympathetic
(cholinergic)
Diffuse sweating
3
2
Sweat imprints
Sweat gland (by
ACh
iontophoresis)
None
Sympathetic
(cholinergic)
Sweat droplets
3
2
Pupil edge light
cycle
Light to edge of
pupil
CN II
Parasympathetic
(cholinergic)
Cycles of
dilation &
constiction
2, 3
2
Comments
Not well
validated;
uncomfortable
Not well
validated
Not well
validated;
uncomfortable
Marked
variability; not
recommended
Insensitive
Uses standard
neurophysiologic
equipment
Needs special
equipment
(sudorometer)
Needs special
equipment
(sweat box);
messy;
cumbersome
Needs special
equipment;
stimulates
sweat glands
directly
Needs special
equipment;
not well
validated
BP, blood pressure; CN, cranial nerves; QSART, quantitative sudomotor axon reflex test, HR, heart rate.
*Modified from Ref. 49.
†Arbitrary scale of 1–4: 1 is lowest or worst and 4 is highest or best.
AAEM Minimonograph #48
MUSCLE & NERVE
August 1997
929
FIGURE 5. The sudorometer and attachments used in quantitative sudomotor axon reflex testing (QSART). Reproduced with permission
from Ref. 49 (Low PA: Laboratory evaluation of autonomic failure, in Low PA (ed): Clinical Autonomic Disorders: Evaluation and
Management. Boston, Little, Brown & Co, 1993, pp 169–197).
the skin is humidified by the sweat. It passes back to
the sudorometer where the humidity is remeasured.
The differences between the output and input humidities are recorded and quantified as a function of
time. Recording continues for 5 min after cessation
of the iontophoresis. The sweating promptly occurs
about 1 to 2 min after the stimulation and generally
returns to baseline about 5 min after the stimulation
has ceased. The multicompartmental sweat cells are
placed over four locations: the foot laterally in the
distribution of the sural nerve, the distal leg proximal to the medial malleolus in the distribution of the
saphenous nerve, the proximal leg just distal to the
fibular head in the distribution of the peroneal
nerve, and in the forearm medially in the distribution of the medial antebranchial nerve. The patient
needs to be supine, comfortable, and warm.
Normal Values. Males have similar latencies to
females but larger sweat outputs. Age in general reduces the sweat output but it is variable by sex and
site.53 In general, the onset of the sweating response
is between 1 and 2 min, depending on site. For
males, the median sweat output is about 2–3 µL/cm2
(approximate range 0.7–5.4 µL/cm2) depending on
site of stimulation. For females, the median sweat
output is 0.25–1.2 µL/cm2 (approximate range
0.2–3.0 µL/cm2) depending on site. The morphology of the sweat output is also important: in addition
to being reduced or absent, sweat output may be
abnormally persistent or excessive, often with associated short latencies; these abnormalities may be seen
in painful neuropathies such as diabetes, mild or
early neuropathies, and florid reflex sympathetic dys-
930
AAEM Minimonograph #48
trophy, and reflect the altered axonal excitability of
these conditions.49,51
Clinical Comments. The main advantages of the
QSART are that it is sensitive, reproducible, accurate, quantitative, involves directly the postganglionic neurosecretory unit, allows delineation of
proximal-to-distal topography, and provides a dynamic record of sudomotor function over time. The
main disadvantages are that it is time-consuming, requires special equipment, and is not widely available.
In patients with autonomic failure syndromes such as
multiple system atrophy and progressive autonomic
failure, abnormalities are detected in 67% of patients, but there is no utility in distinguishing between the clinical subtypes.17 In diabetics, abnormalities are detected in up to 58% of patients—the
diagnostic is comparable to tests of vagal function,
and both tests together are more sensitive to the
detection of autonomic neuropathy than either one
alone.54 Abnormalities have been reported in 83%
of patients with peripheral neuropathy, with the legs
and distal limbs showing more abnormality than the
arms and proximal limbs,51,57 80% of patients with
distal small fiber neuropathy,88 and in myasthenic syndrome.58 The test has been useful in defining a high
incidence of autonomic abnormalities in extrapyramidal and cerebellar disorders.75 The concordance of
QSART testing and SSR testing has been discussed
above.57,78 The QSART and a related test measuring
resting sweat output together may be useful in diagnosing reflex sympathetic dystrophy and predicting
which patients will respond to sympathetic block,16
although the interpretation has been questioned.66
MUSCLE & NERVE
August 1997
Indications. Thermoregulatory sweat test (TST) is indicated in assessing the integrity of sympathetic cholinergic (sudomotor) function. It is indicated in progressive
autonomic failure syndromes, other diseases where
thermoregulation may be affected, peripheral neuropathies where autonomic or other small fiber involvement is suspected, distal small fiber neuropathies, and possibly in sympathetically maintained
pain states.
Normal Responses. The TST evaluates the overall
autonomic regulation of body temperature, specifically cooling, by providing a physiologic stimulus,
heat, and recording the body’s ability to dissipate it
by sweating.26,27 Thus, it assesses central preganglionic as well as peripheral postganglionic function. It
requires a heat environment where the patient is
warmed and an indicator to observe and record the
sweating response. The overall topography of sudomotor function is recorded.
Protocol. The patient is placed in a controlled
heat environment of about 45–50°C and relative humidity of 45–50%. In general, the core body temperature is warmed to 38°C, or 1.4°C above baseline.
Since core body and surface temperatures are not
always concordant, infrared heaters warm skin surface temperature to 39–40°C. The patient has an
indicator powder such as alizarin red mixed with
corn starch and sodium carbonate applied to the
body. Other indicators that can be used include iodinated cornstarch or iodine solution, which is
painted on the body. An older indicator called
quinizarin is no longer available in the United States
because of skin irritations. These indicators change
color when wet to indicate areas of sweating. Alizarin
red, for example, is light orange when dry and
changes to purple when wet. As the body is warmed,
the resulting sweating is recording. After 35–45 min
the sweating response is maximal. The patient’s
sweating pattern is recorded and the pattern and
percent of surface body area sweating are noted.26,27
Normal Results. Normally, sweating is generalized, symmetrical, and with variable involvement of
the proximal limbs and legs. Abnormal patterns include distal anhydrosis, segmental or regional anhydrosis, focal anhydrosis (such as in a peripheral
nerve or dermatomal pattern), or global anhydrosis.
Clinical Comments. The main advantages of the
TST are that it is sensitive and physiological, assesses
overall thermoregulatory function centrally and peripherally, and directly maps the topography of sudomotor function. The main disadvantages are that
it is time-consuming, requires special equipment, is
messy and only semiquantitative, may be hard on the
Thermoregulatory Sweat Test.
AAEM Minimonograph #48
patient, and can cause skin irritation. When used in
conjunction with the QSART, it may be possible to
separate preganglionic from postganglionic lesions.
If both the QSART and TST are abnormal, the lesion
is more likely than not postganglionic. If the TST is
abnormal but the QSART is not, the lesion is likely to
be preganglionic. In patients with autonomic failure
syndromes such as multisystem atrophy and progressive autonomic failure, abnormalities are detected in
most patients, but there is no utility in distinguishing
clinical subtypes.17 Abnormalities have been reported in 72% of patients with distal small fiber neuropathy.88 The test has been useful in defining a
high incidence of autonomic abnormalities in extrapyramidal and cerebellar disorders.75
Sweat Imprint Tests. Indications. Sweat imprint
tests are indicated in assessing the integrity of sympathetic cholinergic (sudomotor) function. They are
indicated in progressive autonomic failure syndromes, other diseases where thermoregulation may
be affected, and peripheral neuropathies where autonomic or other small fiber involvement are suspected.
Normal Responses. Sweat imprint methods measure the sweat output at a fixed time after a stimulus
by visualizing and quantifying sweat droplets secreted by sweat glands. The sweat glands may be
directly stimulated by a cholinergic agonist or else
stimulated by way of the axon reflexes similar to the
QSART. Since sudomotor innervation is necessary
for sweat gland function (they do not follow Cannon’s law of denervation hypersensitivity), absent or
subnormal responses imply denervation whether or
not the stimulation is achieved by axon reflexes or
directly.41,43
Protocol. A variety of methods of sweat imprint
tests are summarized in the review by Kennedy.41
The stimulation to sweat gland secretion may be
physiologic, such as by heat or exercise, or direct,
such as by cholinergic agents. The latter are the most
controllable and can be applied by either intradermal injection or iontophoresis. The cholinergic
agents include acetylcholine, pilocarpine, or methacholine. Kennedy’s protocol involves iontophoresis
of pilocarpine onto 1 cm2 of skin by applying 2 mA
direct current for 5 min. Once stimulated, sweat output is visualized by a variety of techniques. Indicator
dyes can be applied to the skin such as the starch
powders or iodine solutions used in the thermoregulatory sweat tests. Hard copies are made by bond
paper, paper towel absorption, or photographic
techniques. An alternative to indicator dyes is plastic
and silicone imprints. The plastic or silicone is ap-
MUSCLE & NERVE
August 1997
931
plied as a thin film and removed when hardened;
sweat droplets are recorded as holes or imprints in
the material and then can be quantified by various
counting methods. Each droplet corresponds to the
duct of one sweat gland. Kennedy’s protocol calls for
Silastic material to be spread over the region 5 and
20 min after pilocarpine iontophoresis and allowed
to harden, usually within 3 min. The volume of sweat
is estimated by measuring the number of droplets
and their area. The Silastic mold is transilluminated
under a dissecting microscope and the sweat droplets are measured. The mold may be photographed
and the droplets digitized on a digitizer pad. Recently, the analysis has been automated using a system with a video camera, which projects the mold
onto a screen where a software program performs
the operations.42 Typically, two sites are evaluated,
the dorsum of the hand and foot. In a recent study
by Stewart comparing direct sweat gland stimulation
with axon reflex stimulation,89 direct stimulation was
slighly more sensitive to the detection of abnormality
(55% abnormal with a 95% specificity) than axon
reflex stimulation (50% abnormal).
Normal Values. In the hand, there are 311 ± 38
sweat glands per cm2, the lower limit of normal being 255; the sweat droplet size is 25 ± 6 units (arbitrary), the lower limit of normal being 19. In the
foot, there are 281 ± 38 sweat glands per cm2, the
lower limit of normal being 235; the sweat droplet
size is 28 ± 7 units (arbitrary), the lower limit of
normal being 19.41
Clinical Comments. The main advantages of the
sweat imprinting techniques are that they are sensitive, reproducible, accurate, and quantitative. The
main disadvantages are that they are timeconsuming and require special equipment. Unlike
the QSART, which evaluates the dynamic sweat output over time, the various imprint tests evaluate the
sweat output at a fixed time after stimulation. Unlike
the QSART, which requires direct stimulation of the
sudomotor axon in the evaluation, the various imprint methods require direct sweat gland stimulation
and presume abnormal function reflects denervation. In diabetics, 24–36% had abnormally low sweat
function in the hand and 56–60% had abnormalities
in the foot. The abnormalities correlated with other
tests of small fiber function, such as thermal sensation, but not with tests of large fiber function, such as
vibratory sensation and nerve conduction studies.41,89 These findings are similar to those obtained
with SSR and QSART.
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AAEM Minimonograph #48
MISCELLANEOUS TESTS OF
AUTONOMIC REGULATION
Tests of Exocrine and Pupillary Regulation. Anatomy and Physiology. Sympathetic and parasympathetic fibers innervate the pupils, the ciliary muscles,
Mueller’s muscle in the eyelid, and the exocrine
glands controlling lacrimation and salivation.
Sympathetic activity causes pupil dilation and contraction of Mueller’s muscle in the upper lid. Parasympathetic activity causes pupil constriction,
accommodation, lacrimation, and salivation. The afferent pathway for the pupil is the optic nerve, and
central integration is in the dorsal midbrain and
Edinger–Westphal nucleus. The afferent pathway for
exocrine function is primarily along the trigeminal
nerve and central integration is in the brain stem
and central autonomic network.
Indications. Studying pupillary function is indicated in evaluating parasympathetic cholinergic and
sympathetic adrenergic function. It may be useful in
establishing and localizing the site of abnormality of
Horner’s syndrome, Adie’s syndrome, anisocoria,
and syndromes of light-near dissociation. Lacrimation and salivation testing may be useful in objectifying abnormality in patients with complaints of dry
eyes and dry mouth. These problems may occur either in isolation or as part of more generalized autonomic failure.
Normal Responses and Protocols. Evaluating pupil
function is often done by pharmacological testing.
Pupil constriction and accommodation are tested
with parasympathomimetic agents. Pilocarpine and
methacholine are parasympathomimetic agents
which act directly on cholinergic parasympathetic
constrictor muscles to cause pupillary constriction.
In dilute amounts (pilocarpine 0.125% or methacholine 2.5% solution), they cause minimal constriction, but when there is parasympathetic denervation,
there is denervation hypersensitivity, and the pupil
constricts. A dilated pupil that does not constrict to
pilocarpine 1.0% is pharmacologically dilated. Pupil
dilation is tested with either parasympatholytic
agents (which also block accommodation) or sympathomimetics. For example, epinephrine acts directly
on sympathetic adrenergic dilatory muscles to cause
pupillary dilation. In dilute amounts (0.1% solution), it normally causes minimal dilation, but when
there is sympathetic denervation, there is denervation hypersensitivity, and the pupil dilates. Cocaine
(4–5% solution) blocks reuptake of norepinephrine
in sympathetic nerve terminals innervating pupillary
dilator muscles, and it causes pupillary dilation. In
sympathetic denervation, norepinephrine is not pre-
MUSCLE & NERVE
August 1997
sent, and dilation does not occur when cocaine is
applied. Hydroxyamphetamine is a sympathomimetic agent that releases norepinephrine; if the pupil
fails to dilate when it is applied, the site of sympathetic denervation is postganglionic. Nonpharmacological tests of pupil function are not widely available, because special equipment is required and
standardization is difficult. The edge-light pupil
cycle time is a method of assessing parasympathetic
innervation of the pupil.62 Light focused on the
edge of the pupil stimulates the retina, which results
in pupillary constriction. When the pupil constricts,
the light is blocked and the stimulation to constrict
is less strong and the pupil dilates. This oscillation or
cycle mostly depends on the parasympathetic efferent limb of the pupillary light reflex. The cycle time
can be quantitated and is a sensitive measure of the
parasympathetic function.
Lacrimation can be measured with the Schirmer’s test and tear osmolarity.5 In the Schirmer’s test,
the wick end of a filter paper test strip is placed
between the lower lid and the sclera. The length of
wetting at 5 min is then measured. The sensitivity in
detecting dry eyes is about 90%, and the specificity is
about 85%. In measuring tear osmolarity, the sensitivity in detecting dry eyes is 76%, and the specificity
is 84%.
Salivation may be tested by having patients chew
a series of five gauze pads for 1 min each for a total
of 5 min after the sublingual gutter is wiped dry.
Pretest weight is subtracted from posttest weight to
calculate saliva production, normally greater than
7.5 mL/5 min.
Clinical Comments. These tests are important in
evaluating specific problems such as anisocoria or
dry eyes, but they have more limited usefulness in
generalized autonomic failure syndromes.
Tests of Gastrointestinal Autonomic Regulation.
Anatomy and Physiology. The autonomic regulation
of GI function is exerted on the local integrative
system called the enteric nervous system, which consists
of networks of nerves and plexuses embedded in the
wall of the GI tract and integrated into local circuits
for different operations such as contractile activity
(peristalsis), absorption, secretion, and sphincter coordination.31 The sympathetic innervation causes
contraction of the esophageal sphincters, slowing
motility and contraction of the internal rectal
sphincter. The parasympathetic innervation stimulates motility and relaxes the internal rectal sphincter. The external sphincters are innervated by the
pudendal nerve and are under somatic, not auto-
AAEM Minimonograph #48
nomic, control. The afferent pathways synapse locally or in the ganglia, spinal cord, and more rostral
portions of the autonomic nervous system. Central
integration occurs in spinal centers and the central
autonomic network, especially the nucleus of the
tractus solitarius and the nucleus ambiguous.
Indications. Testing GI function may be indicated in patients with dysphagia, gastroparesis,
chronic intestinal pseudo-obstruction, constipation,
and fecal incontinence, especially if there is evidence
of other autonomic dysfunction.
Normal Responses and Protocols. Videofluoroscopy
and pharyngoesophageal motility studies help identify causes of dysphagia. GI motility, including gastric
emptying times and colonic transit times, allows for
identification of neurogenic disorders, but does not
distinguish extrinsic autonomic disorders from intrinsic enteric nervous system disorders. Manometer
or solid-state pressure transducers placed in different portions of the GI tract help localize sites of
stasis. Sympathetic denervation may be identified by
various neurochemical studies including the norepinephrine and epinephrine responses to edrophonium,29 which rise promptly after intravenous administration when there is normal postganglionic
innervation. Parasympathetic denervation may be
identified by the plasma pancreatic polypeptide response to sham feeding or hypoglycemia.14 Anorectal manometry helps identify causes of incontinence.
Motor latencies of the pudendal nerve and electromyography of the anal sphincter are also helpful, but
these assess somatic, not autonomic function.
Clinical Comments. In practice, it is difficult to
distinguish autonomic regulation of GI function
from nonautonomic regulation. In order to make
this distinction, other parts of the autonomic system
need to be tested as described above.15 Tests such as
the heart rate variation with respiration and the Valsalva ratio are easy, reliable, and readily accessible
tests of vagus parasympathetic cardiac regulation
and are sensitive to vagus parasympathetic GI regulation as well. In multiple system atrophy, the rectal
sphincter is frequently denervated from degeneration of Onuf’s nucleus in the sacral spinal cord, 9
and EMG of the rectal sphincter may be abnormal.72
However, this represents somatic, not autonomic,
dysfunction.
Tests of Genitourinary Autonomic Regulation.
Anatomy and Physiology. Sympathetic innervation of
the GU system causes uterine contraction, ejaculation in males, bladder wall inhibition, detrusor and
trigone muscle contraction, and urethral smooth
MUSCLE & NERVE
August 1997
933
muscle contraction. Parasympathetic innervation
causes genital vasodilation, erection in males, bladder wall contraction, detrusor and trigone muscle
relaxation, and internal sphincter relaxation. The
external sphincters are innervated by the pudendal
nerve and are under somatic, not autonomic, control. The GU system’s afferent activity is transmitted
by autonomic and somatic pathways. Central integration occurs in spinal centers and the central autonomic network.
Indications. Testing GU function may be indicated in patients with urinary dysfunction, such as
incontinence and sexual dysfunction, especially if
there is evidence of other autonomic dysfunction.
Normal Responses and Protocols. Urodynamic
studies in incontinent patients assess overall bladder
function—autonomic regulation is a component.
Tests of male erectile function, such as nocturnal
tumescence studies and penile rigidity studies, assess
erectile function, which is largely controlled by vascular and autonomic function. If abnormal, injection of vasoactive agents such as papaverine into the
corpus cavernosum helps differentiate vascular from
nonvascular dysfunction—a poor response to injection means the cause is vascular. A method of electrophysiologic study of the smooth muscle of the
corpus cavernosum by insertion of a concentric
needle electrode through the skin and tunica albuginea has been introduced.95 Spike potentials are
present when the penis is flaccid and attenuate when
it becomes erect, perhaps due to cessation of smooth
muscle activity, which maintains flaccidity by preventing vascular inflow. A variation of this technique
has been described.90 The clinical utility of these
tests is unclear. The bulbocavernosus reflex, an oligosynaptic and polysynaptic reflex contraction of the
bulbocavernosus muscles elicited by stimulation of
sensory nerve such as the dorsal nerve of the penis,
involves somatic, not autonomic, pathways. It has low
sensitivity and specificity in male impotence.92 Similarly, sensory conduction in the dorsal nerve of the
penis, pudendal sensory evoked potentials, motor latencies of the pudendal nerve, and routine and
single-fiber EMG of the sphincters assess somatic,
not autonomic function.
Clinical Comments. The evaluation of GU function is complex and beyond the scope of the current
discussion. Most of the available tests do not isolate
and assess autonomic as opposed to nonautonomic
function. Therefore, in patients with GU dysfunction
which may be caused by autonomic failure, the clinician often looks for evidence of non-GU autonomic failure and depends on the other tests of autonomic function.
934
AAEM Minimonograph #48
APPROACH TO THE PATIENT
Clinical evaluation and understanding are paramount in the evaluation of autonomic dysfunction—
the tests of autonomic function extend, not replace,
this evaluation.50 Autonomic function tests are indirect, relatively imprecise, and fraught with difficulties: autonomic structures such as small unmyelinated nerve fibers which control many autonomic
functions are inaccessible for direct neurophysiologic recording except by microneurographic techniques which are carried out only in specialized laboratories 96 ; numerous technical and physiologic
variables must be controlled; autonomic regulation
is slow, intricate, and complex; and the visceral
physiological systems being regulated are themselves
intricate and complex.50
The purposes of objective testing are to detect
and verify suspected autonomic dysfunction; quantify severity and extent of autonomic dysfunction for
staging, monitoring, and treating; localize the abnormality to the central or peripheral levels; determine
whether the sympathetic or parasympathetic or both
systems are involved; and determine which physiologic organ systems such as parasympathetic cardiac (cardiovagal), sympathetic cardiovascular (adrenergic), sympathetic sudomotor (cholinergic), or
other systems are involved.
Most laboratories perform a battery of tests to
enhance reliability and probe various autonomic
functions. A typical screening battery includes heart
rate variation with breathing, Valsalva ratio and Valsalva maneuver analysis, orthostatic testing, and at
least one of the available tests of thermoregulatory
function. The analysis of heart rate variation with
breathing is considered the best test of cardiovagal
function, but duplicate testing with the Valsalva ratio
is useful because of overlapping sensitivities. Testing
GI, GU, and pupillary function are difficult for most
neurophysiologists to do alone, and if performed at
all are often done in collaboration with respective
subspecialists. Medications with anticholinergic
properties (such as antidepressants, antihistamines,
and certain over-the-counter medications), with adrenergic antagonist action (such as beta blockers),
with sympathomimetic properties, with parasympathomimetic properties, and with fluid-altering
properties (such as diuretics or fludrocortisone)
should be stopped—consultation with the patient’s
primary physician may be necessary. Prior to testing,
patients should abstain from alcohol, caffeine, and
nicotine for at least 3 h and preferably for 12 h.
Patients should be rested and relaxed. Compressive
dressings such as elastic stockings should be removed. Testing patients with significant medical dis-
MUSCLE & NERVE
August 1997
eases such as cardiac failure, atrial fibrillation,
chronic obstructive lung disease, and Sicca syndrome is not reliable, since the end-organ of autonomic regulation is itself dysfunctional.
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