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Autonomic Nervous System
Testing
A
utonomic nervous system testing
is used to document diabetic autonomic failure. Diabetic autonomic failure is defined as impaired
function of the peripheral autonomic
nervous system and can be divided into
two categories: 1) autonomic neuropathy, in which there is a structural lesion
of the peripheral autonomic neuron and
2) functional autonomic failure, in which
no known structural lesion occurs. In
addition to the classic neurotransmitters
(acetylcholine and norepinephrine),
newer neurotransmitters and neuromodulators such as substance P, neuropeptide K, calcitonin gene-related peptide,
and nitric oxide are also involved. Also,
the adrenal medullae are an integral part
of the autonomic nervous system. With
these caveats, the following definition is
proposed, wherein autonomic abnormalities are classified as structural or functional with further subdivisions based on
the overt or subclinical nature of the disorder, the specific subdivisions of the
autonomic nervous system, and the specific organ systems involved.
AUTONOMIC NEUROPATHY IN
DIABETES — In the setting of diabetes
mellitus without other causes of autonomic neuropathy there is a structural
lesion that comprises a diffuse disorder
of small nerve fibers of the cholinergic,
adrenergic, and peptidergic nervous systems. This may be further divided into:
1) subclinical—that which is diagnosed
only by tests and 2) clinical—that which
presents with symptoms or signs.
FUNCTIONAL AUTONOMIC
FAILURE IN DIABETES— Reduced
autonomic responses not attributable to
classic diabetic autonomic neuropathy
also occur and cause clinically important
problems. An example is hypoglycemiaassociated autonomic failure (HAAF;
1,2). HAAF is a recently described functional disorder without a known structural lesion characterized by selectively
reduced adrenomedullary (epinephrine)
and parasympathetic (pancreatic polypeptide) responses to a given degree of
hypoglycemia. It is associated with the
interrelated clinical syndromes of defective glucose counterregulation, hypoglycemia unawareness, and elevated glycemic thresholds for symptoms of and
autonomic responses to hypoglycemia
during effective intensive therapy, and
with a high frequency of iatrogenic hypoglycemia. A further example of functional autonomic failure is the impairment of gastric emptying with severe
hyperglycemia (3).
TESTS OF AUTONOMIC
FUNCTION — The autonomic nervous
system is usually tested by evaluating
reflex arcs. A reflex arc involves a stimulus, a receptor, an afferent nerve, central
processing, an efferent nerve and an endorgan response. In addition to the reflex
arc, there are several synapses involved
throughout the pathway and different
neurotransmitters at each synaptic cleft.
It is important that, where possible, the
confounding variables, standardization
of stimulus, and normal end-organ func-
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO DR. RICHARD KAHN, AMERICAN DIABETES ASSOCIATION, 1660
DUKE STREET, ALEXANDRIA, VA
22314.
THIS MATERIAL IS BEING PUBLISHED SIMULTANEOUSLY IN NEUROLOGY AND MUSCLE AND NERVE.
DIABETES CARE, VOLUME 15, SUPPLEMENT 3 , AUGUST
1992
tion be established before one elicits the
reflex arc to test the autonomic nervous
system.
Many organs are dually innervated. Innervation of parasympathetic
and sympathetic pathways often work as
a check and balance system. Therefore,
where possible, the autonomic nervous
system needs to be evaluated recognizing
that the result may reflect a decrease in
one pathway or an increase in another.
An ideal test should be simple,
noninvasive, easy for the operator and
subjects, reproducible, sensitive, relevant
to known physiological functions, suitable for longitudinal evaluation, and specific. The confounding variables affecting
the test should be fairly well delineated.
Some of the current autonomic tests fulfill nearly all of these obligations.
Standardization of testing
To reduce great variability in assessing
the autonomic nervous system, it is important to standardize the test where
possible. It is known that eating, drinking coffee, smoking, volume status, upright posture, medicines, and exercise
may affect the cardiovascular autonomic
nervous system and, presumably, other
autonomic nervous organ systems.
Therefore, in an ideal situation, studies
should be performed with the patient
having had no acute illness for the preceding 48 h; unaccustomed vigorous exercise for 24 h, anticholinergic drugs (including antidepressants), antihistamines
and over-the-counter cough and cold
medications, 9 -a-fluorohydrocortisone,
diuretics, sympathomimetic and parasympathomimetic medications, and aspirin for 18 h; alcohol or hypoglycemic
episodes for 12 h; or food, caffeine, or
tobacco products for 8 h. Moreover, the
studies should be performed in the
morning in a quiet relaxed atmosphere.
The patient should have been taught and
practiced the procedure, and at the time
of the study should not be wearing compressive clothing or Jobst stockings,
should have the blood glucose stabilized
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Autonomic nervous system testing
Table 1—Some validated tests of specific subdivisions of the autonomic nervous system
SYMPATHETIC
d. Blood pressure/body temperature. These affect the response
in predictable manners based
on the heart-rate response.
e. Heart rate. In normal individuals, heart rate increases and R-R
variation decreases in a predictable manner with aging (7). In
diabetic individuals, changes in
heart rate are more complicated. With increasing duration of diabetes there is initially
an increase followed by a slowing and finally a fixed heart rate
(8). R-R variation, in contrast,
decreases early and rapidly after the diagnosis of diabetes has
been established (9).
f. Position. Both standing and sitting significantly reduce R-R
variation, therefore tests must
be done in the lying position.
BLOOD PRESSURE RESPONSE TO STANDING OR TILT. NOREPINEPHRINE RESPONSE TO
STANDING. DARK-ADAPTED PUPIL SIZE AFTER PARASYMPATHET1C BLOCKADE
QUANTITATIVE SUDOMOTOR AXON REFLEX TEST
PARASYMPATHETIC
R-R INTERVAL VARIATION WITH DEEP BREATHING
PANCREATIC POLYPEPTIDE RESPONSE TO CLAMPED HYPOGLYCEMIA
ADRENOMEDULLARY
EPINEPHRINE RESPONSE TO CLAMPED HYPOGLYCEMIA
(with insulin, if necessary), and should
not be emotionally upset.
To further define neuropathy,
tests have been designed to focus on the
specific subdivision affected (Table 1).
neuropathy or stress, whereas a
large decrease in R-R variation can
result from either parasympathetic
neuropathy or stress (f$-adrenergic stimulation).
SPECIFIC SYSTEM INVOLVEMENT
IN AUTONOMIC NEUROPATHY—
R-R variation is influenced by many
physiological factors:
a. Respiratory rate. There is a decrease in R-R variation with increasing respiration rate. The
greatest R-R variation occurs at
a respiratory rate of 5 breaths/
min. Thus, it is not only important to standardize the respiration rate, but the rate should be
5 breaths/min to optimize the
results.
b. Age. R-R variation decreases
with age and allowance must
be made for this.
c. Weight. Parasympathetic activity is reduced in obese individuals.
The functional changes associated with
autonomic failure are given in Table 2
and the tests for autonomic failure in
Table 3.
Cardiovascular abnormalities
Testing for cardiovascular autonomic
neuropathy involves a series of measurements.
1. Resting heart rate.
2. Beat-to-beat heart-rate variation.
R-R variation is the magnitude of
the sinus arrythmia and is measured by one of several methods
(4): 1) standard deviation, 2)
mean circular resultant, 3) maximal minus the minimal heart rate,
4) expiration-inspiration ratio, 5)
Holter monitoring, and 6) power
spectral analysis. R-R variation
was considered to be exclusively
under the control of the parasympathetic nervous system. However, subsequent studies demonstrate that both P-adrenergic
stimulation (isoproterenol) (5)
and 0-adrenergic blockade (propranolol) (6) decrease R-R variation. Both parasympathetic cholinergic blockade (atropine), and
(3-adrenergic stimulation can
nearly totally abolish R-R variation
(5). Thus, a small decrease in R-R
variation results from sympathetic
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Confounding variables in R-R autonomic testing (4):
a. General: this includes eating,
drinking coffee, and smoking.
b. Sodium salicylate raises the R-R
variation.
c. Dehydration can alter the response.
d. Coronary artery disease: it has
been shown that patients with
Table 2—Functional changes associated with autonomic failure
SYSTEMS INVOLVED
CARDIOVASCULAR
MANIFESTATIONS
RESTING TACHYCARDIA, IMPAIRED EXERCISE-INDUCED
CARDIOVASCULAR
RESPONSES, CARDIAC DENERVATION, ORTHOSTATIC HYPOTENSION, HEAT
INTOLERANCE, IMPAIRED VASODILATAT1ON, IMPAIRED VENOARTER1OLAR
REFLEX (DEPENDENT EDEMA)
EYE
DECREASED DIAMETER OF DARK-ADAPTED PUPIL (DARK-ADAPTED MIOSIS)
GASTROINTESTINAL
ESOPHAGEAL ENTEROPATHY, GALLBLADDER ATONY, IMPAIRED COLONIC
MOTIL1TY (DIARRHEA, CONSTIPATION), ANORECTAL SPHINCTER DYSFUNCTION
(INCONTINENCE)
GENITOURINARY
NEUROGENIC VESICAL DYSFUNCTION (DECREASED BLADDER SENSITIVITY/
INCONTINENCE/RETENTION),
SEXUAL DYSFUNCTION, (MALE: PENILE ERECTILE
FAILURE AND RETROGRADE EJACULATION; FEMALE: DEFECTIVE LUBRICATION)
SUDOMOTOR
ANHIDROSIS/HYPERHIDROSIS
(HEAT INTOLERANCE), GUSTATORY SWEATING
ENDOCRINE
HYPOGLYCEMIA-ASSOCIATED
AUTONOMIC FAILURE
DIABETES CARE, VOLUME 15,
SUPPLEMENT 3, AUGUST
1992
Autonomic nervous system
testing
Table 3—Tests for autonomic failure and their suitability for cross-sectional and longitudinal studies in individual and groups
POPULATION
KEY
TEST
QUANTITATIVE
LONGITUDINAL
REFERENCES
STANDARDIZATION
STUDIES
STUDIES
INDIVIDUAL
GROUP
4
10
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
R - R VARIATION
VALSALVA RATIO
POSTURAL BLOOD PRESSURE TEST
13
14
Q - T INTERVAL
DARK-ADAPTED PUPIL SIZE AFTER PARASYMPATHETIC BLOCKADE
13
No
YES
YES
YES
YES
19,21
YES
No
No
YES
No
20
16
17
22
25,26
23
24
1,2
YES
YES
No
YES
No
YES
YES
YES
YES
YES
No
No
YES
YES
YES
YES
SEMI
YES
YES
YES
YES
YES
YES
YES
YES
YES
SEMI
YES
YES
YES
YES
YES
YES
YES
YES
SOLID PHASE GASTRIC MOTILITY
CYSTOMETROGRAM WITH BETHANECHOL SUPERSENSITIVITY TEST
LATENCY OF SPINAL REFLEX-EVOKED POTENTIALS
NOCTURNAL PENILE TUMESCENCE MONITORING
INTRACAVERNOSAL INJECTION OF VASODILATORS
THERMOREGULATED SWEAT TEST
QUANTITATIVE SUDOMOTOR AXON REFLEX TEST
SKIN POTENTIALS
SWEAT IMPRINT
CLAMPED HYPOGLYCEMIA
EPINEPHRINE
YES
YES
YES
YES
YES
PANCREATIC POLYPEPTIDE
YES
YES
YES
YES
YES
SYMPTOMS SCORE
YES
YES
YES
No
YES
YES
No
YES
YES
YES
33
INSULIN INFUSION TEST
inferior wall myocardial infarctions experience a bradycardiahypotensive syndrome,
whereas patients with anterior
wall myocardial infarctions
experience tachycardia-hypertensive syndromes. Both can
affect the R-R variation.
Valsalva maneuver. The subject
blows into the mouthpiece of a
manometer to 40 mmHg for 15 s
with continuous EKG monitoring
before, during, and after the procedure. Healthy subjects develop
tachycardia and peripheral vasoconstriction during strain, and an
overshoot in blood pressure and
bradycardia on release. The Valsalva ratio is the longest R-R/
shortest R-R. The Valsalva maneuver has also been well evaluated
and studied (10). It encompasses
a complex reflex arc involving
both sympathetic and parasympa-
DIABETES CARE, VOLUME 15,
SUPPLEMENT 3, AUGUST
thetic pathways to the heart, sympathetic pathways to the vascular
tree, and baroreceptors in the
chest and lungs.
4. Blood pressure response to standing. The blood pressure response
is measured with the patient lying
supine at rest and again after 1
and 5 min standing. The absolute
fall is arbitrary but fall in systolic
blood pressure greater than 20
mmHg accompanied by symptoms of orthostasis is taken to be
evidence of sympathetic failure.
Photoplethysmographic beat-tobeat blood pressure recording
may have significant advantages
and can be used to evaluate the
components of the Valsalva maneuver (11). Its role in clinical
studies awaits more extensive
experience.
5. QTc interval. Examination of the
EKG may reveal a prolonged QTc
1992
interval in patients with cardiac
autonomic neuropathy (12,13).
Eye
Dark-adapted pupil size after total parasympathetic blockade may be a useful
reproducible and valuable tool for evaluating autonomic nervous system function, and is related to poor dark vision
(14).
Motor disturbances of
gastrointestinal tract
1. Esophageal and gallbladder enteropathy. These are usually discovered accidentally while reviewing
upper gastrointestinal studies.
2. Gastroparesis. In evaluating a patient with suspected diabetic gastroparesis, the level of glycemic
control should be assessed. Careful
history of medications including
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Autonomic nervous system testing
Table 3—Continued
DEGREE OF
TEST
R - R VARIATION
SENSITIVITY
SPECI-
REPRODUCIBIUTY
(1-4)
FICITY
(1-4)
4
YES
3
How
TO REPORT
E - I RATIO, MEAN CIRCU-
Pvs.
CERTAINTY
NP
(1-4)
COMMENTS
4
NP
4
CONFOUNDING VARIABLES ARE
EASE
1-4
LAR RESULTANT
WELL ESTABLISHED
VALSALVA RATIO
3
YES
3
RATIO
4
P
4
CONFOUNDING VARIABLES ARE
POSTURAL BLOOD PRESSURE
2
YES
2
CHANGE IN BLOOD PRES-
4
NP
4
INTRAVASCULAR VOLUME DE-
Q - T INTERVAL
2
YES
QTc
4
YES
MM
4
2-3
P
P
4
4
ISCHEMIA DEPENDENT
DARK-ADAPTED PUPIL SIZE
4
4
AFFECTED BY RUBEIOSIS
1-2
No
1
MlN
3
NP
2
SOMEWHAT INVASIVE, SPECIAL
UNKNOWN
YES
3
YES/NO
1
NP
3
INVASIVE
3
YES
UNKNOWN
MS
1
UNKN
2
SIGNIFICANCE OF RESULTS IS
3
No
3
RIGIDITY (RELATIVE
2
EQUIP.
3
N O T AN ANS
WELL ESTABLISHED
TEST
PENDENT
SURE
AFTER PARASYMPATHET1C
BLOCKADE
SOLID PHASE GASTRIC M O TIUTY
CYSTOMETROGRAM WITH
FACILITIES, RADIATION
BETHANECHOL SUPERSENS1TIVITYTEST
LATENCY OF SPINAL REFLEX-
EVOKED POTENTIALS
NOCTURNAL PENILE TUMES-
UNCLEAR, INVASIVE
DEPEN.
UNITS), NUMBER OF
CENCE MONITORING
TEST, USED IN
COMBINATION WITH OTHER
ERECTILE EPISODES,
TEST FOR DIAGNOSIS OF
MINUTES OF DURATION
EXCLUSION, RATINGS DONE
ON SLEEP LAB EVALUATION
INTRACAVERNOSAL INJECTION
N/A
No
2
NP
YES/NO (ALTHOUGH
COULD BE MADE
OF VASODILATORS
3 WITH
REPEATED
QUANTITATIVE)
TESTING
THERMOREGULATED SWEAT
3
YES
UNKNOWN
3
YES
3
2
2-3
YES
1-2
YES
3
TEST, USED IN
COMBINATION WITH OTHER
TEST FOR DIAGNOSIS OF
EXCLUSION
SURFACE AREA
2
NP
4
VERY CUMBERSOME AND
ML/CM 2
3
NP
4
NEEDS SPECIAL EQUIPMENT
YES/NO OR MV
3
2
NP
NP
3
4
HABITUATES
MESSY
TEST
QUANTITATIVE SUDOMOTOR
N O T AN ANS
AXON REFLEX TEST
SKIN POTENTIALS
SWEAT IMPRINT
DENSITY OR DIAMETER
NEEDS SPECIAL EQUIPMENT
DISTRIBUTION
CLAMPED HYPOGLYCEMIA
RELATES TO INSULIN-TREATED
DIABETES ONLY
EPINEPHRINE
UNKNOWN
UNKNOWN
4
GLYCEMIC THRESHOLD
1
NP
3
1
NP
3
1
NP
3
2
NP
3
MM
PANCREATIC POLYPEPTIDE
UNKNOWN
UNKNOWN
4
GLYCEMIC THRESHOLD
MM
SYMPTOMS SCORE
UNKNOWN
UNKNOWN
2
GLYCEMIC THRESHOLD
MM
INSULIN INFUSION TEST
3
3
4
YES/NO
ASSESSES ABILITY TO DEFEND
AGAINST HYPOGLYCEMIA
1, Low; 4, High; P, Parametric; NP, Nonparametric.
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DIABETES CARE, VOLUME 15,
SUPPLEMENT 3, AUGUST
1992
Autonomic nervous system testing
Abnormal NPT
Normal Hormonal Profile
Intracavemosal injection of vasodilators
(X 3 with high doses)
No erection
Erection
I
I
Vasculature probably competent but
cannot rule out endothelial injury
Suspicion of neuropathy
Vascular problems
± neuropathy
Figure 1—Diagnosis of diabetic impotence.
ganglionic blocking agents and
psychotropic drugs should be obtained. In addition, gastroduodenoscopy should be performed to
exclude pyloric or other mechanical obstruction. After optimization
of glycemic control, isotope scintigraphy to measure solid-phase
gastric emptying times may be indicated (3).
3. Constipation. The extent of the
evaluation in a diabetic patient
complaining of constipation depends on the severity of the constipation and associated signs. All patients should have a digital
examination to evaluate rectal
sphincter tone. Other causes of
constipation should be excluded.
4. Diarrhea. The diagnosis of diabetic
diarrhea is established by excluding other causes of diarrhea and by
confirming the presence of autonomic neuropathy (15).
5. Fecal incontinence. Anorectal
sphincter function is evaluated by
anorectal manometry, which quantitates maximal basal sphincter
pressure and the rectoanal inhibitory reflex (inflation of a balloon in
the rectum causes a reflex relaxation of the internal anal sphincter). Continence for solids and liq-
DIABETES CARE, VOLUME 15, SUPPLEMENT 3, AUGUST
uids is directly assessed by
simulating the presence of stools
with a solid sphere or rectally infused saline.
Genitourinary tract disturbances
1. Autonomic neuropathy of the penis in diabetes. It is not presently
possible to measure the status of
the autonomic nerves of the penis.
Because of this, diabetic penile
neuropathy is a diagnosis that is
reached after the exclusion of
other causes of erectile dysfunction. The presence of impotence
can be determined by history and
nocturnal penile tumescence
monitoring of sleep-related erections (16). Patients can then be
tested for their response to intracavemosal vasodilators (papaverine, phentolamine, prostaglandin
E : ) (17). If the patient has an abnormal nocturnal penile tumescence test and a normal hormonal
profile, but responds with a full
erection to the vasodilators, significant vascular disease is usually
ruled out, suggesting that neuropathy is the predominant factor.
However, because the vasodilators directly relax the smooth
muscle, it is not possible to exclude vascular endothelial dys-
1992
function as a contributing factor
leading to impotence. If the patient does not respond to several
(3-5) intracavemosal injections,
vascular dysfunction (arterial or
venoocclusive disease), with or
without associated neuropathy, is
likely. The suggested sequence for
the diagnosis of autonomic neuropathy of the penis is given in Fig.
1. The suspicion of diabetic penile
neuropathy cannot be confirmed
with any specific measurement of
penile autonomic nerve function.
Reflex-evoked potential studies
measure function in sensory
(bladder visceral) autonomic and
sensory and motor somatic nerves
but not in motor autonomic penile nerves. Therefore, abnormal
latencies in these reflex-evoked
potential studies support but do
not confirm a diagnosis of autonomic neuropathy of the penile
nerves (18).
2. Female sexual dysfunction. Sexual
dysfunction in the female secondary to autonomic neuropathy has
not been well defined. Anorgasmia may or may not be a feature.
However, difficulty with vaginal
lubrication may occur in diabetic
women with autonomic neuropathy. Female sexual dysfunction
using vaginal plethysmography to
measure lubrication and vaginal
flushing has not been well established. It may be valuable in the
future, but much in the way of
standardization needs to be accomplished before it can be recommended as a routine test.
3. Autonomic neuropathy of the
bladder in diabetes. To arrive at
the diagnosis of diabetic autonomic neuropathy of the bladder,
the sensory and motor function of
the bladder and need to be tested.
Testing requires catheterization of
the bladder, sophisticated urodynamic equipment, and an experienced professional with training
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Autonomic nervous system testing
in the field of neurourology. A
simple, noninvasive, and specific
test to screen for the presence of
bladder autonomic neuropathy is
not available.
A. Testing of bladder sensitivity,
i. The integrity of bladder
proprioception can be tested
by progressive filling of the
bladder with water or gas
(CO2) to record when the
patient first becomes aware
of a desire to void (urge)
and when bladder filling becomes painful (bladder capacity) (19).
ii. Perception of visceral pain
can be evaluated by determining the electrical perception threshold (19). A catheter with s t i m u l a t i n g
electrodes is placed in the
vesicourethral junction; the
intensity of the stimulus is
progressively increased until
the patient first senses it. Elevated electrical perception
thresholds are considered
diagnostic of sensory loss
(19).
iii. Temperature sensation can
also be evaluated by the introduction of warm or cold
fluid through the catheter
(19).
iv. Another way of determining
the status of bladder sensory
nerves is by measuring the
latency of spinal reflexevoked potentials (20).
Electrical s t i m u l a t i o n
through an indwelling catheter in the urethra or vesicourethral junction elicits a
contractile response of the
anal sphincter. This response can be recorded with
a bipolar needle placed in
the sphincter. The latency
between the stimulus and
the response can be measured to assess the integrity
1100
of this reflex pathway, in
which the afferent limb
comprises sensory autonomic fibers traveling in the
pelvic nerves and the efferent limb, motor somatic
nerve fibers in the pudendal
nerve. It is possible that the
abnormality in the reflex
pathway is due to an alteration in the efferent rather
than in the afferent limb. To
differentiate an autonomic
sensory from a somatic motor alteration, the bulbocavernosus reflex can be tested.
In this reflex both limbs are
formed by somatic fibers. If
the latency of this reflex is
normal, it can be concluded
that the increase in the reflex latency after visceral
stimulation is likely due to
neuropathy of the sensory
autonomic fibers. In addition, electromyography of
the anal sphincter after
voluntary contraction will
assist in determining the
presence or absence of neuropathy in this somatic motor pathway. The advantage
of this method over those
described in i, ii, and iii is
that is does not rely on the
patient reporting a sensation
but rather on an electrophysiological measurement.
The disadvantage of measuring the latency of spinal
reflex-evoked potentials is
that there is limited experience with this method and it
requires sophisticated electrophysiological equipment.
Although this method is
quantitative and can be
standardized, its reproducibility and specificity are not
known. The invasive and
complicated nature of this
test makes it a poor candi-
date for longitudinal studies.
B. Testing of bladder motor function.
The ability of the bladder to
empty urine not only depends on the ability of the
detrusor to contract but also
on a nonobstructed bladder
outlet. Therefore, when evaluating the motor function of
the bladder, it is necessary to
rule out bladder outlet obstruction. This is particularly
important in older men in
whom bladder outlet obstruction is prevalent,
i. Detrusor motor function
can be studied by performing a cystometrogram
(19,20). This test studies the
detrusor reflex function.
The normal bladder, when
filled with fluid or gas, responds with a reflex contraction of the detrusor.
This contraction can be
voluntarily suppressed. A
bladder that does not contract with filling is considered an areflexic bladder.
This can be due to an inability to suppress the psychogenic central influence
controlling this reflex, to
neuropathy of sensor autonomic nerves, and/or to
neuropathy of motor autonomic fibers responsible
for contraction of the detrusor muscle. Therefore,
the finding of bladder areflexia alone is not sufficient
for the diagnosis of autonomic motor neuropathy of
the bladder. The bethanechol supersensitivity test is
used to determine the presence of efferent denervation
of the bladder (21). This test
is based on Canon's law of
denervation supersensitivity
DIABETES CARE, VOLUME 15, SUPPLEMENT 3, AUGUST 1992
Autonomic nervous system testing
of an organ to its neurotransmitter. Bethanechol (5
mg), a muscarinic agonist, is
given subcutaneously and
the cystometrogram is repeated. After the bladder
has been filled with 100 ml
of water or gas, if the intravesical pressure is >20 cm
H2O above the intravesical
pressure before the administration of bethanechol, the
test is considered positive. If
motor autonomic neuropathy is present, the test will
be positive. Patients with
psychogenic suppression of
the detrusor reflex or sensory autonomic neuropathy
in the absence of motor neuropathy would have a negative test. The sensitivity of
the test is not known. It is
considered to be specific for
autonomic motor neuropathy, but due to its invasive
nature, it is probably not
useful in longitudinal studies.
ii. Finally, measurement of
volume of residual urine after urination may be used,
in the absence of bladder
outflow obstruction, as an
indicator of bladder motor
function. After the patient
has urinated, the volume of
residual urine can be determined non-invasively with
an ultrasound bladder scanner or, invasively, by catheterization.
Sudomotor sympathetic function
Sudomotor function may be evaluated
with the thermoregulatory sweat test,
quantitative sudomotor axon reflex test,
skin potentials, or sweat imprint quantitation.
The thermoregulatory sweat test
is a sensitive test of sweat distribution
(22). The subject is dusted with an indi-
DIABKTKS CARE, VOLUME
15,
SUPPLEMENT 3 ,
AUGUST
cator powder that turns purple when
moist. This qualitative test can be rendered semiquantitative by charting the
percentage of anterior body surface that
is anhidrotic.
The skin potential can be recorded with standard EMG equipment
from the palm and sole (23). The stimulus is an electric shock, an inspiratory
gasp, or other stimuli that activate type II
and III mechanoreceptor afferents. The
skin potential is readily evoked but habituates.
The silastic skin imprint is obtained after the application of silastic material to stimulated skin (24). The sweat
droplet indents the imprint and the
count and diameter distribution can be
determined. The usual stimulus is pilocarpine administered by iontophoresis.
In the quantitative sudomotor axon reflex test the stimulus consists of the
iontophoresis of acetylcholine via the
stimulus compartment of a multicompartmental sweat cell (25,26). Postganglionic sympathetic nerve terminals are
activated and the nerve impulse travels
retrogradely, reaches a branch point,
then travels orthogradely to activate a
second population of sweat glands. The
sweat response from this second population of sweat glands is recorded by a
sudorometer. The stimulus compartment
surrounds the central recording compartment, separated by an air gap and
two ridges (to block diffusion). This test
evaluates the integrity of the distal postganglionic sympathetic sudomotor axon.
Four recording sites (distal forearm and
3 lower extremity sites) are used. The
test has high sensitivity, a coefficient of
variation of 20%, and, when used in conjunction with the thermoregulatory sweat
test, defines the pre- or postganglionic
site of the lesion. The test requires specialized equipment, trained technicians,
and 20-30 min to complete.
Endocrine tests for functional
autonomic failure in diabetes
HAAF appears to be distinct from classic
diabetic autonomic neuropathy (27).
1992
First, the two disorders can occur independently. Second, deficient autonomic
responses are specific for the stimulus of
hypoglycemia in HAAF, whereas reduced sympathetic and parasympathetic
responses to multiple stimuli characterize autonomic neuropathy. Third,
whereas reduced epinephrine responses
to hypoglycemia are a characteristic feature of HAAF, epinephrine responses
are reduced little if at all in insulindependent diabetes mellitus (IDDM)
with autonomic neuropathy compared
with IDDM without autonomic neuropathy. Fourth, diabetic autonomic neuropathy, in sharp contrast to HAAF, is
not a risk factor for iatrogenic hypoglycemia in IDDM (28,29). The pathogenesis of HAAF is not known; it probably is
multifactorial and may be related to recent antecedent hypoglycemia (30-32).
Tests for functional autonomic
failure in IDDM are complex for the patient as well as the investigator and labor
intensive. Ideally, both glycemic thresholds for symptoms and counterregulatory activation and glycemic defense
against mild to moderate hyperinsulinemia should be determined in patients
with IDDM and appropriate control subjects. Defense against hyperinsulincmic
hypoglycemia is probably the more essential, at least for clinical purposes, because it has been shown in prospective
studies (33,34) to have clinical predictive
power, i.e., to identify patients at markedly increased risk (> 25-fold) for severe
iatrogenic hypoglycemia.
Glycemic thresholds can be defined with the hyperinsulinemic stepped
hypoglycemic clamp technique (1,2,35).
The stepped hypoglycemic clamp technique can be highly standardized (1,2).
However, the test is complex. Precise
quantitation of the glycemic thresholds
requires both a euglycemic control
clamp and a stepped hypoglycemic
clamp in each individual studied. Arterialized blood samples are also required.
The reproducibility of the stepped hypoglycemia clamp technique has not been
assessed systematically. However, the
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Autonomic nervous system testing
fact that identical glycemic thresholds for
symptoms and glucagon and epinephrine release were calculated from data
generated with the technique in two different laboratories (1,2) indicates that
the test is probably reproducible. The
technique is probably more suitable for
populations rather than individuals, i.e.,
it might not identify all patients with
minimally altered glycemic thresholds.
The results of the stepped hypoglycemia clamp test should be reported
as absolute glycemic thresholds (glucose
concentration), with those of the insulin
infusion test as negative (adequate glucose counterregulation) or positive (defective glucose counterregulation). For
the stepped hypoglycemic clamp technique, comparison of each response
(symptom scores, hormone concentrations) of each individual patient with the
95% confidence interval of the corresponding response for a nondiabetic
control group is preferable (1,2), although comparisons of group means can
be used. For the latter, either parametric
or nonparametric tests will be appropriate to a given data set.
Glycemic defense against hyperinsulinemia can be defined with an insulin infusion test (33). The insulin infusion test can be standardized with a
relatively low insulin infusion dose (0.67
mU • kg" 1 • min • - 1 ) and a specific
plasma glucose end point (<2 mM =
defective glucose counterregulation). In
addition, a neuroglycopenic end point
must be included for ethical reasons. Inclusion of neuroglycopenia (difficulty
thinking, blurred vision, dizziness, fatigue
and faintness) as an additional end point
increases the predictive power of the test
(33). Although the test yields only a positive or negative conclusion—defective or
adequate glucose counterregulation—it
has >90% clinical predictive power for
development of hypoglycemia with intensive insulin treatment.
The test is labor intensive, requiring a minimum of two people (typically a
physician and nurse); a third person is
needed if cognitive function is assessed. It
1102
also requires accurate glucose measurements (e.g., with a Beckman or YSI analyzer not with a portable glucose monitor)
at the bedside and the analytical capacity
to perform the hormone measurements.
Cognitive assessment generally requires a
collaborating psychologist (2,36).
The insulin infusion test has been
shown to be highly reproducible (33,34).
With three replicate tests at 3- to 4-wk
intervals, coefficients of variation for glucose and key counterregulatory hormone
(glucagon, epinephrine) responses were
<8% (34). One can estimate sensitivity
and specificity to be ~90% from the data
of White et al. (33). But, these are minimum estimates. In the data of Bolli et al.
(34), none of the patients with a negative
test (nadir >2.2 mM) subsequently suffered severe clinical hypoglycemia,
whereas all of those with a positive test
(nadir <2.2 mM) suffered severe hypoglycemia during subsequent intensive therapy.
SUMMARY AND
RECOMMENDATIONS— Several
organ systems can be monitored by reliable longitudinal testing. These include:
1. Cardiovascular system
a. R-R variation
b. Valsalva maneuver
c. Postural blood pressure testing
2. Sudomotor
a. Postganglionic function with
QSART
3. Eye
a. Dark-adapted pupil size after
total parasympathetic blockade.
Specific research projects may include other tests but these tests do not
lend themselves easily for large, multicenter type of studies. The test listed
above are noninvasive, quantitative, and
are sufficiently standardized to allow longitudinal assessment in diabetic patients.
Furthermore, these tests allow evaluation
of at least three different organ systems.
HAAF, an example of functional
autonomic failure in diabetes, is best assessed by evaluation of the glycemic
thresholds for epinephrine and pancreatic polypeptide secretion and hypoglycemic symptoms using a stepped hypoglycemic clamp protocol. The status of
physiological defense against hyperinsulinemic hypoglycemia can be assessed
with the insulin infusion test.
References
1. Schwartz NS, Clutter WE, Shan SD,
Cryer PE: The glycemic thresholds for
activation of glucose counterregulatory
systems are higher than the threshold for
symptoms. J Clin Invest 79:777-81, 1987
2. Mitrakou A, Ryan C, Veneman T, Mokan
M, Jennssen T, Kiss 1, DurrantJ, Cryer P,
Gerich J: Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am] Physiol 260:E67-74, 1991
3. Achem-Karam SR, Funakoshi A, Vinik
Al: Plasma motilin and migrating motor
complex in diabetic gastroparesis. Gastroenterology 88:492-94, 1985
4. Genovely H, Pfeifer MA: RR-Variation:
the autonomic test of choice in diabetes.
Diabetes Metab Rev 4:255-71, 1988
5. Pfeifer MA, Cook D, BrodskyJ, Tice D,
Reenan A, Swedine S, Halter JB, Porte Jr
D: Quantitative evaluation of cardiac
parasympathetic activity in normal and
diabetic man. Diabetes 31:339-45, 1982
6. Weinberg CR, Pfeifer MA: Development
of a predictive model for symptomatic
neuropathy in diabetes. Diabetes 35:
873-80, 1986
7. Pfeifer MA, Halter JB, Weinber CR, Cook
D, Best J, Reenan A, Porte D Jr: Differential changes of autonomic nervous system function with age in man. Am J Med
75:249, 1983
8. Ewing DJ, Campbell IW, Clarke BF:
Heart rate changes in diabetes mellitus.
Lancet 1:183, 1981
9. Pfeifer MA, Weinberg CR, Cook D, Reenan A, Halter JB, EnsinckJ, Porte Jr D:
Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care 7:447-53, 1984
10. Rothschild AH, Weinberg C, Cook D,
Halter J, Porte D, Pfeifer MA: Sensitivity
of R-R variation and the Valsalva ratio in
the assessment of cardiovascular diabetic
DIABETES CARE, VOLUME 15, SUPPLEMENT 3, AUGUST
1992
Autonomic nervous system testing
11.
12.
13.
14.
15.
autonomic neuropathy. Diabetes Care 40:
735-41, 1987
Sandroin P, Benarroch EE, Low PA:
Pharmacologic dissection of the components of the valsalva maneuver in adrenergic failure. J Appl Physiol 71:1563-67,
1991
KahnJK, Sisson JC, Vinik Al: QT Interval
prolongation and sudden cardiac death
in diabetic autonomic neuropathy. J Clin
Endocrinol Metab 64:751-54, 1987
Gonin JM, Kadrofske MM, Schmaltz S,
Vinik Al: Corrected Q-T interval prolongation as diagnostic tool for assessment
of cardiac autonomic neuropathy in diabetes mellitus. Diabetes Care 13:68-71,
1990
Pfeifer MA, Code DL, BrodskyJ: Quantitative evaluation of sympathetic and
parasympathetic control of iris function.
Diabetes Care 5:518-28, 1982
Barnett JL, Vinik Al: Gastointestinal disturbances in diabetes. In Therapy for Diabetes Mellitus and Related Disorders. Leb-
ovitz AE, Ed. Alexandria, VA, Am.
Diabetes Assoc, 1991, p. 279-87
16. Karacan 1, Salis PJ, Ware JC, Derveut B,
Williams RL, Scott FB, Attia SL, Beutler
LE: Nocturnal penile tumescence and diagnosis in diabetic impotence. AmJ Psychiatry 135:191-97, 1978
17. Krane RJ, Goldstein I, Saenz de Tejada I:
Impotence. N EnglJ Ued 321:1648-59,
1989
18. Sarica Y, Karacan I: Bulbocavernosus reflex to somatic and visceral nerve stimulation in normal subjects and in diabetics
with erectile impotence. J Urol 138:5558, 1987
DIABETES CARE, VOLUME 15,
SUPPLEMENT 3 ,
AUGUST
19. Fridmodt-Moller C: Diabetic cystopathy.
Incidence of severe hypoglycemia in an
Danish Med Bull 25:49-59, 1978
unselected population of patients with insulin-treated diabetes mellitus with special
20. Bradley WE: Diagnosis of urinary bladreference to autonomic neuropathy. Diabeder dysfunction in diabetes mellitus. Ann
tes Nutr Metab 4:303-309, 1990
Intern Med 92:323-26, 1980
21. Lapides J: Denervation supersensitivity 30. Heller SR, Cryer PE: Reduced neuroendocrine and symptomatic responses to
as a test for neurogenic bladder. Surg
subsequent hypoglycemia after one epiGynecol Obstet 114:241-49, 1962
sode of hypoglycemia in nondiabetic hu22. Fealey RD, Low PA, Thomas JE: Themomans. Diabetes 40:223-26, 1991
regulatory sweating abnormalities in diabetes mellitus. Mayo Clin Proc 64:617- 31. Widom B, Simonson DC: Effect of inter28, 1989
mittent hypoglycaemia on counterregu23. Shahani BT, HalperinJJ, Boulu P, Cohen
latory hormone secretion (Abstract). DiJ: Sympathetic skin response: a method
abetologia 33:A484, 1990
of assessing unmyelinated axon dysfunc- 32. Davis M, Shamoon H: Adaptive countertion in peripheral neuropathies. J Neural
regulatory responses to hypogycemia in
Neurosurg Psychiat 47:536-42, 1984
nondiabetic humans (Abstract). Diabetes
24. Kennedy WR, Sakuta M, Sutherland D,
38:5A, 1989
Goetz FC: Quantitation of the sweating 33. White NH, Skor DA, Cryer PE, Bier DM,
deficit in diabetes mellitus. Ann Neurol
Levandoski L, Santiago JV: Identification
15:482-88, 1984
of type 1 diabetic patients at increased
25. Low PA, Zimmerman BR, Dyck PJ: Comrisk for hypoglycemia during intensive
parison of distal sympathetic with vagal
therapy. N EnglJ Med 308:485-91, 1983
function in diabetic neuropathy. Muscle 34. Bolli GB, Defeo P, DeCosmo S, Perriello G,
Nerve 9:592-96, 1986
Ventura MM, Massi-Benedetti M, Santeu26. Low PA, Caskey PE, Tuc RR, Fealey RD,
sanio F, Gerich JE, Brunetti P: A reliable
Dyck PJ: Quantitive sudomotor axon reand reproducible test for adequate glucose
flex test in normal and neuropathic subcounterregulation in type I diabetes mellijects. Ann Neurol 14:573-80, 1983
tus. Diabetes 33:732-37, 1984
27. Cryer PE: Iatrogenic hypoglycemia as a 35. Boyle PJ, Schwartz NS, Shah SD, Clutter
cause of hypoglycemia-associated autoWE, Cryer PE: Plasma glucose concennomic failure in IDDM: a vicious cycle.
trations at the onset of hypoglycemic
Diabetes 41:255-60, 1992
symptoms in patients with poorly con28. Diabetes Control and Complications
trolled diabetes and in nondiabetics. N
Trial Research Group: Epidemiology of
EnglJ Med 318:1487-92, 1988
severe hypoglycemia in the diabetes con- 36. Hirsch IB, Boyle PJ, Draft S, Cryer PE:
trol and complications trial. Am J Med
Higher glycemic thresholds for symp90:450-59, 1991
toms during beta-adrenergic blockade in
29. Bjork E, Palmer M, Schvarcz E, Berne C:
IDDM. Diabetes 40:1177-86, 1991
1992
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