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The sympathetic skin response (SSR) was studied in 47 diabetic patients

selected for the presence of symptoms and clinical signs of peripheral neu-
ropathy and in 24 normal control subjects. The SSR was present in all
controls but was absent at the foot in 66% and at the hand in 27.7% of the
diabetic patients. Absence of the SSR failed to correlate with other electro-
physiologic parameters on routine nerve conduction and electromyographic
studies. Although absent SSR was more often found in patients with symp-
toms of autonomic dysfunction (P < 0.05),there was no correlation with any
specific symptoms of autonomic involvement. The SSR was frequently ab-
sent, at least in the foot, in those patients with abnormal cardiac beat-to-
beat variability (expiratoty:inspiratoy, E: I, ratio) and pupil cycle time (PCT).
In addition there was a good correlation between the amplitude of the SSR
and the value of the E:l ratio (r = 0.81, P < 0.001). The SSR may be a
valuable adjunct in the assessment of autonomic involvement in diabetic
neuropathy, but its sensitivity requires further evaluation.
MUSCLE & NERVE 10:711-716 1987

SYMPATHETIC SKIN RESPONSE IN


DIABETIC NEUROPATHY
BElTY SOLIVEN, MD, RICARDO MASELLI, MD, JONATHAN JASPAN, MD,
ANDREW GREEN, MD, HANK GRAZIANO, MICHELE PETERSEN,
and JEAN-PAUL SPIRE, MD

Autonomic neuropathy is known to result in sub- nomic involvement. We also attempted to correlate
stantial morbidity in diabetic patients. '." Conven- the results of the SSK with findings obtained by
tional electrophysiologic procedures do not ade- other more routine electrophysiological tests as well
quately assess the dcgree of autonomic nervous as with the results of traditional tests of autonomic
system involvement. There recently has been re- function such as the expiratory: inspiratory (E: I)
newed interest in a previously described technique, ratio on electrocardiographyg and pupil cycle
known as the sympathetic skin response (SSR), in time.7.12.1"
which changes in voltage of the skin in response to
a variety of stimuli are T h e SSR was PATIENTS AND METHODS
originally thought to depend on the synchronized
activation of' sweat glancis," although a contribu- Thcrc were 47 diabetic patients (30 male, 17 fe-
male, age 50 2 I7 years) with symptoms and signs
tion of' an epidermal component to the response
of' peripheral neuropathy, as determined by a his-
has been proposed by Edelberg and Wright.' 111
tory and physical examination, chosen for study.
the current investigation we evaluated the uselul-
Patients were otherwise unselected, except for a
ness of the SSK in diabetic patients with peripheral
willingness to be included in the study, which was
neuropathy, most of whom had symptoms of auto-
approved by the Clinical Investigation Committee
of the institution. Written informed consent was
obtained from all participants. Thcre were 37 of
From the Department of Neurology (Drs. Soliven, Maselli. Mr. Graziano. the 47 diabetic patients who had symptoms ofauto-
Ms. Petersen, and Dr. Spire) and Medicine (Drs. Jaspan and Green), nomic involvement, iricluding one or more of the
Brain Research Institute. University of Chicago, Chicago, IL.
following: orzhostatic hypotension ( 13/47), gastro-
Acknowledgements: We are indebted lo Dr Barry Arnason and Dr. Robert
Lovelace for help and advice in the preparation of this paper, Dr. Avertano paresis (20/47), bladder dysfunction (4/47), and male
Noronha for encouraging us. and Cindy Suilivan for the typing of this impotence (24/30).
manuscript.
The SSK was obtained with the subject lying in
Address reprint requests to Dr Soliven at the Department of Neurology, a supine position. Standard EMC; disc electrodes
University of Chicago, 5841 S Maryland Avenue, Chicago, IL 60637
wcre covered with conducting paste and attached
Received for publication May 13, 1986; revised manuscript accepted for
publication October 15, 1986. to the palm (GI) and dorsum (G2) of the right hand
10148-639N1008/0711$04.00/6
as well as to the sole (GI) and dorsum (G2) of the
1987 John Wiley 8 Sons. Inc right foot. Recordings were obtained on a T E C A

Sympathetic Skin Response MUSCLE & NERVE October 1987 711


zw IJV
500 IM

HAND FOOT
FIGURE 1. SSR from a 27-year-old normal control subject.

TE4 electromyograph (TECA Gorp., Pleasantville, thick beam of light is directed perpendicularly to
NY) with a frequency response from 1.6 H z to 3.2 the inferior limbus of the iris. T h e beam is elevated
KHz. T h e amplification sensitivity was between 50 until it intersects the pupillary margin, eliciting a
and 500 pvldivision, and the sweep speed was 500 constriction that shields the beam from the retina.
msec/division. The stimulation consisted of square This causes the pupil to dilate, setting u p a cycle
pulses of 200 psec duration delivered to the skin of constriction dilation. There are 90 cycles timed
of the hand and foot. The skin temperature in all over 3 or 4 periods of 20-30 seconds each and the
patients was kept above 32" C. The SSR consists of mean pupil cycle time thereby obtained.
a biphasic potential with an initial negative peak,
varying in amplitude (peak to peak) from test to STATISTICAL METHODS
test and is subject to habituation (Fig. 1).
Statistical methods included chi-square analysis,
In 25 of the diabetic patients, routine nerve
Student's t-tests, and coefficient of correlation where
conduction velocity studies were performed. In 36
appropriate.
patients the expiratory/inspiratory ratio was deter-
mined on electrocardiography by dividing the
longest R-R interval following expiration by the RESULTS
shortest R-R intervals during inspiration obtained The SSR was present in 100% of controls but was
during steady breathing at 6 cycles/min.'A mean absent in the foot in 31 of 47 (66%) of the diabetic
ratio was calculated from eight consecutive expi- patients (P < 0.01), (Table 1, Fig. 1). Of the patients
ration/inspiration cycles. In 33 patients the pupil with absent foot SSR, 28 (90%) had one or more
cycle time was obtained using a slit-lamp as de- symptoms of autonomic involvement, whereas 3
scribed previously by others.'*'*.''Briefly, a 1/2 mm (10%) had no autonomic symptoms. Conversely, of

Table 1. SSR in controls and diabetics.


Control Diabetics P value
Number of patients 24 47
Age 27-85 years (X = 42.3) 24-80 years (X = 50)
Duration since time 1 month to 58 years
of diagnosis
SSR absent in foot 0% 31/47 = 66% <0.01
SSR absent in 0 Yo 13/47 = 27.7%
hand
SSR present in 100% 16/47 = 34%
hand and foot
-
x latency
Hand 1.31 r 0.18 seconds 1.44 ? 0.09 seconds NS
Foot 1.93 f 0.17 seconds 1.99 f 0.18 seconds NS
jT amplitude
Hand 791.7 ? 346.6 pV 471.9 2 368 pV <0.005
Foot 388.3 2 227 pV 196.5 ? 138.3 pV <0.005
NS = not s!gn!f!cant

712 Sympathetic Skin Response MUSCLE & NERVE October 1987


However there was overlap in amplitude between
351
normals and diabetics (Fig. 3). Among the 25 pa-
tients in whom nerve conduction velocities were
performed, absence of the SSR did not correlate
with nerve conduction velocities or amplitude of
nerve and muscle action potentials (Table 3).
The SSR was frequently abnormal in patients
with other objective signs of autonomic dysfunction
such as abnormal E:I ratio (79%) and abnormal
pupil cycle time (75.8%)(Tables 4 and 5).T h e value
of the E: I ratio correlated well with the amplitude
of foot SSR (r = 0.81, P < 0.001) and with that of
the hand SSR (r = 0.42, P < 0.05) (Fig. 4). On the
other hand there was no correlation between the
amplitude of the SSR in either hand or foot and
pupil cycle time.

SSR ABSENT SSR DISCUSSION


AT LEAST IN PRESENT
THE FOOT The assessment of autonomic function poses a chal-
RGURE 2. SSR and autonomic symptoms. lenging problem because of the inherent limita-
tions of routine electrophysiologic methods that re-
flect the status of fast myelinated fibers only. Using
the patients with autonomic symptoms, 28 (75.6%) microneurography, Fagius and Wallin"' were able
had absent SSR, whereas 9 (24.4%) had normal SSR to demonstrate dissociation of the vasoconstrictor
(Fig. 2). These differences were significant (P < and sudomotor activity of the sympathetic path-
0.05). Thus, there appears to be an association be- ways. One indirect method of studying the integrity
tween absence of the SSR, at least in the foot, and of the sudomotor fiber population is the psycho-
the presence of autonomic neuro athy in diabetic galvanic response,".'.':' which measures changes in

and any single autonomic symptom such as or-


E
patients. However, no correlation etween the SSK skin resistance in response to emotional influences.
T h e method used in this study measures changes
thostatic hypotension, gastroparesis, bladder dys- in voltage from the skin surface as a result of ac-
function, o r impotence was noted. Similarly, no as- tivity in the sudomotor fiber triggered by electrical
sociation was found between the SSR and patient stimulation. Its main advantage is that it can be
age, sex, duration, or type of diabetes (Table 2). readily performed with routine electromyographic
N o age and sex differences in the SSR were ob- equipment.
served in the control subjects. Our findings indicate that the SSR was easily
The mean latencies of the foot and hand SSR recorded and universally present in normal sub-
in the diabetic subjects were not significantly dif- jects. It was found that this reflex was frequently
ferent from the controls. On the other hand, the absent in patients with clinically evident diabetic
mean amplitude of the hand and foot SSR was neuropathy, in agreement with previous re-
significantlyreduced compared with controls in those port~.'.'~These findings are consistent with the ob-
diabetic patients in whom a response was detected. servations that the presence of the SSR depends

Table 2. SSR and age of patients, duration of diabetes, and type of


diabetes.
Normal SSR Abnormal SSR t-test
~~

X age (years) 50.3 t 18.4 50.1 f 14.9 NS


X duration of DM (years) 20.4 t 16.6 16.5 f 10.9 NS
Type l/Type II (%) 38.5/61.5% 355164.5% NS
Type I = insulin dependent.
Type I / = noninsulin dependent.
N S = not significant.

Sympathetic Skin Response MUSCLE & NERVE October 1987 713


"I . HAND SSR FOOT SSR

mo

CONTROLS DIAEETICS

FIGURE 3. Amplitude of SSR in controls and diabetic patients. In the first five diabetic patients, SSR was simply measured as present
or absent, and for this reason, these data from these five patients is not presented in this figure.

Table 3. SSR and electrodiagnostic parameters in diabetics.


Normal hand SSR' Absent hand SSR' t-test
K ulnar SNAP (pV)t 3.87 f 3.89 (16) 1.67 2 2.69 (9) NS
(nl 2 5 pV)
K ulnar CMAP (mV)* 11.3 2 3.64 (16) 9.28 f 4.12 (9) NS
(nl 2 6 mV)
K ulnar SCV (m/sec) 48.3 2 ll.S(ll) 52.5 -t 3.18 (2)s NS
(nl = 44-71 m/sec)
X ulnar MCV (m/sec) 47.1 2 4.25 (16) 48.8 ? 5.27 (9) NS
(nl = 47-60 mlsec)
Normal foot SSR Absent foot SSR t-test
K peroneal CMAP (mV)* 3.03 f 1.9 (6) 2.34 2 2.57 (19) NS
(nl s 2.0 mV)
i?peroneal MCV (m/sec) 35.9 f 4.1 (6) 36.5 5 4.04 (14)s NS
(nl = 38-61 m/sec)
H reflex present 50% (3/6) 47.4% (9119) NS
NS = not significant
'Number of patrents in parenthesis.
tSensory nerve action potential.
$Compound muscle action potential measured from peak to peak.
Discrepancy in the number of subjects when calculating conduction velocity is due to absent ulnar
SNAP or peroneal CMAf in some patients. Such patients are excluded from calculatron.

on intact conduction through the postganglionic sympathetic nervous system to various stimuli. T h e
unmyelinated fibers that are frequently affected in absence of significant ditference in the latency of
diabetics. Although there was a tendency for the the SSR between the normal subjects and diabetics
amplitude of the SSR to be lower in diabetics than may be explained by the fact that large myelinated
in controls, as also noted by others,' the great var- fibers do not contribute to the SSR. Thus, if the
iability of the response and its overlap with controls number of functional fibers is above a certain
makes applitude unreliable as an index of abnor- threshold, the response will be elicited, albeit with
mality. For these reasons w e have considered the decreased amplitude, and if not, it will be absent.
SSK abnormal only when it is absent. Amplitude Interestingly, although perhaps not surpris-
variability is related to the responsiveness of the ingly, absence of the SSR did not correlate with the

Table 4. SSR and expiratory-inspiratory ratio in diabetics Table 5. SSR and pupil cycle time in diabetics
NL SSR ABN SSR Total NL SSR ABN SSR Total
NL E:l ratio (>1.15) 3 0 3 NL PCT (<920 msec) 1 3 4
ABN E:l ratio ( ~ 1 . 1 5 ) 7 26 33 ABN PCT (>920 msec) 7 22 29
Total 10 26 36 Total 8 25 33

714 Sympathetic Skin Response MUSCLE & NERVE October 1987


HAND SSR FOOT SSR

1600 500

1200
400 ..
11V
'" 300.
800.

..
200.

400,
.......-".. I 42 100 I 81

E /I Ratio E l l Ralio

FIGURE 4. Correlation between amplitude of SSR and expiratory-inspiratory ratio

severity of the peripheral demyelination as mea- associated with sudomotor a~tivity.~.~.'" T h e am-
sured by slowing of conduction velocity nor with plitude of the SSR correlated well with the expir-
the severity of axonal damage as indicated by a atory: inspiratory ratio but not with pupil cycle time.
decreased amplitude of the compound muscle and The lack of correlation with the latter may in part
nerve action potentials. This is at variance with the reflect the fact that visual pathways participate in
report by Shahani et al.15who found the SSR to be the reflex arc of pupillary response, in addition to
more frequently abnormal in axonal neuropathies the sympathetic and parasympathetic pathways. It
than in demyelinating neuropathies. This may, would be of interest to correlate the SSR with other
however, simply reflect differences in study pop- tests of sudomotor activity such as quantitation of
ulations, since all of our patients were diabetics. sweat gland output in response to acetylcholine ion-
T h e SSR was abnormal more often in patients with tophoresis,".' ' since this represents another mea-
than without symptoms of' autonomic involvement sure of peripheral autonomic function. We are cur-
(P < 0.05), although no correlation with specific rently pursuing this question.
symptoms was observed. However, it should be noted
that most of the autonomic symptoms such as gas- Addendum: In a subsequent study of 18 patients
troparesis, bladder atony, and to some extent im- with more severe diabetic neuropathy, absence of
potence are due to parasympathetic dysfunction. SSR appeared to correlate with signs of axonal in-
Although orthostatic hypotension is related to sym- volvement such as reduced amplitude of sensory
pathetic dysfunction, it involves vasoconstrictor re- nerve action potentials and/or compound muscle
flexes mediated through fibers different from those action potentials.

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716 Sympathetic Skin Response MUSCLE & NERVE October 1987