Normal sympathetic nervous system response in
reflex sympathetic dystrophy
María de Lourdes Figuerola*,***
Gloria Levin*
Alicia Bertotti**
Jorge Ferreiro***
Marta Barontini*
* CEDIE, CONICET, Ricardo Gutiérrez Children’s Hospital;
** Service of Neurophysiology;
*** Service of Neurology, José de San Martín Hospital,
Buenos Aires, Argentina
Reprint requests to: Prof. María de Lourdes Figuerola
Centro de Investigaciones Endocrinológicas
Hospital de Niños Ricardo Gutiérrez
Gallo 1360
(1425) Buenos Aires, Argentina
E-mail: mfiguerola@intramed.net.ar
Accepted for publication: May 8, 2002
Summary
We evaluated sympathetic nervous system activity by
sympathetic skin response (SSR) recording and we further investigated sympathetic and opioid outflow indirectly in patients with features of reflex sympathetic dystrophy by measuring concentrations of plasma catecholamines (CAs) and their metabolites and plasma metenkephalin (ME), before and after corticoid treatment. Six
patients were studied. Basal SSR latencies, morphologies and amplitudes were normal in five patients. In one
woman, latency and amplitude were also normal but the
morphology was disturbed. Basal plasma ME, CA and
metabolite levels were similar in the affected and non-affected limbs and a significant increase in plasma ME
concentrations was observed in both affected and nonaffected limbs after two weeks of steroid treatment. Altogether these results point to an adaptive supersensitivity
rather than a sympathetic hyperactivity in this syndrome; also, they indicate that the therapeutic effect of
steroids adds, to their known anti-inflammatory action, a
stimulatory action on the endogenous opioid system.
KEY WORDS: Catecholamines, complex regional pain syndrome, metenkephalin, reflex sympathetic dystrophy, sympathetic skin response.
Introduction
Reflex sympathetic dystrophy (RSD) is a complication
occurring even after minor injury to, or operation on, a
limb. RSD is a descriptive diagnostic term that implicates the sympathetic nervous system in a reflex response to injury, with consequent dystrophic changes.
Functional Neurology 2002; 17(2): 77-81
The pathophysiology of RSD remains unknown. In a revised taxonomic system of RSD, disorders previously
considered to be RSD or causalgia were classified under the term complex regional pain syndrome (CRPS),
which is based entirely on clinical criteria. The criteria
for inclusion under this general term CRPS are the
presence of regional pain – spontaneous and/or evoked
– and other sensory changes following a noxious event.
There are two types of CRPS, I and II, corresponding to
RDS and causalgia respectively (1). It has been hypothesized that if injury to a limb normally provokes a
rise in opioid-based modulation of activity in the regional sympathetic ganglia, it is possible that failure of this
process occurs in some susceptible individuals, leading
to localized signs of opioid withdrawal (2). The pain is
associated with changes in skin color and temperature,
abnormal sweating, edema and sometimes motor abnormalities. Hence, the sympathetic skin response
(SSR) has been postulated as a diagnostic test (3).
We evaluated sympathetic nervous system activity by
SSR recording and we further investigated sympathetic
and opioid outflow indirectly in patients with type I CRPS
features, by measuring concentrations of plasma catecholamines (CAs) and their metabolites, and plasma
met-enkephalin (ME). Venous blood was taken from the
painful and normal limbs before and after steroid treatment.
Materials and methods
Six patients, four males and two females aged 26 to 76,
with clinical findings for type I CRPS were studied. Diagnosis was made according to the consensus of the International Association for the Study of Pain. All the patients had an upper limb affected (right side in 4 and left
side in 2). The onset of the syndrome was preceded by
a noxious event involving the limb – distortion (3 cases),
bone fracture (2 cases) and skin lesions (1 case) – occurring 2 weeks to 4 months beforehand. Clinical characteristics of patients are shown in Table I (see over).
All 6 patients were tested for SSR. To obtain SSRs, superficial electrodes were placed on the palm (active)
and referenced to the dorsum of the hand (indifferent).
The ground electrode was proximal to the recording
electrodes. Simultaneous bilateral recordings from the
upper limbs were made (4). The recording time was 10
sec, the lower limit 0.5 Hz, and the upper limit 2000 Hz.
Electrical stimulation was provoked with a constant current stimulus (0.2 msec, supramaximal, usually 10-30
mAmp). The stimulus was strong but well tolerated. It
was applied at irregular intervals and at an approximate
frequency of 1/min to avoid habituation. Patients were
relaxed and free from any acoustic disturbances or time
pressure. Light was dim. Room temperature was com-
77
M. Figuerola et al.
Table I - Clinical characteristics of CRPS type I patients
Patient
Sex
Age
Initial Injury
Duration (mths)
Pain
Temperature
difference
Hyperhydrosis
Edema
1
M
26
upper limb distortion
0.5
yes
yes
yes
yes
2
M
35
elbow fracture
1.6
yes
yes
yes
no
3
F
52
shoulder fracture
4
yes
yes
no
yes
4
M
48
upper limb distortion
3
yes
no
yes
yes
5
M
76
skin injury
3.4
yes
yes
yes
yes
6
F
41
upper limb distortion
4
yes
yes
yes
yes
fortable and skin surface temperature was 32°C. Latencies from the palm ranging from 1.3 to 1.5 msec and
amplitudes > 200 µV were considered normal.
Blood samples for simultaneous plasma ME and CA
measurement were taken from both upper limbs with
subjects resting in supine position. We used an indwelling intravenous needle inserted 30 minutes before
sampling. All subjects were tested between 9 and 10
a.m., before and after two weeks of treatment with
1mg/kg/day prednisone.
Blood for ME measurements was put into polypropylene tubes kept on ice containing 10 mg/ml of a protease inhibitor cocktail (10,000 IUC/ml aprotinin, 0.23
mM citric acid, and 0.024 mM EDTA). Blood was centrifuged at 4°C and plasma was immediately stored at 20°C. ME was extracted from plasma by adsorption
chromatography in Amberlite XAD-2 columns. ME was
measured by radioimmunoassay using specific antiserum (5). Under these experimental conditions, ME
immunoreactivity corresponded to the free ME molecule as evidenced by reverse-phase high pressure liquid chromatography (RP-HPLC) (5). Iodinated ME was
used as a tracer. Antiserum for ME showed a 100%
cross-reactivity with met-(O)-enkephalin, 0.3% with
leucine-enkephalin and less than 0.01% with leuenkephalin-arginine, dynorphin and endorphins (6).
Blood for free plasma CA (adrenaline (A), noradrenaline (NA), dopamine (DA)) and dihydroxyphenylglycol
(DHPG), dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC) measurements was
poured into plastic tubes kept on ice containing 5 µl heparin/ml whole blood. Plasma was immediately separated by centrifugation at 2000 g for 20 min at 4°C and
kept at -70°C until processed. Catechols in 1000 µl
aliquots of plasma were partially purified by batch alumina extraction, and separated by RP-HPLC using a
4.6 x 250 mm Zorbax R xC18 column (New England
Nuclear, Du Pont, Boston, MA, USA). Quantifications
were made by current produced upon exposure of the
column effluent to oxidizing and then reducing potentials in series using a triple-electrode system
(Coulochem II, ESA, Bedford, MA, USA) (7). Recovery
through the alumina extraction step averaged 70-80%
for CAs and 45-55% for DHPG. Catechol concentrations in each sample were corrected for recovery of a
dihydroxybenzylamine internal standard. Levels of DHPG, DOPA and DOPAC were further corrected for dif-
78
ferences in recovery of the internal standard and this
catechol in a mixture of external standard.
Written consent was obtained from all patients.
The significance of the differences found in patient
plasma levels from both sides before and after prednisone treatment was analyzed by T test for paired
samples. Data were expressed as mean ± SEM.
Results
Table II shows data from the SSR studies. Basal SSR
latencies, morphologies and amplitudes were normal in
five patients. In one woman (patient no. 6), amplitude
was lower but still within the normal range. Latency was
also normal but the morphology was disturbed.
Figure 1 shows the recording from a representative patient with normal SSR parameters and from patient 6.
Plasma ME concentrations in basal conditions in both
limbs are shown in Figure 2. Basal plasma ME levels
were similar for the affected and non-affected limbs:
0.21±0.01 and 0.24±0.01 pmol/ml respectively.
In spite of a tendency to lower plasma A and DOPAC
concentrations in the basal samples from the affected
limb, no significant differences could be observed in
plasma levels of DOPA, CA, DHPG (the intraneuronal
metabolite of NA), and DOPAC (the metabolite of DA)
between the two limbs explored (Table III).
After 2 weeks of prednisone treatment all patients im-
Table II - Individual SSR responses obtained after median
nerve stimulation on the affected side.
Patient
Latency
msec
Amplitude
µV
Morphology
1
1.45
1540
normal
2
1.38
2500
normal
3
1.48
750
normal
4
1.33
1700
normal
5
1.40
3410
normal
6
1.33
520
abnormal
Functional Neurology 2002; 17(2): 77-81
Normal SNS response in reflex sympathetic dystrophy
A significant increase in plasma ME concentrations was
observed in both affected and non-affected limbs after
two weeks of prednisone treatment: 0.33±0.02 and
0.34±0.02 pmol/ml respectively (p<0.003 vs basal values) (Fig. 2).
Discussion
Fig. 1 - SSR response. Upper panel: normal bilateral SSR obtained after median nerve stimulation in a representative patient. Lower panel: upper line represents the SSR obtained
from the affected limb (normal latency and amplitude; abnormal
configuration). Lower line represents the normal SSR obtained
from the unaffected limb (patient no. 6).
proved clinically. Clinical improvement was established
by a subjective improvement of spontaneous pain and
lack of painful response to mechanical stimuli.
No differences were found in plasma CA levels after
prednisone treatment (Table III).
Five of the six patients had normal values of plasma DA
(normal range: 0-200 pg/ml) and one patient presented
increased levels of plasma DA in the unaffected limb,
before and after prednisone treatment.
This study evaluates SSR, opioid and sympathetic activity simultaneously in CRPS I.
The pathogenesis of CRPS I is not yet understood, and
diagnosing and treating patients is difficult. SSR has
been advocated as a simple means of assessing sympathetic sudomotor outflow in central and peripheral
nervous system disorders. SSR is a change in skin potential following arousal stimulation, first described by
Tarchanoff (8). It is a polysynaptic reflex that is activated by a variety of afferent inputs (9). The final efferent
pathway involves pre- and post-ganglionic sympathetic
sudomotor fibers and ultimately activation of sweat
glands by the sympathetic outflow. The reflex is coordinated in the posterior hypothalamus, upper brain stem
reticular formation and spinal cord. The responses are
generated in deep layers of the skin by reflex activation
of sweat glands via cholinergic sudomotor sympathetic
efferent fibers. Because the reflex is multisynaptic, latency, amplitude, wave form and tendency to habituation are variable. The potentials may be mono, bi or
triphasic (4,9).
It has been reported that in RSD, the mean amplitude
of SSR in the involved limb is greater than in the uninvolved limb, and onset latency of SSR in the involved
limb is shorter than that of the uninvolved limb (9). Conversely, we found normal responses in 5/6 evaluated
patients. The only patient (number 6) who presented
the abnormal SSR response exhibited no other peculiarity. However, as in other generalized abnormalities
of sympathetic sudomotor dysfunction, autonomic dysfunction or small fiber neuropathy, the correlation of the
abnormal SSR is often poor. There is no close correlation between the presence or the absence of SSR and
the severity of the autonomic dysfunction. So the results are not conclusive.
Early features of CRPS I in a limb (inappropriate pain, altered cutaneous sensation, excessive sweating, periph-
Fig. 2 - Plasma ME levels in basal conditions and after prednisone treatment in both limbs.
Functional Neurology 2002; 17(2): 77-81
79
M. Figuerola et al.
Table III - Plasma levels of CA, DOPA, DOPAC and DHPG in the two limbs explored
Affected Limb
Non Affected Limb
Pre
Treatment
Post
Treatment
37±9
41±10
64±13
70±19
NA pg/ml
246±67
221±60
235±57
259±48
DA pg/ml
168±54
86±20
278±162
366±174
DOPA pg/ml
936±223
1072±283
896±159
898±239
1907±311
2108±191
4829±1136
3141±295
992±119
1100±157
867±135
1208±166
A pg/ml
DOPAC pg/ml
DHPG pg/ml
Pre
Treatment
Post
Treatment
Abbreviations: A = adrenaline; NA = noradrenaline; DA = dopamine; DOPA = dihydroxyphenylalanine; DOPAC = dihydroxyphenylacetic acid; DHPG = dihydroxyphenylglycol.
eral vascular instability and tremor) resemble the general
effects of autonomic arousal associated with opioid withdrawal. Injury to a limb normally provokes a rise in opioid-based modulation of activity in regional sympathetic
ganglia. It is possible that failure of this process occurs
in some susceptible individuals, leading to localized
signs of opioid withdrawal (2). The site of action of the
opioids within the ganglion would most probably be on
the presynaptic terminals of preganglionic nerve fibers
(10). Increased blood concentrations of opioids are
known to occur during strenuous muscular exercise (11).
This effect might be mirrored by decreased opioid activity within the stellate and lumbar sympathetic ganglia
when the adjacent limb is immobilized.
Considering a failure of the opioid-based modulation of
activity in regional sympathetic ganglia as responsible,
at least in part, for the syndrome, it is possible that the
common practice of immobilization of minor limb injuries could contribute to the abolition of regional opioid
modulation, by reducing neural traffic between limb and
spinal cord (2). However, basal plasma ME levels in our
patients were within our control range and we did not
find any differences when comparing painful and nonpainful sides.
The importance of the sympathetic nervous system in
the generation of pain has been the focus of a long, if
controversial, debate (12). Sympatholytic therapy can
abolish pain and hyperalgesia, and in CRPS patients
an intracutaneous injection of adrenoceptor agonists
rekindled pain and hyperalgesia. An explanation consistent with these findings is that primary afferents acquire a sensitivity to CAs, which in some conditions extends to the receptive terminals innervating a symptomatic skin region. On the other hand it has been assumed that an increase in sympathetic outflow causes
sweating and changes in peripheral blood flow in CRPS
I (13). However multiunit-microelectrode recordings of
sympathetic outflow to affected skin failed to confirm
that the sympathetic outflow is increased. Furthermore,
the vasoconstrictor tone was found to be reduced
rather than increased in the affected limb. Since CAs
and ME are released from the periphery (i.e., sympa-
80
thetic ganglia), levels should be similar on both sides of
the body if both limbs are kept in similar environments.
Different plasma concentrations in the painful and normal limbs would indicate that the local clearance rate
differed on the two sides.
Our results show a tendency of adrenaline and DOPAC
to be lower in the painful limb, so this entity appears to
be associated with reduced rather than increased sympathetic outflow.
We have no explanation for the higher plasma DA levels found in one patient in the unaffected limb.
No differences in plasma A concentrations between affected and unaffected limbs have been reported. Besides, plasma NA and DHPG levels have been found to
be lower on the painful side. These findings, like ours,
do not support the view that autonomic disturbances in
CRPS are due to sympathetic overactivity, but are more
consistent with an adaptive supersensitivity of the SNS
(13).
Sudeck in 1902 first attributed an inflammatory pathogenesis to CRPS I. The idea of an inflammatory pathogenesis is based on the observation that in the acute
phase all classical signs and symptoms of inflammation
are present. Moreover, the therapeutic effect of corticosteroids in some patients supports this idea (14). In
addition, scintigraphic investigations with marked immunoglobulins have shown an intraosseous plasma ex travasation in patients with CRPS I, which supports an
inflammatory component of the disorder (15).
It is difficult to explain the whole syndrome as exclusively peripheral. Lesioned afferent axons may generate spontaneous and evoked ectopic impulses, so the
decoding of both nociceptive and non-nociceptive afferent information exerted by supraspinal systems is
changed, resulting in distorted information processing
in CNS.
All our patients were treated with 1mg/kg/day prednisone and their symptoms improved. After two weeks
they were free from pain. At that moment an increase in
plasma ME concentration in both limbs was observed,
pointing to a general effect of steroid action. Previously,
we had found an increase in plasma ME levels after
Functional Neurology 2002; 17(2): 77-81
Normal SNS response in reflex sympathetic dystrophy
prednisone treatment in patients with cluster headache
(16).
Altogether, the results from this study seem to indicate
an adaptive supersensitivity rather than a sympathetic
hyperactivity in this syndrome. The therapeutic effect of
steroids adds to their known anti-inflammatory action a
stimulatory action on the endogenous opioid system.
Acknowledgments
Fundación René Barón kindly supported style correction of this paper.
Drs Barontini and Levin and Prof. Figuerola are senior
researchers from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Argentina.
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