M. Driessens, PhD, G. Verheyen, MD, K. Deckers, MD, H. Dijs, MD, P. Blockx, MD.
Hospital where the work was done:
University Hospital Antwerp, Belgium Department of Physical Medicine and Rehabilitation and Department of Nuclear Medicine.
Authors address:
Prof. Dr. Marc Driessens, PhD, Department of Physical Medicine and Rehahilitation, Antwerp University Hospital, Wilrijkstraat 10, B-2560 Edegem, Belgium. Phone: 00/32/3/821.35.89 Fax: 003/32/3/825.43.17
List with names, current appointment and full postal address of the authors:
M. Driessens, PhD - Head of Department - Department of Physical Medicine & Rehabilitation - University Hospital Antwerp - Wilrijkstraat 10 - B-2650 EDEGEM - Belgium
G. Verheyen, MD - Senior resident - Department of Physical Medicine & Rehabilitation - University Hospital Antwerp - Wilrijkstraat 10 - E3-2650 EDEGEM - Belgium
K. Deckers, MD - Resident- Department of Physical Medicine & Rehabilitation - University Hospital Antwerp - Wilrijkstraat 10 - B-2650 EDEGEM - Belgium
H. Dijs, MD - Resident- Department of Physical Medicine & Rehabilitation - University Hospital Antwerp - Wilrijkstraat 10 - 13-2650 EDEGEM - Belgium
P. Blockx, PhD - Head of Department, Department of Nuclear Medicine - University Hospital Antwerp - Wilrijkstraat 10 - 13-2650 EDEGEM - Belgium
Summary:
The therapeutic and vascular effect of subcutaneously administered calcitonin was evaluated in 56 patients with reflex sympathetic dystrophy (RSD) stage I and compared with a control group of 20 patients. For this purpose, the vascular scintigraphy with 99mTc labeled human serum albumin was used, along with the clinical evolution. A marked improvement or even complete disappearance of the symptoms and complaint was ohserved in almost all patients after 3 to 15 weeks. The vascular scintigraphy showed a significant reduction of the vascular parameters after treatment with calcitonin which parallelled the clinical improvements. This not only allows the vascular scintigraphy to be used for staging of RSD but also to follow the course of the disease during treatment. Furthermore, it also suggests that in man calcitonin has a vasoconstrictive effect on bone tissue, as has previously been shown in dogs.
Keywords:
Reflex sympathetic dystrophy syndrome - drug treatment - calcitonin - bone scintigraphy - vascular scintigraphy.
Reflex Sympathetic Dystrophy (RSD) is still frequently regarded as a rather ill-defined condition. Also, the pathophysiological mechanisms are still largely unknown, although many theories and etiopathological factors have heen postulated (1,2,3,4,5,6,7). It is therefore not surprising, that there appears to exist little uniformity with respect to the diagnostic criteria, treatment and management of the disease (1,3,6,8,9,10,11,12,13), although a late diagnosis or inadequate treatment may have dramatic consequences and lead to severe definite disability.
The clinical course of untreated RSD can be schematically divided into 3 stages (2,12):
- stage I or hypertrophic stage, characterized by pain, oedema and swelling, hypersudation, warm skin and redness.
- stage II or atrophic stage, characterized by pain, articular stiffening, cyanosis, atrophy and cold skin.
- stage III, characterized by a decrease or disappearance of cyanosis and pain with remaining atrophy and permanent loss of joint motion.
The transition from one stage to the other is gradual (between stage I and II one also speaks of the dystrophic stage) and the signs and symptoms may overlap between the various stages. Furthermore, not all signs and symptoms are always present and the clinical picture is in fact usually incomplete. It is therefore often difficult to establish the diagnosis of the disease on clinical grounds only, whereas accurate staging remains impossihle using these criteria.
A positive bone scintigraphy is considered to be a necessary condition to establish the diagnosis of RSD (3). Furthermore, the increased uptake of the bone tracer should extend to an entire region and not be confined to e.g. the site of a fracture. Thus, in RSD of the hand (fig. I) for example, the increased tracer uptake should involve all of the distal radius, carpus, metacarpus and all small joints of the fingers. Exceptions to this rule are the radial, parcellar and partial algodystrophies (5,14), which are characterized by very localized pathological changes in the region of a joint. These conditions, however, occur only rarely.
On the other hand, RSD should be distinguished from pseudodystrophy (2), a syndrome which is often misleadingly called "RSD" with hypofixation on bone scan (15).
In order to determine the correct stage of the disease, the vascular scintigraphy with 99mTc human serum albumine (HSA) was developed (16,17), as the three-phase bone scintigraphy cannot be used for this purpose (l8, l9).
Using the HSA vascular scintigraphy, it was established that in stage I there exists an increased blood volume in the affected parts (joints) as well as an increased blood flow rate and reduced peripheral vascular resistance (vasodilation) (Fig. 2). In stage II, the findings are opposite: decreased blood flow and vasoconstriction (2). As previous animal studies have shown that calcitonin has a vasoconstrictive effect on bone blood vessels (20), it seems logical that, if this is also the case in man, calcitonin should be a suitable therapy in RSD stage I but not in stage II.
Nevertheless, some patients with RSD stage I do not respond to treatment with calcitonin and show further deterioration, followed by an evolution to stage II. This experience can partially be explained by classic phenomena: patient compliance, side effects, antibody formation to calcitonin, ... But also the time at which therapy is started could play an important role. Indeed, those cases with a later diagnosis (dystrophic and atrophic stage) and later onset of treatment are more likely to fail to respond to calcitonin.
The aim of the present study was to evaluate the therapeutic and vascular effect of calcitonin started at a very early stage in patients with RSD stage I by means of the HSA vascular scintigraphy along with the clinical evolution.
A group of 56 patients of the early treatment group (group I) was considered with evidence of RSD on clinical grounds and had positive bone scintigraphy. Only patients with a recent onset of the disease were selected (median duration of symptoms 6 weeks; range 4-9 weeks).
No distinction was made with regard to age or sex of the patients, nor with regard to the different locations of RSD or differences in etiology. Care was taken to include only those patients who had received no previous medical treatment. The vascular scintigraphy was used for staging of the disease. All patients had RSD stage I, which was logical because of the early diagnosis.
This technique is described in detail elsewhere (2,16,17,18,19). To start, 5 mCi 99mTc labeled HSA (185mBq) is injected intravenously as a short bolus into a non-affected part of the body and the radio-activity is registered simultaneously over the affected site and the corresponding heterolateral healthy site. A time-activity curve is then calculated for both sites, in which three phases can be distinguished:
* a vascular inflow phase with a maximal duration of three minutes,
* an intermediate phase: 3 - 10 minutes,
* an equilibrium phase, reached after a maximum of ten minutes after which the tracer activity remains constant.
As has been shown previously (2,18), in RSD stage I the time-activity curve on the pathological (P) site starts sooner and increases more rapidly during the vascular inflow phase than on the normal (N) site, reflecting an increased bloodflow due to local vasodilatation. In the equilibrium phase a higher activity is also obtained, reflecting an increased blood volume (fig.2).
Determination of the ratio of the number of counts at the pathological site to the number of counts at the normal site (P/N ratio) allows quantification and statistical analysis ot the results.
In normal persons, the ratio amounts to 100% + 10%, both during the vascular inflow phase and the equilibrium phase.
In the present study, the vascular scintigraphy was performed at least three times for each patient: once before the start of treatment, once or more during treatment and finally after treatment completion. Differences in the vascular parameters (P/N ratio during the vascular inflow phase and equilibrium phase) were evaluated and correlated with the clinical evolution.
All patients were treated with synthetic salmon calcitonin, administered subcutaneously at a dose of 100 IU daily. The initial frequency of administration was 5 times per week in all cases.
The vascular scintigraphy and clinical examination were repeated at four-weekly intervals.
As soon as a significant improvement (reduction of the P/N ratio by an amount of more than 50% e.g. from 200 to 150 %, and major alleviation of joint tenderness, stifness and swelling) was obtained, the rate of calcitonin administration was reduced to three times per week.
Treatment was discontinued when the clinical recovery was judged satisfactory and the vascular parameters had normalized or stabilized. The total length of treatment was therefore not the same for each patient, but rather dependent on the evolution during treatment.
In addition to the treatment with synthetic salmon calcitonin, patients received supportive physical therapy: mobilisation of the affected parts below pain threshold, interferential currents and sequential bathing of the affected joints in cold and warm water.
In order to evaluate the effect of calcitonin on the vascular parameters in the early treatment group, the P/N ratio's after treatment (8 to 16 weeks) were compared with the P/N ratio's of a group of control patients (n = 20). These latter patients had a comparable time of onset of RSD and the disease extended over 3 to 5 months. Physiotherapy was the sole treatment. At the time of vascular scintigraphy, clinical evidence of disease stage I was still present.
In group I fifty six patients with RSD stage I were entered, 34 female and 22 male. The average age was 50,5 years (range 18 to 82 years). Precipitating factors of RSD included fractures (n=28), distortions (n=ll), surgical intervention (n=2) and acute arthritis of the wrist (n=l). There were 9 cases of shoulder-hand syndrome in hemiplegic patients and 4 cases were judged to be idiopathic.
The localization included most frequently the anklefoot (n=30), followed by the wrist and hand (including the shoulder-hand-syndrome) (n=20), the knee (n=3) and shoulder (isolated) (n=3). The duration of treatment ranged from 8 to 16 weeks (mean 13,1 weeks).
The most common side effects observed in the treatment with calcitonin were pain at the site of injection, flushing and nausea. Twelve patients dropped out during the course of the study due to intolerance to calcitonin (n=1) or to insufficient follow-up (n=11).
The remaining patients in the study group (n=44) all followed treatment with calcitonin until normalization of the vascular scintigraphy or clinical remission, except one patient who showed no improvement after two months ot treatment and evolved to stage II.
The P/N ratio's during the vascular inflow phase and equilibrium phase before and after treatment are shown in table I. Statistical analysis (Wilcoxon test for paired observations) showed a highly significant difference between the P/N ratio's before and after treatment, for both the vascular inflow phase (p<0.005) and the equilibrium phase (p<0.005).
| Group I n=4 | median |
range |
P |
|
| Inflow phase | Before
After |
161
109 |
114-348
63-219 |
<0.005 |
| Equilibrium phase | Before
After |
131
107 |
110-257
89-171 |
<0.005 |
In all patients, except one, the clinical evolution was favourable and seemed to parallel the reduction or normalization of the vascular parameters.
In the control group (group II) 20 patients were included, 12 females, 8 males. The average age was 48 ,0 years (range 25-71). The initial disorder was a fracture in 8 patients, a distortion in 6 patients, 3 shoulder-hand syndromes in hemiplegics and 3 idiopathic cases.
Ankle and foot were affected in 10 cases, hand and wrist in 6, the shoulder in 3 patients and the knee in one patient.
Compared with the control group, there was a highly significant difference in group I for the P/N ratio's after treatment (table II) (Wilcoxon test for unpaired observations).
median |
range |
P |
||
| Inflow | Group I after treatment
Controls |
109
138 |
63-219
108-336 |
<0.0001 |
| Equilibrium | Group I after treatment
Controls |
107
129 |
89-171
109-425 |
<0.0001 |
Complete normalization of the vascular scintigraphic parameters, however, was not always observed, in spite of a very satisfactory clinical condition and good recovely of functionality.
Further analysis of the results (table III) shows that there is no significant difference between the P/N ratio's of the vascular inflow phase and equilibrium phase after treatment, although this did exist before treatment (Wilcoxon test for unpaired observations).
| Group I n=4 | median |
range |
P |
|
| Before treatment | Inflow
Equilibrium |
161
131 |
114-348
110-257 |
<0.0002 |
| After treatment | Inflow
Equilibrium |
111
107 |
63-219
89-171 |
<0.25 |
The results of the present study confirm, that calcitonin is very effective in the treatment of RSD if the diagnosis is based on a positive bone scan and if the treatment is started early in stage I. A marked alleviation or even complete disappearance of clinical symptoms was achieved in nearly all patients after 8 to 16 weeks with good functional recovery of the affected limb. In none of the 44 patients except one a progression to RSD stage II was observed, while this is thought to be the rule in untreated cases of RSD.
Side effects of the treatment with calcitonin were encountered relatively infrequently and in only 1 case had the treatment to be stopped for intolerance (persisting nausea).
Preliminary studies showed a significant reduction of the vascular scintigraphic parameters (P/N ratio during the vascular inflow phase and equilibrium phase) after treatment with calcitonin (17,18). This was confirmed in the present study and it was found that the reduction of the vascular parameters parallelled the clinical improvements.
After calcitonin therapy there was a highly significant difference in P/N ratio's compared with the control group. All patients of the latter groups still showed clinical and scintigraphic evidence of RSD stage I and increased vascular parameters after a compalable period of time elapsed since onset.
These findings point to a decrease of the initially pathologically increased bloodflow, vasodilatation and blood volume and suggest that in man calcitonin has a vasoconstrictive effect on the blood vessels of bone as has previously been shown in dogs (20).
Complete normalization of the vascular parameters after treatment with calcitonin, however, was not always obtained in spite of a very satisfactory clinical and functional recovery. A further progressive normalization of these parameters usually occurs in due time as was observed in a previous study (2).
It was further established, that the significant difference between the P/N ratio's during the vascular inflow phase and equilibrium phase observed before treatment with calcitonin, does no longer exists after treatment. This means that the decrease in peripheral vascular resistance was normalized. The hypothesis is that calcitonin therapy can only be effective when started before the maximal hypervascularization is reached. If this is not the case, the progress to stage II may be irreversible.
The excellent success rate of calcitonin therapy in this study (97%) is in contradiction with most reports in the literature. This can be explained by two facts: only patients with a typical picture of RSD on bone scintigraphy together with recent onset of the disease and a stage I on vascular scintigraphy were included.
When other conditions (pseudodystrophy and disuse, hysteric conversion, posttraumatic arthritis, ...) are incorrectly regarded as RSD and included in clinical studies, it is not surprising that the success rate of different therapies is disappointing.
As already mentioned, the selection of RSD patients for epidemiologic or therapeutic programs is frequently incorrect due to inclusion of patients with the pseudodystrophy syndrome which is usually referred to as " RSD with hypofixation on bone scan".
Obviously, it is difficult to understand in which way the same condition could present as a hyperfxation on bone scan in some patients, and as a hypofixation in others. In reality pseudodystrophy is a consequence of disuse in patients who suffer first of all from psychological or relational problems with secondary deterioration on physical behaviour. Many of them are children or young women, often with a high incidence of hysterical conversion. As in RSD the initial event in pseudodystrophy is often a trauma, but patients with pseudodystrophy disuse show a hypovascularization from the start (2). From a vascular point of view, therapeutic management is of course totally different from RSD stage I where an increase of bone blood flow and volume is found. Also the psychological approach should be different.
Including these syndromes in studies on RSD contributes doubtlessly to the confusion found in the literature about the diagnosis and treatment of the disease. Steps should be taken to come to an international agreement on criteria to be used in the diagnosis of RSD.
A positive bone scan with typical pattern should be mandatory for the diagnosis of RSD. Scintigraphy should help in differentiating RSD from pseudodystrophy and other syndromes.
This study confirms that the vascular scintigraphy, apart from being indispensable in determining the correct stage of RSD, is also useful to follow the course of the disease during treatment. It is suggested that the vascular scintigraphy should be repeated every four weeks. The rate of administration of calcitonin should only be decreased (from daily to three times a week) when a significant reduction of the P/N ratio's has been obtained. The treatment should only be stopped when the vascular parameters have stabilized near normal values, together with a clinical cure.