Reflex sympathetic dystrophy: Does sympathetic dysfunction originate from peripheral neuropathy?

doi:10.1016/S0039-6060(96)80115-2

Surgery

Volume 119, Issue 3, March 1996, Pages 288-296

https://doi.org/10.1016/S0039-6060(96)80115-2 Get rights and content

Background. Sympathetic dysfunction in reflex sympathetic dystrophy (RSD) has been purported to consist of an afferently-induced increase in efferent sympathetic nerve impulses (somato-sympathetic reflex) and/or denervation-induced supersensitivity to catecholamines. In addition, both the central and peripheral nervous systems have been claimed to be involved. It was the aim of this study to obtain more insights into these underlying mechanisms.

Methods. In the affected extremities of 42 patients with RSD we investigated as indirect measures of sympathetic (dys)function: (1) skin blood flow and the vasoconstrictive response to dependency of skin microvessels by means of laser Doppler flowmetry (distal to the site of trauma), (2) relative distention of the brachial artery and changes in relative distention consequent to a cold pressor test by means of ultrasonic vessel wall tracking (proximal to the site of trauma), and (3) arterial blood pressures by means of the Finapres technique. Both provocation tests induce a sympathetically mediated response. Patients were divided into three categories according to their perception of skin temperature in their injured limb (stage I, stationary warmth sensation; stage II, intermittent warmth and cold sensation; or stage III, stationary cold sensation).

Results. Distal to the site of trauma, when compared with controls, skin blood flow was increased at stage I and decreased at stages II and III, whereas the vasoconstrictive response to dependency was impaired at all three stages. Proximally, when compared with controls, relative distention of the brachial artery and its response to the cold pressor test were decreased at all three stages. No differences were observed in pulse pressure between patient groups and controls.

Conclusions. These results suggest that sympathetic dysfunction in extremities of patients with RSD distal to the site of trauma consists of hypersensitivity to catecholamines at stages II and III as a result of autonomic denervation at stage I, whereas proximal to the site of trauma sympathetic nerve impulses may be increased at all three stages.

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Paradoxically, though, norepinephrine levels were found to be lower in the affected than contralateral limb of CRPS patients (Drummond et al., 1991; Harden et al., 1994). Biopsies taken from people with chronic CRPS-1 suggest that this apparent paradox is most likely explained by increased density or responsiveness of alpha adrenoceptors in the skin (Kurvers et al., 1996; Drummond and Finch, 2004). Consistent with this, subcutaneous arteries from the affected side were less responsive to electrical stimulation, but showed a higher sensitivity to α1-adrenoceptor stimulation (Kurvers et al., 1998).
Acute Complex Regional Pain Syndrome (CRPS) is associated with signs of inflammation such as increased skin temperature, oedema, skin colour changes and pain. Pro-inflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-1beta, IL-6) are up-regulated, whereas anti-inflammatory cytokines (IL-4, IL-10) are diminished. Adaptive immunity seems to be involved in CRPS pathophysiology as many patients have autoantibodies directed against β₂ adrenergic and muscarinic-2 receptors. In an animal tibial fracture model changes in the innate immune response such as up-regulation of keratinocytes are also found. Additionally, CRPS is accompanied by increased neurogenic inflammation which depends mainly on neuropeptides such as CGRP and Substance P.
Besides inflammatory signs, sympathetic nervous system involvement in CRPS results in cool skin, increased sweating and sympathetically-maintained pain. The norepinephrine level is lower in the CRPS-affected than contralateral limb, but sympathetic sprouting and up-regulation of alpha-adrenoceptors may result in an adrenergic supersensitivity.
The sympathetic nervous system and inflammation interact: norepinephrine influences the immune system and the production of cytokines. There is substantial evidence that this interaction contributes to the pathophysiology and clinical presentation of CRPS, but this interaction is not straightforward. How inflammation in CRPS might be exaggerated by sympathetic transmitters requires further elucidation.
Complex regional pain syndrome: A comprehensive and critical review
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At first glance this seems to argue against adrenergic supersensitivity due to decreased catecholamine concentrations. However, it actually accords with data showing that sympathetic hypofunction is confined to the distal portion of the affected extremity, whereas there is an increase of sympathetic outflow proximal to the site of the trauma that precipitated RSD, as evidenced by decreased relative brachial artery distention at baseline [112]. It is frequently argued that the increased sweat production observed in patients with CRPS must be centrally mediated because sweat glands do not develop denervation supersensitivity.
Complex regional pain syndrome (CRPS) is a term used to describe a variety of disorders characterized by spontaneous or stimulus-induced pain that is disproportional to the inciting event and accompanied by a myriad of autonomic and motor disturbances in highly variable combinations. There are no standards which can be applied to the diagnosis and would fulfill definitions of evidence-based medicine. Indeed, there are almost as many diagnostic criteria as there are names to this disorder. The umbrella term CRPS has been subdivided into type I and type II. CRPS I is intended to encompass reflex sympathetic dystrophy and similar disorders without a nerve injury; while CRPS II occurs after damage to a peripheral nerve. There are numerous etiological pathophysiological events that have been incriminated in development of CRPS, including inflammation, autoimmune responses, abnormal cytokine production, sympathetic-sensory disorders, altered blood flow and central cortical reorganization. However, the number of studies that have included appropriate controls and have sufficient numbers of patients to allow statistical analysis with appropriate power calculations is vanishingly small. This has led to over-diagnosis and often excessive pharmacotherapy and even unnecessary surgical interventions. In this review we provide a detailed critical overview of not only the history of CRPS, but also the epidemiology, the clinical features, the pathophysiological studies, the proposed criteria, the therapy and, in particular, an emphasis that future research should apply more rigorous standards to allow a better understanding of CRPS, i.e. what it is, if it is, and when it is.
The pattern of norepinephline release in the hypothalamic paraventricular nucleus in response to repeated peripheral nerve injury differs in the acute and chronic stage in conscious rats
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We investigated the change in norepinephrine (NE) release in the hypothalamic paraventricular nucleus (PVN) in response to ligature of the median and ulnar nerves using a brain microdialysis technique in conscious rats. Primary ligature was performed of the right median and ulnar nerves, and then repeated injury was performed on the left nerves 6 h or 3 weeks after the primary ligature. Primary ligature of the nerves produced a significant increase that peaked at a mean 330% above basal NE release in the first 20 min. The NE release after reinjury 6 h later was significantly higher (a peak of 650%) than after primary nerve injury, although that at 3 weeks was significantly lower (a peak of 280%). The present study demonstrated that peripheral nerve injury induces an elevated response of the PVN, which is an integral center of the autonomic nervous system. NE release after reinjury differed in the acute and chronic stages.
Autonomic nervous function assessment using thermal reactivity of microcirculation
2000, Clinical Neurophysiology
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However, during hyperventilation no changes in microcirculation can be measured (Steurer et al., 1995). The vasomotor response was achieved only on the fingers, but not on the volar forearm (Kurvers et al., 1996) and was suppressed by amitriptyline (Muck-Weymann and Rechlin, 1996). Another method uses severe and prolonged local cold to assess the changes on the cutaneous microcirculation.
There are only a few reliable objective methods of diagnosing peripheral neuronal damage suitable for routine use; the most important is based on measurement of nerve conduction velocity, which only shows changes when severe disturbances are already present. However, it is precisely at this stage that the possibilities of therapy are no longer satisfactory. As small fibres are affected earlier in the course of most forms of PNP than the large ones, assessment of afferent as well as efferent C-fibre function gains importance in the management of this widespread disease. In assessment of autonomic dysfunction, variability of the heartbeat with deep breathing or the Valsalva manoeuvre is a good and generally accepted test, although not strongly associated with other PNP test abnormalities. However, axonal degeneration starts in the most distal parts of the axon due to impaired axonal transport. Therefore, the longest C-fibres, i.e. in the lower extremities, are affected first, and incipient changes are most prominent there. For this reason HLDF, a reflex response of the skin blood flow stimulated by heat, has advantages in assessment of early C-fibre dysfunction. Considering the fact that the afferent and efferent sympathetic C-fibres are involved in regulation of microcirculation, the skin blood flow regulation is investigated by means of laser Doppler flowmetry. The microcirculation is stimulated by heat and the reaction of microcirculation is assessed as a value for the function of afferent and efferent (sympathetic) C-fibres. The results of this method are in close correlation with electrophysiologic tests, which is not achieved with sudomotor function.
Leg muscle reflexes mediated by cutaneous A-β fibres are normal during gait in reflex sympathetic dystrophy
2000, Clinical Neurophysiology
Objectives: Reflex sympathetic dystrophy (RSD) is, from the onset, characterized by various neurological deficits such as an alteration of sensation and a decrease in muscle strength. We investigated if afferent A-β fibre-mediated reflexes are changed in lower extremities affected by acute RSD.
Methods: The involvement of these fibres was determined by analyzing reflex responses from the tibialis anterior (TA) and biceps femoris (BF) muscles after electrical stimulation of the sural nerve. The reflexes were studied during walking on a treadmill to investigate whether the abnormalities in gait of the patients were related either to abnormal amplitudes or deficient phase-dependent modulation of reflexes. In 5 patients with acute RSD of the leg and 5 healthy volunteers these reflex responses were determined during the early and late swing phase of the step cycle.
Results: No significant difference was found between the RSD and the volunteers. During early swing the mean amplitude of the facilitatory P2 responses in BF and TA increased as a function of stimulus intensity (1.5, 2 and 2.5 times the perception threshold) in both groups. At end swing the same stimuli induced suppressive responses in TA. This phase-dependent reflex reversal from facilitation in early swing to suppression in late swing occurred equally in both groups.
Conclusions: In the acute phase of RSD of the lower extremity there is no evidence for abnormal A-β fibre-mediated reflexes or for defective regulation of such reflexes. This finding has implications for both the theory on RSD pathophysiology and RSD models, which are based on abnormal functioning of A-β fibres.
Severe complications of reflex sympathetic dystrophy: Infection, ulcers, chronic edema, dystonia, and myoclonus
1998, Archives of Physical Medicine and Rehabilitation
Objective: To determine the prevalence, type of complication, predisposing factors, and treatment for severe complications in a population of reflex sympathetic dystrophy (RSD) patients.
Design: Retrospective analysis of the data from RSD patients collected over a 12-year period, to investigate the involvement of predisposing factors in an RSD population without severe complications compared with an RSD population with severe complications.
Setting: Outpatient clinic of a department of surgery of a university hospital.
Patients: A total of 1,006 patients with the diagnosis of RSD established according to prospectively defined criteria.
Main Outcome Measures: The signs and symptoms of every RSD patient who visited the department were prospectively documented in the medical history; these data were retrospectively analyzed with special regard to RSD with severe complications-infection, ulcers, chronic edema, dystonia, and/or myoclonus for prevalence, type of complication, and treatment.
Results: Seventy-four RSD patients who were mostly young and female developed severe complications. More than one complication occurred in 91% of the affected extremities. Severe complications developed more frequently in the lower extremity (65%). In patients in whom the acute RSD started with a decreased skin temperature of the affected extremity, severe complications developed significantly more often than in acute RSD patients with a warm skin temperature of the extremity from the onset of the disease (p < .001).
Conclusions: It is important to recognize “cold” RSD immediately at the onset of the disease because this group of RSD patients has a higher risk of developing a severe complication, mostly followed by a severe disability that is resistant to therapy.

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^*: Supported by a grant from the Dutch Heart Foundation (NHS, D 89008).

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Reflex sympathetic dystrophy: Does sympathetic dysfunction originate from peripheral neuropathy?*

Am J Surg

Brain Res

Neuropharmacology

Pain

Eur J Vasc Surg

Lancet

Oral Surg Oral Med Oral Pathol

Microvasc Res

Ultrasound Med Biol

J Am Coll Cardiol

J Hand Surg Br

J Hand Surg Am

Pain

Pain

Pain

Neurologic aspects of clinical manifestations, pathophysiology and therapy of reflex sympathetic dystrophy (causalgia, Sudeck's disease)

Nervenarzt

Skeletal trauma

Causalgia and other reflex sympathetic dystrophies

Postgrad Med

Characteristics of a spinal sympathetic reflex

J Physiol

Treatment of postraumatic sympathetic dystrophy (Sudeck's atrophy) with guanethidine and ketanserin

Pain Clinic

Increased venous alpha-adrenoceptor responsiveness in patients with reflex sympathetic dystrophy

Ann Intern Med

Reflex sympathetic dystrophy: the significance of differing plasma catecholamine concentrations in affected and unaffected limbs

Brain

Reflex sympathetic dystrophy, result of autonomic denervation?

Clin Sci

Effect of indirect heating on the postural control of skin blood flow in the human foot

Clin Sci

The relationship between macro-and microcirculation clinical aspects

Acta Pharmacol Toxicol Copenh

Circulatory physiology: the essentials