ReviewReflex sympathetic dystrophy syndrome and neuromediators
Introduction
Despite an abundance of studies [1], the pathophysiology of reflex sympathetic dystrophy syndrome (RSDS) remains obscure [2]. The clinical abnormalities characteristic of RSDS have been ascribed to dysfunction of the sympathetic nervous system since Leriche [3] first put forward this theory in 1916. The increase in local sympathetic outflow in response to heightened afferent activity from the damaged area was thought to cause the symptoms (pain, redness, heat, and edema) [4], [5]. This hypothesis is consistent with the ability of surgical or chemical sympathectomy to alleviate the symptoms in some patients [6], [7]. However, current hypotheses for sympathetic system involvement in the pathogenesis of RSDS differ markedly from this classic theory, and other mechanisms have also been incriminated, most notably neurogenic inflammation.
Section snippets
Abnormalities in sympathetic activity in reflex sympathetic dystrophy syndrome
Several lines of evidence point to a decrease in sympathetic outflow from the affected limb. Thus, local cutaneous blood flow, which indirectly reflects sympathetic activity [8], is decreased in the affected limb [9] or even in both limbs [10], and skin temperature is identical to that in controls [11]. These findings suggest a decrease in sympathetic vasomotor tone at rest in the affected limb [12], [13], [14].
The blood flow difference between the healthy limb and the affected limb is dynamic
Local catecholamine levels are not elevated
One way of evaluating sympathetic function is to assay sympathetic neurotransmitters, i.e., catecholamines, in the bloodstream. Many studies have shown that disorders or procedures associated with a decrease in sympathetic activity are associated with a reduction in plasma catecholamine levels [19], [20], [21] and that these levels are correlated with sympathetic outflow [22].
No animal model for RSDS is available. The model that best replicates the many symptoms and behaviors found in RSDS is
Mechanisms of sensitization
The discovery that sympathetic outflow had decreased or was even normal in the affected limb prompted a search for explanations regarding the abnormal interaction between the sensory and sympathetic nervous systems. Sympathetic denervation increases blood vessel sensitivity to catecholamines [33]. Consequently, the blood vessels of the affected limb should show increased sensitivity to catecholamines. This was confirmed by Arnold et al. [34] for venous α-adrenoceptors. This increased vascular
Why does sympathectomy alleviate the symptoms?
Several studies reported clinical improvements after sympathectomy in patients with RSDS [37], [38], [39]. This effect is difficult to reconcile with the concept of catecholamine sensitization induced by denervation.
The most likely explanation is that sympathetic denervation is incomplete. This may explain the increase in cutaneous blood flow at the early stage of RSDS [9]. Chemical or surgical sympathectomy may reduce the concentrations of noradrenaline released in the synaptic cleft and, in
Neurogenic inflammation
Several neuromediators have been identified within nociceptive afferents, including substance P and calcitonin gene-related peptide (CGRP) [47], [48], [49], [50]. Substance P (SP) can induce vasodilation and plasma extravasation [51]. CGRP, also a potent vasodilator, causes lasting erythema [52], [53].
In 1920, Lewis hypothesized that the inflammatory symptoms seen in RSDS may be related to the release of algogenic vasodilating substances by sensory fiber nerve endings in response to axonal
Substance P
Substance P, a peptide composed of 11 amino acids, is found throughout the central nervous system. Substance P has many functions, and its distribution suggests a neurocrine or paracrine role [57]. Substance P is one of the main neurotransmitters in pain [58]. Its role in joint inflammation [59] and chronic neuropathies [60] is better understood. Substance P also causes vasodilation via direct interaction with endothelial cells. Similar to vasoactive intestinal polypeptide (VIP), neurotensin,
Sympathetic neuromediators may contribute to RSDS
Sympathetic mediators other than catecholamines may contribute to the pathophysiology of RSDS.
Conclusion
Abnormal sympathetic responses cannot explain all the symptoms of RSDS [6], [42], [84]. It has been established that RSDS is not due to sympathetic hyperactivity, and there is evidence suggesting increased adrenergic sensitivity. Neurogenic inflammation at the lesion site with neuromediator accumulation or depletion probably contributes to precipitate and/or perpetuate RSDS [36]. However, other mechanisms are being examined, particularly central mechanisms such as loss of descending inhibition
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