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Rethinking reflex sympathetic dystrophy
Commentary
Rethinking Reflex Sympathetic Dystrophy Sandra R. Chap/an
r. Tanelian raises a number of cogent points in his evaluation of the literature pertaining to the diagnosis, pathophysiological basis, and treatment options for reflex sympathetic dystrophy (RSD). I would like to add my voice to his in questioning some of the assumptions that are prevalent regarding this perplexing disorder and add one or two further ruminations. Tanelian has largely addressed clinical issues; appropriately so, because no laboratory model for RSD presently exists. There are some speculations, however, drawn from laboratory experience with other neuropathic disorders, that may perhaps be legitimately added to consideration of the topic.
D
DIAGNOSIS OF RSD Lack of understanding of the pathophysiological basis of RSD means that, by definition, there can be no firm diagnostic gold standard. This alone should not unduly disturb us, given that there are many medical diagnoses that rest on a constellation of findings rather than a single test: rheumatic fever, systemic lupus erythematosis, and, under certain circumstances, preeclampsia, to name just a few. However, lack of a gold standard means that there is no criterion of "truth" against which to judge the sensitivity and specificity of the various diagnostic tests. Until the pathophysiology is better understood, the use of any "confirmatory" study such as a technetium scan may be questionable, because it opens the door to circular reasoning: defining a subclass of patients who are positive for that one study, whereas at best the study documents epiphenomena whose relationships to the true underlying disorder are From the Anesthesiology Research Laboratory, University of California-San Diego, La Jolla, CA. Reprint requests: Sandra R. Chaplan, MD, Anesthesiology Research Laboratory, 0818, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818.
Pain Forum 5(4): 257-261, 1996
unclear. Among the practical implications of this are the inability to define the "true" spectrum of RSD, from subclinical to clinical, and the risk of nonhomogeneity of groups in clinical studies due to lack of hard criteria for patient inclusion or exclusion. Most clinicians think they know RSD when they see it. Confidently affixinq a diagnosis of RSD, however, may at times be challenging. Although some patients appear to have stepped right from the textbook pages, others defy classification. What do we make of patients who have pain in the absence of marked trophic changes? Are these patients who have maintained activity of the limb despite pain and therefore have counteracted the manifestations of disuse, who have received some treatment and are partial treatment successes, or do they have a different form of neuropathic complaint-or are they malingerers? What about patients who have extremities with abnormal appearance, including edema, discoloration, and trophic changes, but who do not complain of pain (as may be encountered for example with poststroke patients)? Does the lack of pain complaint indicate that there exists a painless form of RSD, that these patients suffer from a different, painless disorder, or that the patient is unable to sense pain due to additional neurologic impairment?
WHAT ARE THE SIMILARITIES AND DIFFERENCES BETWEEN CAUSALGIA AND RSD? Dr. Tanelian raises the valid question of where RSD falls with respect to the spectrum of normal responses to injury of the nervous system. Do different injury etiologies cause the same picture, and does this matter? An additional refinement to this question is whether RSD and causalgia are legitimately considered together. These pain syndromes are often spoken of in the same breath; RSD has been grouped under the heading of "the causalgiform disorders." The International Associ-
257
258
COMMENTARY/Chaplan
ation for the Study of Pain defines RSD as a painful syndrome arising in the absence of nerve injury, whereas injury to a major peripheral nerve is required to meet the definition of causalgia. Are the two disorders indeed pathophysiologically similar, or do they just present similarly due perhaps to stereotypical injury responses of the nervous system? in clinical practice, it becomes difficult at times to decide what to call a given syndrome. Although a role for nerve damage in RSD has not been identified based on physical findings or conventional electrodiagnostics, any tissue injury necessarily injures some nerve endings, no matter how small. If damage to the cutaneous arborization of a nerve does not constitute causalgia, what about damage to a digital nerve? What about damage to the median nerve, as in carpal tunnel syndrome? Based on what practical and scientific considerations should we draw the line? The blurred distinction has pervaded many otherwise excellent clinical studies. Lack of homogeneity in studies, the presence of both patients who clearly have had identifiable peripheral nerve injuries as well as those who have not, makes it more difficult to decide to what extent RSD and causalgia in fact share features. An analogy drawn from a different field may be illustrative of the pitfalls of grouping similar-appearing disorders: The evolutionary biologist Ernst Mayr has defined what he termed the morphological fallacy, to which the Linnaean system of taxonomy, which distinguishes plant and animal species on the basis of appearances, is vulnerable. Because of the insufficiently recognized fact that similarity of appearances, resultinq from various evolutionary pressures toward convergence, are common in nature, many genetically differing species were previously erroneously grouped together under the Linnaean system. (Conversely, many closely related forms may display surprisingly different appearances: Previously, males and females of the same species were sometimes assigned to different species due to unrecognized sexual dimorphism.) A similar fallacy may underlie the unthinking grouping of these two pain syndromes: Superficial similarities may conceal important differences. On the other hand, if RSD and causalgia represent different points in a continuum of nerve injury, are there useful lessons to be learned from laboratory models of nerve injury? Causalgia has become easier to study with the creation of several preclinical nerve injury models permitting experimental investigations [5,13,15,29]. It is not known which findings may be generalized to RSD. What looks like a nerve injury, behaves like a nerve injury, but is not per se a nerve injury? The answer, were it known, might provide telling insights into the pathogenesis of neuropathic pain.
WHY IS THERE ATROPHY? What is the interplay between trophic changes, extremity injury, pain, and disuse? Denervation leads to loss of trophic interplay between nerve and muscle with resulting changes at the cellular and molecular level as well as an atrophic appearance (33]. Forced immobilization, such as casting, also causes reversible trophic changes not generally considered (rightly or wrongly) to fall within the spectrum of RSD. With regard to trophic changes and RSD: Which comes first, the chicken or the egg? Are the trophic changes secondary to injuryrelated humoral factors or alterations, or are they due to the inhibited use of the extremity? Does directing treatment specifically at the atrophy alter the clinical course, and if so, is this a direct effect or an indirect effect that could be more directly achieved if we could pharmacologically treat the "bad humors" affecting the site or replace the missing "good humors"? Better understanding of this subject would either increase or decrease the degree of responsibility we place on RSD patients to "heal themselves" through painful active physical therapy programs, and the degree of blame we assign to them for developing the syndrome in the first place. It would also help in the interpretation of physical findings in patients with trophic changes in immobilized limbs whose pain complaints may be difficult to evaluate due to stroke, dementia, or other communication barriers.
ROLE OF BRAIN/CORD INJURY Indeed, RSD shows morphological similarities not only to causalgia, but also to poststroke edema. The incidence of RSD-like syndromes seems to be quite high in brain- and spinal cord-injured patients [2,8,11,12,14,23, 31,35]. In these patients, the injury seems to "flow" the wrong way, from the central to peripheral nervous system. Neuropathic pain conditions clearly involve facilitated states in the spinal cord/and higher, including the possibility of a pathological state of neural excitation, which may lead to transsynaptic neuronal degeneration and death or "excitotoxicity" [30]. It may be reasonable to hypothesize a central nervous system structures lesion that arises under one set of circumstances from peripheral injury leading to excessive neural activity and under another from direct injury to the CNS itself, perhaps impairing inhibition.
WHAT IS THE LESION IN RSD? The pathophysiology of RSD remains obscure. Historically, the disorder has been blamed on abnormalities of the sympathetic nervous system triggered by trauma, at times seemingly minor. However, a number of leading
COMMENTARY/Chaplan
clinicians and researchers in the field have questioned the role of the sympathetic nervous system [3,4,17,21, 28,36,37]. Numerous patients who meet most other criteria for RSD do not obtain analgesia from a sympathetic blockade. We rationalize this by concluding that they have moved from an "early," sympathetically responsive stage to a later stage, where responsiveness to sympatholysis is "lost;' according to a dimly outlined understanding of the natural history of the disorder. However, other disorders of the autonomic nervous system are not painful. Stimulation of the sympathetic nervous system per se is not painful in normal individuals, nor is administration of catecholamines. And sympathetic efferent tone is probably below normal, not elevated, in patients with sympathetically maintained pain (experiencing relief after sympathetic blockade). Patients have shown decreased rather than elevated levels of catecholamines in venous blood from affected extremities in patients with dystrophic (causalgiform) pain syndromes [10]. In a popular rat model of causalgiform pain, it was recently shown that although temperatures in affected extremities varied in a way that might be considered comparable to clinical causalgia, no relationship between paw temperature and increased or decreased norepinephrine content was found [36]. It is true that many studies have shown intriguing correlations between patterns of sympathetic nervous system regeneration and pain in nerve injury models, such as sympathetic efferent sprouting into the area of nerve injury and the involved dorsal root ganglia [6,20]. It is not known what critical stimulus initiating such sprouting is provided by nerve injury.Thus, although abnormalities of sympathetic innervation do occur in peripheral nerve injury, their causative role is not clear, nor is it not known if RSD is in fact a forme fruste of nerve injury.
AN IMPORTANT ASPECT OF RSD THAT RECEIVES LITTLE ATTENTION IS THE WELL-DOCUMENTED EXISTENCE OF MOTOR DYSFUNCTION Of note, in both RSD and causalgia populations, there are motor and sensory deficits. In the latter, however, there are deficits consistent with peripheral nerve pathology, including electrophysiological deficits, whereas in the former there are not. The consistent presence of weakness in RSD (95%, according to Veldman et al. [34]) has been largely overlooked in discussions of RSD [25, 26]. Motor dysfunction (Le., weakness, tremor, and decreased range of motion) is not solely due to the presence of pain and/or edema, because it persists during successful sympathetic blockade for analgesia, nor disuse alone, because it exceeds the weakness observed with passively immobilized extremities. Thus, a marked
259
disorder of afferent neural function is accompanied by efferent dysfunction as well. Again, these disorders do not manifest on electromyography/nerve conduction studies suggesting that alternative explanations must be sought. Neglected clues to the pathogenesis of RSD may be staring us in the face.
TREATMENT "Where many remedies exist, you may be sure there is no cure" (Chekhov). Dr. Tanelian rightly points out that few treatments have rigorously proven worth. Numerous studies have addressed the pharmacology of the disorder in a shotgun fashion; it is not clear whether some of these are therapeutic or merely provide temporary analgesia while healing occurs by other means. In the case of causalgia, the disease state has been documented to persist for decades. This certainly seems to indicate persistent, anatomical change.
WHY DO SYMPATHETIC BLOCKS WORK IN SOME PATIENTS? As numerous investigators have pointed out, we perform sympathetic blockade with good results in patients who give evidence of not sympathetic excess but lack of sympathetic tone. It makes no sense why they should experience relief. The hypothesis has been advanced that lack of sympathetic tone to the affected extremity causes local upregulation of adrenoreceptors and thus overreaction to systemically perfused catechols. This does not really bear up well under inspection, because it might be thought that (1) the presence of systemic catechols sufficient to occupy receptors would prevent local upregulation of receptors or (2) activation of upregulated receptors by systemic catecholamines would cause an eventual "tolerizing" effect causing a restoration of receptor balance (suppression). Furthermore, (3) the infusion of catechols per se, recall, is not normally painful. Additionafly,(4) if the offending catechols are systemically provided, performance of a regional blockade (thus lessening the sympathetic supply emanating only from the involved extremity) should not lead to analgesia because the extremity is still perfused by bloodborne catechols. It has been suggested that sympathetic blockade provides analgesia by a different mechanism altogether. While myelinated afferents probably convey the immediate sensation of allodynia, it has been proposed that an important component of the pain in RSD may be mediated by visceral afferents [27] which supply deep structures such as blood vessels. Where effective, sympathectomy may anatomically be interrupting both pathways but providing analgesia due to interruption of not
260
COMMENTARY/Chaplan
the efferent but the afferent limb. The manifestation of cutaneous hypersensitivity would thus be at least in part a referred pain. Investigations in animal models are conflicting as to whether depletion of unmyelinated fibers (including visceral afferents) prevents the development of cutaneous allodynia, althouqh it appears to reduce or abolish thermal hyperalgesia [16,29]. If so, then why should (1) visceral afferents be actively triggering pain signals and (2) catecholamines cause painful activation of afferents? An explanation could be offered invoking plasticity in the types and functions of nerve-associated receptors and ion channels expressed after trauma. It has been demonstrated that nerve injury can give rise to novel adrenoreceptor expression [24]. For the present discussion, however, we must seek a mechanism not invoking measurable nerve injury. Such a mechanism could exist if there is sufficient injury to target tissue or to nonneuronal nerve cells, for example, Schwann cells, as to cause elaboration of nerve growth factor (or other neurotrophins). The injection of nerve growth factor (NGF) has been shown to cause sustained thermal and mechanical hypersensitivity in adult rats [18] after systemic administration and to cause reflex smooth muscle irritability when instilled into the bladder [9]. The thermal hyperalgesia appears to require the presence of sympathetic ganglion cells [1]. The pinpointing of NGF as the responsible agent may represent a gross simplification of the complex interactions between trophic factors, cytokines, and other mediators involved in postinjury states. NGF is, however, intriguing, as an agent that appears to possess intrinsic excitatory properties and is capable of causing both extensive second messenger pathway activation and alterations in the pattern of gene expression of the cell nucleus [32]. In cell lines, NGF may cause the expression of alternate forms of sodium channels [7] as well as altered patterns of neuromodulatory peptides [19]. Preliminary work suggests that similar effects may also pertain in vivo [22]. Perhaps injury not sufficient to cause electrophysiologically detectable peripheral nerve injury is still adequate to traumatize Schwann or other supporting cells, provoking plasticity through a cascade of cytokines and trophic factors. In this case, we may have a useful working laboratory model of RSD; of nonelectrodiagnostically apparent nerve injury, sufficient to cause sustained neuropathic pain.
References 1. Andreev N, Dimitrieva N, Koltzenburg M, McMahon SB: Peripheral administration of nerve growth factor in the adult rat produces a thermal hyperalgesia that requires the presence of sympathetic post-ganglionic neurones. Pain 63:109-115, 1995 2. Andrews LG, Armitage KJ: Sudeck's atrophy in traumatic quadriplegia. Paraplegia 9:159-165, 1971
3. Bennett GJ: The role of the sympathetic nervous system in painful peripheral neuropathy (editorial). Pain 45:221-223, 1991 4. Bennett GJ, Ochoa JL:Thermographic observations on rats with experimental neuropathic pain. Pain 45:61-167,1991 5. Bennett GJ, Xie V-K: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87-107,1988 6. Chung K, Kim HJ, Na HS et al: Abnormalities of sympathetic innervation in the area of an injured peripheral nerve in a rat model of neuropathic pain. Neurosci Lett 162:85-88, 1993 7. D'Arcangelo G, Paradiso K, Shepherd 0 et al: Neuronal growth factor regulation of two different sodium channel types through distinct signal transduction pathways. J Cell Bioi 122:915-921, 1993 8. Davis SW, Petrillo CR, Eichberg RD, Chu OS: Shoulderhand syndrome in a hemiplegic population: a 5-year retrospective study. Arch Phys Med Rehabil 58:353-356, 1977 9. Dmitrieva N, Rice ASC, Shelton DL, McMahon SB: The role of NGF in a model of persistent visceral pain. Soc Neurosci Abs 21, No.227.12:550, 1995 10. Drummond PO, Finch PM, Smythe GA: Reflex sympathetic dystrophy: the significance of differing plasma catecholamine concentrations in affected and unaffected limbs. Brain 114:2025-2036, 1991 11. Gellman H, Eckert RR, Botte MJ et al: Reflex sympathetic dystrophy in cervical spinal cord injury patients. Clin Orthop 233:126-131,1988 12. Gellman H, Keenan MA, Stone Let al: Reflex sympathetic dystrophy in brain-injured patients. Pain 51 :307-311, 1992 13. Govrin-Lippmann R, Devor M: Ongoing activity in severed nerves: source and variation with time. Brain Res 159: 406--410, 1978 14. Greyson NO, Tepperman PS: Three-phase bone studies in hemiplegia with reflex sympathetic dystrophy and the effect of disuse. J Nucl Med 25:423-429, 1984 15. Kim SH, Chung JM: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355-363, 1992 16. Kim VI, Na HS, Han JS, Hong SK: Critical role of the capsaicin-sensitive nerve fibers in the development of the causalgic symptoms produced by transecting some but not all of the nerves innervating the rat tail. J Neurosci 15:4133-4139, 1995 17. Koltzenburg M, McMahon SB: The enigmatic role of the sympathetic nervous system in chronic pain. Trends Pharmacol Sci 12:399-402, 1991 18. Lewin GR, Ritter AM, Mendell LM: Nerve growth factorinduced hyperalgesia in the neonatal and adult rat. J Neurosci 13:2136-2148, 1993 19. Lindsay RM, Harmar AJ: Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons. Nature 337:362-364, 1989 20. McLachlan EM, Janig W, Devor M, Michaelis M: Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 363:543-546, 1993
COMMENTARV/Chaplan
21 . McMahon SB: Mechanisms of sympathetic pain. Br Med Bull 47:584-600 , 1991 22. Moss BL, Rueff A, Tonra JR et al: NGF induces expression of a peripheral nerve sodium channel gene in vivo. Soc Neurosci Abs 20 , No. 287.1 :671, 1994 23 . Ohry A, Brooks ME, Steinbach TV, Rozin R: Shoulder complications as a cause of delay in rehabilitation of spinal cord injured patients. (Case reports and review of the literature.) Paraplegia 16:310-316, 1978 24 . Sato J, Perl ER: Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury. Science 251 :1608-1610,1991 25 . Schott GO: The relationship of peripheral trauma and pain to dystonia. J Neurol Neurosurg Psychiatry 48 : 698-701,1985 26 . Schott GO: Induction of involuntary movements by peripheral trauma: an analogy with causalgia. Lancet 2: 712-716,1986 27. Schott GO: Visceral afferents: their contribution to 'sympathetic dependent' pain. Brain 117 :397-413, 1994 28. Schott GO: An unsympathetic view of pain. Lancet 345 : 634-636, 1995 29. Shir Y, Seltzer Z: A-fibers mediate mechanical hyperesthesia and allodynia and C-fibers mediate thermal hyperalgesia in a new model of causalgiform pain disorders in rats. Neurosci Lett 115:62-67, 1990
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30 . Sugimoto T, Bennett GJ, Kajander KC: Transsynaptic degeneration in the superficial dorsal horn after sciatic nerve injury: effects of a chronic constriction injury, transection, and strychnine. Pain 42:205-213, 1990 31 . Tepperman PS, Greyson NO, Hilbert L et al: Reflex sympathetic dystrophy in hemiplegia. Arch Phys Med Rehabil 65:442-447, 1984 32 . Thoenen H: Neurotrophins and neuronal plasticity. Science 270:593-598, 1995 33 . Trimmer JS, Cooperman SS, Agnew WS, Mandel G: Regulation of muscle sodium channel transcripts during development and in response to denervation. Oev Bioi 142:360-367,1990 34 . Veldman PH, Reynen HM, Arntz IE, Goris RJ: Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet 342: 1012-1016, 1993 35 . Wainapel SF, Freed MM: Reflex sympathetic dystrophy in quadriplegia: case report. Arch Phys Med Rehabil 65: 35-36,1984 36 . Wakisaka S, Kajander KC, Bennett GJ: Abnormal skin temperature and abnormal sympathetic vasomotor innervation in an experimental painful peripheral neuropathy. Pain 46 :299-313, 1991 37. Wakisaka S, Kajander KC, Bennett GJ: Increased neuropeptide Y (NPY)-like immunoreactivity in rat sensory neurons following peripheral axotomy. Neurosci Lett 124:200-203, 1991
Rethinking Reflex Sympathetic Dystrophy Sandra R. Chap/an
r. Tanelian raises a number of cogent points in his evaluation of the literature pertaining to the diagnosis, pathophysiological basis, and treatment options for reflex sympathetic dystrophy (RSD). I would like to add my voice to his in questioning some of the assumptions that are prevalent regarding this perplexing disorder and add one or two further ruminations. Tanelian has largely addressed clinical issues; appropriately so, because no laboratory model for RSD presently exists. There are some speculations, however, drawn from laboratory experience with other neuropathic disorders, that may perhaps be legitimately added to consideration of the topic.
D
DIAGNOSIS OF RSD Lack of understanding of the pathophysiological basis of RSD means that, by definition, there can be no firm diagnostic gold standard. This alone should not unduly disturb us, given that there are many medical diagnoses that rest on a constellation of findings rather than a single test: rheumatic fever, systemic lupus erythematosis, and, under certain circumstances, preeclampsia, to name just a few. However, lack of a gold standard means that there is no criterion of "truth" against which to judge the sensitivity and specificity of the various diagnostic tests. Until the pathophysiology is better understood, the use of any "confirmatory" study such as a technetium scan may be questionable, because it opens the door to circular reasoning: defining a subclass of patients who are positive for that one study, whereas at best the study documents epiphenomena whose relationships to the true underlying disorder are From the Anesthesiology Research Laboratory, University of California-San Diego, La Jolla, CA. Reprint requests: Sandra R. Chaplan, MD, Anesthesiology Research Laboratory, 0818, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818.
Pain Forum 5(4): 257-261, 1996
unclear. Among the practical implications of this are the inability to define the "true" spectrum of RSD, from subclinical to clinical, and the risk of nonhomogeneity of groups in clinical studies due to lack of hard criteria for patient inclusion or exclusion. Most clinicians think they know RSD when they see it. Confidently affixinq a diagnosis of RSD, however, may at times be challenging. Although some patients appear to have stepped right from the textbook pages, others defy classification. What do we make of patients who have pain in the absence of marked trophic changes? Are these patients who have maintained activity of the limb despite pain and therefore have counteracted the manifestations of disuse, who have received some treatment and are partial treatment successes, or do they have a different form of neuropathic complaint-or are they malingerers? What about patients who have extremities with abnormal appearance, including edema, discoloration, and trophic changes, but who do not complain of pain (as may be encountered for example with poststroke patients)? Does the lack of pain complaint indicate that there exists a painless form of RSD, that these patients suffer from a different, painless disorder, or that the patient is unable to sense pain due to additional neurologic impairment?
WHAT ARE THE SIMILARITIES AND DIFFERENCES BETWEEN CAUSALGIA AND RSD? Dr. Tanelian raises the valid question of where RSD falls with respect to the spectrum of normal responses to injury of the nervous system. Do different injury etiologies cause the same picture, and does this matter? An additional refinement to this question is whether RSD and causalgia are legitimately considered together. These pain syndromes are often spoken of in the same breath; RSD has been grouped under the heading of "the causalgiform disorders." The International Associ-
257
258
COMMENTARY/Chaplan
ation for the Study of Pain defines RSD as a painful syndrome arising in the absence of nerve injury, whereas injury to a major peripheral nerve is required to meet the definition of causalgia. Are the two disorders indeed pathophysiologically similar, or do they just present similarly due perhaps to stereotypical injury responses of the nervous system? in clinical practice, it becomes difficult at times to decide what to call a given syndrome. Although a role for nerve damage in RSD has not been identified based on physical findings or conventional electrodiagnostics, any tissue injury necessarily injures some nerve endings, no matter how small. If damage to the cutaneous arborization of a nerve does not constitute causalgia, what about damage to a digital nerve? What about damage to the median nerve, as in carpal tunnel syndrome? Based on what practical and scientific considerations should we draw the line? The blurred distinction has pervaded many otherwise excellent clinical studies. Lack of homogeneity in studies, the presence of both patients who clearly have had identifiable peripheral nerve injuries as well as those who have not, makes it more difficult to decide to what extent RSD and causalgia in fact share features. An analogy drawn from a different field may be illustrative of the pitfalls of grouping similar-appearing disorders: The evolutionary biologist Ernst Mayr has defined what he termed the morphological fallacy, to which the Linnaean system of taxonomy, which distinguishes plant and animal species on the basis of appearances, is vulnerable. Because of the insufficiently recognized fact that similarity of appearances, resultinq from various evolutionary pressures toward convergence, are common in nature, many genetically differing species were previously erroneously grouped together under the Linnaean system. (Conversely, many closely related forms may display surprisingly different appearances: Previously, males and females of the same species were sometimes assigned to different species due to unrecognized sexual dimorphism.) A similar fallacy may underlie the unthinking grouping of these two pain syndromes: Superficial similarities may conceal important differences. On the other hand, if RSD and causalgia represent different points in a continuum of nerve injury, are there useful lessons to be learned from laboratory models of nerve injury? Causalgia has become easier to study with the creation of several preclinical nerve injury models permitting experimental investigations [5,13,15,29]. It is not known which findings may be generalized to RSD. What looks like a nerve injury, behaves like a nerve injury, but is not per se a nerve injury? The answer, were it known, might provide telling insights into the pathogenesis of neuropathic pain.
WHY IS THERE ATROPHY? What is the interplay between trophic changes, extremity injury, pain, and disuse? Denervation leads to loss of trophic interplay between nerve and muscle with resulting changes at the cellular and molecular level as well as an atrophic appearance (33]. Forced immobilization, such as casting, also causes reversible trophic changes not generally considered (rightly or wrongly) to fall within the spectrum of RSD. With regard to trophic changes and RSD: Which comes first, the chicken or the egg? Are the trophic changes secondary to injuryrelated humoral factors or alterations, or are they due to the inhibited use of the extremity? Does directing treatment specifically at the atrophy alter the clinical course, and if so, is this a direct effect or an indirect effect that could be more directly achieved if we could pharmacologically treat the "bad humors" affecting the site or replace the missing "good humors"? Better understanding of this subject would either increase or decrease the degree of responsibility we place on RSD patients to "heal themselves" through painful active physical therapy programs, and the degree of blame we assign to them for developing the syndrome in the first place. It would also help in the interpretation of physical findings in patients with trophic changes in immobilized limbs whose pain complaints may be difficult to evaluate due to stroke, dementia, or other communication barriers.
ROLE OF BRAIN/CORD INJURY Indeed, RSD shows morphological similarities not only to causalgia, but also to poststroke edema. The incidence of RSD-like syndromes seems to be quite high in brain- and spinal cord-injured patients [2,8,11,12,14,23, 31,35]. In these patients, the injury seems to "flow" the wrong way, from the central to peripheral nervous system. Neuropathic pain conditions clearly involve facilitated states in the spinal cord/and higher, including the possibility of a pathological state of neural excitation, which may lead to transsynaptic neuronal degeneration and death or "excitotoxicity" [30]. It may be reasonable to hypothesize a central nervous system structures lesion that arises under one set of circumstances from peripheral injury leading to excessive neural activity and under another from direct injury to the CNS itself, perhaps impairing inhibition.
WHAT IS THE LESION IN RSD? The pathophysiology of RSD remains obscure. Historically, the disorder has been blamed on abnormalities of the sympathetic nervous system triggered by trauma, at times seemingly minor. However, a number of leading
COMMENTARY/Chaplan
clinicians and researchers in the field have questioned the role of the sympathetic nervous system [3,4,17,21, 28,36,37]. Numerous patients who meet most other criteria for RSD do not obtain analgesia from a sympathetic blockade. We rationalize this by concluding that they have moved from an "early," sympathetically responsive stage to a later stage, where responsiveness to sympatholysis is "lost;' according to a dimly outlined understanding of the natural history of the disorder. However, other disorders of the autonomic nervous system are not painful. Stimulation of the sympathetic nervous system per se is not painful in normal individuals, nor is administration of catecholamines. And sympathetic efferent tone is probably below normal, not elevated, in patients with sympathetically maintained pain (experiencing relief after sympathetic blockade). Patients have shown decreased rather than elevated levels of catecholamines in venous blood from affected extremities in patients with dystrophic (causalgiform) pain syndromes [10]. In a popular rat model of causalgiform pain, it was recently shown that although temperatures in affected extremities varied in a way that might be considered comparable to clinical causalgia, no relationship between paw temperature and increased or decreased norepinephrine content was found [36]. It is true that many studies have shown intriguing correlations between patterns of sympathetic nervous system regeneration and pain in nerve injury models, such as sympathetic efferent sprouting into the area of nerve injury and the involved dorsal root ganglia [6,20]. It is not known what critical stimulus initiating such sprouting is provided by nerve injury.Thus, although abnormalities of sympathetic innervation do occur in peripheral nerve injury, their causative role is not clear, nor is it not known if RSD is in fact a forme fruste of nerve injury.
AN IMPORTANT ASPECT OF RSD THAT RECEIVES LITTLE ATTENTION IS THE WELL-DOCUMENTED EXISTENCE OF MOTOR DYSFUNCTION Of note, in both RSD and causalgia populations, there are motor and sensory deficits. In the latter, however, there are deficits consistent with peripheral nerve pathology, including electrophysiological deficits, whereas in the former there are not. The consistent presence of weakness in RSD (95%, according to Veldman et al. [34]) has been largely overlooked in discussions of RSD [25, 26]. Motor dysfunction (Le., weakness, tremor, and decreased range of motion) is not solely due to the presence of pain and/or edema, because it persists during successful sympathetic blockade for analgesia, nor disuse alone, because it exceeds the weakness observed with passively immobilized extremities. Thus, a marked
259
disorder of afferent neural function is accompanied by efferent dysfunction as well. Again, these disorders do not manifest on electromyography/nerve conduction studies suggesting that alternative explanations must be sought. Neglected clues to the pathogenesis of RSD may be staring us in the face.
TREATMENT "Where many remedies exist, you may be sure there is no cure" (Chekhov). Dr. Tanelian rightly points out that few treatments have rigorously proven worth. Numerous studies have addressed the pharmacology of the disorder in a shotgun fashion; it is not clear whether some of these are therapeutic or merely provide temporary analgesia while healing occurs by other means. In the case of causalgia, the disease state has been documented to persist for decades. This certainly seems to indicate persistent, anatomical change.
WHY DO SYMPATHETIC BLOCKS WORK IN SOME PATIENTS? As numerous investigators have pointed out, we perform sympathetic blockade with good results in patients who give evidence of not sympathetic excess but lack of sympathetic tone. It makes no sense why they should experience relief. The hypothesis has been advanced that lack of sympathetic tone to the affected extremity causes local upregulation of adrenoreceptors and thus overreaction to systemically perfused catechols. This does not really bear up well under inspection, because it might be thought that (1) the presence of systemic catechols sufficient to occupy receptors would prevent local upregulation of receptors or (2) activation of upregulated receptors by systemic catecholamines would cause an eventual "tolerizing" effect causing a restoration of receptor balance (suppression). Furthermore, (3) the infusion of catechols per se, recall, is not normally painful. Additionafly,(4) if the offending catechols are systemically provided, performance of a regional blockade (thus lessening the sympathetic supply emanating only from the involved extremity) should not lead to analgesia because the extremity is still perfused by bloodborne catechols. It has been suggested that sympathetic blockade provides analgesia by a different mechanism altogether. While myelinated afferents probably convey the immediate sensation of allodynia, it has been proposed that an important component of the pain in RSD may be mediated by visceral afferents [27] which supply deep structures such as blood vessels. Where effective, sympathectomy may anatomically be interrupting both pathways but providing analgesia due to interruption of not
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the efferent but the afferent limb. The manifestation of cutaneous hypersensitivity would thus be at least in part a referred pain. Investigations in animal models are conflicting as to whether depletion of unmyelinated fibers (including visceral afferents) prevents the development of cutaneous allodynia, althouqh it appears to reduce or abolish thermal hyperalgesia [16,29]. If so, then why should (1) visceral afferents be actively triggering pain signals and (2) catecholamines cause painful activation of afferents? An explanation could be offered invoking plasticity in the types and functions of nerve-associated receptors and ion channels expressed after trauma. It has been demonstrated that nerve injury can give rise to novel adrenoreceptor expression [24]. For the present discussion, however, we must seek a mechanism not invoking measurable nerve injury. Such a mechanism could exist if there is sufficient injury to target tissue or to nonneuronal nerve cells, for example, Schwann cells, as to cause elaboration of nerve growth factor (or other neurotrophins). The injection of nerve growth factor (NGF) has been shown to cause sustained thermal and mechanical hypersensitivity in adult rats [18] after systemic administration and to cause reflex smooth muscle irritability when instilled into the bladder [9]. The thermal hyperalgesia appears to require the presence of sympathetic ganglion cells [1]. The pinpointing of NGF as the responsible agent may represent a gross simplification of the complex interactions between trophic factors, cytokines, and other mediators involved in postinjury states. NGF is, however, intriguing, as an agent that appears to possess intrinsic excitatory properties and is capable of causing both extensive second messenger pathway activation and alterations in the pattern of gene expression of the cell nucleus [32]. In cell lines, NGF may cause the expression of alternate forms of sodium channels [7] as well as altered patterns of neuromodulatory peptides [19]. Preliminary work suggests that similar effects may also pertain in vivo [22]. Perhaps injury not sufficient to cause electrophysiologically detectable peripheral nerve injury is still adequate to traumatize Schwann or other supporting cells, provoking plasticity through a cascade of cytokines and trophic factors. In this case, we may have a useful working laboratory model of RSD; of nonelectrodiagnostically apparent nerve injury, sufficient to cause sustained neuropathic pain.
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