Handchir Mikrochir Plast Chir 2010; 42(1): 8-14
DOI: 10.1055/s-0029-1246211
Übersichtsarbeit

© Georg Thieme Verlag KG Stuttgart · New York

Aktuelle Erkenntnisse zur Pathophysiologie des CRPS I

Current Concepts in Pathophysiology of CRPS IF. T. Nickel1 [*] , C. Maihöfner1 [*]
  • 1Universität Erlangen, Neurologische Klinik, Erlangen
Further Information

Publication History

Publication Date:
04 March 2010 (online)

Zusammenfassung

In den letzten Jahren konnten zur Pathophysiologie des komplexen regionalen Schmerzsyndroms (CRPS) einige neue Erkenntnisse gewonnen werden. Während in der Vergangenheit das Konzept des sympathisch unterhaltenen Schmerzes („sympathetically maintained pain”, SMP) im Vordergrund stand, stellt sich nun die Erkrankung als komplexes Zusammenspiel von somatosensorischen, motorischen, inflammatorischen und autonomen Veränderungen dar. Wie bei anderen neuropathischen Schmerzsyndromen kommt es beim CRPS zu einer peripheren und zentralen Sensibilisierung. Hierbei sind unter anderem postsynaptische NMDA-Rezeptoren im Hinterhorn beteiligt. Auch das endogene Schmerzhemmsystem ist bei CRPS-Patienten defizient. Zentrale neuroplastische Veränderungen im Bereich des somatosensorischen Kortex bedingen sensible Phänomene. Häufige motorische Störungen können durch zentrale Reorganisationsvorgänge im motorischen Kortex erklärt werden. Im Bereich der neurogenen Inflammation beim CRPS konnten neben dem Calcitonin-gene related peptide (CGRP) und Substanz P inzwischen weitere beteiligte proinflammatorische Zytokine identifiziert werden. Hinsichtlich des sympathischen Nervensystems weisen aktuelle Erkenntnisse weniger auf eine erhöhte efferente Aktivität, als auf eine Sensibilisierung peripherer adrenerger Rezeptoren hin. Insbesondere die Expression von α1-Adrenozeptoren auf C-Fasern spielt hier eine Rolle. Diese im Artikel weiter ausgeführten Konzepte schließen sich keineswegs aus, vielmehr ergänzen sie sich. Die verschiedenen Pathomechanismen greifen ineinander. Das intra- und interindividuell variable klinische Erscheinungsbild des CRPS wird durch die unterschiedliche Beteiligung der Systeme erklärbar.

Abstract

Knowledge about the pathophysiology underlying the complex regional pain syndrome (CRPS) has increased over the last years. Classically, CRPS has been considered to be mainly driven by sympathetic dysfunction with sympathetically maintained pain being its major pathogenetic mechanism. Currently, the disease is understood as result of a complex interplay between altered somatosensory, motor, autonomic and inflammatory systems. Peripheral and central sensitization is a common feature in CRPS as in other neuropathic pain syndromes. One important mechanism is the sensitization of spinal dorsal horn cells via activation of postsynaptic NMDA-receptors by chronic C-fiber input. Differential activity of endogenous pain modulating systems may play a pivotal role in the development of CRPS, too. Neuronal plasticity of the somatosensory cortex accounts for central sensory signs. Also the motor system is subject to central adaptive changes in patients with CRPS. Calcitonin-gene related peptide (CGRP) and substance P mediate neurogenic inflammation. Additionally other proinflammatory cytokines involved in the inflammatory response in CRPS have been identified. In terms of the sympathetic nervous system, recent evidence rather points to a sensitization of adrenergic receptors than to increased efferent sympathetic activity. Particularly the expression of α1-adrenoceptors on nociceptive C-fibers may play a major role. These pathophysiological ideas do not exclude each other. In fact they complement one another. The variety of the involved systems may explain the versatile clinical picture of CRPS.

Literatur

  • 1 Baron R. Mechanisms of disease: neuropathic pain – a clinical perspective.  Nat Clin Pract Neurol. 2006;  2 95-106
  • 2 Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management.  Lancet. 1999;  353 1959-1964
  • 3 Lanz S, Maihofner C. Symptome und pathophysiologische Mechanismen neuropathischer Schmerzsyndrome.  Nervenarzt. 2009;  80 430-444
  • 4 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain.  Science. 2000;  288 1765-1769
  • 5 Kiefer RT, Rohr P, Ploppa A. et al . Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study.  Pain Med. 2008;  9 1173-1201
  • 6 Kiefer RT, Rohr P, Ploppa A. et al . A pilot open-label study of the efficacy of subanesthetic isomeric S(+)-ketamine in refractory CRPS patients.  Pain Med. 2008;  9 44-54
  • 7 Sigtermans MJ, van Hilten JJ, Bauer MC. et al . Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1.  Pain. 2009;  145 304-311
  • 8 Seifert F, Kiefer G, DeCol R. et al . Differential endogenous pain modulation in complex-regional pain syndrome.  Brain. 2009;  132 788-800
  • 9 De Col R, Maihofner C. Centrally mediated sensory decline induced by differential C-fiber stimulation.  Pain. 2008;  138 556-564
  • 10 Pleger B, Ragert P, Schwenkreis P. et al . Patterns of cortical reorganization parallel impaired tactile discrimination and pain intensity in complex regional pain syndrome.  Neuroimage. 2006;  32 503-510
  • 11 Maihofner C, Handwerker HO, Neundorfer B. et al . Patterns of cortical reorganization in complex regional pain syndrome.  Neurology. 2003;  61 1707-1715
  • 12 Flor H, Nikolajsen L, Staehelin Jensen T. Phantom limb pain: a case of maladaptive CNS plasticity?.  Nat Rev Neurosci. 2006;  7 873-881
  • 13 Maihofner C, Handwerker HO, Neundorfer B. et al . Cortical reorganization during recovery from complex regional pain syndrome.  Neurology. 2004;  63 693-701
  • 14 Maihofner C, Forster C, Birklein F. et al . Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study.  Pain. 2005;  114 93-103
  • 15 Geha PY, Baliki MN, Harden RN. et al . The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions.  Neuron. 2008;  60 570-581
  • 16 Galer BS, Jensen M. Neglect-like symptoms in complex regional pain syndrome: results of a self-administered survey.  J Pain Symptom Manage. 1999;  18 213-217
  • 17 Forderreuther S, Sailer U, Straube A. Impaired self-perception of the hand in complex regional pain syndrome (CRPS).  Pain. 2004;  110 756-761
  • 18 Karin Swart CM, Stins JF, Beek PJ. Cortical changes in complex regional pain syndrome (CRPS).  Eur J Pain. 2009;  13 902-907
  • 19 Schwartzman RJ, Kerrigan J. The movement disorder of reflex sympathetic dystrophy.  Neurology. 1990;  40 57-61
  • 20 Birklein F, Riedl B, Sieweke N. et al . Neurological findings in complex regional pain syndromes – analysis of 145 cases.  Acta Neurol Scand. 2000;  101 262-269
  • 21 Maihofner C, Baron R, DeCol R. et al . The motor system shows adaptive changes in complex regional pain syndrome.  Brain. 2007;  130 2671-2687
  • 22 Desmurget M, Epstein CM, Turner RS. et al . Role of the posterior parietal cortex in updating reaching movements to a visual target.  Nat Neurosci. 1999;  2 563-567
  • 23 Schwenkreis P, Janssen F, Rommel O. et al . Bilateral motor cortex disinhibition in complex regional pain syndrome (CRPS) type I of the hand.  Neurology. 2003;  61 515-519
  • 24 Juottonen K, Gockel M, Silen T. et al . Altered central sensorimotor processing in patients with complex regional pain syndrome.  Pain. 2002;  98 315-323
  • 25 van Rijn MA, Marinus J, Putter H. et al . Onset and progression of dystonia in complex regional pain syndrome.  Pain. 2007;  130 287-293
  • 26 Veldman PH, Reynen HM, Arntz IE. et al . Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.  Lancet. 1993;  342 1012-1016
  • 27 Breakefield XO, Blood AJ, Li Y. et al . The pathophysiological basis of dystonias.  Nat Rev Neurosci. 2008;  9 222-234
  • 28 van de Beek WJ, Vein A, Hilgevoord AA. et al . Neurophysiologic aspects of patients with generalized or multifocal tonic dystonia of reflex sympathetic dystrophy.  J Clin Neurophysiol. 2002;  19 77-83
  • 29 van Hilten BJ, van de Beek WJ, Hoff JI. et al . Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy.  N Engl J Med. 2000;  343 625-630
  • 30 van Rijn MA, Munts AG, Marinus J. et al . Intrathecal baclofen for dystonia of complex regional pain syndrome.  Pain. 2009;  143 41-47
  • 31 de Mos M, Sturkenboom MC, Huygen FJ. Current understandings on complex regional pain syndrome.  Pain Pract. 2009;  9 86-99
  • 32 Blaes F, Tschernatsch M, Braeu ME. et al . Autoimmunity in complex-regional pain syndrome.  Ann N Y Acad Sci. 2007;  1107 168-173
  • 33 Birklein F, Schmelz M. Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS).  Neurosci Lett. 2008;  437 199-202
  • 34 Birklein F, Schmelz M, Schifter S. et al . The important role of neuropeptides in complex regional pain syndrome.  Neurology. 2001;  57 2179-2184
  • 35 Schinkel C, Gaertner A, Zaspel J. et al . Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome.  Clin J Pain. 2006;  22 235-239
  • 36 Blair SJ, Chinthagada M, Hoppenstehdt D. et al . Role of neuropeptides in pathogenesis of reflex sympathetic dystrophy.  Acta Orthop Belg. 1998;  64 448-451
  • 37 Huygen FJ, De Bruijn AG, De Bruin MT. et al . Evidence for local inflammation in complex regional pain syndrome type 1.  Mediators Inflamm. 2002;  11 47-51
  • 38 Heijmans-Antonissen C, Wesseldijk F, Munnikes RJ. et al . Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1.  Mediators Inflamm. 2006;  2006 28398
  • 39 Uceyler N, Eberle T, Rolke R. et al . Differential expression patterns of cytokines in complex regional pain syndrome.  Pain. 2007;  132 195-205
  • 40 Alexander GM, van Rijn MA, van Hilten JJ. et al . Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS.  Pain. 2005;  116 213-219
  • 41 Guo TZ, Offley SC, Boyd EA. et al . Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I.  Pain. 2004;  108 95-107
  • 42 Guo TZ, Wei T, Kingery WS. Glucocorticoid inhibition of vascular abnormalities in a tibia fracture rat model of complex regional pain syndrome type I.  Pain. 2006;  121 158-167
  • 43 Weber M, Birklein F, Neundorfer B. et al . Facilitated neurogenic inflammation in complex regional pain syndrome.  Pain. 2001;  91 251-257
  • 44 Leis S, Weber M, Schmelz M. et al . Facilitated neurogenic inflammation in unaffected limbs of patients with complex regional pain syndrome.  Neurosci Lett. 2004;  359 163-166
  • 45 Borsook D, Sava S. Pain: Do ACE inhibitors exacerbate complex regional pain syndrome?.  Nat Rev Neurol. 2009;  5 306-308
  • 46 Blaes F, Schmitz K, Tschernatsch M. et al . Autoimmune etiology of complex regional pain syndrome (M.  Sudeck). Neurology. 2004;  63 1734-1736
  • 47 Kohr D, Tschernatsch M, Schmitz K. et al . Autoantibodies in complex regional pain syndrome bind to a differentiation-dependent neuronal surface autoantigen.  Pain. 2009;  143 246-251
  • 48 Goebel A, Vogel H, Caneris O. et al . Immune responses to Campylobacter and serum autoantibodies in patients with complex regional pain syndrome.  J Neuroimmunol. 2005;  162 184-189
  • 49 de Rooij AM, Florencia Gosso M, Haasnoot GW. et al . HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia.  Pain. 2009;  145 82-85
  • 50 Kemler MA, van de Vusse AC, van den Berg-Loonen EM. et al . HLA-DQ1 associated with reflex sympathetic dystrophy.  Neurology. 1999;  53 1350-1351
  • 51 Zahn S, Leis S, Schick C. et al . No alpha-adrenoreceptor-induced C-fiber activation in healthy human skin.  J Appl Physiol. 2004;  96 1380-1384
  • 52 Ali Z, Raja SN, Wesselmann U. et al . Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain.  Pain. 2000;  88 161-168
  • 53 Torebjork E, Wahren L, Wallin G. et al . Noradrenaline-evoked pain in neuralgia.  Pain. 1995;  63 11-20
  • 54 Baron R, Schattschneider J, Binder A. et al . Relation between sympathetic vasoconstrictor activity and pain and hyperalgesia in complex regional pain syndromes: a case-control study.  Lancet. 2002;  359 1655-1660
  • 55 Drummond PD, Finch PM, Skipworth S. et al . Pain increases during sympathetic arousal in patients with complex regional pain syndrome.  Neurology. 2001;  57 1296-1303
  • 56 Drummond PD. Mechanism of complex regional pain syndrome: no longer excessive sympathetic outflow?.  Lancet. 2001;  358 168-170
  • 57 Drummond PD, Finch PM, Smythe GA. Reflex sympathetic dystrophy: the significance of differing plasma catecholamine concentrations in affected and unaffected limbs.  Brain. 1991;  114 ((Pt 5)) 2025-2036
  • 58 Drummond PD, Skipworth S, Finch PM. alpha 1-adrenoceptors in normal and hyperalgesic human skin.  Clin Sci (Lond). 1996;  91 73-77
  • 59 Cepeda MS, Lau J, Carr DB. Defining the therapeutic role of local anesthetic sympathetic blockade in complex regional pain syndrome: a narrative and systematic review.  Clin J Pain. 2002;  18 216-233
  • 60 Arnold JM, Teasell RW, MacLeod AP. et al . Increased venous alpha-adrenoceptor responsiveness in patients with reflex sympathetic dystrophy.  Ann Intern Med. 1993;  118 619-621
  • 61 Wasner G, Schattschneider J, Heckmann K. et al . Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): mechanisms and diagnostic value.  Brain. 2001;  124 587-599
  • 62 Birklein F, Riedl B, Neundorfer B. et al . Sympathetic vasoconstrictor reflex pattern in patients with complex regional pain syndrome.  Pain. 1998;  75 93-100
  • 63 Dayan L, Salman S, Norman D. et al . Exaggerated vasoconstriction in complex regional pain syndrome-1 is associated with impaired resistance artery endothelial function and local vascular reflexes.  J Rheumatol. 2008;  35 1339-1345
  • 64 Groeneweg JG, Huygen FJ, Heijmans-Antonissen C. et al . Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1.  BMC Musculoskelet Disord. 2006;  7 91
  • 65 Koban M, Leis S, Schultze-Mosgau S. et al . Tissue hypoxia in complex regional pain syndrome.  Pain. 2003;  104 149-157
  • 66 Heerschap A, den Hollander JA, Reynen H. et al . Metabolic changes in reflex sympathetic dystrophy: a 31P NMR spectroscopy study.  Muscle Nerve. 1993;  16 367-373
  • 67 Birklein F, Weber M, Ernst M. et al . Experimental tissue acidosis leads to increased pain in complex regional pain syndrome (CRPS).  Pain. 2000;  87 227-234
  • 68 Eisenberg E, Shtahl S, Geller R. et al . Serum and salivary oxidative analysis in Complex Regional Pain Syndrome.  Pain. 2008;  138 226-232
  • 69 Schlereth T, Dittmar JO, Seewald B. et al . Peripheral amplification of sweating – a role for calcitonin gene-related peptide.  J Physiol. 2006;  576 823-832
  • 70 Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy?.  Ann Neurol. 2009;  65 629-638
  • 71 Novak V, Freimer ML, Kissel JT. et al . Autonomic impairment in painful neuropathy.  Neurology. 2001;  56 861-868
  • 72 van der Laan L, ter Laak HJ, Gabreels-Festen A. et al . Complex regional pain syndrome type I (RSD): pathology of skeletal muscle and peripheral nerve.  Neurology. 1998;  51 20-25
  • 73 Albrecht PJ, Hines S, Eisenberg E. et al . Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome.  Pain. 2006;  120 244-266
  • 74 Oaklander AL, Rissmiller JG, Gelman LB. et al . Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy).  Pain. 2006;  120 235-243

1 Beide Autoren sind gleichberechtigte Autoren.

Korrespondenzadresse

PD Christian Maihöfner

Universität Erlangen

Neurologische Klinik

Schwabachanlage 6

91054 Erlangen

Email: christian.maihoefner@uk-erlangen.de