Clinical features and pathophysiology of complex regional pain syndrome

Abstract

A complex regional pain syndrome (CRPS)--multiple system dysfunction, severe and often chronic pain, and disability--can be triggered by a minor injury, a fact that has fascinated scientists and perplexed clinicians for decades. However, substantial advances across several medical disciplines have recently improved our understanding of CRPS. Compelling evidence implicates biological pathways that underlie aberrant inflammation, vasomotor dysfunction, and maladaptive neuroplasticity in the clinical features of CRPS. Collectively, the evidence points to CRPS being a multifactorial disorder that is associated with an aberrant host response to tissue injury. Variation in susceptibility to perturbed regulation of any of the underlying biological pathways probably accounts for the clinical heterogeneity of CRPS.

Conflict of interest statement

Conflicts of interest

JM:	none declared.
GLM:	none declared.
FB:	received fees as consultant and/or speaker from Pfizer, Grünenthal, Lilly, MedUpdate, Glaxo, and for expert testimony for Jerini.
RB:	received grants or research report from Pfizer, Genzyme, Grünenthal; is a member of the IMI “Europain” collaboration and industry members of this are: Astra Zenica, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal, Eli Lilly, Neuroscience technologies and Boehringer Ingelheim; received fees as consultant and/or speaker from Pfizer, Genzyme, Grünenthal, Mundipharma, Allergan, Sanofi Pasteur, Medtronic, Eisai, UCB BioSciences, Lilly, Boehringer Ingelheim, Astellas and Novartis.
CM:	received fees as consultant and/or speaker from Pfizer, Bionorica, Allergan and Grünenthal.
WK:	none declared.
JJvH:	received fees as consultant and speaker from Medtronic, GSK and Novartis.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Photo’s: a) acute CRPS, b) chronic (cold) CRPS, c) CRPS dystonia

Photographs of clinical CRPS cases. Panel (A): Acute CRPS with hyperemia, swelling and glossy skin. Panel (B): Chronic, cold type CRPS with blue discoloration of the fingers, glossy skin, and increased hair and nail growth. Panel (C): CRPS-related dystonia of the left ankle and foot with plantar flexion and inversion of the ankle, and flexion of the toes; edema and increased hair growth are also clearly visible.

Figure 1. Photo’s: a) acute CRPS, b) chronic (cold) CRPS, c) CRPS dystonia

Photographs of clinical CRPS cases. Panel (A): Acute CRPS with hyperemia, swelling and glossy skin. Panel (B): Chronic, cold type CRPS with blue discoloration of the fingers, glossy skin, and increased hair and nail growth. Panel (C): CRPS-related dystonia of the left ankle and foot with plantar flexion and inversion of the ankle, and flexion of the toes; edema and increased hair growth are also clearly visible.

Figure 1. Photo’s: a) acute CRPS, b) chronic (cold) CRPS, c) CRPS dystonia

Photographs of clinical CRPS cases. Panel (A): Acute CRPS with hyperemia, swelling and glossy skin. Panel (B): Chronic, cold type CRPS with blue discoloration of the fingers, glossy skin, and increased hair and nail growth. Panel (C): CRPS-related dystonia of the left ankle and foot with plantar flexion and inversion of the ankle, and flexion of the toes; edema and increased hair growth are also clearly visible.

Figure 2. Fluorescence photomicrographs of NK1 receptor expression in keratinocytes in skin samples obtained from a CRPS patient

Representative fluorescence photomicrographs of NK1 receptor expression in keratinocytes in skin samples obtained from a CRPS patient at 3 months post-fracture. Co-immunostaining of NK1 (green) and keratin, (a keratinocyte marker, red) in the epidermis demonstrates greater NK1 receptor expression in keratinocytes in the affected limb than in the contralateral side. Also note the keratinocyte proliferation, epithelial thickening, and the increased thickness of the stratum corneum. Scale bar = 40 μm.

Figure 3. Cortical reorganization.

Cortical reorganization and maladaptive plasticity in patients with CRPS. Panel (A): The distance between the peak response over the contralateral somatosensory cortex to stimulation of the first digit (D1) and fifth digit (D5) on the affected and healthy hands in a patient with CRPS. Note that the distance between D1 and D5 is less for the affected limb. Panel (B): Normalisation of primary sensory cortex reorgnisation occurs in association with the resolution of CRPS symptoms. With friendly permission from Maihöfner et al.

Figure 4. Illustration of clinical features and proposed pathophysiological model

Illustration showing clinical features and their (assumed or demonstrated) underlying pathophysiological mechanisms. IL= interleukin; TNF = tumor necrosis factor; NGF = nerve growth factor; CGRP = Calcitonin-Gene-Related Peptide; SP = substance P; NO = nitric oxide; ET = endothelin.