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Complex regional pain syndrome — phenotypic characteristics and potential biomarkers

Nature Reviews Neurology volume 14, pages 272–284 (2018)Cite this article

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Key Points

  • Complex regional pain syndrome (CRPS) is a persistent pain condition that often results from an injury and usually affects a single limb.

  • An unusually high level of pain during the week after the injury seems to be the most robust risk factor for CRPS development.

  • Post-traumatic inflammation has been identified as a major component of acute CRPS, and growth factors, catecholamines and autoantibodies have also been implicated in CRPS pathogenesis.

  • A growing body of evidence indicates that disturbances of body representation and body perception are key features of the CRPS phenotype.

  • Small non-coding RNAs (microRNAs) are emerging as diagnostic and prognostic biomarkers for CRPS.

  • A single marker for CRPS is unlikely to be found; however, a range of biomarkers might assist in clinical diagnosis and guide prognosis and treatment.

Abstract

Complex regional pain syndrome (CRPS) is a pain condition that usually affects a single limb, often following an injury. The underlying pathophysiology seems to be complex and probably varies between patients. Clinical diagnosis is based on internationally agreed-upon criteria, which consider the reported symptoms, presence of signs and exclusion of alternative causes. Research into CRPS biomarkers to support patient stratification and improve diagnostic certainty is an important scientific focus, and recent progress in this area provides an opportunity for an up-to-date topical review of measurable disease-predictive, diagnostic and prognostic parameters. Clinical and biochemical attributes of CRPS that may aid diagnosis and determination of appropriate treatment are delineated. Findings that predict the development of CRPS and support the diagnosis include trauma-related factors, neurocognitive peculiarities, psychological markers, and local and systemic changes that indicate activation of the immune system. Analysis of signatures of non-coding microRNAs that could predict the treatment response represents a new line of research. Results from the past 5 years of CRPS research indicate that a single marker for CRPS will probably never be found; however, a range of biomarkers might assist in clinical diagnosis and guide prognosis and treatment.

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Figure 1: Hypothetical conceptual frameworks for CRPS.
Figure 2: Mast cell accumulation in CRPS.
Figure 3: The possible role of keratinocytes in CRPS pathophysiology.

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Acknowledgements

F.B. acknowledges support from the Deutsche Forschungsgemeinschaft (Germany; grant Bi579/8-1) and the Dietmar-Hopp Foundation. F.B. and C.S. acknowledge support from the European Commission (ncRNAPain, FP7 grant 602133). A.G. has received funding from the Pain Relief Foundation, Liverpool, UK. S.K.A. has received grants from the NIH (National Institute of Neurological Disorders and Stroke 1R21NS082991-01), the Rita Allen Foundation and the Drexel University Clinical and Translational Research Institute.

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Author notes

  1. Roberto S. G. M. Perez: Deceased: Roberto S. G. M. Perez.

Authors and Affiliations

  1. Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

    Frank Birklein

  2. Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA

    Seena K. Ajit

  3. Pain Research Institute, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    Andreas Goebel

  4. The Walton Centre NHS Foundation Trust, Liverpool, UK

    Andreas Goebel

  5. Department of Anesthesiology, VU University Medical Center, Amsterdam, Netherlands

    Roberto S. G. M. Perez

  6. Department of Neurology, University of Würzburg, Würzburg, Germany

    Claudia Sommer

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All authors contributed equally to researching data for the article, discussions of the content, writing the article, and review and editing of the manuscript before submission.

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Correspondence to Frank Birklein.

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Birklein, F., Ajit, S., Goebel, A. et al. Complex regional pain syndrome — phenotypic characteristics and potential biomarkers. Nat Rev Neurol 14, 272–284 (2018). https://doi.org/10.1038/nrneurol.2018.20

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