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January 28, 2020; 94 (4) Article

Clinical phenotypes and classification algorithm for complex regional pain syndrome

Violeta Dimova, Myriam Selma Herrnberger, Fabiola Escolano-Lozano, View ORCID ProfileHeike Lydia Rittner, Eva Vlckova, Claudia Sommer, Christian Maihöfner, Frank Birklein
First published December 24, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008736
Violeta Dimova
From the Department of Neurology (V.D., M.S.H., F.E.-L., F.B.), University Medical Center of the Johannes Gutenberg University Mainz; Departments of Anesthesiology (H.L.R.) and Neurology (C.S.), University Hospital Würzburg, Germany; Central European Institute of Technology and Medical Faculty (E.V.), Masaryk University, Brno; Department of Neurology (E.V.), University Hospital Brno, Czech Republic; and Department of Neurology (C.M.), General Hospital Fürth of the Friedrich-Alexander University Erlangen-Nürnberg, Germany.
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Myriam Selma Herrnberger
From the Department of Neurology (V.D., M.S.H., F.E.-L., F.B.), University Medical Center of the Johannes Gutenberg University Mainz; Departments of Anesthesiology (H.L.R.) and Neurology (C.S.), University Hospital Würzburg, Germany; Central European Institute of Technology and Medical Faculty (E.V.), Masaryk University, Brno; Department of Neurology (E.V.), University Hospital Brno, Czech Republic; and Department of Neurology (C.M.), General Hospital Fürth of the Friedrich-Alexander University Erlangen-Nürnberg, Germany.
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Fabiola Escolano-Lozano
From the Department of Neurology (V.D., M.S.H., F.E.-L., F.B.), University Medical Center of the Johannes Gutenberg University Mainz; Departments of Anesthesiology (H.L.R.) and Neurology (C.S.), University Hospital Würzburg, Germany; Central European Institute of Technology and Medical Faculty (E.V.), Masaryk University, Brno; Department of Neurology (E.V.), University Hospital Brno, Czech Republic; and Department of Neurology (C.M.), General Hospital Fürth of the Friedrich-Alexander University Erlangen-Nürnberg, Germany.
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Heike Lydia Rittner
From the Department of Neurology (V.D., M.S.H., F.E.-L., F.B.), University Medical Center of the Johannes Gutenberg University Mainz; Departments of Anesthesiology (H.L.R.) and Neurology (C.S.), University Hospital Würzburg, Germany; Central European Institute of Technology and Medical Faculty (E.V.), Masaryk University, Brno; Department of Neurology (E.V.), University Hospital Brno, Czech Republic; and Department of Neurology (C.M.), General Hospital Fürth of the Friedrich-Alexander University Erlangen-Nürnberg, Germany.
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  • ORCID record for Heike Lydia Rittner
Eva Vlckova
From the Department of Neurology (V.D., M.S.H., F.E.-L., F.B.), University Medical Center of the Johannes Gutenberg University Mainz; Departments of Anesthesiology (H.L.R.) and Neurology (C.S.), University Hospital Würzburg, Germany; Central European Institute of Technology and Medical Faculty (E.V.), Masaryk University, Brno; Department of Neurology (E.V.), University Hospital Brno, Czech Republic; and Department of Neurology (C.M.), General Hospital Fürth of the Friedrich-Alexander University Erlangen-Nürnberg, Germany.
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Claudia Sommer
From the Department of Neurology (V.D., M.S.H., F.E.-L., F.B.), University Medical Center of the Johannes Gutenberg University Mainz; Departments of Anesthesiology (H.L.R.) and Neurology (C.S.), University Hospital Würzburg, Germany; Central European Institute of Technology and Medical Faculty (E.V.), Masaryk University, Brno; Department of Neurology (E.V.), University Hospital Brno, Czech Republic; and Department of Neurology (C.M.), General Hospital Fürth of the Friedrich-Alexander University Erlangen-Nürnberg, Germany.
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Christian Maihöfner
From the Department of Neurology (V.D., M.S.H., F.E.-L., F.B.), University Medical Center of the Johannes Gutenberg University Mainz; Departments of Anesthesiology (H.L.R.) and Neurology (C.S.), University Hospital Würzburg, Germany; Central European Institute of Technology and Medical Faculty (E.V.), Masaryk University, Brno; Department of Neurology (E.V.), University Hospital Brno, Czech Republic; and Department of Neurology (C.M.), General Hospital Fürth of the Friedrich-Alexander University Erlangen-Nürnberg, Germany.
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Frank Birklein
From the Department of Neurology (V.D., M.S.H., F.E.-L., F.B.), University Medical Center of the Johannes Gutenberg University Mainz; Departments of Anesthesiology (H.L.R.) and Neurology (C.S.), University Hospital Würzburg, Germany; Central European Institute of Technology and Medical Faculty (E.V.), Masaryk University, Brno; Department of Neurology (E.V.), University Hospital Brno, Czech Republic; and Department of Neurology (C.M.), General Hospital Fürth of the Friedrich-Alexander University Erlangen-Nürnberg, Germany.
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Clinical phenotypes and classification algorithm for complex regional pain syndrome
Violeta Dimova, Myriam Selma Herrnberger, Fabiola Escolano-Lozano, Heike Lydia Rittner, Eva Vlckova, Claudia Sommer, Christian Maihöfner, Frank Birklein
Neurology Jan 2020, 94 (4) e357-e367; DOI: 10.1212/WNL.0000000000008736

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Abstract

Objective We pursued the hypothesis that complex regional pain syndrome (CRPS) signs observed by neurologic examination display a structure allowing for alignment of patients to particular phenotype clusters.

Methods Clinical examination data were obtained from 3 independent samples of 444, 391, and 202 patients with CRPS. The structure among CRPS signs was analyzed in sample 1 and validated with sample 2 using hierarchical clustering. For patients with CRPS in sample 3, an individual phenotype score was submitted to k-means clustering. Pain characteristics, quantitative sensory testing, and psychological data were tested in this sample as descriptors for phenotypes.

Results A 2-cluster structure emerged in sample 1 and was replicated in sample 2. Cluster 1 comprised minor injury eliciting CRPS, motor signs, allodynia, and glove/stocking-like sensory deficits, resembling a CRPS phenotype most likely reflecting a CNS pathophysiology (the central phenotype). Cluster 2, which consisted of edema, skin color changes, skin temperature changes, sweating, and trophic changes, probably represents peripheral inflammation, the peripheral phenotype. In sample 3, individual phenotype scores were calculated as the sum of the mean values of signs from each cluster, where signs from cluster 1 were coded with 1 and from cluster 2 with −1. A k-means algorithm separated groups with 78, 36, and 88 members resembling the peripheral, central, and mixed phenotypes, respectively. The central phenotype was characterized by cold hyperalgesia at the affected limb.

Conclusions Statistically determined CRPS phenotypes may reflect major pathophysiologic mechanisms of peripheral inflammation and central reorganization.

Glossary

ANOVA=
analysis of variance;
BDI=
Beck Depression Inventory;
CDT=
cold detection threshold;
CPT=
cold pain threshold;
CRPS=
complex regional pain syndrome;
CSS=
complex regional pain syndrome severity score;
DFNS=
German Research Network on Neuropathic Pain;
HPT=
heat pain threshold;
MDT=
mechanical detection threshold;
MPT=
mechanical pain threshold;
PCS=
Pain Catastrophizing Scale;
PPT=
pressure pain threshold;
QNS=
Questionnaire of Neglect-like Symptoms in CRPS;
QST=
quantitative sensory testing;
STAI-T=
trait anxiety subscale of the State-Trait Anxiety Inventory;
WDT=
warm detection threshold;
WSS=
within-cluster sum of squares

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • ↵* These authors contributed equally to this work.

  • Received December 13, 2018.
  • Accepted in final form July 18, 2019.
  • © 2019 American Academy of Neurology
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