Background & Aims

Complex regional pain syndrome (CRPS) is a rare chronic pain disorder following trauma or injury to the extremities that is diagnosed using the new IASP CRPS crite-ria. Bone metabolism with local osteoporosis plays an important role. Bisophosphonate trials were negative – maybe due to lack of identification of suitable patients. Although three-phase bone scintigraphy (TPBS) has been widely used in clinical practice, its significance remains controversial due to inconsistent evaluations. Alternatively, mo-lecular blood parameters [1] could be used for the validation of diagnostics [2] or for therapy control: Osteoprotegerin (OPG) belongs to the TNF receptor family, is mainly produced by osteoblasts and prevents osteoclast activation. Alkaline phosphatase (AP) is elevated when released from the bone matrix. The roles of both biomarkers in CRPS remains unclear.

Methods

Prospective cohort study of patients with CRPS compared to healthy controls (HC). Complete phenotyping with recording of clinical parameters, quantitative sensory test-ing including deep pain (Pressure Pain Threshold (PPT)), and serum determination of OPG, AP, and, if available, evaluation of TPBS images using deep learning-based im-age analysis: annotation of “regions of interest”: whole foot/hand for phases 1-3, as well as subregions for phase 3 of the hands (carpal (cR), metacarpophalangeal (mR), and proximal interphalangeal (pR)). An ensemble of three models (neural network) was created by iterative training, and congruence with the test data was evaluated using a dice score (0 for no match, 1 for a perfect match between manual and auto-matic segmentation). Ratios were formed from the quantitative absorption values (af-fected/control side), with values >1 representing greater accumulation on the affected side. In addition, PPT ratios were formed on affected/control side.

Results

Between August 2018 and October 2023, 108 patients and 48 HC were recruited. The CRPS cohort with a median disease duration of 152 days displayed typical characteristics (median age, 53 years; 74% female; 69% upper extremity affected; 52% warm CRPS). Segmentation of the TPBS images showed excellent congruence (Dice values of 0.819–0.861 for all phases and extremities). Scintigraphy ratios of the hands were already elevated in phases 1 and 2 and increased further in phase 3 for all subregions: cR was 1.52 (1.13, 1.85), mR was 1.45 (1.12, 2.07) pR was 1.54 (1.10, 1.97). The hand ratios in phases 1 and 2, as well as in cR and mR, were moderately inversely correlated with the PPT ratio (?= -0.3 to -0.45; P<0.05). The median OPG level did not differ between the CRPS cohort at 178 pg/ml and HC at 191 pg/ml (P=0.47). Howev-er, AP was higher in the CRPS group at 73 U/L than in the HC group at 60 U/L (P=0.011), particularly in warm CRPS (78 U/L) than in cold CRPS (66 U/L, P=0.003).

Conclusions

Alkaline phosphatase levels are elevated in a comprehensive CRPS cohort, and asso-ciated with the warm subtype of CRPS. Osteoprotegerin levels were not elevated; therefore, the higher alkaline phosphatase levels may have appeared due to increased inflammation. These patients possibly respond better to immunosuppressive therapy. Automatic quantification of three-phase bone scintigraphy showed very good results, even detecting the smallest increase in accumulations. Together with pathological deep pain, this could be used as an indicator of disturbed bone metabolism and may show a better response to anti-resorptive therapies such as bisphosphonates.

References

[1] Reinhold AK, Kindl G, Dietz C, Scheu N, Mehling K, Brack A, Birklein F, Rittner HL. Molecular and clinical markers of pain relief in complex regional pain syndrome: An observational study. Eur J Pain 2023;27:278–288. doi:10.1002/ejp.2058.
[2] Harnik MA, Kesselring P, Ott A, Urman RD, Luedi MM. Complex Regional Pain Syndrome (CRPS) and the Value of Early Detection. Curr Pain Headache Rep 2023. doi:10.1007/s11916-023-01124-3.

Presenting Author

Michael Alexander Harnik

Poster Authors

Michael Alexander Harnik

Dr. med.

University Hospital Inselspital Bern

Lead Author

Annemarie Sodmann (Phd.)

University Hospital Würzburg, Department of Neurology, Würzburg, Germany

Lead Author

Beate Hartmannsberger

Universitätsklinikum Würzburg

Lead Author

Abdelrahman Sawalma

Uniklinikum Würzburg

Lead Author

Ann-Kristin Reinhold

Universitätsklinikum Würzburg

Lead Author

Eva Herrmann

University Hospital of Würzburg, Würzburg, Germany

Lead Author

Ulrich Dischinger

PD Dr. med.

University Hospital of Würzburg, Würzburg, Germany

Lead Author

Juliane Becker

Dr. med.

University Hospital of Würzburg, Würzburg, Germany

Lead Author

Andreas Buck

Prof. Dr. med.

University Hospital of Würzburg, Würzburg, Germany

Lead Author

Frank Birklein

Department of Neurology, University Medical Center, Mainz, German

Lead Author

Heike Rittner

University Hospital Wuerzburg

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Complex Regional Pain Syndrome (CRPS)