A New Hypothesis for the Pathophysiology of Complex Regional Pain Syndrome


Complex Regional Pain Syndrome (CRPS) is an enigmatic disease and has defied a clear unified pathological explanation to date. It is a devastating, painful condition that may develop in a limb after an injury, surgery or other trauma.

What we do know about the disease is that is involves disturbances to multiple body systems and biological processes, causing them to behave abnormally. Furthermore, what makes this condition so complex is that symptoms can vary from each individual and will change throughout the disease progress. Not surprisingly, the nature of the disease along with not being able to pinpoint who will or will not develop disease makes treating patients with CRPS difficult.

Our paper was written with the aim to tie together current research findings, especially those that focus on the role of the immune system in CRPS, and to propose a new hypothesis that might help explain what is going on in the body that would lead to the development of CRPS (the pathophysiology).

In the paper, we discuss four components that we believe are driving CRPS:

  1. Tissue trauma (such as injury, surgery, burns, wounds, fractures);
  2. Pathological pain processing (when the nervous systems respond to pain signals abnormally);
  3. Autonomic dysregulation (imbalance between the sympathetic [“fight or flight”] and parasympathetic [“rest and digest”] nervous systems);
  4. Immune dysfunction (immune cells behaving abnormally).
New hypothesis
The timeline image above shows when these four components might appear and activate / contribute to CRPS. The timeline is only a guide and will probably differ between patients.

While some researchers may not agree with our hypothesis, we are currently collaborating with expert science researchers to investigate the immune “signature” present in the bloodwork of CRPS patients compared to healthy people. The study uses an advanced laboratory technique known as mass cytometry and allows for up to 40 different immune markers, including those for specific dendritic cell populations, which are a major focus of this hypothesis to be analysed. The next step is to be performed will be to analyze the other tissue sites referred to in our paper.

While the medical profession is yet to find the single “magic bullet” approach to treat this multi-pathway disease, with this new understanding we might be able to work towards a multi-modal treatment strategy.

Our hypothesis will only be useful if researchers conduct experiments that would test and support the components discussed in our paper. We hope our paper will encourage researchers to test our hypothesis.

The paper is free to access and read via this link.

For more information download this document

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