A hypothesis for the cause of complex regional pain syndrome-type I (reflex sympathetic dystrophy): pain due to deep-tissue microvascular pathology

Abstract

Complex regional pain syndrome-type I (CRPS-I; reflex sympathetic dystrophy) is a chronic pain condition that usually follows a deep-tissue injury such as fracture or sprain. The cause of the pain is unknown. We have developed an animal model (chronic post-ischemia pain) that creates CRPS-I-like symptomatology. The model is produced by occluding the blood flow to one hind paw for 3 hours under general anesthesia. Following reperfusion, the treated hind paw exhibits an initial phase of hyperemia and edema. This is followed by mechano-hyperalgesia, mechano-allodynia, and cold-allodynia that lasted for at least 1 month. Light microscopic analyses and electron microscopic analyses of the nerves at the site of the tourniquet show that the majority of these animals have no sign of injury to myelinated or unmyelinated axons. However, electron microscopy shows that the ischemia-reperfusion injury produces a microvascular injury, slow-flow/no-reflow, in the capillaries of the hind paw muscle and digital nerves. We propose that the slow-flow/no-reflow phenomenon initiates and maintains deep-tissue ischemia and inflammation, leading to the activation of muscle nociceptors, and the ectopic activation of sensory afferent axons due to endoneurial ischemia and inflammation. These data, and a large body of clinical evidence, suggest that in at least a subset of CRPS-I patients, the fundamental cause of the abnormal pain sensations is ischemia and inflammation due to microvascular pathology in deep tissues, leading to a combination of inflammatory and neuropathic pain processes. Moreover, we suggest a unifying idea that relates the pathogenesis of CRPS-I to that of CRPS-II. Lastly, our hypothesis suggests that the role of the sympathetic nervous system in CRPS-I is a factor that is not fundamentally causative, but may have an important contributory role in early-stage disease.

Figures

Fig. 1

Schematic of the hypothesized pathophysiological mechanisms in the CPIP model and at least a subset of CRPS-I patients. In CRPS-I patients, deep tissue injury leads to edema and a compartment-like syndrome. Reperfusion (release of the tourniquet in the animal model) leads to injury of the microvascular endothelial cells induced by free radicals. These events lead to arterial vasospasms and slow flow/no-reflow in deep tissue microvasculature, which produces persistent ischemia that both spreads the I-R injury, and causes chronic inflammation. In muscle and bone, the resulting ischemia and inflammation (including generation of lactate) activates and sensitizes nociceptors. In nerve, the ischemia and inflammation cause ectopic nociceptor discharge. Injury to a neurovascular bundle may also evokes arterial vasospasm, and this may initiate the same vicious cycle in patients with CRPS-II (causalgia).