Complex Regional Pain Syndrome (CRPS): From Past to Present

By Severija Saladziute

Complex Regional Pain Syndrome (CRPS) is a debilitating condition characterized by non-dermatomal patterns of pain, sensory abnormalities, autonomic dysfunction, and motor changes. It can be differentiated into two  types based on the absence (CRPS I) or presence (CRPS II) of detectable nerve trauma, yet the distinction is not often made in scientific literature due to limited clinical differences [1].

CRPS is one of the diseases originally classified by the neurologist Dr. Jean-Martin Charcot in the late 19th century as hysteria minor [2]. Some physicians attribute the sensory and motor abnormalities of CRPS to psychogenic issues. Given the overlapping diagnostic criteria, CRPS is often mistaken for somatoform disorders such as conversion disorder or pain disorder [2, 3]. In contrast, the past decade has provided significant evidence towards the inflammatory and autoimmune processes associated with the initiation of CRPS, and the central nervous system (CNS) changes believed to sustain the disease.

Following a nerve injury, a number of well-characterized changes take place, both locally and systemically. The injured nerve induces the release of cytokines from neuro-inflammatory immune cells [1]. This neuroinflammation is the initiating mechanism believed to produce the various clinical manifestations of CRPS. Early stages of the disease often present with cardinal signs of inflammation including swelling, redness, temperature increase, pain, and reduction in function in the affected limb [4]. Several studies have found increases in pro-inflammatory cytokines (TNF-α, IL-6, IL-12) in samples of patient serum, CSF, and blister fluid of affected limbs [4, 5]. Nonetheless, this evidence was found in only a subset of patients and is further complicated by the fact that cytokine profiles show variation in different stages of the disease. Although, neuropeptides are normally responsible for the visible signs of inflammation, CRPS patients respond with a much stronger neuropeptide-mediated inflammation. When both affected and unaffected limbs are experimentally activated they result in increased levels of bradykinin, CGRP and substance P in the serum [4, 5].

In addition to the neuroinflammatory etiology of CRPS, recent discoveries indicate the presence of an autoimmune component in many patients. Several studies have revealed that CRPS patients had autoantibodies to either the beta2-adrenergic receptor (β2AR) or the muscarinic acetylcholine receptor (MR2) [2, 4]. These findings are of particular interest in that they propose a link to the sympathetic dysregulation observed in CRPS. Common clinical presentations of autonomic dysfunction (altered temperature regulation, sweating, altered skin color) previously led clinicians to believe that the disorder was sympathetically mediated [1]. On the contrary, the acute phase hyperactivity of the sympathetic nervous system can now be explained by neuropeptides [5]. Recent evidence also indicates that sympathetically maintained pain that can be reduced by sympathetic blockade is rare in long-standing CRPS [4].

If CRPS is not successfully treated in its early stages (approximately 3-6 months), symptoms begin to occur that cannot be explained by a peripheral pathophysiology. These later symptoms are a result of the reorganization of multiple brain centers. The term “central sensitization” is often used to describe CNS changes associated with neuroinflammatory diseases. In CRPS, central sensitization appears to occur via complex interactions involving NMDA receptors, glial cells, pro-inflammatory cytokines and leukocytes [1, 2]. Following the spread of neuroinflammation to the CNS, the microscopic structural lesions produced lead to functional changes in local neuronal circuits [2]. Although these small structural lesions are largely undetectable, studies utilizing functional imaging methods such as magnetoencephalography and fMRI have provided some insights into the various CNS changes involved in the sustainment of CRPS. Prominent alterations have been found in the somatosensory and motor cortices as a result of constant nociceptive inputs which interfere with tactile and nociceptive processing networks [6]. Representations of affected extremities in the primary somatosensory cortex are altered (homunculus is shrunk and shifted) to a degree that corresponds to the patient’s pain intensity, yet pain reduction can reverse these changes [4-6]. In the motor cortex, representations of unaffected limbs were significantly larger than affected limbs, although a direct relationship between asymmetry and pain intensity were not established [6]. A handful of studies have also found alterations in other brain regions of CRPS patients. In particular, individuals with allodynia have been shown to have stronger activations in the cingulate gyrus, and those with motor deficits display stronger activations in the parietal lobe [5]. Additionally, grey matter atrophy has been observed in regions important in stress processing including the right insular cortex, the nucleus accumbens, and the ventromedial prefrontal cortex [1, 5]. Although neuroimaging techniques have provided new insights into CNS changes in CRPS, the range of behaviors processed in specific brain regions make defining specificity in results a challenge [1].

How do recent advances in our understanding of the disease pathophysiology translate to current therapeutic approaches? The consensus is that early therapeutic intervention and a multidisciplinary approach is highly desirable to prevent transition to chronic CRPS [2, 4, 5]. Patients are encouraged to use affected extremities even with transient increases in pain to prevent functional impairment over time. Due to the predominance of inflammatory symptoms in acute stages, steroids, bisphosphonates and dimethyl sulfoxide topical applications were effective in some patients in the early stages of the disease [4, 5]. Ketamine infusions have been deemed the most effective in reducing pain for long-standing CRPS, yet they pose the risk of serious side effects [5]. Spinal cord stimulation is another effective therapeutic option if noninvasive measures have been exhausted without benefit.

For many years, a lack of understanding of the disease process left patients with CRPS without appropriate care and treatment interventions. The precise pathophysiology of CRPS still remains elusive. Promising new treatment approaches appear to be right around the corner but require confirmation in long-term trials. Thus, further research is urgently needed to improve early diagnostic methods and improve the quality of life for individuals struggling with this condition.

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