Scientific PresentationsExperts from a wide variety of clinical and basic research areas, including neuro-imaging, pain, neural plasticity, the sympathetic nervous system and the immune system were invited to bring their knowledge and research approaches to bear on the difficult clinical problem of RSD/CRPS. The participants considered the current knowledge about RSD/CRPS in the context of the state-of-the-art research tools used in their laboratories and proposed ways to apply these approaches to RSD/CRPS. It is hoped that new opportunities for innovative research into the mechanism(s), epidemiology and treatment of RSD/CRPS will be fostered by their cross-disciplinary discussions.
During their presentations, the participants suggested that the mechanism(s) that cause RSD/CRPS are elusive, primarily because of the number of complex systems affected. It became obvious that a single mechanism can barely account for all of the changes seen in patients with RSD/CRPS. Several innovative hypotheses were presented at the workshop and it was agreed on the notion that several mechanisms interact to produce the symptoms of RSD/CRPS.
Drs. Ralf Baron and Wilfrid Jänig presented clear evidence of sympathetic nervous system dysfunction in their experimental studies of human patients with RSD/CRPS. Activating the sympathetic nervous system by lowering body temperature results in increased pain in the affected area in a subgroup of RSD/CRPS patients, whose pain is relieved by sympathetic nerve block or sympathectomy (destruction of the sympathetic innervation to the affected area). However, this sympathetically maintained pain (SMP) mainly involves the deep somatic tissues. While it is not known how autonomic dysfunction relates to the myriad tissue pathologies in RSD/CRPS, this evidence led the participants to generally agree on the following key issues: 1) RSD/CRPS is a neurological (rather than psychological) disorder, and 2) RSD/CRPS is likely to be a disorder of the central (in addition to the peripheral) nervous system.
Dr. Clifford Woolf provided evidence that some types of neuropathic pain are related to changes in pain signaling pathways, including in the neurons of the spinal cord. Such modifications could distort the signaling process so that normally painless stimuli begin to produce pain, and stimuli that should be slightly discomforting actually produce severe, long-lasting pain. New technologies in gene and protein expression profiling should permit researchers to explore these issues further. However, it must be kept in mind that RSD/CRPS in most patients is triggered by traumas without nerve lesions. Thus the pain in these RSD/CRPS patients is not neuropathic pain in the strict sense.
Dr. Linda Watkins suggested that the immune system might play a role in the disorder since signs of inflammation (redness, swelling, increased blood flow and tissue accumulation of immune cells) in the painful region are common in RSD/CRPS patients. The release of pro-inflammatory cytokines in response to neural and glial activation may be one connection between the abnormal regulation of the sympathetic nervous system and the characteristics of inflammatory immune reactions seen in the disorder. These thoughts connect to the idea that peripheral inflammatory processes are involved in the pathogenesis of early RSD/CRPS. However, the exact mechanisms of the initiation and maintenance of these inflammatory reactions, their connection to the sympathetic and afferent (peptidergic) innervation of the affected tissues and their relation to the central changes (e.g., the spinal cord, as addressed by Dr. Watkins) are far from clear. Dr. Levine, who presented several similarities between RSD/CRPS and autoimmune inflammatory diseases such as rheumatoid arthritis, provided support for this idea.
Dr. Wilfrid Jänig approached the problem from a systems level and proposed that the inappropriate integration of sensory, autonomic and motor components at several levels in the central nervous system could be a cause of RSD/CRPS. The initial insult mostly occurs in the periphery and triggers changes in the central representations of the sensory, motor and sympathetic systems which are reflected in the changes of the respective output systems observed in the RSD/CRPS patients. Subsequent interactions with the immune, endocrine and vascular systems could lead to changes in the long-term responsiveness of the central nervous system that finally determines the disease symptomatology in the chronic state.
Dr. Catherine Bushnell applied her expertise in neuroimaging to the question of nervous system activation in RSD/CRPS. She presented comparative imaging of pain in the brain after cutaneous or visceral stimuli to identify brain regions that are uniquely responsive to a particular type of painful stimulus. Similar comparisons between “normal” pain and pain in RSD/CRPS patients should help to clarify which regions of the nervous system are abnormally activated in this disease state. This is a very attractive and promising idea in view of the finding that many chronic RSD/CRPS patients have generalized sensory deficits (cold, warm, pain, touch perception) that can be quantified. If this is a CNS abnormality, functional imaging could suggest CNS sites that should be explored.
Dr. Stephen Bruehl presented clear evidence that psychological distress in patients with CRPS is not a causative factor but might evolve secondary to the chronic pain syndrome. Furthermore, statistical factor analysis of multiple signs and symptoms in CRPS shows that the diagnostic criteria that have been defined so far should be extended by particular signs (e.g. by motor symptoms) in order to increase diagnostic sensitivity and specificity.
In summary, based on evidence from clinical observations, experimentation on humans, and experimentation on animals the general hypothesis has been put forward that RSD/CRPS is a disease of the central nervous system. RSD/CRPS patients exhibit changes which occur in somatosensory systems processing noxious, tactile and thermal information, in sympathetic systems innervating blood vessels, sweat glands and possibly other targets, and in the somatomotor system, indicating that the central representations of these systems are changed. The way these central changes are triggered by the peripheral trauma, which is often minor compared to the dramatic expression of the clinical phenomena, remains an enigma. Furthermore, the way these central changes connect to the peripheral inflammatory/immune changes is entirely unclear. Finally, we cannot explain why pain and the other changes associated with the sympathetic nervous system (including swelling), the motor system and the somatosensory system may disappear, in RSD/CRPS patients with sympathetically maintained pain (SMP), after sympathetic blockade (e.g., with a local anesthetic or with guanethidine). It was agreed that, based on the clinical changes observed in the RSD/CRPS patients which can be measured quantitatively, it should be possible to formulate hypotheses about the underlying mechanisms. These hypotheses should be tested by using a multidisciplinary approach, which includes clinical experimentation and human models. Such an approach is imperative to reach to a mechanism-based diagnostic classification of the RSD/CRPS patients and ultimately to the development of a mechanism-based therapeutic strategy.