Reflex Sympathetic Dystrophy Syndrome
Complex Regional Pain Syndrome
RSD(S)/CRPS Scientific Presentations
Experts 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.