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.