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Reflex Sympathetic Dystrophy/ Complex Regional Pain Syndromes (CRPS): State-of-the-Science
December 15, 2001
On December 15, 2001, the National Institute of Neurological Disorders and Stroke and the NIH Office of Rare Diseases convened
a workshop on RSD/CRPS chaired by Dr. Jon Levine (UCSF) and Dr. Cheryl Kitt (NINDS). The participants included neurologists,
neuroscientists, patient advocates and NINDS staff. The goal of the meeting was to bring together leading pain researchers
to consider RSD/CRPS in the context of their own research paradigms, determine the state of the science and identify new directions
for research on this disorder.
Reflex Sympathetic Dystrophy (RSD), also known as Complex Regional Pain Syndrome (CRPS) Type I (here called RSD/CRPS), is
a chronic condition characterized by burning pain and abnormalities in the sensory, motor and autonomic nervous systems. The syndrome typically appears after an acute injury to a joint or limb, though it may occur with no obvious precipitating
event. In most cases, regardless of the site of injury the symptoms begin and remain most intense in the distal most extremity.
In the initial stages of RSD/CRPS, pain and swelling from the injury do not subside but actually intensify, spreading from
the site of the injury to other parts of the limb, to the contralateral limb or to remote regions of the body. The skin in
affected areas and particularly deep somatic tissues are painfully sensitive to touch, often red and abnormally warm due to
alterations in regional blood flow. Changes in sweating patterns, hair growth, subcutaneous tissues, muscles, joints or bones
and difficulty moving the joint or limb are other hallmarks of the disorder. In addition to the evidence of inflammation and
abnormal autonomic nervous system function, there are changes in motor systems including tremor, weakness and dystonia, which
strongly suggest a central nervous system component to the disease in a subgroup of patients. The syndrome may evolve through
three stages (acute, dystrophic, atrophic), although this is very much debated, each marked by progressive pain and physical
changes in the skin, muscles, joints and bones. RSD/CRPS can affect both genders and all ages (including children), although
it is thought to be more common between the ages of 40 and 60 and may be more frequent in women. The cause of RSD/CRPS is
unknown, and current treatments are not effective for many patients.
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
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.
New Research Directions
The workshop participants identified several critical needs in our basic understanding of RSD/CRPS, as well as potential directions
for basic and clinical research on new treatment strategies. These needs were in the areas of 1) diagnostic criteria, 2) epidemiology,
3) RSD/CRPS model systems, 4) disease mechanisms, 5) integration between basic research and clinical research, and 6) therapy:
- A consensus definition of RSD/CRPS with standardized diagnostic criteria. There is practical agreement among neurologists, anesthesiologists and others about the minimal clinical criteria (signs
and symptoms) that define RSD/CRPS. However, without a universally accepted definition and diagnostic criteria and a further
validation and extension of the present clinical criteria, it is difficult to accurately identify RSD/CRPS patients, select
patients for clinical trials, validate experimental human and animal model systems for research, and last-but-not-least to
formulate testable hypotheses. The participants suggested that an expert meeting to specifically define the clinical and diagnostic
criteria, based on what is known, should be a high priority for the field. Once determined, these consensus criteria should
be disseminated to the medical, research and advocacy communities, in particular to those groups involved in the epidemiological
studies, design of appropriate models for symptoms in RSD/CRPS, research on underlying mechanisms and the design of RSD/CRPS
therapies tested in prospective clinical trials.
- Epidemiological studies of RSD/CRPS using well-defined diagnostic criteria. Epidemiological studies to identify characteristics of patients at high risk for developing RSD/CRPS, to better define the
relationship between certain clinical signs and disease onset, progression and distribution on the body, and to find out the
incidence of patients with RSD/CRPS were considered a high priority. Patients with RSD/CRPS exhibit different combinations
of symptoms. Does the individual RSD/CRPS patient progress through the three stages of the disorder as described in the literature.
Most patients do not seem to go through different stages, although this has not been thoroughly investigated. Currently the
symptomatic variability among RSD/CRPS patients makes it difficult to draw firm conclusions about mechanisms of the disorder
based on clinical profiles, and could contribute to unclear findings in clinical trials. Strict patient selection based on
defined clinical criteria could help to resolve this problem. Epidemiological studies may also help to clarify the anecdotal
evidence regarding different incidence rates between women and men and the differences in the disease state between children
and adults with RSD/CRPS. Finally, epidemiological studies may serve to work out prospective studies in order to find predictors
for the development of RSD/CRPS.
- Validate the existing models of CRPS and generate new models that recapitulate the unique features of RSD/CRPS. Appropriate experimental systems in which to study RSD/CRPS are required to advance the field; current model systems do not
accurately reflect all of the symptoms experienced by patients, such as the potential gender disparity. We have models to
study mechanisms operating in CRPS II (which may develop after trauma with nerve lesion); however, as noted by Dr. Gary Bennett,
we almost totally lack animal models to study mechanisms operating in RSD/CRPS. Further, there are few simple in vivo or in
vitro experimental model systems available to study potential RSD/CRPS disease mechanisms or to predict the efficacy of potential
- Define disease mechanisms that give rise to RSD/CRPS in susceptible individuals. Several theories about disease mechanisms were presented at the workshop, but most questions addressing mechanisms clearly
remain open. The participants felt that further research efforts focused on determining underlying mechanisms that cause RSD/CRPS
are absolutely necessary to make progress in the design of a more appropriate (mechanism-based) diagnostic classification
of RSD/CRPS patients and in the design of better therapeutic strategies. In the past, research efforts relevant to RSD/CRPS
have generally focused on one component of the syndrome, such as pain, or blood flow, or bone/joint changes, but very little
or not at all on central nervous system components related to the sensory, motor and sympathetic systems. Because RSD/CRPS
affects multiple body systems, it is important to investigate the interactions between these peripheral and central components.
- Integrate research on animal and human models with clinical research on patients. The workshop participants found it essential (and attractive) that research on animal and human models and clinical investigations
of RSD/CRPS should be closely aligned. Thus research on mechanisms performed on different models must be interactive with
clinical research. Any model, even the human one, is only an approximation to the clinical situation. Research on mechanisms
in the models should concentrate on symptoms but not on syndromes.
- New RSD/CRPS therapies tested in prospective clinical trials. To date, there are no clinical trials on the efficacy of various treatments of RSD/CRPS available that used evidence-based-medicine
criteria (Dr. David Borsook). The participants presented preliminary anecdotal evidence for therapeutic approaches, such as
long-term sympathetic and/or spinal cord blockade and physical therapy that could be tested in controlled, prospective clinical
trials. Trials designed to treat patients at risk for developing RSD/CRPS (e.g., those undergoing knee-replacement surgery)
would help to standardize the patient populations and may contribute to more reliable clinical results. As suggested by Dr.
Howard Fields, a collaborative, multi-disciplinary, multi-site translational research program on RSD/CRPS may help to facilitate
the development and testing of new therapies for this disorder.
In summary, there was a consensus amongst the participants of the workshop that future research on the mechanisms of RSD/CRPS must be
much better integrated with the observation on the human patients, i.e. with the clinic. Design of both animal and human models
must be more closely integrated with each other and with the clinic in order to focus the scientific questions, the formulation
of hypotheses and the experimental approaches. Only such an interdisciplinary and multidisciplinary approach has a realistic
chance of uncovering the pathophysiology and improving treatment of RSD/CRPS. Such an approach should be optimal to use and
focus the different methodological techniques that are available to reach these aims. The best way to achieve this overall
aim is to create research programs in association with the clinic in which the RSD/CRPS patients are diagnosed and treated.
- Dr. Ralf Baron (Germany)
- Dr. Gary Bennett (McGill)
- Dr. David Borsook (Harvard)
- Dr. Stephen Bruehl (Vanderbilt)
- Dr. Cathy Bushnell (McGill)
- Dr. Howard Fields (UCSF)
- Dr. Wilfrid Jänig (Germany)
- Dr. Cheryl Kitt (NINDS)
- Dr. Jon Levine (UCSF)
- Dr. Audrey Penn (NINDS)
- Dr. Linda Watkins (University of Colorado)
- Dr. Clifford Woolf (Harvard)
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Published meeting report from December 2002 issue of Anesthesia & Analgesia (subscription required): (http://www.anesthesia-analgesia.org/cgi/content/full/95/6/1812)