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Study Finds Loss of Small Nerve Fibers in Complex Regional Pain Syndrome (CRPS)


For release: Friday, May 19, 2006

A new study shows that a reduction in small-diameter nerve fibers is evident in the devastating chronic pain syndrome known as complex regional pain syndrome-type I (CRPS-I), which was formerly known as reflex sympathetic dystrophy.  This finding of nerve damage could provide a biomarker, or aspecific physical trait, that clinicians could use in the future to help diagnose and measure the natural history ofCRPS. 

The study of human skin biopsies provides some of the first evidence of a physical abnormality underlying CRPS-I.  The results are published in the February issue of the journal Pain* and were funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

CRPS develops when a portion of the nervous system that normally conducts pain signals becomes electrically overactive.  This phenomenon results in spontaneous pain.  In the past, many doctors believed that this mysterious pain syndrome was a psychosomatic illness.  CRPS type II, once known as causalgia, refers to pain after a nerve injury.  CRPS-type I, formerly known as reflex sympathetic dystrophy (RSD), occurs in patients most often after trauma, but without clear nerve injury.  Pain and other symptoms persist long after the initial injury has healed.  The chronic pain of CRPS-I may emerge following a cut, burn, fracture, sprain, infection, surgery, or arthritis. Coronary artery disease and stroke may also be associated with onset of the disorder.  Unlike conditions such as stroke, CRPS has no known risk factors and can affect anyone.  The patient's arms or legs are usually involved, but CRPS may affect any part of the body.  Patients also have other changes in the pain site such as swelling or changes in skin color   

“CRPS is not really a disease process but a symptom complex.  It has been difficult to accurately identify CRPS patients,” says lead author Anne Louise Oaklander, MD, PhD, from Massachusetts General Hospital and Harvard Medical School in Boston. “However, absence of proof is not the proof of absence.  With CRPS a great cross-section of people can be affected, since even drawing blood can bring it on.  The person can look absolutely fine on the outside but still can suffer from devastating pain,” says Dr. Oaklander.

Currently, cases of CRPS are hard to prove or disprove.  "It is difficult to see a patient who appears to be in distress, particularly if it's severe, and who's pleading with you to help, when you don't quite know what to do, ," Dr. Oaklander says.  “Patients want an objective cause for their symptoms to be identified.”

The typical neurology tests used to diagnose nerve injuries involve electromyography (EMG) and nerve conduction techniques that measure major motor or sensory nerve changes.  Unfortunately the fiber nerve injuries in CRPS are not detected by this standard exam, which only measures large-fiber function.  The difficulty in measuring small-fiber damage led Dr. Oaklander and her colleagues to propose skin biopsy for detection of CRPS.  Skin biopsy, a procedure in which a sample of skin tissue is removed and examined, provides a very sensitive method for detecting small nerve fiber damage.  “Skin biopsies are a window into the peripheral nervous system,” says Dr. Oaklander.

In the study, small skin samples were taken from 18 adults with CRPS-I and seven people who had chronic pain from osteoarthritis, but not CRPS.  Each subject identified the location of his or her maximum pain, a nearby symptom-free area on the same limb, and a pain free area on the opposite limb.  Skin biopsies were taken from all three spots and the density of tiny projections extending from each nerve cell – small nerve fibers, or neurites – was measured. The results showed a decrease in the number of neurites in the CRPS-affected regions only. On average, about 30 percent of the neurites were missing in the affected limbs.  The loss of neurites may cause the pain of CRPS by triggering a hyper-response on the part of the remaining neurons.

The next step for the researchers will be to create and test animal models that replicate the unique features of CRPS.  This animal model may identify other biomarkers for the presence of the pain in CRPS patients and could improve medical care for patients with CRPS by providing the first and most important step of identification.  In the meantime, the evidence now suggests that CRPS is a classifiable neurologic disorder.  It also guides CRPS patients to seek treatments appropriate for nerve injury. 

The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system.  The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services.  It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit http://www.nih.gov.

*Oaklander AL, Rissmiller JG, Gelman LB, Zheng L, Chang Y, Gott R.  “Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy).”  Pain, February 2006, Vol. 120, pp. 235-243.

-By Michelle D. Jones-London, Ph.D.

Last Modified January 31, 2007