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Where is the pathophysiologic origin of neuropathic pain – is it in the skin, the brain, the psyche, or somewhere in between? The question is nowhere more puzzling – and the answers potentially various – than when the subject is “complex regional pain syndrome” (CRPS), a cluster of symptoms that includes chronic pain, somatosensory, autonomic, and sometimes motor systems. The syndrome was formerly called reflex sympathetic dystrophy.

Typical features of CRPS can include changes in the color and temperature of the skin over affected limbs and body parts accompanied by burning or aching pain, skin sensitivity, sweating, and swelling. Like other conditions, there is a spectrum of severity. Some patients with intense pain have had affected limbs amputated, and suicides have been reported. Secondary depression is common as in all chronic pain syndromes.

Weir Mitchell described this syndrome (causalgia or CRPS-II) after major nerve injuries, but it has been unclear why other patients with sometimes trivial-seeming injuries report similar pain and disability. Some patients experience long-lasting pain and crippling changes in spite of often radical and invasive treatments, others experience spontaneous remission of symptoms.

In some cases – which have been dubbed CRPS II – there is clear evidence of previous neurological trauma; in other cases (CRPS I, the more common syndrome) there is no apparent trauma that would account for the pain.

Various explanations have been proposed, with passionate believers on all sides. Some say CRPS is psychogenic and that some patients are malingerers or neurotic. Others say the condition involves initial triggering and subsequent over-stimulation of the sympathetic nervous system resulting in characteristic inflammatory signs. Still others suspect a complex interaction of peripheral and central systems along with psychological factors.

About all that everyone agrees on is that CRPS is controversial. Cases are not infrequently litigated for workmen's compensation, but because of the difficulty of proving the biological existence of the condition – and because of the suspicion of malingering – claims are typically turned-down. Now, two papers in the journal Pain seem to show evidence of neurological damage in patients with CRPS.


In one study, led by Anne Louis Oaklander, MD, PhD, results from quantitative mechanic and quantitative sensory testing (QST) and skin biopsies of 18 patients with CRPS-I were compared to seven symptom-matched individuals experiencing chronic pain as a result of trauma or osteoarthritis (Pain 2006;120:235–243).

Dr. Oaklander, Associate Professor of Neurology at Harvard and Director of the Nerve Injury Unit at Massachusetts General Hospital in Boston, and colleagues assessed three sites on CRPS-affected and matching contralateral limbs – the CRPS-affected site, and nearby unaffected ipsilateral and matching contralateral control sites.

They reported evidence of focal small-fiber axonal degeneration in CRPS patients, a surprising number of whom had had previous medical procedures. Axonal densities at the CRPS-affected sites were diminished in 17 of the 18 patients by an average of 29 percent. In contrast, the control subjects with similar symptoms from osteoarthritis had no painful-site neurite reductions. Moreover, QST revealed mechanical allodynia and heat-pain hyperalgesia at affected sites in the CRPS patients. Data from the control group suggest that small fiber damage is not merely a consequence of limb swelling, disuse, or pain, Dr. Oaklander said.


This image is an immunofluorescence photomicrograph of a skin biopsy from the arm of a patient with complex regional pain syndrome type-1. The loss of epidermal endings is shown in green dye; disrupted vascular endothelial cells in red; and nuclei of the various types of skin cells in blue.


This previously healthy young scientist underwent routine bunionectomy in 2004 that left her with chronic left foot pain and focal autonomic changes.

Dr. Oaklander told Neurology Today that the study demonstrates that CRPS I, like CRPS II, is a neurological condition associated with damage to small-diameter axons caused by major, or sometimes seemingly insignificant trauma, such as needlesticks or mild injuries.

And because typical EMG and nerve conduction tests measuring function are insensitive to small-fiber damage, the neurological basis of the symptoms goes unrecognized, she said.

“These are post-traumatic neuralgias,” said Dr. Oaklander. “The injuries that precede symptom onset may seem mild, but we have shown that they are sufficient to have damaged underlying small-nerve fibers. Since most neurologists focus on motor signs and electrodiagnostic abnormalities to diagnose nerve injuries, these subtle sensorineural injuries are often missed.”

She added: “We were also dismayed to see that medical procedures, including surgery, casting, and even routine phlebotomy are perhaps the most common cause of this syndrome in our arena.”

Dr. Oaklander said that the study is not the first to show neurologic injury in patients with CRPS-I, and she said the use of a control group of chronic pain patients demonstrates a specific association between small-fiber damage and CRPS.

She added that the loss of axonal density of 29 percent suggests that trauma preceding the onset of symptoms can be mild. “You don't have to have severe damage to get this syndrome,” she said. “That is one of the reasons it is so difficult to diagnose. The neurologist has a critical role in the diagnosis of this syndrome,” Dr. Oaklander said. “Only neurologists have the training in careful examination and neuroanatomical localization that will enable these patients to get a diagnosis, and then perhaps definitive treatment.”


A second paper also appearing in Pain analyzed glabrous and hairy skin samples from an arm and a leg amputated from two CRPS patients (Pain 2006;120:244–266). Using a battery of antibodies directed against neural-related proteins and mediators of nociceptive sensory function, they found a wide range of neuropathic alterations corresponding with clinical symptoms.

Lead author Frank L. Rice, PhD, acknowledged that there is no way of knowing what the initiating event triggering the neurological changes was, and that the amputation itself may be involved. But he said the results, in tandem with Dr. Oaklander's report, at least suggest the possibility of underlying neurologic damage in some cases of CRPS. Dr. Rice is Professor at the Center for Neuropharmacology and Neuroscience at Albany Medical College in New York.

In the study, Dr. Rice and colleagues reported the presence of abnormal axons innervating hair follicles; a decrease in epidermal, sweat gland, and vascular innervation; loss of expression of calcitonin gene-related peptide on remaining innervation to blood vessels and sweat glands; and a loss of vascular endothelial integrity and extraordinary vascular hypertrophy.

“Everywhere you look, the norm of how nerve endings look was disrupted, including nerve fibers that we didn't view as pain-mediating to begin with,” Dr. Rice told Neurology Today.

Dr. Rice emphasized that the changes correlate directly with clinical symptoms. For instance, nerve endings around hair follicles were disrupted in patients who had experienced extreme allodynia associated with the light movement of air over hairy skin. “We detected an appropriate set of nerve endings that have been deranged and that fit to the symptoms,” he said.


Neurologist Paola Sandroni, MD, PhD, who reviewed the papers for Neurology Today, said they would do little to clarify a condition that remains a clinical conundrum. She authored a landmark study of incidence and prevalence of CRPS in Pain (2003;103:199–207). In that report she found an incidence rate of 5.46 per 100,000 person-years at risk, and a period prevalence of 20.57 per 100,000, with a female-to-male ratio of four-to-one.

Seventy-four percent of patients underwent remission, often spontaneously. She and fellow researchers concluded that CRPS I is of low prevalence and that invasive treatment of CRPS may not be warranted in most cases.

Dr. Sandroni, a neurologist at the Mayo Clinic in Rochester, MN, said the study led by Dr. Oaklander was intriguing, but offered little that was conclusive. “A lot more work needs to be done,” he said. “These are small numbers and I still don't know whether the changes Dr. Oaklander detected are secondary to endogenous substances and treatments that may have been applied. A little bit of reduction [in small nerve fibers] in the affected painful site – is that the whole story?”

Dr. Rice agreed that CRPS remains a catch-all syndrome that may offer different explanations for different patients. “We can't say carte blanche that there is always real injury,” he said. “That may not always be the case.”

But he noted that many patients report experiencing the most extreme form of pain, and often take drastic measures to relieve themselves. And he said that both Pain papers suggest that nerves may be more fragile – and damage to them more consequential – than previously recognized.


  • ✓ Two papers in the journal Pain report neurological evidence of chronic regional pain syndrome. But an expert in pain management commented that the evidence may not be conclusive.


• Albrecht PJ, Hines S, Rice FL, et al. Pathological alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain 2006;120:244–266.
• Oaklander AL, Rissmiller JG, Gott R, et al. Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain 2006:120:235–243.
• Sandroni P, Benrud-Larson LM, Low PA, et al. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003;103:199–207.