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.”
NEUROPATHIC ALTERATIONS WITH CLINICAL SYMPTOMS
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.
ARTICLE IN BRIEF
✓ 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 American Academy of Neurology
• 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
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