Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy)

Abstract

CRPS-I consists of post-traumatic limb pain and autonomic abnormalities that continue despite apparent healing of inciting injuries. The cause of symptoms is unknown and objective findings are few, making diagnosis and treatment controversial, and research difficult. We tested the hypotheses that CRPS-I is caused by persistent minimal distal nerve injury (MDNI), specifically distal degeneration of small-diameter axons. These subserve pain and autonomic function. We studied 18 adults with IASP-defined CRPS-I affecting their arms or legs. We studied three sites on subjects' CRPS-affected and matching contralateral limb; the CRPS-affected site, and nearby unaffected ipsilateral and matching contralateral control sites. We performed quantitative mechanical and thermal sensory testing (QST) followed by quantitation of epidermal neurite densities within PGP9.5-immunolabeled skin biopsies. Seven adults with chronic leg pain, edema, disuse, and prior surgeries from trauma or osteoarthritis provided symptom-matched controls. CRPS-I subjects had representative histories and symptoms. Medical procedures were unexpectedly frequently associated with CRPS onset. QST revealed mechanical allodynia (P<0.03) and heat-pain hyperalgesia (P<0.04) at the CRPS-affected site. Axonal densities were highly correlated between subjects' ipsilateral and contralateral control sites (r=0.97), but were diminished at the CRPS-affected sites of 17/18 subjects, on average by 29% (P<0.001). Overall, control subjects had no painful-site neurite reductions (P=1.00), suggesting that pain, disuse, or prior surgeries alone do not explain CRPS-associated neurite losses. These results support the hypothesis that CRPS-I is specifically associated with post-traumatic focal MDNI affecting nociceptive small-fibers. This type of nerve injury will remain undetected in most clinical settings.

Paclitaxel- and vincristine-evoked painful peripheral neuropathies: Loss of epidermal innervation and activation of Langerhans cells

“…For example, a loss of IENF like that reported here for paclitaxel-and vincristineevoked pain has been documented in the neuropathic pain syndromes that accompany diabetes and glucose intolerance (Sumner et al, 2003), post-herpetic neuralgia (Oaklander, 2001), complex regional pain syndrome type-I (Albrecht et al, 2006;Oaklander et al, 2006), and burning mouth syndrome (Lauria et al, 2005b). We are still unable to identify the neural lesion that accompanies the painful peripheral neuropathy produced by ddC, but doses of ddC that are larger than those we tested do produce an anatomical lesion (Keswani et al, 2003).…”

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

“…Early concerns that CRPS was caused by psychopathology were resolved by pathological demonstration of somatotopic dysfunction and degeneration of small unmyelinated axons (Fig. 3) [42][43][44], and epidemiological studies finding no association with psychopathology [45,46]. As CRPS resolves, which it usually does even without treatment [47], the edema, temperature changes, hyperhidrosis, and abnormal hair growth usually resolve before the pain [48,49], so late-stage patients often no longer meet diagnostic criteria for CRPS but only for posttraumatic neuralgia, demonstrating that these are on a continuum (Fig.…”

Classification of the Pain Nature of CRPS Type 1, Based on Patient complaints, into Neuropathic Pain and Nociceptive/Inflammatory Pain, Using the McGill Pain Questionnaire

“…On the other hand, other researchers have suggested that CRPS type 1 is neuropathic pain based on direct evidence of nerve injury. Oaklander et al demonstrated loss of axons in the CRPS-affected limb by means of skin biopsy, indicating hypoesthesia of CRPS-affected limbs; and Blaes et al reported autoantibodies to the surface of peripheral autonomic neurons in sera from CRPS type 1 patients, which produced sympathetic dysfunction in CRPS-affected limbs [13,14]. Thus, the controversy as to whether CRPS type 1 is primarily neuropathic or nociceptive has raged for more than two decades.…”