Marked loss of sympathetic nerve fibers in chronic Charcot foot of diabetic origin compared to ankle joint osteoarthritis

Abstract

The pathogenesis of Charcot foot is based on three disputed factors: (1) loss of neurotrophic influence, (2) microtraumatic lesions, and (3) neurovascular disturbances. These etiological causes were uncovered by clinicophysiological tests. However, no results of quantitative nerve density studies of sympathetic and sensory substance P-positive (SP+) nerve fibers are available. We studied the density of sympathetic and SP+ nerve fibers in three distinct areas of the tarsus. Fifteen patients with ankle osteoarthritis (OA) and 15 patients with diabetic Charcot foot were included. Patients with OA did not differ from those with Charcot foot in SP+ sensory nerve fiber density. However, at all three areas, the density of sympathetic nerve fibers was significantly lower in patients with Charcot foot compared to OA (p = 0.006). In addition, we found that the sympathetic nerve repellent factor semaphorin 3C was highly expressed in inflamed tissue in Charcot patients. In Charcot foot of diabetic origin a severe loss of sympathetic nerve fibers was observed. These findings in chronically inflamed Charcot foot lend support to the neurovascular theory in the late chronic phase, which probably depends on the inflammatory upregulation of nerve repellent factors.