The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia

Abstract

Characterization and quantitation of the spatial distribution of pathological abnormalities along the length of nerves may be helpful in understanding the underlying mechanisms of diabetic polyneuropathy. To this end, by examining transverse sections of nerve roots and proximal-to-distal levels of lower limb nerves in 9 controls and 15 diabetic patients with polyneuropathy, we have determined the myelinated fiber (MF) number, size distribution, median diameter, and variability of density (MFs/mm2) among frames and among fascicles. Even in cases with mild polyneuropathy, fiber loss, a decrease in the median diameter, and an increase in the variability of density among frames and among fascicles began in proximal nerve and extended to distal levels. Multifocal fiber loss along the length of nerves and sprouting provide the best explanation for these findings. The pattern is dissimilar from that observed in diffuse metabolic disease of Schwann cells, neuronal degeneration, and dying-back neuropathy, but like that found in experimental ischemic neuropathy induced by embolization of nerve capillaries.

Magnetic resonance neurography detects diabetic neuropathy early and with Proximal Predominance

“…In accord with the distal dominance of symptoms and signs, the longitudinal gradient of fiber loss along lower extremity nerve trunks is also directed from distal (where it is most severe) to proximal 4, 5, 6, 7, 9. Such a distally marked reduction in fiber density appears not only in sural nerve biopsies, but also in skin punch biopsies, which reveal the density of cutaneous innervation by small fibers (intraepidermal nerve fiber density; IENF).…”

“…It is generally agreed that fiber loss in lower extremity peripheral nerves is the most prominent histological fingerprint of DPN and involves large myelinated and/or small fibers 3, 4, 5, 6, 7, 8, 9. In accord with the distal dominance of symptoms and signs, the longitudinal gradient of fiber loss along lower extremity nerve trunks is also directed from distal (where it is most severe) to proximal 4, 5, 6, 7, 9.…”

“…Through very extensive and meticulous histological analyses, a few studies have reported results for the distal levels of the sural, peroneal, and tibial nerves and, importantly, also for defined proximal levels, including several serial sections of spinal nerves, the plexus, and the sciatic nerve at the thigh level 4, 6, 13. In these studies, Dyck et al,4 Sugimura and Dyck,13 and Johnson et al6 consistently showed that fiber loss at more proximal levels (eg, in the sciatic nerve at the thigh level) occurs not diffusely, but instead within focal and multifocal zones that appear “punched out” from the sciatic nerve fascicles, increasing in severity at more distal levels. This focal/multifocal lesion pattern on sciatic nerve cross‐sections at the thigh level closely resembled the focal/multifocal fiber loss observed after experimentally induced ischemic insults, for example, by microsphere embolization into vessels supplying the sciatic nerve18 or in human necrotizing vasculitic neuropathy 19.…”

“…Because of the considerable time needed for the acquisition of the extensive imaging protocol for coverage of large anatomical areas and simultaneous high spatial resolution, signal quantification was not possible over the entire area covered and was possible only within this anatomically restricted imaging slab. We chose the thigh level for signal quantification because preliminary measurements in a few patients with DPN and the results from a pilot study12 indicated that the lesion burden would be highest at the thigh level and because historical histological data reported proximal nerve lesions at the thigh level 4, 13. Comprehensive statistical analyses of both quantitative measures were performed by ordered logistic regression on group .…”

“…One important aspect of DPN pathogenesis that remains poorly understood is the spatiotemporal distribution and propagation of microstructural nerve alteration. The most prominent histological fingerprint of DPN is a distally dominant, mixed axonal loss involving all types of nerve fibers 3, 4, 5, 6, 7, 8, 9. However, where along the lower extremity peripheral nerves, including their terminal fibers, and the microvascular and/or metabolic pathologic mechanisms by which axon structure degeneration occurs first remain controversial issues.…”