As can be surmised from this discussion, uncertainties persist about the pathogenesis of the diabetic neuropathies. Both the cranial and peripheral mononeuropathies, as well as the painful, asymmetrical, predominantly proximal neuropathy of sudden onset, have been considered by most neuropathologists to be ischemic in origin, secondary to a vasculopathy of the vasa nervorum. Obliterative microvascular lesions were well illustrated by Raff and coworkers and corresponding multiple small infarcts were found in the nerve trunks in other studies. The observations of Dyck et al (1986b) and of Johnson and their associates also suggested that all forms of diabetic neuropathy had the same microvascular basis. The latter authors described multiple foci of fiber loss throughout the length of the peripheral nerves, beginning in the proximal segments and becoming more frequent and severe in the distal. This pattern of change differs from that observed in diffuse metabolic disease of Schwann cells and in the dying-back type of neuropathy. Fagerberg had earlier noted that the fascicular capillaries and epineural arterioles have thickened and hyalinized basement membranes, similar to the microvascular changes seen in the retina, kidney, and other organs. But occlusion of vessels and frank infarction of nerve has not been observed in most cases of polyneuropathy for which reason a vascular pathogenesis remains unsettled.
An alternative view has been offered, based largely on the work of Dyck and colleagues (2000) and of Said and coworkers (2003). They have found areas of perivascular inflammation and adjacent damage to nerve fascicles in the proximal radicular plexus syndrome. These findings, if valid, have implications for possible treatment with anti-inflammatory drugs.
Several biochemical findings implicated in diabetic polyneuropathy and their interpretations were reviewed by Brown and Greene, who advanced the idea that persistent hyperglycemia inhibits sodium-dependent myoinositol transport. Low levels of intraneural myoinositol reduce phosphoinositide metabolism and sodium- potassium adenosine triphosphatase (ATPase) activity. Others have emphasized a deficiency of aldose reductase and an elevation of polyols (particularly sorbitol) as being causally important. The role of factors other than hyperglycemia that are subsumed under the “metabolic syndrome” mentioned earlier is also unclear. In reviewing these studies, one can only conclude that a convincing biochemical pathogenesis for neuropathy in diabetes has yet to be formulated.
Another group of novel findings holds that there is a reduction in trophic factors within diabetic nerves (nerve growth factor [NGF], vascular endothelial growth factor [VEGF], erythropoietin); partial reversal of the polyneuropathy has been obtained in animals by replacement of these factors through gene therapy. Trials addressing this mode of treatment are noted later.