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4 Pathogenesis and Pathology of Diabetic Neuropathy
Histopathology
A.P. Mizisin and H.C. Powell
The frequent occurrence of neurologic complications of diabetes has long been recognized and no doubt contributed to the erroneous belief of nineteenth-century physicians that diabetes mellitus was a disease of the nervous system. While disturbances in the central nervous system related to insulin deficiency are recognized, the major neurologic complication is the peripheral neuropathy occurring in both insulin-dependent and insulin-independent forms of diabetes mellitus. Although conventional medical treatment prolongs life span and attenuates neurologic complications of diabetes, hyperglycemic control is not sufficient to prevent the development of neuropathy. The peripheral nerve disorders related to diabetes mellitus are clinically heterogeneous and often subdivided into symmetric polyneuropathies and focal or multifocal neuropathies.
The pathology of diabetic neuropathy and its interpretation have been a continuing source of controversy. Points of contention have ranged from whether peripheral nerve injury is primary or secondary to neuronal degeneration to whether demyelination or axonal loss is the primary or main lesion. The pathogenesis of diabetic neuropathy has also been contentious and variously described as having a metabolic or ischemic etiology. Despite disagreement about the primary role of a particular lesion or the etiology of diabetic neuropathy, it is clear that diabetes mellitus has the potential to induce pathologic changes in most cellular and noncellular components of the peripheral nerve. This chapter will consider first the histopathologic changes induced by hyperglycemia in the peripheral nerve and then the relationship of this pathology to the type of diabetic neuropathy.
Hyperglycemia-Induced Histopathology
Myelinated Nerve Fibers
Loss of myelinated nerve fibers has been repeatedly documented. While fiber loss is most prominent distally, it may also be apparent in spinal roots, particularly in dorsal roots. Some have suggested that proximal multifocal fiber loss in the sciatic nerve summates to produce diffuse distal lesions in the peroneal, tibial, and sural nerves [1]. Although marginal fiber loss is difficult to assess qualitatively, moderate to gross loss has been extensively illustrated (Fig. 4.1a), often with considerable variation between adjacent fascicles. A diabetes-induced decrease in the density and occupancy of myelinated fibers represents quantitative evidence of loss affecting both large and small fibers [2–4].
Changes noted prior to the axoplasmic dissolution that constitutes axonal degeneration include accumulation of glycogen and dystrophic accumulation of vesicular and cytoskeletal elements [5,6]. Demyelination secondary to axonal degeneration has been observed [7]. Characteristic of axonal degeneration of the Wallerian type, osmiophilic lipid droplets can be observed within otherwise vacant neurilemmal tubes in teased fiber preparations (Fig. 4.2a). The Schwann cell basal laminae that form neurilemmal tubes are frequently circular, as if failing to collapse, and assume the corrugated profile seen in typical Wallerian degeneration [8]. In earlier stages of diabetic neuropathy, axonal regeneration has been reported to be robust and greater than that in control subjects [2]. Regenerative clusters appear in plastic sections as a group of myelinated sprouts within a residual, circular basal lamina [5,8].
In human diabetic neuropathy, the existence of axonal atrophy or the diminution of axonal caliber without myelin or axonal degeneration is disputed. Axonal atrophy was suggested by an early report of teased fibers with long internodes and inappropriately small diameters [9]. However, despite qualitative descriptions [5] and quantitative evidence employing multiple parameters [4,10,11], axonal atrophy has not been observed in other studies [12,13], including one involving a large sample size and claiming an improved morphometric method for detecting this change [14].
Segmental demyelination has long been described as a pathologic change occurring in diabetic neuropathy [2,9,15,17]. It is recognized in teased fibers as an internode lacking myelin or with an inappropriately thin myelin sheath compared to the myelin surrounding the adjacent internodes (Fig. 4.2b). In plastic section, demyelination was described as splitting of myelin sheaths with accumulation of granular and vesicular debris [5]. Early reports of segmental demyelination without prominent axonal degeneration no doubt contributed to the view that demyelination is the primary lesion of diabetes-induced nerve injury. However, some investigators [9] noted that certain clinical features of diabetic neuropathy were best explained as resulting from a combination of segmental demyelination and axonal degeneration. Indeed, both
