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 primary segmental demyelination and demyelination secondary to axonal degeneration have been documented in the same nerve biopsy [7].
Fig. 4.1 Myelinated fiber loss in chronic human diabetic neuropathy. A A sural nerve biopsy shows fascicles with severe fiber loss. Several fascicles also show increased subperineurial structureless space, consistent with endoneural edema. B Higher magnification view of a plastic section from a sural nerve showing subperineurial edema (asterisks) and myelinated fiber loss
Schwann cell changes that appear to precede the dissolution of the myelin sheath have been observed in human diabetic neuropathy by several investigators [5,6,18]. Nonspecific, reactive changes include: accumulation of lipid droplets, paracrystalline inclusions (Pi granules of Reich) and glycogen granules: increased numbers of plasmalemmal vesicles; and cytoplasmic expansion and capping (Fig. 4.3a). Enlarged mitochondria with effaced cristae and disintegration of abaxonal and adaxonal cytoplasm and organelles have been described as degenerative Schwann cell changes (Fig. 4.3b). Thickening and reduplication of the Schwann cell basal lamina of myelinated fibers have also been illustrated [6].
Fig. 4.2 Pathological abnormalities of teased nerve fibers from sural nerve biopsies in human diabetic neuropathy. A Wallerian degeneration, characterized by nerve fiber breakdown and consequent formation of myelin ovoids (arrows), is seen above an intact myelinated fiber. B A teased fiber from another biopsy shows an internode with severe myelin loss, consistent with either segmental demyelination or early remyelination. (Micrographs kindly provided by Nigel A. Calcutt, PhD)
Remyelination following segmental demyelination has been observed in diabetic neuropathy and is recognized in teased fiber preparations [9,16] and plastic section [12,18,19] by axons with inappropriately thin myelin sheaths. In some but not all nerve biopsies, proliferative Schwann cell changes are evident as clusters of Schwann cells in a concentric arrangement (Fig. 4.4) [5,9,20]. These concentric arrangements resemble small “onion bulbs,” a nonspecific hypertrophic change consisting of supernumerary Schwann cell processes surrounding individual axons. “Onion bulbs” are thought to result from recurrent segmental demyelination and remyelination [20].
Paranodal abnormalities described in diabetic neuropathy include demyelination, paranodal swelling and axo-glial dysjunction. Several investigators [4,9,10] have emphasized the occurrence of restricted paranodal demyelination (Fig. 4.5a), which may be resolved with selective remyelination by surviving Schwann cells or with the formation of an intercalated internode as noted in teased fibers [2]. Paranodal swelling has been suggested to precede paranodal demyelination and is thought to be associated with axo-glial dysjunction, the loss of the gap-junction-like connections of terminal Schwann cell loops to the axolemma on either side of the node of Ranvier [4]. The existence of paranodal swelling and axo-glial dysjunction is a contentious issue. Although repeatedly documented by some in experimental and human diabetic neuropathy [4,10], others [21] have not detected these abnormalities.
Fig. 4.3 Reactive and degenerative Schwann cell changes in poorly controlled human diabetic neuropathy. A Lysosomal inclusions (Pi granules of Reich), a nonspecific reactive change characteristic of chronic neuropathies with extensive myelinated fiber loss, are evident in an intemodal