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 band of Schwann cell cytoplasm in this myelinated fiber. B A small myelinated fiber with degenerative changes shows conspicuous Schwann cell cytoplasmic enlargement with glycogen accumulation (arrows) and darkened profiles of giant mitochondria with effaced cristae (asterisks)
Fig. 4.4 Proliferative Schwann cell changes in chronic human diabetic neuropathy. Concentric arrays of supernumerary Schwann cells form an “onion bulb” around a myelinated fiber
Fig. 4.5 Paranodal demyelination of a teased nerve fiber in human diabetic neuropathy. A The paranodal region (arrow) of this teased fiber is incompletely ensheathed by myelin, resulting in an exaggeration of the length of the node of Ranvier. B A normal-appearing node of Ranvier in a teased fiber is shown for comparison. (Micrographs kindly provided by Nigel A. Calcutt. PhD)
Unmyelinated Nerve Fibers
Early electron microscopic studies of diabetic neuropathy noted a distinct loss of unmyelinated fibers [6]. Characteristic degenerative changes of these fibers include shrinkage of axons, accumulation of enlarged vesicular elements, and deterioration of tubular and filamentous elements of the cytoskeleton. Edematous Schwann cell cytoplasm has also been observed, as well as hyperplasia of surrounding basal lamina [6]. Complete degeneration results in empty or denervated Schwann cell subunits surrounded by a basal lamina. It is thought that eventually the Schwann cells degenerate, leaving the basal lamina that persists before disappearing. In the sural nerve of a patient dying with diabetes mellitus, unmyelinated fiber density was only a third of that observed in control patients [3]. Although unmyelinated fiber density is a quantitative reflection of fiber loss, empty Schwann cell subunits are considered by some to be a better indicator of such loss [22].
Vasa Nervorum
The blood supply of peripheral nerve trunks, the vasa nervorum, consists of intrinsic endoneurial vessels and extrinsic vessels of the epineurium and perineurium. In diabetes mellitus, histopathologic changes have been described in all components of this vasculature. In the endoneurium, vessels with thickened walls and reduced luminal caliber were documented in an early report [23]. Subsequent qualitative and quantitative work has demonstrated endothelial cell hypertrophy and hyperplasia with a reduction in luminal size [11,24-29]. Fenestrated endothelial cells, a feature normally present only in epineurial vessels, have been observed in endoneurial vessels [26], as has endothelial cell dysjunction or the loss of junctional contacts between cells [29]. Desquamation of endothelial cells [30] and degeneration of pericytes have also been described [31]. Reduplication of the basal lamina of endoneurial microvessels, although a feature of other chronic neuropathies, appears to be more pronounced in diabetic neuropathy (Fig. 4.6a). Luminal occlusion resulting from endothelial hyperplasia or fibrin plugs has been documented [30,32,33] but not confirmed in subsequent studies [24,28,29].
With respect to the extrinsic circulation, epineurial capillary abnormalities include endothelial cell hyperplasia and thickening of the basal lamina [25]. The intima of epineurial arterioles is increased in diabetic neuropathy [34]. However, in spite of these changes, endoneurial microvessels show significantly more pathology than epineurial microvessels with respect to basal lamina thickening, endothelial cell hypertrophy, and luminal narrowing [25]. Similar findings are reported for the transperineurial circulation, with hypertrophy and hyperplasia of endothelial cells and reduced luminal area [35]. Diabetic patients exhibit a greater degree of abnormal innervation of the epineurial and transperineurial circulation in that there appears to be a reduction in the vessels with perivascular axons and an increase in vessels with denervated Schwann cell units [36]. In the media of denervated arterioles, structural changes, such as an increase in glycogen, edematous smooth muscle cells, accumulation of cellular debris, and collagenous scarring, have been reported.
Fig. 4.6 Vascular and perineurial abnormalities in chronic human diabetic neuropathy. A Markedly thickened and reduplicated basal lamina is evident surrounding an endoneurial microvessel.
