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. B The perineurial sheath is shown with focal basal laminar thickening (asterisks). A subperineurial capillary (arrow) shows a reduplicated basal lamina
Connective Tissue
Where substantial loss of myelinated fibers was apparent in diabetic neuropathy, early workers noted fibrosis and probable increase in endoneurial collagen and, in one instance, an accumulation of fibrillar material in an enlarged endoneurial interstitium [9]. Recent work points to extensive deposition of endoneurial collagen in nerves from diabetic patients, predominantly involving collagen types I and III [37]. Type VI collagen is increased in the endoneurium surrounding groups of Schwann cells, with types IV, V, and VI increased around endoneurial microvessels. The diameter of endoneurial collagen fibrils is increased in diabetic nerves. The hyperplasia and reduplication of basal laminae surrounding Schwann cells and micro-vessels have been noted above.
An increase in endoneurial area in diabetic neuropathy has been observed in plastic section [2,18,24,38] and considered by some to represent endoneurial edema (Fig. 4.1b). In several studies using noninvasive magnetic resonance spectroscopy [39,40], hydration was increased in nerves from both asymptomatic and symptomatic diabetic patients but not in those receiving treatment with aldose reductase inhibitors. Edematous nerves appear to be an inconstant feature of diabetic neuropathy.
In diabetic patients, there are several abnormalities in the perineurium, the lamellar cellular ensheathment of individual fascicles of peripheral nerves. Thickening of the basal lamina surrounding cells of each layer of the perineurium has been documented (Fig. 4.6b) [8,41-43]. Reduplication as seen in basal laminae of Schwann cells and endoneurial microvessels is not present [43]. Calcification of the extracellular matrix of the perineurium has also been documented in diabetic neuropathy and is thought to result from deposition on matrix vesicles or lipid droplets derived from perineurial cells [44].
Relationship of Histopathology to Type of Diabetic Neuropathy
Because most cellular and noncellular components of peripheral nerves are affected in diabetes mellitus, it is difficult to ascribe a corresponding set of pathologic changes to any clinical presentation. Nevertheless, the topic has received sufficient attention in the literature to warrant consideration.
Symmetric Polyneuropathy
Among the various clinical presentations of diabetic neuropathy, distal symmetrical polyneuropathy with a “glove and stocking” distribution is the most typical. While causation remains uncertain, hyperglycemia underlies other putative mechanisms and there are some differences in patterns of structural injury in treated versus untreated patients. In treated diabetic patients with chronic neuropathy, fibers undergoing axonal degeneration predominate [45]. In contrast, in untreated diabetics with symptomatic neuropathy, both segmental demyelination and axonal degeneration are evident. Segmental demyelination appears to precede axonal degeneration and is in some instances accompanied by proliferative changes of Schwann cells including “onion bulbs” [12,18,46].
Although the most severe neuropathies are associated with profound loss of myelinated and unmyelinated axons, disturbances of lesser severity do not lend themselves to ready morphologic distinction. It appears that even in mild neuropathy, there is significant loss of myelinated fibers [19]. Although axonal regeneration may be more vigorous in milder cases of diabetic sensory neuropathy [12], it is diminished in proportion to the amount of myelinated nerve fiber loss [47]. In addition to proliferative changes of Schwann cells, marked thickening of vessel walls including thickening and reduplication of basal lamina has been found in asymptomatic patients with minimal or no signs of neuropathy [46].
Studies of painful diabetic neuropathy have investigated possible morphologic correlates of pain in patients with differing presentations of pain-related symptoms [11]. Axonal degeneration and reductions in fiber density were present in both patients with chronic neuropathy and those with diabetic pain