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 of recent onset. In another study of patients with active acute painful neuropathy and patients with recently remitted pain [48], the occurrence of nerve fiber degeneration and regeneration was not sufficient to account fully for diabetic neuropathic pain. However, certain stages of the pathologic process of Wallerian degeneration may be linked to painful symptoms [48]. Another large clinicopathologic study also failed to establish a correlation between axonal degeneration or regeneration and painful neuropathy [12].
In severe diabetic neuropathy, autonomic disturbances are prominent but the disease is often painless. In such cases, nerve fiber loss may be profound [12]. Recurrent foot ulcers are most likely to occur in this group [11]. In the most severe neuropathies, sometimes presenting in untreated patients, demyelination and remyelination are prominent. An increase in capillary wall thickness was most pronounced in patients in whom neuropathy was painless, the degree of thickening in patients with painful neuropathy being less exaggerated [11]. With respect to capillary mural thickening, similar findings have been reported in asymptomatic patients [46].
Asymmetric Neuropathy
Focal neuropathic disorders in patients with diabetes mellitus are not symmetric in distribution and may involve cranial nerves or spinal roots. With respect to cranial nerves, the most frequently cited examples describe lesions involving the oculomotor nerve [49–51], although the trochlear and abducens nerves may be affected. Neuropathies affecting these cranial nerves are characterized by relatively sudden onset, focal distribution, and limited course [51]. Early published reports linked these neuropathies to ischemic events, and evidence of centrofascicular degeneration observed in postmortem studies reinforces this view. Nerve fiber atrophy and microfasciculation have also been documented in oculomotor nerves [51].
Proximal diabetic neuropathy is a severe form of asymmetric neuropathy that has been subject to confusing terminology and incomplete pathologic information. The clinical presentation typically involves one leg or thigh with eventual spreading to the buttock and opposite lower limb. In contrast to symmetrical polyneuropathy, this disorder appears to have an inflammatory basis [52–54]. Centrofascicular axonal loss in association with vasculitis [53] and evidence of epineurial vasculitis [54] support an ischemic causation. Occlusive vascular disease has also been detected in proximal diabetic neuropathy [53]. The presence of both axonal degeneration and demyelination attests to the role of ischemia in producing these changes in association with the inflammatory process [54].
R.E. Schmidt
Neuropathology of Clinical Diabetic Autonomic Neuropathy
The neuropathology of diabetic autonomic neuropathy has, until recently, been largely unstudied despite its substantial clinical importance and wealth of pathophysiologic characterization of autonomic function in humans.
Sympathetic Ganglia
Degenerative changes culminating in the significant loss of sympathetic neurons have been claimed and disputed in classical nonquantitative studies [55–57]. Quantitative, although nonstereologic, analysis of neuronal density (expressed as number/mm2) in the diabetic paravertebral superior cervical (SCG) and prevertebral superior mesenteric ganglia (SMG) in one large series [58] showed only a small (14%), although statistically significant, decrease in neuronal density in diabetic subjects and did not identify significant numbers of actively degenerating neurons. The size and plexiform anatomy of human prevertebral ganglia and the existence of preferentially targeted subpopulations of sympathetic neurons may even complicate nonbiased stereologic analysis. Chromatolytic neurons or nodules of Nageotte (i.e., collections of satellite cell nuclei at sites of neuronal dropout) were not more common in diabetic human ganglia than in agematched nondiabetics [59]. One often-quoted study by Duchen and colleagues [55] involved the detailed histopathologic characterization of
