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 the sympathetic ganglia of five patients with symptomatic diabetic autonomic neuropathy and reported a variety of apparently pathologic findings including neuronal necrosis, an inflammatory infiltrate, neuronal gigantism, dilated perikaryal endoplasmic reticulum, vacuolated neurons, and neuroaxonal dystrophy (NAD). Unfortunately, no controls were included in the study. In a large controlled study of NAD (Fig. 4.7), the distinctive and marked enlargement of distal preterminal axons and synapses, also represented the most striking histologic alteration in diabetic sympathetic ganglia. Dystrophic swellings consisted either of disorganized neurofilamentous aggregates (Fig. 4.7) or collections of mitochondria, dense bodies, lucent proteinaceous material, and tubulovesicular elements [59]. Quantitative studies demonstrated a progressive increase in the frequency of dystrophic axons as a function of age, diabetes, and gender (males more affected than females). Diabetic patients developed lesions (immunohistochemically and ultrastructurally identical to those in aged subjects) earlier and in greater numbers than age-matched control subjects, suggesting possible shared pathogenetic mechanisms in aging and diabetes. Perikarya of diabetic principal sympathetic neurons, although compressed and distorted by presynaptic NAD, were otherwise unremarkable.
Fig. 4.7 A swollen dystrophic axon (arrow) filled with neurofilaments distorts the contours of an adjacent principal sympathetic neuron in diabetic human sympathetic SMG (magnification 3000×)
Not all sympathetic ganglia are equally affected in human diabetics. The frequency of NAD in prevertebral SMG and celiac ganglia was more than 10-fold that of the paravertebral SCG. We have reexamined (R.E. Schmidt, unpublished data) multiple prevertebral and paravertebral chain ganglia of one of Duchen's original patients [55] who had symptomatic diabetic autonomic neuropathy with prominent alimentary dysfunction. Although the prevertebral celiac ganglia and paravertebral SCG were extensively and minimally involved, respectively, in that case the paravertebral lumbar sympathetic chain ganglia showeda frequency of NAD intermediate between those of the SCG and celiac ganglia. Prominent NAD in the celiac ganglia of the relatively young diabetics with symptomatic alimentary autonomic neuropathy [55] suggests possible pathophysiologic significance.
Lymphocytic infiltrates in postmortem sympathetic diabetic ganglia [55] have been interpreted as evidence of an autoimmune pathogenesis [60]; however, similar infiltrates were present in nearly half of all examined SCG and SMG in a large series [59] and their presence failed to correlate statistically with age, gender, or diabetes. Although the presence of antibodies against sympathetic ganglia and vagus nerve has also been reported to correlate [60] with autonomic dysfunction in diabetics, other studies have failed to show such a relationship [61].
Studies of prevertebral sympathetic ganglia in man and experimental animals have demonstrated the complexity and importance of function of prevertebral ganglion neurons in the integration of visceral reflexes [62]. Nerve terminals in the SMG reflect the contribution of neurons originating in the spinal cord intermediolateral nucleus, dorsal root ganglia, parasympathetic nervous system, other sympathetic ganglia or intraganglionic projections from neighboring principal sympathetic neurons, and from myenteric neurons projecting retrogradely. Dystrophic terminals in diabetic human SMG [58] were immunoreactive for neuropeptide Y (NPY), tyrosine hydroxylase, dopamine-β-hydroxylase, trkA (the cognate receptor for NGF), and p75; however, adjacent substance P, vasoactive intestinal peptide (VIP), gastrin-releasing polypeptide (GRP)/bombesin, and met-enkephalin terminals were spared. In some cases, ganglia contained increased numbers of delicate NPY processes, thought to represent axonal sprouts. This immunophenotype is consistent with origination of dystrophic axons from a subpopulation of NPY-containing noradrenergic neurons, most likely originating within the sympathetic nervous system, either intrinsic or extrinsic to the SMG, and, possibly, as locally recurrent collaterals. The neurofilaments (NF) which accumulated in diabetic and aged dystrophic sympathetic nerve terminals consisted almost exclusively of extensively phosphorylated 200-kDa NF-H epitopes [63]. Antisera directed against NF-L, NF-M, and nonphosphorylated epitopes of 200-kDa NF-H as well as MAP-2 preferentially labeled sympathetic neuronal perikarya and principal dendrites and did not label dystrophic axons. Peripherin, a 58-kDa cytoskeletal element distinct from any NF subunit which is present in subpopulations of sympathetic and DRG neurons,