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 We have reexamined (R.E. Schmidt, unpublished data) multiple prevertebral and paravertebral chain ganglia of one of Duchen's original patients [55] who had symptomatic diabetic autonomic neuropathy with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, was colocalized with highlyphosphorylated NF-H in many dystrophic elements [63], suggesting the possibility of a shared degradative pathogenetic mechanism, rather than altered synthesis, as a target of diabetes.
Although the development of neuroaxonal dystrophy represents unambiguous and compelling pathology in the sympathetic ganglia of diabetic humans, early studies described axon loss in preganglionic sympathetic communicating (“white”)rami and greater splanchnic [57,64,65] nerves. Loss of preganglionic sympathetic innervation may, together with NAD, result in diminished numbers of normal presynaptic elements innervating principal sympathetic neurons.
Autonomic Axons in Somatic Nerves
Autonomic axons, particularly small unmyelinated axons, may be lost in somatic nerves as part of symmetrical sensorimotor neuropathy [66], which is thought to have an ischemic basis, resulting in local, distally accentuated autonomic symptoms. The loss of autonomic innervation of the vasa nervorum of somatic nerves, thought to affect blood flow to the nerve trunk, may significantly contribute to nerve ischemia described in somatic sensory polyneuropathy [67].
Diabetic Parasympathetic Nervous System
Although significant loss of vagal axons and active axonal degeneration have been described in various studies of diabetic autonomic neuropathy [68,69], the number of patients examined has typically been small. In one case of diabetic gastroparesis, dramatic axon loss in the abdominal vagus nerve was described [70]; however, a similar study failed to identify morphological abnormalities in the gastric wall or abdominal vagus nerve [71]. Immunofluorescence studies of diabetic human penis have shown preferential loss of VIP-containing axons in the corpora cavernosa [72,73].
Miscellaneous
Neuropeptide immunolocalization techniques have described decreased substance P content of human rectal mucosa in diabetic patients compared to nondiabetic controls [74]. The involvement of distal axons innervating diabetic bladder [75], skin, and penile corpora [76] has been proposed. Meissner's and Auerbach's plexuses in patients with diabetic diarrhea have failed to demonstrate reproducible histopathology [77], although one ultrastructural study has claimed the demonstration of marked axonal swellings within intramural ganglia [78]. PET scanning techniques have demonstrated the loss of sympathetic innervation in the distal myocardium in diabetic patients with autonomic neuropathy, although proximal segments were hyperinnervated, perhaps reflecting disorganized axonal sprouting and reinnervation [79].
Experimental Diabetic Autonomic Neuropathy
Animal models of diabetic autonomic neuropathy have been sought to provide insight into the pathogenetic mechanisms of the latter and to develop rational forms of therapy.
Sympathetic Nervous System
An unequivocal neuropathy of the alimentary tract of the streptozotocin (STZ)-diabetic and genetically diabetic BB rat and Chinese hamster has been characterized in detail [80–82]. The regular occurrence of degenerating, regenerating, and pathologically distinctive dystrophic axons has been demonstrated in: (1) preterminal axons and synapses within the prevertebral celiac and superior mesenteric sympathetic ganglia (Figs. 4.8-4.10), and (2) noradrenergic axons contained in ileal mesenteric nerves innervating the distal alimentary tract (Fig. 4.11) in rats with chronic long term STZ-induced diabetes. As in diabetic humans, NAD again developed in the prevertebral superior mesenteric and celiac ganglia but not comparably in the paravertebral superior cervical ganglia. Dystrophic swellings involved postganglionic sympathetic noradrenergic distal ileal paravascular mesenteric nerve axons and their terminals on intramural myenteric and submucosal ganglia; however, the equally lengthy noradrenergic axons which innervate the adjacent
