Diabetic Neuropathy--A Review

Pathology of Diabetic Neuropathies

Distal Symmetrical Diabetic Neuropathy

Abnormalities reported in diabetic neuropathy include axonal degeneration in nerve fibers, primary demyelination resulting from Schwann cell dysfunction, secondary segmental demyelination related to impairment of the axonal control of myelination, remyelination, proliferation of Schwann cells, atrophy of denervated bands of Schwann cells, onion-bulb formations, and hypertrophy of the basal lamina (Figures 1,2,3). Dying-back fibers and fibers with distal sprouting of the proximal stump subsequent to degeneration of the distal axon have also been identified in LDDP.^{[5,9,17,18,28,39]} Axon loss predominates distally, and there is no correlation between axon loss and demyelination in nerve biopsies.^[39] Early morphological changes include minimal alteration of myelinated and unmyelinated fibers, and axonal regeneration.^[40]

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Figure 1.

Nerve biopsy findings in length-dependent diabetic polyneuropathy. 1 μm-thick sections of superficial peroneal nerve biopsy specimens of two insulin-dependent diabetic patients in their 30s with a severe length-dependent diabetic polyneuropathy. (A) This patient had a severe small-fiber sensory and autonomic polyneuropathy. (B) This patient had a severe length-dependent sensory, autonomic and motor deficit. The arrows point to the marked thickening of capillaries walls in the endoneurium.

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Figure 2.

Abnormalities of unmyelinated fibers in severe length-dependent diabetic polyneuropathy. Electron micrograph of a superficial peroneal nerve biopsy specimen from a patient with a severe length-dependent sensory and autonomic diabetic polyneuropathy, illustrating degeneration of unmyelinated fibers. Stained with uranyl acetate and lead citrate. (1) Normal unmyelinated fiber. (2) Degenerating unmyelinated fiber. (3) Pocket of collagen occupying the space left empty by degenerated unmyelinated fiber. (4) Denervated bands of Schwann cells.

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Figure 3.

Abnormalities of isolated fibers in length-dependent diabetic polyneuropathy. This schematic diagram illustrates the types of abnormalities observed on osmicated isolated fibers.^[9,62] Osmium tetroxide stains myelin in shades of gray to black depending on the thickness of the myelin sheath. (A) The fiber at the top of the figure is normal, with regularly spaced nodes of Ranvier. (B) The second fiber from the top shows segmental demyelination associated with distal axonal degeneration. (C,D) Subsequent remyelination with replacement of the original internode with two shorter internodes and axonal regeneration by sprouting of the proximal axonal stump occurs (C), with remyelination of axon sprouts of the fiber (D).

Predominant and early involvement of small myelinated and unmyelinated somatosensory fibers in diabetic neuropathy is supported by recent morphological and physiological studies. Small-fiber sensory neuropathy presenting with reduced IENF densities and correlated elevation of warm thresholds is a major manifestation of type 2 diabetes. The extent of skin denervation increases with the duration of diabetes.^[12] Evaluation of C-nociceptive-fiber function using the nerve-axon reflex has also shown that small-fiber impairment is an early event in the natural history of diabetic neuropathy.^[41]

Genetic factors might explain why some individuals develop a more severe polyneuropathy than others with similar diabetic status. Polymorphisms of the AKR1B1 gene, which codes for aldose reductase, are strongly associated with hot thermal threshold discrimination in patients with type 1 diabetes.^[42]

Endoneurial capillaries often show signs of diabetic microangiopathy, with marked thickening of the basal lamina.^[43] The presence of multifocal nerve lesions and alterations of endoneurial capillaries have indicated a role for circulatory factors in symmetrical diabetic neuropathy.^[43,44,45] Dissociated sensory loss, severe autonomic dysfunction and predominant loss of unmyelinated axons cannot, however, be explained by nerve ischemia alone.

Focal and Multifocal Diabetic Neuropathies

In a patient with proximal neuropathy of the lower limbs, biopsy specimens of the intermediate cutaneous nerve of the thigh—a sensory branch of the femoral nerve that conveys sensation from the anterior aspect of the thigh, a territory commonly involved in PDN—showed lesions characteristic of nerve ischemia, associated with inflammatory infiltrates around epineurial and perineurial blood vessels (Figure 4). The inflammatory lesions consisted of B and T lymphocytes mixed with macrophages.^[38] Similar observations were made by others in biopsy specimens of the intermediate cutaneous nerve of the thigh,^[46] and in the sural nerve.^[47] My group showed that the presence of inflammatory infiltrates did not preclude spontaneous recovery.^[48] In patients with MDN, nerve biopsy specimens sampled in an affected territory showed asymmetric axonal lesions associated with vasculitis of perineurial and endoneurial blood vessels. In most nerve specimens, perivascular mononuclear cell infiltrates are associated with endoneurial red cell seepage. In MDN, nerve lesions seem to be related to precapillary blood vessel damage in elderly diabetic patients with a secondary inflammatory and hemorrhagic response.^[38,48] It is not known why lesions predominate on lower spinal roots, the lumbar plexus and nerves of the lower limbs in proximal and multifocal diabetic neuropathies.

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Figure 4.

Multifocal diabetic neuropathy. Cross section of a paraffin-embedded superficial peroneal nerve specimen from a patient with a subacute progressive multifocal diabetic neuropathy, showing massive lymphoplasmacytic inflammatory infiltrate of the perineurium and nerve blood vessels (arrows). Stained with hematoxylin and eosin.

The finding of inflammatory lesions in PDN initially came as a surprise; however, it is now clear that complex relationships exist between obesity and type 2 diabetes, both of which conditions seem to have a close association with subcellular 'inflammation' characterized by abnormal cytokine production and activation of a network of inflammatory signaling pathways.^[49] Increased inflammatory reactions in patients with type 2 diabetes might result from damage to the vessel wall, which induces further lesions of blood vessels.

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