Peripheral Nerves of Feet, Painful Peripheral Neuropathies

Peripheral nerve degeneration is the underlying pathophysiologic mechanism. Axons require their neuronal cell bodies to remain healthy to maintain appropriate nerve activity and function; however, when neuronal damage occurs, the part of the axon most distal from the lesion is the first to degenerate. This is known as “dying back.” (It is comparable to a tree dying where its top, most distal part, loses its leaves first because this area is most remote from its roots.) The cell body remains intact and begins a process to redirect growth of the remaining axon to reestablish connection or form new ones. In addition, sometimes loss of blood supply from disorders, such as polyarteritis nodosa, affecting the vasa nervorum, results in peripheral nerve ischemia, leading to similar injury.

PATHOPHYSIOLOGY OF DIABETIC PERIPHERAL NEUROPATHY (DPN)

The pathogenesis of DPN is attributed to increased oxidative stress, accumulation of sorbitol, and decreased nitric oxide, leading to microvascular damage. Oxidative stress results from hyperactivity of the polyol pathway, causing the intracellular accumulation of polyol. Nerve cells are permeable to glucose independent of insulin. Aldose reductase converts the glucose into sorbitol and polyol within the cell. Because polyol cannot diffuse out of the cell, it accumulates within the neuron, making the cell osmotically active, leading to excess salt and water influx. In turn, sorbitol is converted to fructose, and its increased levels lead to advanced glycosylation end-product (AGE) precursors. AGEs, in turn, accumulate on neurovascular proteins and damage tissues. These two pathways lead to a reduction in the cell’s Na⁺/K⁺ adenosine triphosphatase (ATPase) activity, further impairing endothelial function. In addition, nitric oxide is also a key modulator of Na⁺/K⁺ ATPase, and endothelial superoxide radicals from the excess glucose reduce nitric oxide’s stimulation of the ion pump via decreased nitric oxide synthase activity.

Other cellular changes include protein kinase C activation, and alterations in fatty acid metabolism, which also contribute to vascular damage.

Decreased perfusion of the peripheral nerve per se is another possible cause for the development of PPN. Hyalinization and hyperplasia of the vasa nervorum impairs nerve fiber function. This is particularly true with unmyelinated fibers that innervate arterioles needed to shunt arterial and venous supply within the nerve. This leads to damage by hypoxia and ischemic insult. These metabolic changes, oxidative stressors, and hypoperfusion are responsible for the endothelial and nerve damage observed in DPN.

Although the degree of hyperglycemia affects the overall severity of a polyneuropathy, this may not be specifically causative in its development. There is a trend toward more active degeneration of unmyelinated fibers in patients with peripheral diabetic neuropathy when making comparative morphometric parameter evaluations between diabetic patients with and without peripheral neuropathy. However, there is no significant difference in the degree of myelinated nerve fiber loss. Skin biopsy studies evaluating intraepidermal nerve fiber (IENF) density demonstrate more severe loss of IENF in patients with neuropathic pain, suggesting that IENF damage may partially explain pain in this condition. IENF density measurement from skin biopsy can be used to evaluate small fiber involvement and is useful for detection of early changes in patients with diabetes.

CLINICAL MANIFESTATIONS

The characteristic historical features of chronic painful neuropathy include burning, shooting, or stabbing sensations (with or without “pins and needles”) that are particularly prominent in the evening and while trying to get to sleep, sometimes frequently awakening patients from their sleep. The pain can be severe, compromising the patient’s ability to walk. that is, an antalgic gait. These individuals walk gingerly, trying to avoid pressure-induced painful feet. A thorough history to define other potential etiologies is essential to the diagnostic process. Neurologic examination demonstrates reduced or absent muscle stretch reflexes with diminished or absent sensation, particularly for modalities subserved by the small unmyelinated nerve fibers transmitting temperature and pain modalities as well as touch pressure and vibration. This occurs maximally in a distal superficial sensory distribution, leading to a stocking-glove distribution. A distal symmetric polyneuropathy, the commonest form of diabetic PN, is characterized by numbness and paresthesias beginning in the toes and spreading upward to the legs. In the most severe instances, involvement of the fingers and hands develops in a “glovelike” pattern. Typically, DPN has a predilection for the most distal nerves fibers. Ataxia, motor, and autonomic deficits may also be present in later stages of the disease.

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