Current And Emerging Tools For Assessing Diabetic Peripheral Neuropathy
A Closer Look At The Pathogenesis Of Diabetic Neuropathy
Diabetic peripheral neuropathy most commonly occurs as a symmetric distal polyneuropathy affecting large and small fibers. Although the cause is multifactorial, the most accepted theories involve direct axonal injury secondary to metabolic abnormalities and inadequate microvasculature.9,10 This theory involves the accumulation of sorbitol, which is the product formed from glucose by the aldose reductase enzyme. For those with hyperglycemia, elevated levels of sorbitol result in the swelling of cells, increased activity of protein kinase C and decreased intracellular levels of myo-inositol and taurine. These processes in turn lead to limited intracellular metabolism and damage to blood vessels. Additionally, glycosylation of axon and microvessel proteins may cause reduction of endoneural blood flow and nerve ischemia, causing nerve and ganglia hypoxia with oxidative stress.11,12 Regardless of the cause, we understand the effects.9-12 The three main types of neuropathy that we generally encounter are sensory, motor and autonomic in nature. Sensory neuropathy presents with an insidious onset and has a stocking and glove distribution in the distal extremities. The disease first affects smaller unmyelinated fibers. This in turn compromises the patient’s ability to detect thermal and mechanical pain. With continued exposure to hyperglycemia, the larger fibers become affected and influence the sensation of sharp pain, proprioception and pressure. Although the importance and impact of this sensory neuropathy are clear, the motor and autonomic components may be just as damaging from a pathogenesis perspective. Sensorimotor neuropathy is a combination pathologic process with symptoms ranging from pain, numbness and paresthesia to decreased strength and atrophy of lower limb muscles. This form of neuropathy typically affects the smaller intrinsic muscles first. One can readily appreciate how atrophy of the intrinsics can lead to muscular imbalance, particularly about the digits at the metatarsophalangeal joint (MPJ) level, and subsequent deformity. This motor neuropathy can lead directly to foot deformity, which is a part of the aforementioned critical triad. An additional form of motor neuropathy, diabetic amyotrophy, affects the proximal lower extremities and can lead to additional muscle atrophy and weakness. This may clinically manifest itself as subjective complaints of difficulty walking, sensations of instability and a history of falls.13 In fact, these patients can have up to 15 times the risk for injury when walking in comparison to those without diabetic motor neuropathy.14 Additionally, research has suggested that Charcot neuroarthropathy may be influenced by diabetic motor neuropathy. Jeffcoate and colleagues have proposed that motor neuropathy results in joint instability and subluxation with altered force distribution throughout the foot.15 The motor portion of neuropathy clearly comes with its own set of associated risks and potential outcomes if it is undetected and undertreated. Some treatment options may include muscle strengthening and gait training through physical therapy, orthotics and bracing when indicated. It is important to note that pharmacologic agents such as pregabalin (Lyrica, Pfizer) or tricyclic antidepressants are antinociceptive in nature, and are unlikely to play a significant role in motor neuropathy management.16 Autonomic neuropathy primarily involves the cardiovascular system, gastrointestinal system and the genitourinary system, but it can have effects on the lower extremity as well in the form of an altered and at-risk cutaneous system. Sweat gland dysfunction may lead to dry, cracked skin while microvascular shunting produces negative effects on capillary blood flow in the setting of this type of neuropathy. Gibbons and co-workers sought to evaluate the density of nerve fibers innervating sweat glands in healthy controls and patients with diabetes.17 The authors conducted skin biopsies at three sites (proximal thigh, distal thigh and distal leg) and examined the nerve fibers innervating sweat glands. They found that patients with diabetes had reduced sweat gland nerve fiber density, which was associated with a worsening severity of neuropathy.