Current And Emerging Tools For Assessing Diabetic Peripheral Neuropathy

An international study of patients with diabetes presenting with incident foot ulceration identified the “critical triad” of peripheral neuropathy, trauma and foot deformity in the pathogenesis of approximately 63 percent of patients.1 The most common component was peripheral neuropathy, which was present in nearly 80 percent of the patients in this study.    Podiatric physicians are generally well aware of both the prevalence and potential complications associated with diabetic peripheral neuropathy.2 We are also fairly quick to recognize and diagnose the sensory component of this sequela. What we may be guilty of, however, is neither appreciating the breadth of diabetic neuropathy nor quantifying our examination of the patient with diabetic neuropathy.    The effect of diabetes and hyperglycemia on patient outcomes is well established. The Portland Diabetic Project shows results that are simply staggering with respect to patient morbidity and mortality following cardiovascular interventions.3 Further investigations into orthopedic-specific postoperative outcomes have also shown that diabetes contributes to adverse patient morbidity, length of hospital stay, cost of hospital admission and infection rates among other variables.4-7    What we have recently been learning, however, is the interesting effect that neuropathy may specifically have on these outcomes.    Wukich and colleagues recently published a study that highlights this concept.8 The retrospective chart review focused on over 1,000 patients who had elective orthopedic foot and ankle surgery. The authors found that patients with diabetes were five times as likely to experience a severe infection requiring hospitalization in comparison to non-diabetic patients.    Interestingly, though, there was no significant difference when researchers removed neuropathy from the analysis. In other words, diabetic patients without neuropathy were as likely to have a significant postoperative infection in comparison to non-diabetic patients. Further, neuropathy as a single factor demonstrated an odds-ratio analysis of 9.32 as a predictor for postoperative infection. This means a patient with neuropathy was more than nine times as likely to develop a postoperative infection in this cohort.8

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.    Autonomic dysfunction presents with significant lower extremity and systemic effects. Edmonds and co-workers studied an interesting facet of autonomic neuropathy in three groups of patients.18 They found that heart rate during deep breathing and stance was significantly slower in diabetic patients with foot ulceration in comparison to normal controls and diabetic patients without a history of foot ulceration. The authors concluded that severely abnormal autonomic function occurs in association with neuropathic foot ulceration but patients without ulcers have lesser degrees of autonomic neuropathy.    Another condition to be aware of is known as “hypoglycemic unawareness.” During this, a patient does not experience the normal symptoms of hypoglycemia (sweating, rapid heartbeat) that act as a warning system.

What Are The Best Methods Of Detecting Neuropathy?

It is well accepted that peripheral neuropathy is a risk factor for developing foot ulceration and that early detection leading to adequate foot care can reduce amputation rates by about 50 to 80 percent.19 This emphasizes the need for assessment tools that are simple, objective, reproducible and comprehensive. How well are we doing in this respect?    The simplest and likely most frequently utilized instrument for assessing neuropathy is the Semmes-Weinstein (SW) monofilament. Lee and colleagues attempted to determine the reliability of the SW monofilament in patients with diabetes.20 They applied the monofilament to the 10 recommended sites and found the sensitivity and specificity of the plantar metatarsal region to be 93 percent and 100 percent respectively. Other studies have confirmed their conclusion that the device is a sensitive, specific and inexpensive screening tool for identifying diabetic peripheral neuropathy.21,22    A critique of this instrument is its fairly limited scope. It is unable to quantify or stage a level of neuropathy, and also does not provide any information about the motor and autonomic components of the disease process.    One should fully assess motor neuropathy and autonomic neuropathy during an examination, but this can represent a challenging problem when attempting to have objective and reproducible results.    One means for attempting to quantify all components of diabetic peripheral neuropathy is the Michigan neuropathy screening instrument (MNSI). This consists of a history portion that the patient completes and a physical exam portion that the healthcare professional completes. The patient portion consists of 15 questions such as “Are your legs and/or feet numb?” and “Are you able to sense your feet when you walk?” The exam portion looks at such factors as appearance (deformities, calluses, etc.), ulceration, ankle reflexes, vibration perception at the hallux and monofilament detection.23,24    This simple screening test encompasses all sensory, motor and autonomic components of neuropathy, and allows for a quantitative and objective measurement. The developers of the instrument have found it to be sensitive and reproducible for screening and diagnosis.    Moghtaderi and co-workers assessed the validity of the MNSI and aimed to determine the diagnostic performance of the test characteristics for the diagnosis of peripheral neuropathy.25 This study found that the accuracy of the MNSI made it a useful screening test for diabetic neuropathy. In deciding which patients one should refer to a neurologist or for electrophysiological studies, the authors specifically suggested a cutoff score of “2” during the physical examination portion for diagnosis and referral.

In Conclusion

Large prospective clinical studies, such as the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetic Study, have shown tight glucose control and euglycemia prevent the onset or slow the progression of diabetic neuropathy. Unfortunately, we usually deal with patients whose hyperglycemia has already caused significant damage to the peripheral nervous system.    It is important for clinicians to appreciate the full breadth of diabetic peripheral neuropathy, specifically how the motor and autonomic components contribute to the pathogenesis in addition to the sensory dysfunction. It is also important that we are consistent, objective and reliable with respect to our clinical examination of these patients. The Michigan neuropathy screening instrument provides a simple means to accomplish this task that may help improve your overall evaluation and treatment of patients with diabetes.    Dr. Piemontese is a resident with the Temple University Hospital Podiatric Surgical Residency Program at Temple University Hospital in Philadelphia.    Dr. Meyr is an Assistant Professor in the Department of Podiatric Surgery at the Temple University School of Podiatric Medicine in Philadelphia.    Dr. Steinberg is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. Dr. Steinberg is a Fellow of the American College of Foot and Ankle Surgeons.    For further reading, see “How To Diagnose Diabetic Peripheral Neuropathy” in the March 2006 issue of Podiatry Today or “Essential Insights On Managing Symptomatic Diabetic Neuropathy” in the October 2009 issue.
 

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