A Practical Approach to the Management Of Diabetic Neuropathy
Diabetes mellitus is the leading cause of peripheral neuropathy. Diabetic peripheral neuropathy (DPN) affects up to 50% of people with diabetes. Diabetic neuropathies represent a heterogeneous group of disorders whose specific abnormalities can present with diverse clinical manifestations—from distal symmetric polyneuropathy (DSPN) to mononeuropathy, diabetic amyotrophy, autonomic dysfunction, cranial neuropathies, and entrapment neuropathies. Duration of diabetes, glycemic control, and preexisting cardiovascular risk factors independently correlate with the development and progression of DPN as well as cardiovascular autonomic neuropathy.
To this day, the pathogenesis of diabetic neuropathy remains unclear. Several factors have been implicated, among which are insulin resistance, oxidative stress, abnormal glucose metabolism, advanced glycation end products, and protein kinase C activation.
The presentation of DPN varies depending on the forms. Diabetic neuropathy usually has a long subclinical latency period whose identification and management are challenging. It is important to identify neuropathy in its earliest stages to prevent the extreme morbidity and healthcare costs associated with its progression. Treatment options include several pharmacologic agents, but only two are FDA-approved for painful neuropathy. Most importantly, strict glycemic control remains the only available treatment option to prevent the development of diabetic neuropathy.
This article focuses on the epidemiology and pathogenesis as well as clinical features, diagnosis, and management of DSPN, the most common form of diabetic neuropathy.
Defining Diabetic Neuropathy
The definition of diabetic neuropathy has remained elusive. In most cases, its detection is based on symptoms, but this complication of diabetes can be present and silent for a long time prior to diagnosis. Traditionally, diabetic neuropathy has been defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after excluding other causes.1 In 2009, preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the Eighth International Symposium on Diabetic Neuropathy in Toronto, a panel of experts convened to provide updates on classification, definitions, diagnostic criteria, and treatments of DPN (see Table 1).2
The epidemiology of diabetic neuropathy depends on the case definitions used. If presence of symptoms was used as a criterion, 10% to 15% of diabetic patients would have neuropathy. The prevalence increases to 50% when sensory testing and nerve conduction study criteria are included.3
The incidence and prevalence of diabetic neuropathy has been studied in several small- and large-scale trials in the United States, Canada, and Europe. The Rochester Diabetic Neuropathy Study was a longitudinal population-based study of 380 patients, of whom 102 had type 1 diabetes. The mean duration of diabetes was 14.5 years for type 1 and 8.1 years for type 2, respectively, and in this cohort the prevalence of polyneuropathy was 35.5% based on one abnormal nerve conduction test in two or more nerves. Only 14% of patients were symptomatic, however, and none had severe, disabling neuropathy.3
One of the landmark studies in the literature regarding diabetes complications is the DCCT (Diabetes Control and Complication) trial, which enrolled 1,441 patients with diabetes type 1 in 29 centers in the United States and Canada between 1983 and 1989. Patients with severe neuropathy were excluded. At the end of the study, 19% of all enrolled patients fulfilled criteria for definite clinical neuropathy (which at that time included abnormal findings in at least two categories from neuropathic symptoms, sensory deficits, or impaired reflexes attributable to distal symmetric polyneuropathy).4
Another large, prospective study conducted in Europe, EURODIAB (European Diabetes Prospective Complications) study, enrolled 3,250 patients with type 1 diabetes from 31 centers in Europe between 1989 and 1991. At baseline, 29% of patients had evidence of neuropathy. Subsequently, neuropathy developed in 276 of 1,172 patients after a mean follow-up of 7.3 years, bringing the cumulative incidence to 23.5%.5
Pathogenesis and Risk Factors
The exact pathogenesis of diabetic neuropathy remains unclear and may involve metabolic and vascular dysfunction. Proposed vascular etiologies include nerve dysfunction secondary to disease of vasa nervorum, the microvasculature to the nerves. Other proposed metabolic etiologies include insulin resistance, accumulation of sorbitol, oxidative stress, abnormal glucose metabolism, advanced glycation end products, and protein kinase C activation. In addition, cardiovascular risk factors (eg, hypertension, smoking, dyslipidemia, and male gender) are independent risk factors for the development of diabetic neuropathy, especially with the presence of overt cardiovascular disease at baseline.6
It is now known that multiple factors influence the development and progression of diabetic neuropathy. In the Rochester Diabetic Neuropathy Study, researchers concluded that the order of importance for the development and progression of diabetic neuropathy appeared to be microvascular disease, total hyperglycemic exposure, and type of diabetes.3 Similarly, the DCCT not only provided definitive proof of the association between chronic hyperglycemia and neuropathy, but also found that treatment significantly decreased the risk for developing diabetic neuropathy.4
The EURODIAB study found that diabetes duration, A1c values at baseline, and changes in A1c over time were risk factors for the development of neuropathy along with cardiovascular risk factors; risk for neuropathy increased with progressive worsening of hemoglobin A1c.5
Recent literature has shown that diabetic neuropathy may be a presenting symptom of diabetes, and that a small percentage of patients may have overt neuropathy at the time of diabetes diagnosis. The AusDiab (Australian Diabetes, Obesity and Lifestyles) study identified 1,154 patients with impaired glucose tolerance or impaired fasting glucose among 11,247 individuals aged 25 years and older in Australia.7 These patients were screened for neuropathy using modified neuropathy symptoms, disability, pressure perception scores, and postural hypotension.
An association was found between neuropathy scores and retinopathy; these findings confirm that neuropathy onset may precede the diagnosis of diabetes and that the mechanisms involved are at least partly related to microvascular complications of chronic hyperglycemia.7
Finally, most recently, a review of abstracts presented at the American Diabetes Association (ADA) scientific sessions in 2010 showed that 19% of patients with diabetes receiving metformin for 1 year had vitamin B12 levels lower than 250 ng/mL, and 23% had vitamin B12 levels of 250 to 400 ng/mL. Peripheral neuropathy was present in 77% and 23% of these patients, respectively, and also was found in 7% of those with normal B12 levels.8