Nerve damage may be present long before diagnosis. Early diagnosis and treatment is paramount to preventing long-term disability.
By Grazia Aleppo, MD, FACE, FACP and Gary W. Jay, MD, FAAPM
Diabetes mellitus is the leading cause of peripheral neuropathy. In fact, the National Institute of Diabetes and Digestive and Kidney Diseases reports that 60% to 70% of people with either type 1 or type 2 diabetes will develop some type of diabetic nerve pain over their lifetime, including diabetic peripheral neuropathy (DPN).1
Increasing the risk of developing a neuropathy include the duration of diabetes, poor glycemic control, smoking and excessive drinking, and preexisting cardiovascular risk factors (high cholesterol); these factors also independently correlated with progression of DPN as well as the development of cardiovascular autonomic neuropathy. Although nerve damage can be present long before the diagnosis of diabetes, the highest rates of neuropathy are among people who have had diabetes for at least 25 years.1
Increasing the risk of diabetic neuropathy include duration of diabetes, poor glycemic control, smoking and excessive drinking, and preexisting cardiovascular risk factors (high cholesterol).
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 amyo-trophy, autonomic dysfunction, cranial neuropathies, and entrapment neuropathies. Peripheral neuropathy is the most likely to cause pain, but proximal neuropathy can also cause pain.
Strict glycemic control remains the only available treatment option to prevent the development of diabetic neuropathy. For the treatment of DPN symptoms, there are several pharmacologic agents that can be used alone or in combination, including 3 FDA-approved therapies for painful neuropathy.
This article focuses on the epidemiology and pathogenesis as well as clinical features, diagnosis, and management of DPN, the most common form of diabetic neuropathy.
Defining Diabetic Neuropathy
Diabetic neuropathy usually has a long subclinical latency period whose identification and management are challenging. It is important, however, to identify neuropathy in its earliest stages to prevent the extreme morbidity and healthcare costs associated with its progression.
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.2 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 (Table 1).3
The epidemiology of diabetic neuro-pathy 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.4
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 2 or more nerves. Only 14% of patients were symptomatic, however, and none had severe, disabling neuropathy.4
As in all small-fiber polyneuropathies, the main drawback of nerve conduction studies (NCS) is that small myelinated and unmyelinated nerve fibers, which are affected early in the disease course of diabetic neuropathy, do not contribute to the sensory action potential detected by routine NCS. The sensory action potential is altered only after involvement of larger myelinated fibers, which is often a late event in patients with diabetes. Electrophysiological data must, therefore, always be evaluated in a clinical context.
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 type 1 diabetes 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 2 categories from neuropathic symptoms, sensory deficits, or impaired reflexes attributable to distal symmetric polyneuropathy).5
Another large, prospective study conducted in Europe, EURODIAB (European Diabetes Prospective Complications), 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%.6
Pathogenesis and Risk Factors
To date, the pathogenesis of diabetic neuropathy remains unclear. Several factors have been implicated, including genetics, insulin resistance, oxidative stress, accumulation of sorbitol, abnormal glucose metabolism, advanced glycation end products, and protein kinase C activation.
Proposed vascular etiologies include nerve dysfunction secondary to disease of vasa nervorum, the microvasculature to the nerves. 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.7
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.4 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.5
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.6
- National Institute of Diabetes and Digestive and Kidney Disease. Diabetic neuropathies: The nerve damage of diabetes. http://www.niddk.nih.gov/health-information/health-topics/Diabetes/diabetic-neuropathies-nerve-damage-diabetes/Pages/diabetic-neuropathies-nerve-damage.aspx. Accessed February 24, 2016.
- Boulton AJM, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies.Diabetes Care. 2004;27(6):1458-1486.
- Tesfaye S, Boulton AJM, Dyck PJ, et al. On behalf of The Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments.Diabetes Care. 2010;33(10):2285-2293.
- Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.Neurology. 1993;43:817-824.
- The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.N Engl J Med. 1993;329:977-986.
- Tesfaye S, Chaturvedi N, Eaton SE, et al; EURODIAB Prospective Complications Study Group. Vascular risk factors and diabetic neuropathy.N Engl J Med. 2005;352(4):341-350.
- Kuritzky L. Managing diabetic peripheral neuropathic pain in primary care.J Fam Pract. 2010;59(suppl 5):S15-S22.
- Barr EL, Wong TY, Tapp RJ, et al. Is peripheral neuropathy associated with retinopathy and albuminuria in individuals with impaired glucose metabolism? The 1999–2000 AusDiab.Diabetes Care. 2006;29(5):1114-1116.
- Bloomgarden ZT. Neuropathy, retinopathy, and glucose-lowering treatments.Diabetes Care. 2010;33(6):e73-e78.
- Shillo PR, Selvarajah D, Greig M et al.Low vitamin D levels in patients with painful diabetic peripheral neuropathy: a potential role in pathogenesis? Presented at: American Diabetes Association 2015 Scientific Sessions; June 6, 2015: Boston, Massachusetts. Abstract 627-P.
- Jay GW, Barkin RL. Neuropathic pain: Etiology, pathophysiology, mechanisms, and evaluations.Dis Month. 2014;60:6-47
- Freeman R. Not all neuropathy in diabetes is of diabetic etiology: differential diagnosis of diabetic neuropathy.Curr Diab Rep. 2009;9(6):423-431.
- Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes.Diabetes Care. 2006;29(7):1518-1522.
- Ziegler D. Painful diabetic neuropathy: advantage of novel drugs over old drugs?Diabetes Care. 2009;32(suppl 2):S414-S419.
- American Diabetes Association. Standards of medical care in diabetes—2016.Diabetes Care. 2016; 39(suppl 1):S72-80 .
- Feng Y, Schlösser FJ, Sumpio BE. The Semmes Weinstein monofilament examination as a screening tool for diabetic peripheral neuropathy.J Vasc Surg. 2009;50(3):675-682.
- Meijer IW, Smit A, Lefrandt ID, et al. Back to basics in diagnosing diabetic polyneuropathy with the tuning fork!Diabetes Care. 2005;28(9):2201-2205.
- Oyer DS, Saxon D, Shah A. Quantitative assessment of diabetic peripheral neuropathy with use of the clanging tuning fork test.Endocr Pract. 2007;13(1):5-10.
- Smith AG, Lessard M, Reyna S, Doudova M, Singleton JR. The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy. J Diabetes Complications. 2014;28(4):511-516.
- Javed S, Alam U, Malik RA. Burning through the pain: treatments for diabetic neuropathy.Diabetes Obes Metab. 2015:17(12):1115-125.
- Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365-2370.
- Hammes H, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.Nat Med. 2003;9:294-299.
- Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel R. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study.Exp Clin Endocrinol Diabetes. 2008;116:600-605.
- Oates PJ. Polyol pathway and diabetic peripheral neuropathy.Int Rev Neurobiol. 2002;50:325-392.
- Boulton A, Kempler P, Ametov A, Ziegler D. Whither pathogenetic treatments for diabetic polyneuropathy?Diabetes Metab Res Rev. 2013;29:327-333.
- Goto Y, Hotta N, Shigeta Y, Sakamoto N, Kikkawa R. Effects of an aldose reductase inhibitor, epalrestat, on diabetic neuropathy. clinical benefit and indication for the drug assessed from the results of a placebo-controlled double-blind study.Biomed Pharmacother. 1995;49:269-277.
- Hotta N, Akanuma Y, Kawamori R, et al. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial.Diabetes Care. 2006;29(7):1538-1544.
- Kajdasz DK, Iyengar S, Desaiah D, et al. Duloxetine for the management of diabetic peripheral neuropathic pain: evidence-based findings from post hoc analysis of three multicenter, randomized, double-blind, placebo-controlled, parallel-group studies.Clin Ther. 2007;29:2536-2546.
- Lunn M, Hughes R, Wiffen P. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia.Cochrane Database Syst Rev. 2014;(1): CD007115.
- Freeman R, Durso-DeCruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses.Diabetes Care. 2008;31(7):1448-1454.
- Nucynta [package insert]. Titusville, NJ: Janssen Pharmaceuticals, 2014.
- Habib AA, Brannagan TH. Therapeutic strategies for diabetic neuropathy.Curr Neurol Neurosci Rep. 2010;10(2):92-100.
- Sang C, Booher S, Gilron I, Parada S, Max M. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose–response trials.Anesthesiology. 2002;96:1053-1061.
- Shaibani A, Pope L, Thisted R, Hepner A. Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study.Pain Med. 2012;13:243-254.
- Thisted R, Klaff L, Schwartz S, et al. Dextromethorphan and quinidine in adult patients with uncontrolled painful diabetic peripheral neuropathy: A 29-day, multicenter, open-label, dose-escalation study.Clin Ther. 2006;28:1607-1618.
- The Capsaicin Study Group. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study.Arch Intern Med. 1991;151:2225-2229.
- Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin J, McArthur J. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy.Brain. 2004;127:1606-1615.
- Barbano R, Herrmann D, Hart-Gouleau S, Pennella-Vaughan J, Lodewick P, Dworkin R. Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy.Arch Neurol. 2004;61:914-918.
- Spallone V. Management of painful diabetic neuropathy: guideline guidance or jungle?Curr Diab Rep. 2012;12:403-413.
- Bril V, England J, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy.Neurology. 2011;76(20):1758-1765.
- Yuan RY, Sheu JJ, Yu JM, Chen WT, Tseng IJ, Chang HH, Hu CJ. Botulinum toxin for diabetic neuropathic pain: a randomized double-blind crossover trial.Neurology. 2009;72(17):1473-1478.
- Javed S. Alam U, Malik RA. Treating Diabetic Neuropathy: Present Strategies and Emerging Solutions.Rev Diabet Stud. 2015;12(1-2):63-83.
Leave a Reply
You must be logged in to post a comment.