Clinical Manifestations and Current Treatment Options for Diabetic Neuropathies

Carolina M. Casellini, MD; Aaron I. Vinik, MD, PhD, FCP, MACP

Disclosures

Endocr Pract. 2007;13(5):550-566. 

In This Article

Abstract and Introduction

Objective: To review the clinical manifestations and current treatment options for diabetic neuropathies, one of the most common complications of diabetes mellitus.
Methods: We performed a MEDLINE search of the English-language literature using a combination of words (diabetic neuropathy, diabetic autonomic neuropathy, diagnosis and treatment) to identify original studies, consensus statements, and reviews on diabetic neuropathies published in the past 25 years. Emphasis was placed on clinical manifestations of distal polyneuropathy and its treatment, especially new therapies.
Results: Distal symmetric polyneuropathy, the most common form of diabetic neuropathy, usually involves small and large nerve fibers. Small-nerve fiber neuropathy often presents with pain and loss of intraepidermal nerve fibers, but without objective signs or electrophysiologic evidence of nerve damage. This type of neuropathy is a component of impaired glucose tolerance and the metabolic syndrome. The greatest risk from small-fiber neuropathy is foot ulceration and subsequent gangrene and amputation. Large-nerve fiber neuropathy produces numbness, ataxia, and incoordination, thus impairing activities of daily living and causing falls and fractures. Successfully treating diabetic neuropathy requires addressing the underlying pathogenic mechanisms, treating symptoms to improve quality of life, and preventing progression and complications of diabetes mellitus. Two new drugs, duloxetine hydrochloride and pregabalin, have recently been approved for treatment of neuropathic pain associated with diabetes mellitus.
Conclusion: Symptomatic therapy has become available and newer and better treatment modalities, based on etiologic factors, are being explored with potential for clinically significant reduction of morbidity and mortality. Preventive strategies and patient and physician education still remain key factors in reducing complication rates and mortality.

Diabetic neuropathies (DNs) are among the most frequent complications of diabetes mellitus. Of affected individuals, 1 in 4 is symptomatic, almost 50% have objective features identified by clinical examination, and up to 95% have objective signs when evaluated using sophisticated techniques for the assessment of nerve function.[1] Asymptomatic DN is still capable of leading to increased morbidity and mortality. Unfortunately, neither endocrinologists nor non-endocrinologists have been trained to recognize the condition,[2] and even when patients are symptomatic, fewer than one-third of physicians recognize the cause or discuss this with their patients. DN is the most common form of neuropathy in developed countries and is responsible for 50% to 75% of nontraumatic amputations. The major morbidity is foot ulceration, which can lead to gangrene and ultimately to limb loss. Each year, 96 000 amputations are performed on diabetic patients in the United States, yet up to 75% of these procedures are preventable.[3] Globally, an amputation occurs every 30 seconds. DN also has a tremendous impact on patients' quality of life predominantly by causing weakness, ataxia, and incoordination predisposing to falls and fractures.[4]

DNs are a heterogeneous group of conditions that involve different components of the somatic and autonomic nervous systems. They can be focal or diffuse, proximal or distal. Causative factors include persistent hyperglycemia, microvascular insufficiency, oxidative and nitrosative stress, defective neurotrophism, and autoimmune-mediated nerve destruction.[5]

The epidemiology and natural history of DN remain poorly defined, in part because of variable criteria for the diagnosis, failure of many physicians to recognize and diagnose the disease, and lack of standardized methodologies used for the evaluation of these patients.[6]

This discussion mainly focuses on clinical manifestations of distal polyneuropathy (DPN) and its treatment, with emphasis on new therapies. We performed a MEDLINE search of the English-language literature using a combination of words (diabetic neuropathy, diabetic autonomic neuropathy, diagnosis and treatment) to identify original studies, consensus statements, and reviews on diabetic neuropathies published in the past 25 years.

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