Clinical Manifestations and Current Treatment Options for Diabetic Neuropathies

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


Endocr Pract. 2007;13(5):550-566. 

In This Article

Clinical Manifestations

Reversible abnormalities of nerve function with distal sensory symptoms may occur in patients with recently diagnosed or poorly controlled diabetes mellitus. Recovery soon follows restoration of euglycemia.[6]

Acute painful sensory neuropathy is a distinctive variant of DPN and is characterized by severe pain, cachexia, weight loss, depression, and—in males—erectile dysfunction.[9] Patients report unremitting burning, deep pain, and hyperesthesia especially in the feet. Other symptoms include sharp stabbing or electric shock-like sensations in the lower limbs that appear more frequently during the night. Signs are usually absent with relatively normal findings on clinical examination, except for allodynia (exaggerated response to nonpainful stimuli) and, occasionally, absent or reduced ankle reflexes.

Acute painful sensory neuropathy is usually associated with poor glycemic control, but may also appear after rapid improvement of glycemia.[11] Some refer to it as the insulin neuritis syndrome, but this is a misnomer because it may also occur with the use of oral hypoglycemic drugs. It has been hypothesized that changes in blood glucose flux produces alterations in epineurial blood flow, leading to ischemia.[12] Other authors propose an immune-mediated mechanism.[13]

The key to managing this syndrome is achieving blood glucose stability. Most patients also require medication to treat neuropathic pain. The natural history of this disease is resolution of symptoms within 1 year.[11]

Clinical Presentation DPN is probably the most common variety of diabetic neuropathy.[6,13] It is seen in both type 1 and type 2 diabetes mellitus with similar frequency, and it may be present at the time of diagnosis in patients with type 2 diabetes mellitus.[13] Investigators of a population survey reported that 30% of patients with type 1 diabetes mellitus and 36% to 40% of patients with type 2 diabetes mellitus experienced neuropathic symptoms.[14] Findings from several studies have suggested that impaired glucose tolerance and the metabolic syndrome may account for 30% to 50% of idiopathic neuropathies.[15,16,17,18]

Most frequently, DPN is a mixed sensorimotor neuropathy. However, sensory symptoms are more prominent than motor symptoms and usually involve the lower limbs. Sensory symptoms include pain, paresthesiae, and hyperesthesia, deep aching, burning, and sharp stabbing sensations in addition to allodynia wherein patients report pain with nonpainful stimuli such as touch, contact with bedclothes, and warm and cold tactile stimulation. In addition, patients may experience negative symptoms such as numbness in the feet and legs leading in time to painless foot ulcers and subsequent amputations if the neuropathy is not promptly recognized and treated. Unsteadiness frequently occurs due to abnormal proprioception and muscle sensory function.[19,20] Some patients may be completely asymptomatic, and signs may be only discovered by a detailed neurologic examination.

On physical examination of patients with DPN, there is usually a symmetrical stocking-like distribution of sensory abnormalities in both lower limbs. In severe cases, the hands may be involved. All sensory modalities can be affected, particularly loss of vibration, touch, and position perception (large A alpha- and A beta-fiber damage), and abnormal heat and cold temperature perception (small A delta- and unmyelinated C-fiber damage) (Fig. 1). Ankle reflexes may be absent or reduced. Small-muscle weakness and wasting occurs in the hands and feet and is referred to as intrinsic minus wasting because of the loss of the small muscles, which leads to overcompensation of large muscles causing the hammer toe deformities and loss in handgrip power. Large-muscle wasting such as in the calf or thigh may be observed, but severe weakness is rare and, if present, should raise the question of a possible nondiabetic neuropathy, particularly the chronic inflammatory demyelinating polyneuropathy, which occurs 11 times more frequently in people with diabetes mellitus and has an inflammatory autoimmune pathogenesis.[6,13,21,22] DPN is frequently accompanied by autonomic neuropathy, which has recently been reviewed and is not a part of this article.[23,24] All patients with DPN are at increased risk of foot ulceration and Charcot's neuroarthropathy.

A simplified view of the peripheral nervous system and description of the underlying causes of small- and large-fiber neuropathies.[8] A alpha fibers are large myelinated fibers, in charge of motor functions and muscle control. A alpha/beta fibers are large myelinated fibers too, with sensory functions such as perception to touch, vibration, and position. A delta fibers are small myelinated fibers, in charge of pain stimuli and cold perception. C fibers can be myelinated or unmyelinated and have both sensory (warm perception and pain) and autonomic functions (blood pressure, heart rate regulation, sweating, etc.). GIT indicates gastrointestinal tract; GUT indicates genitourinary tract.

Diagnosis Symptoms of neuropathy are personal experiences and can vary markedly from one patient to another, making the correct assessment sometimes difficult. For this reason, symptom questionnaires with similar scoring systems have been developed. These are useful to assess responses to treatment. The nerve system score questionnaire has 38 items that capture symptoms of muscle weakness, sensory disturbances, and autonomic dysfunction.[25]

A comprehensive clinical examination is key to the diagnosis of DPN and requires evaluation of strength, wasting, and loss of reflexes with testing of different cognitive functions such as touch, pressure, warm and cold thermal perception, and vibration detection. A composite score has been generated—the nerve impairment score—that is used to track changes and response to interventions. Feet must be examined in detail to detect ulcers, calluses, and deformities, and footwear should be inspected at every visit. The American Diabetes Association recommends that all patients with type 2 diabetes mellitus be screened for DN at diagnosis, and all patients with type 1 diabetes mellitus be screened 5 years after diagnosis. Thereafter, screening should be repeated annually and must include sensory examination of the feet and ankle reflexes.[10] One or more of the following can be used to assess sensory function: pinprick, temperature, vibration perception (using 128-Hz tuning fork) and 1- and 10-g monofilament pressure perception at the distal halluces. A simple substitute is to use 25-pound strain fishing line and cut 4-cm and 8-cm lengths, which translate to 10- and 1-g monofilaments.[26] The most sensitive one is the vibration detection threshold, but combinations of more than one test have more than 87% sensitivity in detecting DPN.[10,27] Results from longitudinal studies have shown that these simple tests are good predictors of foot-ulcer risk.[28] Numerous composite scores to evaluate clinical signs of DN such as the nerve impairment score are useful in documenting and monitoring neuropathic deficits.[29]

Quantitative sensory testing is of value in detecting subclinical neuropathy, assessing progression, and predicting risk for foot ulceration.[27,30] These standardized measures of vibration and thermal thresholds also act as primary efficacy end points in multicenter clinical trials.

The use of electrophysiologic (nerve conduction velocity) measures in multicenter clinical trials is recommended.[31,32] In patients with type 2 diabetes mellitus, nerve conduction velocity abnormalities in the lower limbs increased from 8% at baseline to 42% after 10 years of disease.[33] A slow progression of nerve conduction velocity abnormalities in type 1 diabetes mellitus was observed in the Diabetes Control and Complications Trial (DCCT).[34] The sural and peroneal nerve conduction velocities diminished by 2.8 and 2.7 m/s, respectively, over a 5-year period. After 5 years, patients who were free of neuropathy at baseline had a 40% incidence of abnormal nerve conduction velocity in the conventionally treated group vs 16% in the intensive therapy treated group. However, small unmyelinated nerve fibers are affected early in diabetes mellitus, and this is not reflected in the results from nerve conduction velocity studies. Other methods that do not depend on conduction such as quantitative sensory testing or skin biopsy with quantification of intraepidermal nerve fibers, are necessary to identify these patients.[13] Nerve conduction velocity nevertheless is key in ruling out other causes of neuropathy and is essential for the identification of focal and multifocal neuropathies and for the diagnosis of entrapment syndromes.[6,35]

The importance of the skin biopsy as a tool for diagnosing DPN is increasingly being recognized.[36,37,38] This technique quantitates small epidermal nerve fibers through antibody staining of the pan-axonal marker protein gene product 9.5 (PGP 9.5). Though minimally invasive (3-mm diameter punch biopsies), it enables a direct study of small fibers, which cannot be evaluated by nerve conduction velocity studies. It has led to the recognition of the small-nerve fiber syndrome as part of impaired glucose tolerance and the metabolic syndrome (Fig. 2). When patients present with the "burning foot or hand syndrome," evaluation of glucose tolerance and features of the metabolic syndrome such as waist circumference, plasma triglyceride and high-density lipoprotein cholesterol levels as well as blood pressure become mandatory. Therapeutic lifestyle changes.[39]and the use of topiramate[40] can reverse this form of neuropathy and alleviate symptoms with nerve-fiber regeneration (see following text).

Skin biopsies demonstrating loss of cutaneous nerve fibers in patients with metabolic syndrome (A) and diabetes mellitus (B) compared with a control subject (C). Small epidermal nerve fibers stain positive for the neuronal antigen protein gene product 9.5 (PGP 9.5).

It is widely recognized that neuropathy per se can affect the quality of life of the diabetic patient. The Norfolk Quality of Life questionnaire for DN is a validated tool addressing specific symptoms and effect of large, small, and autonomic nerve-fiber functions. The tool has been used in clinical trials and is available in several validated language versions.[4] The Neurological Quality of Life questionnaire measures patients' perceptions of the impact of neuropathy and foot ulcers.[41]

The diagnosis of DPN is mainly clinical, aided by specific diagnostic tests according to the type and severity of the neuropathy; however, nondiabetic causes of neuropathy must always be excluded, depending on the clinical findings (Fig. 3).

Classifications of neuropathic syndromes and a diagnostic algorithm for assessment of neurologic deficit. B12 indicates vitamin B12; BUN indicates serum urea nitrogen; CIDP indicates chronic inflammatory demyelinating polyneuropathy; EMG indicates electromyogram; GM1 antibodies indicates ganglioside GM1 antibodies; NCV indicates nerve conduction velocity studies; NIS indicates neurologic impairment score (sensory and motor evaluation); NSS indicates neurologic symptoms score; QAFT indicates quantitative autonomic function tests; QST indicates quantitative sensory tests; TSH indicates thyroid-stimulating hormone.


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