Diabetic Neuropathies: A Statement by the American Diabetic Association

Boulton AJM, Vinik AI, Arezzo JC, et al. Diabetes Care. 2005;28:956-962.

This paper provides a broad overview of diabetic neuropathies, including definitions, diagnostic criteria, epidemiology, and management. Because up to 50% of sensorimotor distal symmetric polyneuropathy can be asymptomatic, patients are at risk for foot injuries that may occur without their knowledge. Autonomic neuropathy can involve every major bodily system, causing considerable mortality and morbidity among people with diabetes. Thus, proper and timely diagnosis is important so that patients can be appropriately educated and treated.

Definitions and Classification

There are 2 primary categories of neuropathies: 1) generalized symmetric polyneuropathies, which includes acute sensory, chronic sensorimotor, and autonomic; and 2) focal and multifocal neuropathies, which includes cranial, truncal, focal limb, proximal motor (amyotrophy), and coexisting chronic inflammatory demyelinating polyneuropathy (CIDP).

Diagnostic Criteria

The diagnosis of diabetic peripheral neuropathy is generally made after signs and/or symptoms of nerve dysfunction have been observed and all other plausible causes have been ruled out, as nondiabetic neuropathies may be present in patients with diabetes. Clinical examination of the lower limbs is essential, because lack of symptoms is not synonymous with lack of signs.

Acute Sensory Neuropathy

This type of neuropathy is rare and generally accompanies poor metabolic control or a change in metabolic control. Severe sensory symptoms that are worse in the evening mark its onset. Few neurological signs are present in the legs.

Chronic sensorimotor diabetic peripheral neuropathy

This type of neuropathy is the most common among people with diabetes. Among the 50% of patients who report symptoms, burning, electrical, or stabbing sensations, parasthesiae, hyperasthesiae, and deep aching pain are common. Symptoms occur most frequently in the lower limbs and tend to be worse at night. Careful questioning of patients is essential, as patients may not report symptoms unless asked. Some common signs include loss of vibration, pressure, pain, and temperature; absent ankle reflexes; warm or cold feet possibly accompanied by distended dorsal veins (in the absence of peripheral vascular disease); dry skin; and calluses. Diagnosis involves ruling out other forms of neuropathy (eg, CIDP, B₁₂ deficiency, hypothyroidism, and uremia) and performing a thorough clinical examination. The clinical examination should include testing for pinprick, temperature, and vibration perception; testing the ability to sense pressure sensation; and testing ankle reflexes.

Focal and multifocal neuropathies

Mononeuropathies involve the median, ulnar, and common peroneal nerves. Cranial neuropathies, which are very rare, involve cranial nerves III, IV, VI, and VII. Entrapment is far more common, affecting approximately a third of people with diabetes and involving the ulnar, median, peroneal, and medial plantar nerves. Diabetic amyotrophy can occur in older type 2 patients. Symptoms include neuropathic pain and either unilateral or bilateral muscle atrophy in the proximal thigh muscles.

Autonomic neuropathy

This type of neuropathy includes cardiovascular autonomic neuropathy (CAN); gastrointestinal disturbances such as gastroparesis, esophageal enteropathy, constipation, diarrhea, and fecal incontinence; and genitourinary disturbances. There are a number of clinical indicators of CAN, including resting tachycardia, orthostasis without appropriate heart rate response, or other autonomic disturbances. Three tests are recommended for diagnosis, including R-R variation, Valsalva maneuver, and postural blood pressure testing. It is especially important to screen for CAN among individuals with diabetes who are planning a moderate- or high-intensity exercise program. Gastroparesis is a common cause of highly erratic glucose control. Again, it is important to perform additional tests such as barium studies or endoscopy to rule out other causes. Autonomic neuropathy also includes genitourinary disturbances such as bladder and/or sexual dysfunction. Symptoms can include frequent urinary tract infections, pyelonephritis, incontinence, a palpable bladder, loss of erection, and/or retrograde ejaculation in men.

Management

Tight glycemic control remains the best strategy for prevention of diabetic neuropathies. Treatment is divided into pathogenic treatments and symptomatic treatments. Pathogenic treatments have yet to be successfully translated from animal models into a viable therapeutic strategy. Many of the aldose reductase inhibitors have been withdrawn due to adverse events. Gamma-linolenic acid and aminoguanidine have also been withdrawn. Nerve growth factor, brain-derived neurotropic factor, and acetyl-L-carnitine all have been proven ineffective. Results of studies with myo-inositol have been equivocal. A number of agents still in development show promise, including α-lipoic acid, a variety of vasodilators (including ACE inhibitors and prostaglandin analogs), the protein kinase C-β inhibitor ruboxistaurin, and C-peptide. Because no pathogenic treatments are currently available, symptom management remains a focus of treatment. Improving and stabilizing glycemic control may have a beneficial impact not just on the prevention of neuropathy, but also on the amelioration of neuropathic symptoms, although randomized trial evidence supporting this claim is lacking. Currently, only pregabalin and duloxetine are approved for the management of neuropathic pain. Other commonly used agents, including tricyclic antidepressants and anticonvulsants such as gabapentin, are not approved for this indication.

Recommendations

Because no pathogenic treatment exists, the best hope lies in prevention. Tight glycemic control, in addition to tight lipid and blood pressure control, is recommended for all patients with diabetes. Screening for neuropathy should be done at diagnosis of type 2 diabetes, within 5 years of diagnosis with type 1 diabetes, and annually thereafter. Screening for diabetic peripheral neuropathy should consist of a detailed patient interview and a careful clinical examination that includes sensory function testing, ankle reflex testing, and a visual foot inspection. Education should be provided and a podiatric referral should be considered. Screening for autonomic neuropathy should include a history, an examination for signs of autonomic dysfunction, and tests for heart rate variabilities.