ABSTRACT: The early signs of diabetic neuropathy can be detected during a routine clinical examination. Inspect patients' feet for deformities and sensory loss, which indicate risk of ulceration. Prolonged poor glycemic control, alcohol abuse, and obesity increase the risk of amputation. Autonomic dysfunction, which can lead to sexual dysfunction and gastropathy, can be detected by measurement of heart rate and blood pressure. A resting heart rate of about 100 beats per minute and a decrease of about 30 mm Hg in systolic blood pressure within 2 minutes of standing are abnormal findings. Electromyography and nerve conduction studies confirm the diagnosis. Improved metabolic control is the main goal of treatment. Analgesics, neuromodulators, and tricyclic antidepressants are effective for managing pain. In patients with autonomic neuropathy, treat the associated symptoms.
An estimated 150 million persons worldwide have diabetes, and the prevalence of the disorder is expected to triple in the next 25 years.1 In the United States, 18.2 million persons (6.3% of the population) have diabetes.2
Before insulin was discovered in 1922 by Banting and Best, patients with diabetes usually died of acute complications, such as diabetic acidosis and infection, within a year of diagnosis. Once insulin became the mainstay of diabetes therapy, patients began to live longer, but diabetes-related complications frequently developed.
Vascular and neurologic complications are the most common causes of morbidity and mortality in patients with diabetes. Hyperglycemia is a major risk factor for neurologic and microcirculatory complications that involve the retina, renal glomeruli, and peripheral nerves.3
Neuropathy is one of the most common complications; the lifetime prevalence is between 25% and 50% in persons with diabetes.4 The painful and even disabling symptoms can adversely affect patients' quality of life. In developed countries, diabetic neuropathy accounts for 50% to 75% of nontraumatic amputations.5 Mortality in patients with autonomic neuropathy is 25% to 50% within 10 years of the onset of symptoms.6
Annual surveillance for evidence of neuropathy and intensive diabetes management can reduce the incidence of complications. Here I describe a structured approach to the diagnosis and treatment of diabetic neuropathy.
Diabetic neuropathy is directly related to the length of time that nerve fibers are exposed to hyperglycemia.The mechanism by which hyperglycemia mediates vascular and neuronal cell dysfunction is not completely understood. A number of biochemical mechanisms may be involved, including nonenzymatic glycosylation, increases in oxidative stress, activation of the polyol pathway, and activation of the protein kinase C (PKC) pathway.
Nonenzymatic glycosylation and oxidation of proteins and lipids are natural phenomena of aging that occur at a very slow rate. As glucose becomes incorporated into proteins, advanced glycated end products (AGEs) are formed in an irreversible chemical reaction. During this process, reactive oxygen species, such as superoxide and hydrogen peroxide, are also produced. In patients with diabetes, hyperglycemia results in the production of higher levels of AGEs and reactive oxidants. The formation of AGEs in connective tissue and matrix components causes alterations in collagen structure, basement membrane thickening, and arterial stiffness. AGEs can also bind to AGE receptor sites on endothelial cell surfaces, leading to increased inflammatory responses, vascular permeability, and procoagulant activity.7
An increase in oxidative stress also may result in neuropathy. Hyperglycemia can increase intracellular sorbitol and fructose levels within neuronal tissue, which may lead to the production of harmful free radicals and an alteration of neuronal function.8
Research into treatment strategies for diabetic neuropathy is focusing on PKC-a family of enzymes that play an important role in intracellular signal transduction for hormones and cytokines. Hyperglycemia activates PKC production, which initiates a complex intracellular signaling cascade that affects gene expression and enzymes in many organs and tissues throughout the body. PKC inhibitor drugs, once developed, may suppress the activation of these enzymes and may reduce diabetes- related complications.9,10
DEFINITION AND CLASSIFICATION
The common neuropathies associated with both type 1 and type 2 diabetes mellitus can be divided into two broad categories: peripheral, which can be subdivided into focal and generalized; and autonomic (Table 1). Generalized neuropathies represent an insidious and progressive process. Peripheral sensory neuropathy can initiate the pathophysiologic pathways that lead to distal extremity ulceration and amputation. Autonomic impairments can lead to erectile dysfunction, gastropathy, and cardiovascular complications.
DIAGNOSIS OF PERIPHERAL GENERALIZED AND AUTONOMIC NEUROPATHY
Although complex electrophysiologic and autonomic function tests are required to confirm the diagnosis of diabetic neuropathies, routine clinical examination in the primary care office often can be used for screening.
Screening for diabetic neuropathy is an important component of routine diabetes care. Most patients with mild sensory neuropathy have no detectable clinical findings. Evaluate all patients with newly diagnosed diabetes as well as those who are new to your practice for peripheral neuropathy, and re-examine patients every year. Screening at an early stage may forestall progression to more severe, disabling, or irreversible disease.
Inspection of the feet. This is mandatory for all patients with diabetes at the time of their initial visit and annually thereafter. Dry skin, distended veins, callosity, and multiple deformities (such as clawfoot and prominent metatarsal heads) may suggest Charcot foot. In this condition, increased pressure on the plantar surface may lead to ulceration. Foot ulceration and amputation are the most common consequences of diabetic neuropathy and are major causes of morbidity and disability in persons with diabetes (Figure). Table 2 lists risk factors for amputation.11,12
Monofilament test.This is the most commonly used method for assessing foot ulcer risk. Most screening is performed with the 10-g monofilament. The device is placed perpendicular to a foot surface until it bends, and the patient is asked whether sensation is perceived. Protocols differ as to the number of sites on the foot that are tested and the criteria for a positive test for ulcer risk.
Quantitative sensory testing. Risk of ulceration can also be determined by quantification of the results of sensory testing using the neuropathy disability score (Table 3).13 One sensory test is performed by applying a 128-Hz tuning fork on the hallux and asking the patient whether he or she can perceive vibration. Loss of vibration sense indicates that the patient has significant sensory neuropathy. The same tuning fork can be used to assess hot/cold sensation, which is altered in diabetic neuropathy. In addition, check for loss of ankle reflexes-a sign of advanced peripheral neuropathy.
Self-inspection. Educate patients who have clinical evidence of neuropathic disease about how to prevent the development of foot ulcers. Discuss self-inspection of the feet and the use of properly fitting footwear.
Cardiovascular evaluation. Simple tests for evaluation of cardiovascular autonomic neuropathy have also been developed. Table 4 lists the measures and the normal values; the abnormal measures are signs of autonomic neuropathy.14
MANAGEMENT OF PERIPHERAL GENERALIZED AND AUTONOMIC NEUROPATHY
Improved metabolic control. This is the primary goal of management. The Diabetes Control and Complications Trial research group reported a 64% reduction in electrophysiologic evidence of neuropathy in patients treated with intensive insulin therapy (3 or 4 injections per day or use of an insulin pump) compared with patients treated with conventional therapy (2 injections daily).3 In the United Kingdom Prospective Diabetes Study, patients with type 2 diabetes given intensive treatment showed improvement in vibration perception compared with patients treated with diet and exercise alone.15 Care must be taken to manage not only glycemia but also lipid levels, blood pressure, weight, lifestyle intervention (smoking and alcohol cessation), while encouraging the use of aspirin.
Magnesium supplementation. Observational studies suggest that intracellular magnesium deficiency in patients with diabetes may account for abnormal nerve conduction studies.16 Oral magnesium oxide supplements have been shown to improve nerve conduction velocities in patients who have type 1 diabetes mellitus of short duration. Magnesium is a noncompetitive NMDA (N-methyl D-aspartate) receptor antagonist that affects the perception of pain within the spinal cord in animal models.17 I have noted that supplemental oral magnesium oxide (250 to 750 mg, taken on an empty stomach at bedtime) has been effective in eliminating paresthesias and reducing pain in patients with diabetic neuropathy.
Treatment of painful diabetic neuropathy. Peripheral sympathetic nerve fibers are small unmyelinated C-fibers that use substance P as their neurotransmitter pain inducer. Thus, drugs that can reduce substance P can reduce neuropathic pain. Over-the-counter capsaicin ointment can be applied to a neuropathic painful limb. The ointment must be applied with a gloved hand and rubbed in for 5 minutes twice daily for 2 weeks. Contact with the face and eyes should be avoided. Patients who complain of burning pain usually respond well to a combination of oral magnesium and capsaicin.
For pain described as gnawing or deep-seated ("toothache-like"), oral tramadol may be required. This nonopioid centrally acting analgesic is used to treat moderate to severe pain. A tricyclic antidepressant also may be effective.
Carbamazepine can be used for pain described as "lancinating"; however, higher doses may be difficult for some patients to tolerate. The neuromodulator gabapentin has shown promise in managing painful neuropathies.18 Other anticonvulsant agents, such as topiramate, may be useful in treating diabetic neuropathy.19,20 Topiramate can cause an increase in numbness as well as some cognitive dysfunction. Studies of patients with type 2 diabetes have demonstrated secondary positive metabolic effects from topiramate, such as weight reduction,21 lower hemoglobin A1c levels,22 and improved blood pressure control.23 Table 5 summarizes the drugs used to manage pain associated with diabetic neuropathy.
Management of autonomic neuropathy.This involves treatment of the associated symptoms. Erectile dysfunction can be successfully managed with a variety of oral medications (phosphodiesterase-5 inhibitors), transurethral alprostadil pellets, and intracavernosal injections.24 Encourage women with vaginal dryness to use vaginal lubricants before sexual intercourse.
Avoid medications (antihypertensives, antidepressants, cardiac drugs, α-blockers) that may cause syncope in patients who have autonomic dysfunction. Restrict excessive outdoor exercise regimens and instruct patients to replace fluids to avoid dehydration if they have evidence of dishydrosis.
Instruct patients with hypoglycemic unawareness to check their blood glucose levels more frequently, especially before driving, to detect low blood sugar levels. Frequently discuss with patients the proper treatment of hypoglycemia. Use of continuous subcutaneous insulin infusion therapy (insulin pumping) may help reestablish hypoglycemic awareness in patients with autonomic dysfunction.25
Cardiac autonomic neuropathy. Preventionof cardiac autonomic neuropathy is often difficult because few effective therapies are available once these neuropathic changes develop. However, the overall risk of cardiac autonomic neuropathy can be reduced by 70% with physiologic management of hyperglycemia, hyperlipidemia, and hypertension, as well as with the use of angiotensin-converting enzyme (ACE) inhibitors.6 Effective glycemic control may reverse a cardiac autonomic neuropathy in the early stages of development.
The symptoms of postural hypotension may be reduced by increasing water consumption and by using gradient compression stockings.26 Fludrocortisone can increase blood pressure in patients with orthostatic hypotension; however, it may also potentiate congestive heart failure, edema, and hypertension. Antihypertensive drugs may produce a paradoxical increase in blood pressure by activating or antagonizing α- or β-adrenergic receptors that are inappropriately expressed as a result of autonomic denervation or dysfunction.27
Use clonidine with extreme care in patients with cardiac autonomic neuropathy. Imbalances in sympathetic and parasympathetic activities may be corrected with ACE inhibitors and β-blockers.7 Dihydroergotamine, midodrine, caffeine, and octreotide are the drugs of choice for refractory cardiac autonomic neuropathy.28
GI autonomic neuropathy. Improvement in overall glycemic control is the primary goal of treatment of diabetic GI autonomic neuropathy. Hyperglycemia retards gastric emptying and reduces GI motility.29 Management of insulin therapy can be challenging in patients with delayed gastric emptying, because matching the timing of the injection with the anticipated rise in postprandial glucose absorption is difficult, if not impossible, to predict. Advise patients with delayed gastric emptying who use an insulin pump to take an "extended wave bolus" at mealtime. Extended administration allows insulin to be absorbed over 2 to 3 hours rather than as a large dose with a meal. This reduces the incidence of postprandial hypoglycemia in patients with GI autonomic neuropathy.25
Metoclopramide is effective in treating severe diabetic gastropathy; however, long-term use of this agent increases the risk of CNS adverse effects.30 Pharmacologic management of diabetic gastroesophageal reflux, constipation, and diarrhea has not been successful. Moreover, treatment of GI autonomic dysfunction and acceleration of gastric emptying may not reduce or resolve patient symptoms. The best approach is to target physiologic insulin replacement therapy and to improve overall glycemic control.
Focal and multifocal neuropathies are confined to the distribution of a single peripheral nerve (mononeuropathy) or multiple peripheral nerves (mononeuropathy multiplex). Mononeuropathies are caused by vasculitis and subsequent ischemia or nerve infarcts.27 Commonly, a cranial nerve (III, IV, VI, or VII) or a peroneal, sural, sciatic, femoral, ulnar, or median nerve is involved. A typical mononeuropathy begins acutely, is associated with pain, and resolves spontaneously within 6 weeks.
Nerve entrapment syndromes begin gradually and may become disabling over time without intervention. Commonly, the median, ulnar, or pe-roneal nerve or the lateral cutaneous tibial nerve within the tarsal tunnel is involved. Entrapment syndromes affect up to 30% of patients with diabetes and should be evaluated carefully in all those with signs and symptoms of neuropathy.31
Carpal tunnel syndrome (median neuropathy) is a clinically relevant problem in 6% of patients with diabetes.32 Painful paresthesias of the fingers may progress to a deep-seated ache that radiates up the forearm. Symptoms are worse at night. Motor weakness can become progressive, and thenar wasting occurs over time.
Two clinical tests with a high false-positive rate are commonly employed to detect carpal tunnel syndrome. The Phalen test-forearms held vertically and hands held in complete flexion for 1 minute-is positive if paresthesia develops in the median nerve distribution within 30 seconds. The Tinel sign-percussion over the median nerve that induces paresthesia over the distribution of the nerve-is suggestive of carpal tunnel syndrome. However, nerve conduction studies are required to confirm the diagnosis.
Treatment options include wrist splints for nocturnal symptoms. Cortisone injections in the carpal tunnel may provide symptomatic relief; however, they often need to be repeated. Surgical intervention is required for pain relief and to prevent the acceleration of muscle wasting.
Ulnar neuropathy occurs in 2% of diabetic patients as a result of nerve compression immediately distal to the ulnar groove beneath the edge of the flexor carpi ulnaris aponeurosis in the cubital tunnel. Alcoholism is a risk factor. Typical symptoms include painful paresthesias in the fourth and fifth digits associated with hypothenar and interosseous muscle wasting. Treatment is conservative; however, patients with motor loss and muscle wasting may require surgical intervention.
Compression of the lateral femoral cutaneous nerve (meralgia paresthetica), although uncommon in diabetes, can result in pain, paresthesias, and sensory loss over the lateral aspect of the thigh. Most cases resolve spontaneously. In cases associated with severe pain, allodynia, and disability, corticosteroid injections using focal nerve blocks at the inguinal ligament or surgical decompression may be indicated.
Tarsal tunnel syndrome is a painful lower limb entrapment that involves the tibial nerve, which passes through the tarsal tunnel. The tibial nerve innervates only the muscles of the sole. This results in severe burning pain over the plantar aspect of the foot when the patient stands or walks. Tinel sign on the underside of the medial malleolus with atrophy of the sole muscles is typical. Sensation over the dorsum of the foot is normal; however, nerve conduction studies demonstrate asymmetry compared with the normal leg. Ankle reflexes are maintained.
Treatment options include nighttime splinting in a neutral position and targeted injections of local anesthetics and corticosteroids into the tarsal tunnel.31 Surgical decompression remains a controversial option in patients with diabetes who have severe pain and abnormal nerve conduction studies.
Cranial neuropathy in diabetic patients is rare. It typically affects older persons with a long history of diabetes.33 Cranial nerve III, IV, or VI may be involved. The classic presentation is acute-onset diplopia with ptosis and papillary sparing associated with ipsilateral headache. Neurologic deficits resolve on average within 2.5 months. Recurrence is rare, but it has been noted in 25% of diabetic patients.33 Advise patients with a cranial neuropathy to wear a patch over the affected eye and to adhere to strategies that improve glycemic control.
Diabetic amyotrophy typically occurs in patients aged 50 to 60 years with type 2 diabetes mellitus. Presenting symptoms include severe pain and unilateral or bilateral muscle weakness associated with atrophy of the proximal thigh muscles.34 The cause is unknown; however, it may be related to infarcts in the lumbosacral plexus.35 Diabetic amyotrophy results in significant pain and difficulty in climbing stairs or getting out of cars, but it can be managed with drugs such as tramadol and gabapentin. Improvement in overall glycemic control is imperative in these patients.
Diabetic truncal radiculoneuropathy affects middle-aged and el-derly men. The primary feature is pain of acute onset that resolves spontaneously within 4 to 6 months. The pain-which is worse at night-is described as an aching or burning sensation with superimposed lancinating stabs. Patients describe the location of pain as being in a girdle-like distribution over the lower thoracic or abdominal wall. The pain may be unilateral or bilateral. Patients may experience profound weight loss associated with the onset of their symptoms. Clinical findings range from no abnormalities to sensory loss and hyperesthesia in a complete dermatomal pattern.
Diabetic truncal radiculoneuropathy shares many features with diabetic amyotrophy, except the latter is much more painful and occurs in patients whose glycemic control is much worse.36 Therapy is directed toward improving glycemic control and pain management.
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