AUTHOR INFORMATION

Section 1 of 12

Authored by Dianna Quan, MD, Director, Electromyography Laboratory, Assistant Professor, Department of Neurology, University of Colorado Health Sciences Center

Coauthored by Emad Soliman, MD, MSc, Consulting Staff, Department of Neurology, St John's Riverside Hospital; Charles Gellido, MD, Laboratory Director, Assistant Professor, Department of Neurology, Jacobi Medical Center, Albert Einstein College of Medicine

Dianna Quan, MD, is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa

Edited by Milind J Kothari, DO, Professor and Vice-Chair for Education and Training, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Hershey Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, University of Pittsburgh Medical Center - Shadyside, Clinical Associate Professor, Department of Neurology, University of Pittsburgh School of Medicine; Selim R Benbadis, MD, Professor of Neurology, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine, Tampa General Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Dianna Quan, MD
Editor's Email:	Milind J Kothari, DO

eMedicine Journal, September 28 2006, VOLUME 7, Number 9

INTRODUCTION

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Background: Neuropathies are characterized by a progressive loss of nerve fibers that can be assessed noninvasively by several tests of nerve function, including nerve conduction studies and electromyography, quantitative sensory testing, and autonomic function tests. A widely accepted definition of diabetic peripheral neuropathy is "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes" (Boulton, 1998). Diabetic neuropathy is classified into several syndromes, each with a distinct pattern of involvement of peripheral nerves. Patients often have multiple or overlapping syndromes.

Peripheral neuropathies have been described in patients with primary (types 1 and 2) and secondary diabetes of diverse causes, suggesting a common etiologic mechanism based on chronic hyperglycemia. The contribution of hyperglycemia has received strong support from the Diabetes Control and Complications Trial (DCCT). The dose dependent effect of hyperglycemia on nerves has been supported further in recent years by increasing recognition of an association between impaired glucose tolerance (prediabetes) and peripheral neuropathy. Pathologically, numerous changes have been demonstrated in both myelinated and unmyelinated fibers.

Pathophysiology: The factors leading to the development of peripheral neuropathy in diabetes are not understood completely, and multiple hypotheses have been advanced. It is generally accepted to be a multifactorial process. The best-supported mechanisms include the following:

Metabolic theory

This theory proposes that hyperglycemia causes increased levels of intracellular glucose in nerves, leading to saturation of the normal glycolytic pathway. Extra glucose is shunted into the polyol pathway and converted to sorbitol and fructose by the enzymes aldose reductase and sorbitol dehydrogenase. Accumulation of sorbitol and fructose lead to reduced nerve myoinositol, decreased membrane Na⁺/K⁺-ATPase activity, impaired axonal transport, and structural breakdown of nerves, causing abnormal action potential propagation. This is the rationale for the use of aldose reductase inhibitors to improve nerve conduction.

Vascular (ischemic-hypoxic) theory

According to this theory, endoneurial ischemia develops because of increased endoneurial vascular resistance to hyperglycemic blood. Various metabolic factors, including formation of advanced glycosylation end products, also have been implicated. The end results are capillary damage, inhibition of axonal transport, reduced Na⁺/K⁺-ATPase activity, and finally axonal degeneration.

Altered neurotrophic support theory

Neurotrophic factors are important in the maintenance, development, and regeneration of responsive elements of the nervous systems. Nerve growth factor (NGF) is the best studied. This protein promotes survival of sympathetic and small-fiber neural crest–derived elements in the peripheral nervous system. In animals with diabetes, both production and transport of NGF are impaired. Antioxidants have been used to enhance the effects of NGF.

Laminin theory

Laminin is a large, heteromeric, curariform glycoprotein composed of a large alpha chain and two smaller beta chains, beta 1 and beta 2. In cultured neurons, laminin promotes neurite extension. Lack of normal expression of the laminin beta 2 gene may contribute to the pathogenesis of diabetic neuropathy.

Autoimmune theory

Autoimmune diabetic neuropathy is postulated to result from immunogenic alteration of endothelial capillary cells. This is the basis for the use of intravenous immunoglobulin (IVIg) to treat some variants of diabetic neuropathy.

Frequency:

• In the US: An estimated 10-65% of patients with diabetes have some form of peripheral neuropathy. Neuropathy is estimated to be present in 7.5% of patients at the time of diabetes diagnosis. One half of patients have distal symmetric polyneuropathy, and one fourth have compression or entrapment neuropathies (mainly carpal tunnel syndrome).

  The wide variability in diabetic neuropathy prevalence data is due to lack of consistent criteria for the diagnosis of peripheral neuropathy, variable methods of selecting patients for study, and differing assessment techniques. In addition, because most patients with diabetic polyneuropathy are initially asymptomatic, detection is extremely dependent on careful neurologic examination by the primary care clinician.

• Internationally: In a cohort of 4400 Belgian patients, Pirart et al found that 7.5% patients already had neuropathy when diagnosed with diabetes. After 25 years, the number with neuropathy rose to 45%. Using additional methods of detection, such as autonomic or quantitative sensory testing, the prevalence may be higher.

Mortality/Morbidity: Patients with untreated or inadequately treated diabetes have higher morbidity and complication rates related to neuropathy than patients with tightly controlled diabetes. Repetitive trauma to affected areas may cause skin breakdown, progressive ulceration, and infection. Amputations and death may result.

Race: No definite racial predilection has been demonstrated for diabetic neuropathy.

Sex: Male patients with diabetes usually have a higher incidence of diabetic neuropathy than female patients.

Age:

• Diabetic neuropathy can occur at any age but is more common with increasing severity and duration of diabetes.

• Symptomatic presentation is most common in patients older than 50 years.

• Some theories suggest that diabetic neuropathy begins early in the hyperglycemic process, often before the clinical diagnosis of diabetes is made.

CLINICAL

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History: In type 1 diabetes mellitus, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia. Conversely, in type 2, it may present after only a few years of known poor glycemic control. Occasionally, patients with type 2 diabetes mellitus may already have neuropathy at the time of diagnosis.

• Since diabetic neuropathy can manifest with a wide variety of sensory, motor, and autonomic symptoms, a structured list of symptoms can be used to help screen all diabetic patients for possible neuropathy.


• • Sensory symptoms may be negative or positive, diffuse or focal. Negative sensory symptoms include feelings of numbness or deadness, which patients may describe as being akin to wearing gloves or socks. Loss of balance, especially with the eyes closed, and painless injuries due to loss of sensation are common. Positive symptoms may be described as burning, prickling pain, tingling, electric shock–like feelings, aching, tightness, or hypersensitivity to touch.
  
  
  
  • Motor problems may include distal, proximal, or more focal weakness. In the upper extremities, distal motor symptoms include impaired fine hand coordination and difficulty with tasks such as opening jars or turning keys. Foot slapping and toe scuffing or frequent tripping may be early symptoms of foot weakness. Symptoms of proximal limb weakness include difficulty climbing up and down stairs, difficulty getting up from a seated or supine position, falls due to the knees giving way, and difficulty raising the arms above the shoulders.
  
  
  
  • Autonomic symptoms may be sudomotor (dry skin due to lack of sweating or excessive sweating in defined areas), pupillary (poor dark adaptation, sensitivity to bright lights), cardiovascular (postural lightheadedness, fainting), urinary (urgency, incontinence, dribbling), gastrointestinal (diarrhea, constipation, nausea, or vomiting), and sexual (erectile impotence and ejaculatory failure in men, loss of ability to reach sexual climax in women).
  
  
  
• A generally accepted classification of diabetic neuropathies divides them broadly into symmetric and asymmetric neuropathies. Development of symptoms depends on total hyperglycemic exposure and other risk factors such as elevated lipids, blood pressure, and increased height. Establishing the diagnosis requires careful evaluation, since 5-10% of patients with diabetes have neuropathy from another cause.



• Symmetric polyneuropathies involve multiple nerves diffusely and symmetrically.


• • Distal symmetric polyneuropathy
    • Most common manifestation of diabetic neuropathy

    • Chronic symmetrical symptoms affecting peripheral nerves in a length-dependent pattern (the longest nerves affected first)

    • Sensory, motor, and autonomic functions affected in varying degrees, with sensory abnormalities predominating

    • Commonly presents as painful paresthesias and numbness, which begin in the toes and ascend proximally in a stockinglike distribution over months and years

    • When sensory symptoms reach the knees, hands develop similar symptoms, progressing proximally in a glovelike distribution

    • Anterior aspect of the trunk and vertex of the head may be affected at a very late stage

    • Weakness of foot muscles and decreased ankle and knee reflexes occur commonly

    • Loss of sensation predisposes to development of foot ulcers and gangrene

    • With impaired proprioception and vibratory perception, gait may be affected (sensory ataxia)
  
  
  
  • Small-fiber neuropathy
    • Less common distal symmetrical neuropathy involving predominantly small-diameter sensory fibers (A delta and C fibers)

    • Manifests as painful paresthesias that patients perceive as burning, stabbing, crushing, aching, or cramplike, with increased severity at night

    • Loss of pain and temperature sensation with relative sparing of distal reflexes and proprioception
  
  
  
  • Diabetic autonomic neuropathy
    • Pure autonomic is neuropathy rare.

    • Some degree of autonomic involvement is present in most patients with diabetic polyneuropathy.

    • Signs may include orthostatic hypotension, resting tachycardia, loss of sinus arrhythmia, anhydrosis, bowel or bladder dysfunction, and small pupils sluggishly reactive to light.
  
  
  
  • Diabetic neuropathic cachexia
    • Precipitous and profound weight loss followed by severe and unremitting cutaneous pain, small-fiber neuropathy, and autonomic dysfunction

    • Occurs more often in older men; impotence is common.

    • Muscle weakness is uncommon.

    • Symptoms usually improve with prolonged hyperglycemia control.

    • Symptoms are often refractory to other pharmacologic treatment. Limited anecdotal improvement is reported with nonpharmacologic treatments such as sympathectomy, spinal cord blockade, and electrical spinal cord stimulation.
  
  
  
• Asymmetric neuropathies include single or multiple cranial mononeuropathies (eg, median neuropathy of the wrist, ulnar neuropathy of the elbow, single or multiple somatic mononeuropathies, single or multiple monoradiculopathies, diabetic lumbosacral radiculoplexoneuropathy [DLSRPN], diabetic amyotrophy, diabetic thoracolumbar radiculoneuropathy). These syndromes are distinguished from typical distal diabetic polyneuropathy by the following characteristics: (1) they often have a monophasic course, (2) some are associated with inflammatory angitis and ischemia (eg, DLSRPN) and may appear acutely or subacutely, and (3) they have a weaker association with total hyperglycemic exposure than symmetrical polyneuropathies.


• • Cranial mononeuropathy
    • Cranial nerves (CN) III, IV, VI, VII, and II are most often involved.

    • CN III, IV, and VI disease manifests as acute or subacute periorbital pain or headache followed by diplopia. Muscle weakness is typically in the distribution of a single nerve, and pupillary light reflexes are usually spared. Complete spontaneous recovery usually occurs within 3 months.

    • Facial neuropathy manifests as acute or subacute facial weakness (taste is not normally involved) and can be recurrent or bilateral. Most recover spontaneously in 3-6 months.

    • Anterior ischemic optic neuropathy manifests as acute visual loss or visual field defects (usually inferior altitudinal). The optic disk appears pale and swollen; flame-shaped hemorrhages may be present.
  
  
  
  • Somatic mononeuropathies
    • Focal neuropathies in the extremities caused by entrapment or compression at common pressure points or by ischemia and subsequent infarction.

    • Entrapment and compression tend to occur in the same nerves and at the same sites as in individuals without diabetes.

    • Common sites include median nerve at the wrist (carpal tunnel syndrome), ulnar nerve at the elbow, and common peroneal nerve at the fibular head. Symptoms often are bilateral.

    • Neuropathy secondary to nerve infarction presents acutely with focal pain associated with weakness and variable sensory loss in the distribution of the affected nerve. Multiple nerves may be affected (mononeuritis multiplex).
  
  
  
  • Diabetic polyradiculopathy
    • Burning, stabbing, boring, belt-like, or deep aching pain usually begins unilaterally; then may become bilateral. Skin hypersensitivity and allodynia (pain with normally innocuous touch) may occur. Numbness in a dermatomal distribution, most prominent in distal distribution of intercostal nerves.

    • Single or more commonly multiple spinal roots are involved. Contiguous territorial extension of symptoms may occur in a cephalad, caudal, or contralateral direction.

    • In the trunk, thoracoabdominal neuropathy or radiculopathy may cause chest and/or abdominal pain in the distribution of thoracic and/or upper lumbar roots.

    • Weakness presents in the distribution of the affected nerve root, eg, bulging of the abdominal wall from abdominal muscle paresis (thoracic root) or weakness of quadriceps muscles (L3-4 roots).

    • Patients older than 50 years are affected most often; it is more common in diabetes mellitus type 2 and is often associated with significant weight loss.

    • Coexisting diabetic distal symmetrical polyneuropathy often is present.
  
  
  
  • Diabetic radiculoplexopathy
    • Synonyms include symmetric proximal motor neuropathy, diabetic amyotrophy, diabetic femoral neuropathy, femorosciatic neuropathy, and diabetic myelopathy (Bruhn-Garland syndrome).

    • This condition often occurs in patients older than 50 years with poorly controlled diabetes. It is more common in men than in women.

    • Significant weight loss occurs in 50% of patients.

    • Symptoms begin unilaterally and later may spread to the opposite limb.

    • Starts as sudden, severe, unilateral pain and may occur in the hip/lower back or shoulder/neck.

    • Weakness develops days to weeks later. Atrophy of the limb musculature is common.

    • Reflexes in the affected limb may be depressed.

    • Numbness and paresthesias may occur.
  
  
  
• Chronic inflammatory demyelinating polyneuropathy (CIDP) may be seen in patients with diabetes.
  • Krendel et al described 15 patients with polyneuropathy, amyotrophy, or mononeuropathy multiplex due to type 2 diabetes mellitus. Electrophysiologic and histologic analyses of nerve or muscle were performed. Perivascular and vascular lymphocytic infiltrates were noted in 7 patients. Neurological improvement with immunosuppressive therapy, often including IVIg, was noted among some patients. Six additional patients with type 1 diabetes mellitus had electrophysiologic evidence of demyelinating neuropathy. Although no vascular inflammation was seen on biopsy, “onion bulbs” were found, reflecting a chronic demyelinating process. These patients responded to immunosuppressive treatment. The authors postulated that these patients had CIDP and that type 1 diabetes mellitus may predispose patients to CIDP.

  • Patients with CIDP typically have a more chronic course (up to 180 months), do not lose weight, and are more likely to have a distal neuropathy, commonly involving the upper extremities. However, as in the case of inflammatory vasculopathy, the distribution is often asymmetric.

  • In patients with diabetes, demyelination on nerve conduction study should prompt evaluation for CIDP, just as it does in those without diabetes. Why patients with diabetes may be predisposed to CIDP is unknown. The fact that demyelination has been found more often in association with type 1 diabetes than with type 2 diabetes suggests autoimmune factors may be important, since these patients more often have other associated autoimmune diseases.

  • Patients with demyelinating neuropathy by nerve conduction study criteria can reasonably be assumed to have CIDP. The available data suggest that diabetic patients with these findings may improve with IVIG treatment. Nerve biopsy with immunohistochemistry to look for evidence of vasculitis or other causes of neuropathy is reasonable.

  • Overall, diabetes mellitus-CIDP differs from idiopathic CIDP in the following ways:
    • Older age at presentation in patients with diabetes

    • Duration of symptoms at the time of evaluation is longer in patients with diabetes

    • Prominent axonal loss in the diabetes group

    • Less response to therapy in the diabetes group

Physical:

• Diabetic polyneuropathy often develops as generalized asymptomatic dysfunction of peripheral nerve fibers. The first clinical sign that usually develops in tandem with abnormal nerve conductions is decrease or loss of ankle jerks, or decrease or loss of vibratory sensation over the great toes. With more severe involvement, the patient may lose deep tendon reflexes and develop weakness of small foot muscles. More focal findings may be seen with injury to specific nerves as described above.



• Five criteria are needed to establish the diagnosis of diabetic polyneuropathy.


• • The patient has diabetes mellitus by National Diabetes Data Group criteria.
  
  
  
  • Diabetes mellitus has caused prolonged chronic hyperglycemia.
  
  
  
  • The patient has predominantly distal sensorimotor polyneuropathy in the lower extremities.
  
  
  
  • Diabetic retinopathy or nephropathy is approximately similar in severity to polyneuropathy.
  
  
  
  • Other causes of sensorimotor polyneuropathy have been excluded.
  
  
  

DIFFERENTIALS

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Alcohol (Ethanol) Related Neuropathy
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Nutritional Neuropathy
Sarcoidosis and Neuropathy
Thyroid Disease
Toxic Neuropathy
Uremic Neuropathy
Vasculitic Neuropathy

Other Problems to be Considered:

Amyloid polyneuropathy
Spinal cord tumors
Vitamin B-12 deficiency

Differential diagnoses to consider in the following situations:

Cranial mononeuropathy
Intracranial aneurysms
Bell palsy

Thoracoabdominal neuropathy
Herpes zoster
Spinal tumors
Myocardial infarction
Acute cholecystitis
Acute appendicitis
Diverticulitis

Lumbosacral radiculoplexopathy
Anterior disk protrusion
Spinal cord tumors
Malignant nerve root infiltrations
Inflammatory neuropathies

WORKUP

Section 5 of 12

Lab Studies:

• The following basic studies are suggested to exclude common causes of neuropathy other than diabetes:


• • Complete blood cell count
  
  
  
  • Complete metabolic panel (electrolytes and liver function panel)
  
  
  
  • Vitamin B-12 and folate levels
  
  
  
  • Thyroid-stimulating hormone and thyroxine
  
  
  
  • Erythrocyte sedimentation rate
  
  
  
  • Serum protein electrophoresis with immunofixation electrophoresis
  
  
  
• Examples of other studies that can be ordered depending on the patient’s history and examination findings include the following:


• • Antinuclear antibody
  
  
  
  • Rheumatoid factor
  
  
  
  • Paraneoplastic antibodies
  
  
  
• Patients with diabetic neuropathies will likely have elevated hemoglobin A1c levels, although the severity of the elevation does not always correlate with the severity of the diabetic neuropathy.

Imaging Studies:

• In the appropriate clinical setting, MRI of the cervical, thoracic, and/or lumbar regions may help to exclude another cause for symptoms mimicking diabetic neuropathy. For patients who cannot have MRI, CT myelogram is an alternative to exclude compressive lesions and other pathology in the spinal canal, eg, in lumbosacral radiculoplexopathy and thoracoabdominal neuropathy. In cranial nerve palsies, brain imaging, usually with MRI, is helpful to exclude intracranial aneurysms, compressive lesions, and infarcts.

Other Tests:

• Electrophysiologic studies are the most sensitive, reliable, and reproducible measures of nerve function. Electrophysiologic findings usually correlate with morphologic changes on nerve biopsy. Common early findings are abnormal nerve conduction studies or reduced variability of heart rate with deep breathing or Valsalva maneuver. Although electrodiagnostic studies can characterize and quantitate nerve dysfunction, they cannot distinguish diabetic neuropathy from neuropathy of other causes.

  Composite scores, combining clinical, quantitative sensory, and electrophysiologic measures, are often used in natural history and efficacy studies. Examples include the Neuropathy Impairment Score in the Lower Limbs + 7 and the Michigan Diabetic Neuropathy score.




• Electromyography and nerve conduction studies


• • Findings on nerve conduction studies depend on the pattern of nerve damage. Patients with distal symmetrical polyneuropathy from predominant axonal loss have reduced or absent sensory nerve action potentials, especially in the legs. With progression of neuropathy, compound motor action potential amplitudes may also be reduced and abnormalities may be observed in the hands. These changes reflect length-dependent degeneration of large-diameter myelinated nerve fibers.
  
  
  
  • Conduction velocities are generally within the normal range or only mildly slowed in distal symmetrical polyneuropathy. If conduction velocities are less than 70% the lower limit of normal, or if conduction block is present, the patient may have superimposed peripheral nerve demyelination in addition to the more typical axonal loss seen in distal symmetrical polyneuropathy. Generalized demyelinating changes on nerve conduction studies should prompt further evaluation for CIDP. Focal slowing of conduction velocity at common sites of entrapment may indicate one of the mononeuropathy syndromes discussed above.
  
  
  
  • Nerve conduction study abnormalities may be found in patients with diabetes even without clinical symptoms of polyneuropathy.
  
  
  
  • Electromyographic sampling of distal lower extremity muscles may reveal acute and ongoing denervation in the form of positive sharp waves and fibrillation potentials (spontaneous discharges). Reinnervation changes such as large-amplitude, long-duration, polyphasic motor unit potentials reflect chronicity. Abnormalities in paraspinal muscles (eg, spontaneous discharges) usually reflect disease in spinal nerve roots.
  
  
  

Procedures:

• Sural nerve biopsy is now rarely indicated in the diagnosis or longitudinal assessment of diabetic peripheral neuropathy (see Images 1-2). Reasons for this move away from biopsies in clinical trials include the invasive nature of the procedure with its attendant risks, discomfort to the patient, high cost, problems with reproducibility due to sampling error, and availability of other methods to obtain similar information.



• The following new diagnostic approaches for diabetic neuropathy are currently under intense study. Details of these techniques are beyond the scope of this review.


• • Skin punch biopsy/intraepidermal nerve fiber density testing and immunohistochemical staining of peripheral nerves
  
  
  
  • Quantitative sensory testing
  
  
  
  • Imaging using MRI and ultrasonography
  
  
  

A common staging scale of diabetic polyneuropathy follows.

• NO - No neuropathy



• N1a - Asymptomatic neuropathy detected as nerve conduction abnormality in at least 2 nerves



• N1b - N1a and abnormal neurologic examination



• N2a - Symptomatic mild diabetic polyneuropathy; sensory, motor, or autonomic symptoms; patient able to heel walk



• N2b - Severe symptomatic diabetic polyneuropathy (as in N2a, but patient unable to heel walk)



• N3 - Disabling diabetic polyneuropathy

TREATMENT

Section 6 of 12

Medical Care: Throughout this discussion on treatment, distinction is made between therapies for symptomatic relief and those that may slow the progression of neuropathy.

• General aspects of treatment
  • Consider any patient with clinical evidence of diabetic peripheral neuropathy to be at risk for foot ulceration and provide education on foot care. If necessary, a podiatry referral should be provided.

  • Patients with diabetic peripheral neuropathy require more frequent follow-up, with particular attention to foot inspection to reinforce the need for regular self-care. The provision of regular foot examinations and reinforcement of the educational message on foot care have been shown in several studies to have a major impact on rates of ulceration and even amputation.



• Current treatments for pain
  • Of all treatments, tight and stable glycemic control is probably the most important for slowing the relentless progression of neuropathy. Because rapid swings from hypoglycemia to hyperglycemia have been suggested to aggravate and induce neuropathic pain, the stability of glycemic control may be as important as the actual level of control in relieving neuropathic pain. The DCCT demonstrated that tight blood sugar control decreased the risk of neuropathy by 60% in 5 years.

  • Many medications are available for the treatment of diabetic neuropathic pain. These include tricyclic antidepressants, gabapentin, pregabalin, topical lidocaine, and duloxetine. Other medications such as carbamazepine, oxcarbazepine, phenytoin, lamotrigine, and opioids may also be used. Topical therapy with capsaicin or lidocaine patches may be useful in some patients, especially those with more localized pain. Any of these medications may be associated with side effects, and patients should be counseled on possible problems before initiating treatment.

  • Alternative and complementary therapies for pain (eg, acupuncture) are under investigation.



• Treatments for autonomic dysfunction
  • Until now, the main therapy for erectile impotence of nonvascular or nonpsychological origin has been the intracorporeal injection of vasoactive substances such as papaverine. Encouraging results have been presented for the oral agent sildenafil in the treatment of erectile dysfunction of diverse causes, including diabetes. Sildenafil is a potent and competitive inhibitor of type V cyclic guanosine monophosphate-specific phosphodiesterase enzyme, the predominant isoenzyme in human corpus cavernosum. Clinical trials of this agent in diabetes are currently underway.

  • Glycopyrrolate is an antimuscarinic compound that is the first specific treatment for diabetic gustatory sweating. When applied topically to the affected area, it results in a marked reduction in sweating while eating a meal.



• A number of medications to slow the progression of diabetic neuropathy are currently undergoing evaluation in clinical trials. Some are licensed for use in other countries.
  • Aldose reductase inhibitors (eg, alrestatin, sorbinil, tolrestat): Although numerous studies of aldose reductase inhibitors have been published in the past 30 years, none is currently available in the United States. Aldose reductase inhibitors block the rate-limiting enzyme in the polyol pathway that is activated in hyperglycemic states. Many earlier aldose reductase inhibitor trials had problems related to poor study design (eg, enrolling patients with advanced neuropathy who were unlikely to benefit from treatment). Clinical trials are ongoing.

  • Alpha-lipoic acid: Ziegler and colleagues conducted a multicenter placebo-controlled trial of the antioxidant alpha-lipoic acid in 382 patients with type 2 diabetes and symptomatic neuropathy. They reported short-term symptomatic relief. A more recent trial in autonomic neuropathy suggested that this agent also may have a beneficial effect in the natural history of autonomic dysfunction.

  • Gamma-linolenic acid: The first step in the metabolism of the essential fatty acid linolenic acid is impaired in diabetes, and this defect can be bypassed by administration of gamma-linolenic acid. Several studies have suggested clinical and electrophysiologic improvement in peripheral nerve function when gamma-linolenic acid is administered to patients with neuropathy. Further studies are needed.

  • NGF: Deficiencies in endogenous NGFs, which are trophic to sensory and autonomic nerve fibers, have been described in diabetic neuropathy. Treatment with exogenous NGF may be beneficial. Trials of parenteral NGF are ongoing.

Surgical Care: Pancreatic transplantation in patients with diabetes and end-stage renal disease can stabilize neuropathy and in some instances improve motor, sensory, and autonomic function for as long as 48 months after uremia plateaus.

MEDICATION

Section 7 of 12

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Tricyclic antidepressants -- This complex group of drugs has central and peripheral anticholinergic effects as well as sedative effects. They have central effects on pain transmission. They also block the active reuptake of norepinephrine and serotonin.

Drug Name	Amitriptyline (Elavil) -- By inhibiting reuptake of serotonin and/or norepinephrine by presynaptic neuronal membrane, may increase synaptic concentration in CNS. Useful as analgesic for certain types of chronic and neuropathic pain.
Adult Dose	10-25 mg/d PO hs Increase to 30-100 mg PO qhs over several wk as needed
Pediatric Dose	Children: 0.1 mg/kg/d PO hs and increase, as tolerated, over 2-3 wk to 0.5-2 mg/d hs Adolescents: 10-25 mg/d PO; increase gradually to 100 mg/d as needed
Contraindications	Documented hypersensitivity; MAOIs in past 14 d
Interactions	Metabolized by P-450 2D6 system, thus drugs that inhibit this enzyme system (eg, cimetidine, quinidine) may increase tricyclic levels; phenobarbital may increase metabolism, decreasing its effects; may block uptake of guanethidine, thus preventing its hypotensive effects; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients with cardiac conduction disturbances, cardiac arrhythmias, seizures, glaucoma, urinary retention history, hyperthyroidism, and renal or hepatic impairment; because of its pronounced effects in cardiovascular system, best to avoid in elderly persons

Drug Name	Nortriptyline (Pamelor, Aventyl HCl) -- Has demonstrated effectiveness in treatment of chronic pain; by inhibiting reuptake of serotonin and/or norepinephrine by presynaptic neuronal membrane, may increase synaptic concentration in CNS; pharmacodynamic effects such as desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors also appear to be involved in mechanisms of action.
Adult Dose	25 mg PO qhs and increase over several wk as needed; not to exceed 150 mg/d
Pediatric Dose	<25 kg: Not established 25-35 kg: 10-20 mg/d PO 35-54 kg: 25-35 mg/d PO >54 kg: Administer as in adults
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; MAOIs in past 14 d
Interactions	Cimetidine may increase levels; may increase PT in patients whose coagulation parameters have been stabilized with warfarin
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal or hepatic impairment, cardiac conduction disturbances, or history of hyperthyroidism

Drug Category: Anticonvulsants -- These agents likely have central and peripheral effects on pain modulation.

Drug Name	Gabapentin (Neurontin) -- Has properties common to other anticonvulsants and antineuralgic effects. Exact mechanism of action not known. Structurally related to GABA but does not interact with GABA receptors.
Adult Dose	100 mg PO tid; titrate dose upward prn
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids may reduce bioavailability significantly (administer > 2 h following antacid); cimetidine may reduce clearance, but this may not be of clinical significance; may significantly increase norethindrone levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe renal disease

Drug Name	Carbamazepine (Tegretol, Carbatrol, Epitol) -- Has antineuralgic effects; may depress activity of nucleus ventralis of thalamus or decrease synaptic transmission or summation of temporal stimulation, leading to neural discharge by limiting influx of sodium ions across cell membrane or other unknown mechanisms. Target blood serum concentration 4-12 mg/L.
Adult Dose	200 mg PO bid initial dose; increase gradually prn over 2 wk to 200 mg tid SR form: Therapeutic dose bid
Pediatric Dose	<6 years: 10-20 mg/kg/d PO initial dose; titrate dose prn 6-12 years: 100 mg PO bid initial dose; titrate dose prn >12 years: 200 mg PO bid initial dose; titrate dose prn
Contraindications	Documented hypersensitivity; bone marrow suppression; MAOIs within last 14 d
Interactions	Cyclosporine, oral contraceptives, TCAs, warfarin, phenytoin, doxycycline, neuroleptics, fentanyl, calcium channel blockers, macrolide antibiotics, isoniazid, cimetidine, lamotrigine, propoxyphene
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	MAOIs should be discontinued for minimum of 14 d before starting this medication; use cautiously in patients with history of cardiac damage or hepatic disease; blood cell abnormalities have been reported following this medication; may worsen primary generalized epilepsy or atypical absence seizures; 0.5-1% risk of spina bifida in children born to mothers who take carbamazepine during pregnancy

Drug Name	Phenytoin (Dilantin) -- May stabilize neuronal membranes and treat neuralgia by increasing efflux or decreasing influx of sodium ions across cell membranes in motor cortex during generation of nerve impulses. When serum level in or near therapeutic range, adjust dose in 30- to 50-mg increments. Small-dose increments may cause greater than expected increases in serum concentration (ie, Michaelis-Menten drug kinetics). Steady-state serum levels may take up to 3 wk to occur because half-life is concentration dependent.
Adult Dose	300 mg/d PO initial dose; adjust to maintain serum levels of 10-20 mg/L
Pediatric Dose	5 mg/kg/d PO bid
Contraindications	Documented hypersensitivity; heart block; sinus bradycardia
Interactions	Rifampin, cisplatin, vinblastine, bleomycin, folic acid, theophylline, and continuous NG feedings may decrease serum levels and effects; may decrease effects of oral contraceptives, itraconazole, mebendazole, methadone, oral midazolam, valproic acid, cyclosporine, theophylline, doxycycline, quinidine, mexiletine, and disopyramide; isoniazid, chloramphenicol, or fluconazole may increase serum concentrations; may increase warfarin effects and rate of conversion of primidone to phenobarbital, resulting in increased phenobarbital serum concentrations
Pregnancy	D - Unsafe in pregnancy
Precautions	Discontinue if rash or lymphadenopathy develops; caution in patients with hepatic dysfunction; is approximately 90% protein bound; during pregnancy or low albumin states, better to adjust PO dose to maintain free serum concentrations of 1-2 mg/L

Drug Name	Lamotrigine (Lamictal) -- Triazine derivative useful in treatment of neuralgia. Inhibits release of glutamate and inhibits voltage-sensitive sodium channels, which stabilizes neuronal membrane. Follow manufacturer's recommendation for dose adjustments.
Adult Dose	50-100 mg/d PO divided bid initial dose; 100-400 mg/d PO qd or divided bid maintenance; not to exceed 500 mg/d
Pediatric Dose	2-12 years Weeks 1-2: 0.6 mg/kg/d PO divided bid, rounded down to nearest 5 mg Weeks 3-4: 1.2 mg/kg/d PO divided bid, rounded down to nearest 5 mg Maintenance: 5-15 mg/kg/d PO; not to exceed 400 mg/d divided bid; to achieve usual maintenance dose, increase subsequent doses q1-2wk as follows: calculate 1.2 mg/kg/d and round down to nearest 5 mg; add this amount to previously administered daily dose >12 years Weeks 1-2: 50 mg/d PO Weeks 3-4: 100 mg/d PO divided bid Maintenance: 300-500 mg/d PO divided bid; to achieve maintenance, increase by 100 mg/d q1-2wk
Contraindications	Documented hypersensitivity
Interactions	Acetaminophen increases renal clearance, decreasing effects; phenobarbital and phenytoin increase metabolism, causing decrease in levels; concomitant valproic acid increases half-life
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with impaired renal or hepatic function

Drug Name	Pregabalin (Lyrica) -- Structural derivative of GABA. Mechanism of action unknown. Binds with high affinity to alpha2-delta site (a calcium channel subunit). In vitro, reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.
Adult Dose	50 mg PO tid initially; if needed, may increase to 100 mg tid within 1 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea with abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain, and peripheral edema; may elevate creatinine kinase level, decrease platelet count, and increase PR interval; doses >300 mg/d associated with higher rate of adverse effects and treatment discontinuation; decrease dose with renal impairment (ie, CrCl <60 mL/min)

Drug Category: Analgesics, topical -- Topical analgesics may provide localized, temporary pain relief.

Drug Name	Lidocaine (Anestacon, Dermaflex gel, Dilocaine, Lidoderm) -- Several recent studies have advocated topical administration of lidocaine as treatment of postherpetic neuralgia. Lidocaine gel (5%) in placebo-controlled study showed significant relief in 23 patients studied. Lidocaine tape also decreases severity of pain.
Adult Dose	Apply to affected area prn
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	For external or mucous membrane use only; do not use in eyes

Drug Name	Capsaicin cream (Dolorac, Capsin, Zostrix) -- Natural chemical derived from plants of Solanaceae family. By depleting and preventing reaccumulation of substance P in peripheral sensory neurons, may render skin and joints insensitive to pain. Substance P thought to be chemomediator of pain transmission from periphery to CNS.
Adult Dose	Apply to skin tid/qid for 3-4 consecutive wk and evaluate efficacy; not to exceed 4 applications per day
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; do not use on areas of broken or irritated skin
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid contact with eyes; do not bandage tightly; if condition worsens or symptoms persist for 14-28 d, discontinue use and consult physician; for external use only

Drug Category: Selective serotonin and norepinephrine reuptake inhibitors -- Potentiates serotonergic and noradrenergic activity in the CNS.

Drug Name	Duloxetine (Cymbalta) -- Indicated for diabetic peripheral neuropathic pain. Potent inhibitor of neuronal serotonin and norepinephrine reuptake.
Adult Dose	60 mg PO qd; may initiate with lower dose in patient unable to tolerate 60 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncontrolled narrow-angle glaucoma; do not administer within 14 d after stopping MAOI use or initiate MAOIs within 5 d after stopping duloxetine
Interactions	Metabolized by CYP1A2 and CYP2D6; coadministration with drugs that inhibit CYP1A2 (eg, fluvoxamine, cimetidine, ciprofloxacin, enoxacin) may increase duloxetine blood levels and toxicity; coadministration with drugs that inhibit CYP2D6 (eg, paroxetine, fluoxetine, quinidine) may increase duloxetine blood levels and toxicity; duloxetine moderately inhibits CYP2D6 and may decrease elimination of CYP2D6 substrates (eg, tricyclic antidepressants, phenothiazines [eg, thioridazine], type 1C antiarrhythmics [eg, propafenone, flecainide]); coadministration with MAOIs may cause serious, sometimes fatal reactions that include hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes including extreme agitation, delirium, and coma (see Contraindications)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Observe closely for clinical worsening and suicidality when initiating treatment or following dosage change; gradually decrease dose when discontinuing, do not abruptly discontinue; caution with hepatic impairment or end-stage renal disease; may cause slight blood pressure increase; may activate mania or hypomania; common adverse effects include nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating

FOLLOW-UP

Section 8 of 12

Deterrence/Prevention:

• The importance of protection and care of insensitive feet cannot be overemphasized. Patients should be instructed to trim their toenails with great care and to be fastidious about foot hygiene. Any fungal or bacterial infection mandates prompt medical attention. The need for well-fitting shoes should be stressed. In addition, lack of sensation makes insensitive feet more susceptible to damage from frostbite in winter, and patients should be counseled on proper foot wear and limiting activities in extreme cold.



• Diabetic polyneuropathy is usually associated with diabetic retinopathy and nephropathy. Patients with neuropathy should be counseled to seek appropriate eye care and discuss renal care and follow-up with their primary care physicians or endocrinologists.

Complications:

• The presence of neuropathy increases the risk of foot ulceration and infection, which in turn may lead to gangrene and the need for amputation.



• The economic burden of taking care of patients with diabetic neuropathy is huge.

Prognosis:

• Treating diabetic neuropathy is a difficult task for the physician and patient. Most of the medicines mentioned above do not lead to complete symptom relief. Clinical trials are underway to help in early diagnosis and better management.

Patient Education:

• Patient education should begin in the primary care office with discussion of the following issues:



• What is diabetic neuropathy?
  • Diabetic neuropathy is nerve damage caused by diabetes. Diabetic neuropathy is a specific type of peripheral neuropathy.

  • Diabetic neuropathy can also affect the nerves that regulate unconscious vital functions, such as heart rate and digestion. This type of problem is called autonomic neuropathy.



• How does diabetic neuropathy occur?
  • Doctors have been studying this problem for many years, but they do not yet understand exactly how diabetes damages the nervous system. However, they have observed that good control of blood sugar levels helps prevent diabetic neuropathy and slows its progression.



• What are the symptoms?
  • Symptoms of diabetic neuropathy may include the following:
    • Numbness or loss of feeling (usually in the feet and legs first, then the hands)

    • Pain ranging from minor discomfort or tingling in toes to severe pain: Pain may be sharp or lightninglike, deep and aching, or burning. Extreme sensitivity to the slightest touch can also occur (allodynia).

    • Muscle weakness.

  • Symptoms of autonomic neuropathy may include the following:
    • Low blood pressure and dizziness when rising quickly from sitting or lying down

    • Rapid or irregular heartbeats

    • Trouble having an erection

    • Nausea or vomiting

    • Difficulty swallowing

    • Constipation or diarrhea
    
    
  
  
  
  • How can I help prevent diabetic neuropathy?
    • The best way to help prevent diabetic neuropathy is to take the following actions:

    • Control diabetes. Try to keep blood sugar at a normal level.

    • Maintain normal blood pressure.

    • Exercise regularly, according to the healthcare provider's recommendation.

    • Stop smoking.

    • Limit the amount of alcohol intake because excessive alcohol also can cause neuropathy or make it worse.

    • Eat a healthy diet.

    • Keep follow-up appointments with the healthcare provider.
    
    
  
  
  
  • How is diabetic neuropathy treated?
    • No treatment is available to reverse neuropathy. The best approach is to control the diabetes.

    • Muscle weakness is treated with support, such as braces. Physical therapy and regular exercise may help patients maintain the muscle strength they have.

    • Pain-killing drugs or medications applied to the skin may help make pain more tolerable.

    • Medications can be used to treat nausea, vomiting, and diarrhea.

    • Men who have trouble having erections because of neuropathy should talk to their healthcare providers. Prosthetic devices can be put in the penis and medications can help a man achieve and maintain an erection

    • Preventing injuries such as burns, cuts, or broken bones is especially important, because patients with neuropathy have more complications from simple injuries and may not heal as quickly as healthy individuals.

  • For excellent patient education resources, visit eMedicine's Diabetes Center and Erectile Dysfunction Center. Also, see eMedicine's patient education articles, Diabetes, Impotence/Erectile Dysfunction, Erectile Dysfunction FAQs, and Nonsurgical Treatment of Erectile Dysfunction.



• How can I take care of myself?
  • Work with primary care physicians and endocrinologists to control glucose levels.

  • Look for injuries on the skin of feet and lower legs regularly.

  • See a healthcare provider promptly for calluses, sores on the skin, or other potential problems so they can be treated properly.

  • Wear good-fitting, comfortable shoes that protect the feet.



• How long will the problem last?
  • Once a patient has neuropathy, the symptoms will persist indefinitely.

  • Patients may be able to stop neuropathy from worsening by keeping blood sugar under good control.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Management of diabetic neuropathy should begin at the initial diagnosis of diabetes. The primary care physician is responsible for educating patients about the acute and chronic complications of diabetes.


• • Failure to diagnose diabetic polyneuropathy can lead to serious consequences, including disability and amputation.
  
  
  
  • Addressing the psychological impact of sexual dysfunction in both men and women is also a responsibility of the primary care giver.
  
  
  
  • The importance of involving a neurologist (preferably with expertise in peripheral neuropathy) in the treatment of patients with diabetic neuropathy cannot be overemphasized.
  
  
  

TEST QUESTIONS

Section 10 of 12

CME Question 1: What is the general prevalence of neuropathy among patients with diabetes?

A: 2%
B: 7%
C: 60%
D: 90%
E: 100%

The correct answer is C: Up to 65% of patients with diabetes (including types 1 and 2) have some type of neuropathy. In a cohort of Belgian patients, 7.5% of patients with newly diagnosed diabetes already had neuropathy.

CME Question 2: What is the most important factor in delaying the occurrence of diabetic neuropathy?

A: Supplemental vitamins
B: Foot care
C: Good glycemic control
D: Reducing fasting blood sugar levels
E: Reducing exposure to cold

The correct answer is C: The Diabetes Control and Complications Trial (DCCT) showed that tight glycemic control can delay the development of neuropathy and other diabetic complications.

Pearl Question 1 (T/F): The most common form of diabetic neuropathy is diabetic amyotrophy.

The correct answer is False: Distal symmetric polyneuropathy is the most common form of diabetic neuropathy.

Pearl Question 2 (T/F): Diabetes-related neuropathy is more common in men than in women.

The correct answer is True: Retrospective and cohort studies have demonstrated a higher incidence of diabetes-related neuropathy among men than among women.

Pearl Question 3 (T/F): Aldose reductase provides symptomatic relief for diabetic neuropathy.

The correct answer is False: Several trials have studied the effect of aldose reductase in treating patients with diabetic neuropathy, and the most accepted theory is that it slows the progression of the disease.

Pearl Question 4 (T/F): Diabetic neuropathy is more common in the Hispanic population than in other populations.

The correct answer is False: No race predilection has been observed for the disease.

PICTURES

Section 11 of 12

Caption: Picture 1. Lymphocytic inflammation of a small epineurial artery in a femoral cutaneous nerve biopsy from a 70-year-old man with type 2 diabetes, 4 months of weight loss, progressive asymmetric diabetic polyneuropathy, and electrophysiologic evidence of axonopathy. Hematoxylin and eosin stain, original magnification 200X.
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Caption: Picture 2. Sural nerve biopsy with a collection of lymphocytes around a small epineurial vessel.
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BIBLIOGRAPHY

Section 12 of 12

• Abbott CA, Vileikyte L, Williamson S, et al: Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 1998 Jul; 21(7): 1071-5[Medline].
• Apfel SC, Kessler JA, Adornato BT, et al: Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology 1998 Sep; 51(3): 695-702[Medline].
• Apfel SC: Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med 1999 Aug 30; 107(2B): 34S-42S[Medline].
• Ayad H: Diabetic neuropathy: classification, clinical manifestations, diagnosis and management. In: Baba S et al, eds. Diabetes Mellitus in Asia. Amsterdam: Excerpta Medica; 1977: 222-4.
• Boulton AJ, Malik RA: Diabetic neuropathy. Med Clin North Am 1998 Jul; 82(4): 909-29[Medline].
• Boulton AJ, Vinik AI, Arezzo JC, et al: Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005 Apr; 28(4): 956-62[Medline].
• Bromberg MB: Peripheral neurotoxic disorders. Neurol Clin 2000 Aug; 18(3): 681-94[Medline].
• Galer BS, Gianas A, Jensen MP: Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract 2000 Feb; 47(2): 123-8[Medline].
• Goetz CG, Pappert EJ: Textbook of Clinical Neurology. Philadelphia: WB Saunders Co; 1999.
• Greene DA, Arezzo JC, Brown MB: Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology 1999 Aug 11; 53(3): 580-91[Medline].
• Harati Y, Gooch C, Swenson M, et al: Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998 Jun; 50(6): 1842-6[Medline].
• Harati Y: Diabetes and the nervous system. Endocrinol Metab Clin North Am 1996 Jun; 25(2): 325-59[Medline].
• Krendel DA, Zacharias A, Younger DS: Autoimmune diabetic neuropathy. Neurol Clin 1997 Nov; 15(4): 959-71[Medline].
• Martin CL, Albers J, Herman WH, et al: Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care 2006 Feb; 29(2): 340-4[Medline].
• Meijer JW, van Sonderen E, Blaauwwiekel EE, et al: Diabetic neuropathy examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care 2000 Jun; 23(6): 750-3[Medline].
• Miller RD: Anesthesia. 5th ed. New York: Churchill Livingstone; 2000.
• O'Brien SP, Schwedler M, Kerstein MD: Peripheral neuropathies in diabetes. Surg Clin North Am 1998 Jun; 78(3): 393-408[Medline].
• Pirart J: Diabetes mellitus and its degenerative complication: a prospective study of 4,400 patient observed between 1947 and 1973. Diabetes Care 1978; 1: 168-188.
• Pourmand R: Diabetic neuropathy. Neurol Clin 1997 Aug; 15(3): 569-76[Medline].
• Skyler JS: Diabetic complications. The importance of glucose control. Endocrinol Metab Clin North Am 1996 Jun; 25(2): 243-54[Medline].
• Slovenkai MP: Foot problems in diabetes. Med Clin North Am 1998 Jul; 82(4): 949-71[Medline].
• Smith AG, Russell J, Feldman EL, et al: Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 2006 Jun; 29(6): 1294-9[Medline].
• Sugimoto K, Murakawa Y, Sima AA: Diabetic neuropathy--a continuing enigma. Diabetes Metab Res Rev 2000 Nov-Dec; 16(6): 408-33[Medline].
• Sumner CJ, Sheth S, Griffin JW, et al: The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003 Jan 14; 60(1): 108-11[Medline].
• Vinik AI, Park TS, Stansberry KB, Pittenger GL: Diabetic neuropathies. Diabetologia 2000 Aug; 43(8): 957-73[Medline].
• Waldman SD: Diabetic neuropathy: diagnosis and treatment for the pain management specialist. Curr Rev Pain 2000; 4(5): 383-7[Medline].
• Wilson JD: Williams Textbook of Endocrinology. 9th ed. Philadelphia: WB Saunders Co; 1998.
• Ziegler D, Reljanovic M, Mehnert H, Gries FA: Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes 1999; 107(7): 421-30[Medline].

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