eMedicine Specialties > Neurology > Neuromuscular Diseases

Diabetic Neuropathy

Dianna Quan, MD, Associate Professor of Neurology, Director, Electromyography Laboratory, University of Colorado Health Sciences Center

Updated: Oct 22, 2009

Introduction

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."¹ 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).² 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.³ Pathologically, numerous changes have been demonstrated in both myelinated and unmyelinated fibers.

For related information, see Medscape's Incretin Hormones in Diabetes and Metabolism and Diabetic Microvascular Complications Resource Centers.

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. Important contributing biochemical mechanisms in the development of the more common symmetrical forms of diabetic polyneuropathy likely include the following:

Polyol pathway

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.⁴

Advanced glycation end products (AGE)

The nonenzymatic reaction of excess glucose with proteins, nucleotides, and lipids results in advance glycation end products that may have a role in disrupting neuronal integrity and repair mechanisms through interference with nerve cell metabolism and axonal transport.⁵   

Oxidative stress

The increased production of free radicals in diabetes may be detrimental via several mechanisms that are not fully understood. These include direct damage to blood vessels leading to nerve ischemia and facilitation of AGE reactions. Despite the incomplete understanding of these processes, use of the antioxidant alpha lipoic acid may hold promise for improving neuropathic symptoms.⁶

Related contributing factors

Problems that are a consequence of or co-contributors to these disturbed biochemical processes include altered gene expression with altered cellular phenotypes, changes in cell physiology relating to endoskeletal structure or cellular transport, reduction in neurotropins, and nerve ischemia. Clinical trials of the best studied neurotropin, human recombinant nerve growth factor were disappointing. However, with future refinements, one or more of these mechanisms may provide reasonable targets for pharmacological intervention.

In the case of focal or asymmetrical diabetic neuropathy syndromes, vascular injury or autoimmunity may play more important roles.

Frequency

United States

A large American study estimated that 47% of patients with diabetes have some peripheral neuropathy.⁷ Neuropathy is estimated to be present in 7.5% of patients at the time of diabetes diagnosis. More than half of patients have distal symmetric polyneuropathy. Focal syndromes such as carpal tunnel syndrome (14-30%)⁸ , radiculopathies/plexopathies, and cranial neuropathies account for the rest. Solid prevalence data for the latter 2 less common syndromes is lacking.   

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

International

In a cohort of 4400 Belgian patients, Pirart et al found that 7.5% of patients already had neuropathy when diagnosed with diabetes.⁹ After 25 years, the number with neuropathy rose to 45%. In the United Kingdom, the prevalence of diabetic neuropathy among the hospital clinic population was noted to be around 29%.¹⁰ 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

Age

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

Clinical

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. Patients with type 2 diabetes mellitus may sometimes 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 may 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. In the most common presentation of diabetic neuropathy with symmetrical sensorimotor symptoms, minor weakness of the toes and feet may be seen, but severe weakness is uncommon and should prompt investigation into other causes, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), or vasculitis. More severe weakness may be observed in asymmetrical diabetic neuropathy syndromes (see Asymmetric neuropathies). 
  • 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, smoking, increased height, and high exposure to other potentially neurotoxic agents such as ethanol. Establishing the diagnosis requires careful evaluation since patients with diabetes may have neuropathy from another cause. Depending on the physician practices studied, this group may represent 10-26% of diabetic patients with neuropathy.^7,12  
• Symmetric polyneuropathies involve multiple nerves diffusely and symmetrically.
  • Distal symmetric polyneuropathy
    • Most common manifestation of diabetic neuropathy
    • Sensory, motor, and autonomic functions affected in varying degrees, with sensory abnormalities predominating
    • Chronic symmetrical symptoms affecting peripheral nerves in a length-dependent pattern (the longest nerves affected first). 
    • 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
    • Mild weakness of foot muscles and decreased ankle and knee reflexes occur commonly
    • Loss of sensation predisposes to development of foot ulcers and gangrene¹³
    • With impaired proprioception and vibratory perception, gait may be affected (sensory ataxia)
  • Small-fiber neuropathy
    • 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 glycemia 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.
    • Recovery may be incomplete and prolonged over many months
• Asymmetric neuropathies include single or multiple cranial or somatic mononeuropathies. Syndromes include median neuropathy of the wrist (carpal tunnel syndrome), single or multiple somatic mononeuropathies, thoracic radiculoneuropathy, lumbosacral radiculoplexus neuropathy, and cervical radiculoplexus neuropathy. 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, lumbosacral radiculoplexus neuropathy) 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.
    • Median nerve entrapment at the wrist (carpal tunnel syndrome) is more common in patients with diabetes and can be treated in the same manner as in patients without diabetes. Symptoms are often bilateral. The susceptibility to ulnar nerve entrapment at the elbow or common peroneal nerve entrapment at the fibular head is not definitely increased among patients with diabetes.
    • 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 thoracic radiculoneuropathy
    • 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 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).
    • 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 radiculoplexus neuropathy 
    • The syndrome may occur in the cervical or lumbosacral distributions and is referred to in the literature by various designations including diabetic amyotrophy, Bruns-Garland syndrome, and diabetic plexopathy, among others.
    • The most frequent initial symptom is sudden, severe, unilateral pain in the hip/lower back or shoulder/neck. Weakness then develops days to weeks later. Atrophy of the limb musculature may occur. Allodynia, paresthesias, and sensory loss are common. 
    • Symptoms usually begin unilaterally and may later spread to the opposite side.
    • Reflexes in the affected limb may be depressed or absent.
    • 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.
    • The course is generally monophasic with improvement over many months;  however, some residual deficits often remain.

Physical

• The first clinical sign that usually develops is decrease or loss of vibratory and pinprick sensation over the toes. As disease progresses, the level of decreased sensation may move upward into the legs and then into the hands and arms, a pattern often referred to as "stocking and glove" sensory loss. Very severely affected patients may lose sensation in a shield distribution on the chest. Deep tendon reflexes are commonly hypoactive or absent and weakness of small foot muscles may develop. More focal findings may be seen with injury to specific nerves as described above.
• Distal symmetrical sensorimotor polyneuropathy due to diabetes has been defined in many ways but a few criteria are commonly accepted.
  • The patient must have diabetes mellitus by one of the widely accepted definitions such as those outlined by the American Diabetes Association or World Health Organization.^14,15
  • The severity of polyneuropathy should be commensurate with the duration and severity of the diabetes. 
  • Other causes of sensorimotor polyneuropathy have been excluded.

Differential Diagnoses

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

Laboratory 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 function tests
  • 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
  • Anti-SSA and SSB antibodies
  • Rheumatoid factor
  • Paraneoplastic antibodies
• Patients with diabetic neuropathies likely have elevated hemoglobin A1c levels, but the test is useful to assess the adequacy of diabetes control. In some cases, especially with asymmetrical syndromes, the severity of the elevation does not always correlate with the severity of the nerve disease. A urinalysis is also helpful to screen for nephropathy and proteinuria.

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. Plexus MRI may be helpful to exclude other problems (eg, tumor) in patients with radiculoplexus neuropathy syndromes. For patients who cannot have MRI, CT myelogram is an alternative to exclude compressive lesions and other pathology in the spinal canal. 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. 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, 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 testing¹⁶ and immunohistochemical staining of peripheral nerves
  • Quantitative sensory testing
  • Imaging using MRI and ultrasonography

Staging

Different clinical neurological scales can be used to assess the severity of diabetic polyneuropathy.

A common staging scale of diabetic polyneuropathy is as follows:¹⁷

• NO - No neuropathy
• N1a - Signs but no symptoms of neuropathy
• 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

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.¹⁸ 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.¹⁹
• Current treatments for pain
  • Of all treatments, tight and stable glycemic control is probably the most important for slowing the progression of neuropathy.²⁰ 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 in patients with type 1 diabetes decreased the risk of neuropathy by 60% in 5 years.² The effect of tight glycemic control on polyneuropathy in patients with type 2 diabetes or those with impaired glucose tolerance/impaired fasting glucose is not as clear and requires further prospective study.
  • Many medications are available for the treatment of diabetic neuropathic pain. These include tricyclic antidepressants, gabapentin, pregabalin, duloxetine, topical lidocaine, and capsaicin. 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 or those in whom interactions with existing oral medications is a concern. Any of these medications may be associated with side effects, and patients should be counseled about possible problems before initiating treatment.²¹
  • Chou et al performed a meta-analysis of head-to-head trials comparing the results of gabapentin and tricyclic antidepressants for pain relief in diabetic neuropathy. They reported no difference between gabapentin and tricyclic antidepressants in the likelihood of achieving pain relief of diabetic neuropathy or postherpetic neuralgia.²²
  • Alternative and complementary therapies for pain (eg, acupuncture) are under investigation.²³
• Treatments for autonomic dysfunction
  • Until now, the main therapy for erectile dysfunction of nonvascular or nonpsychological origin has been the intracorporeal injection of vasoactive substances such as papaverine. The oral agent sildenafil and related phosphodiesterase type 5 (PDE5) inhibitors are now available for the treatment of erectile dysfunction of diverse causes, including diabetes. Sildenafil is a selective inhibitor of cyclic guanosine monophosphate-specific PDE5, the predominant isoenzyme in human corpus cavernosum.
  • 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 are currently undergoing evaluation in clinical trials. Some are licensed for use in other countries.
  • Aldose reductase inhibitors (eg, alrestatin, sorbinil, tolrestat, epralrestat): Although numerous studies of aldose reductase inhibitors have been published in the past 30 years, these inhibitors are not currently available in the United States.^24,25 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). Epralrestat is currently marketed only in Japan.
  • Alpha-lipoic acid: Ziegler and colleagues conducted a multicenter placebo-controlled trial of the antioxidant alpha-lipoic acid patients with type 2 diabetes and symptomatic neuropathy. They reported short-term symptomatic relief.⁶ Studies of this drug are ongoing.
  • Actovegin, a deproteinized hemoderivative of calf blood, contains inorganic substances (eg, electrolytes, trace elements) and organic components (eg, amino acids, oligopeptides, nucleosides, glycosphingolipids). Actovegin also contains inositol phospho-oligosaccharides (IPOs), which are thought to elicit central and peripheral insulin effects. In a multicenter, randomized, double-blind trial, the efficacy and safety of actovegin was evaluated in 567 patients with type 2 diabetes mellitus and diabetic polyneuropathy. Patients were randomized to receive 20 IV infusions of actovegin (2000 mg/d; n=281) or placebo (n=286) followed by actovegin 1800 mg/d PO or placebo for 140 days. Findings showed significant improvement in lower limb symptoms and sensory with sequential IV and oral actovegin compared with placebo.²⁶

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.¹⁹

Consultations

Patients with diabetic neuropathy should have regular monitoring by a primary care physician. Most patients benefit from consultation with an endocrinologist at periodic intervals, and those with more brittle diabetes may benefit from regular endocrinology consultations to assist in diabetes management. Patients with diabetes who develop neuropathy should see a neurologist early in the course of neuropathy. Patients who go on to develop neuropathy symptoms or signs that appear out of proportion to the severity of diabetes should be evaluated by a neurologist to help exclude other underlying causes of neuropathy.

Diet

Patients with diabetic neuropathy should work with nutritionists or their primary care physicians to develop a realistic diet for lowering blood glucose and minimizing large fluctuations in blood glucose.

Activity

Patients with diabetic neuropathy should be encouraged to remain as active as possible. However, those with significant sensory loss or autonomic dysfunction should be cautioned about exercising in extreme weather conditions, which may result in injury. For example, patients with extremity numbness may not be aware of frostbite injuries during prolonged cold exposure, or those with abnormal sweating may become easily overheated in hot conditions. In most cases, consultation with the patient's regular physician is reasonable before the initiation of a regular exercise program.

Medication

The pharmacologic agents listed below are used for the symptomatic treatment of diabetic neuropathy.

For related CME, see Medscape's CME Activity Treatment With Pregabalin May Reduce Pain of Diabetic Neuropathy. 

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.

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.

Dosing

Adult

10-25 mg/d PO hs
Increase to 30-100 mg PO qhs over several wk as needed

Pediatric

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

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

Contraindications

Documented hypersensitivity; MAOIs in past 14 d

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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

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.

Dosing

Adult

25 mg PO qhs and increase over several wk as needed; not to exceed 150 mg/d

Pediatric

<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

Interactions

Cimetidine may increase levels; may increase PT in patients whose coagulation parameters have been stabilized with warfarin

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; MAOIs in past 14 d

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, cardiac conduction disturbances, or history of hyperthyroidism

Anticonvulsants

These agents likely have central and peripheral effects on pain modulation.

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.

Dosing

Adult

100 mg PO tid; titrate dose upward prn

Pediatric

<12 years: Not established
>12 years: Administer as in adults

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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in severe renal disease

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.

Dosing

Adult

200 mg PO bid initial dose; increase gradually prn over 2 wk to 200 mg tid
SR form: Therapeutic dose bid

Pediatric

<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

Interactions

Cyclosporine, oral contraceptives, TCAs, warfarin, phenytoin, doxycycline, neuroleptics, fentanyl, calcium channel blockers, macrolide antibiotics, isoniazid, cimetidine, lamotrigine, propoxyphene

Contraindications

Documented hypersensitivity; bone marrow suppression; MAOIs within last 14 d

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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.

Dosing

Adult

300 mg/d PO initial dose; adjust to maintain serum levels of 10-20 mg/L

Pediatric

5 mg/kg/d PO bid

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

Contraindications

Documented hypersensitivity; heart block; sinus bradycardia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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

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.

Dosing

Adult

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

<2 years: Not established
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

Interactions

Acetaminophen increases renal clearance, decreasing effects; phenobarbital and phenytoin increase metabolism, causing decrease in levels; concomitant valproic acid increases half-life

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with impaired renal or hepatic function

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.

Dosing

Adult

50 mg PO tid initially; if needed, may increase to 100 mg tid within 1 wk

Pediatric

Not established

Interactions

May cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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)

Analgesics, topical

Topical analgesics may provide localized, temporary pain relief.

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.

Dosing

Adult

Apply to affected area prn

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

For external or mucous membrane use only; do not use in eyes

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.

Dosing

Adult

Apply to skin tid/qid for 3-4 consecutive wk and evaluate efficacy; not to exceed 4 applications per day

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; do not use on areas of broken or irritated skin

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

Selective serotonin and norepinephrine reuptake inhibitors

Potentiates serotonergic and noradrenergic activity in the CNS.

Duloxetine (Cymbalta)

Indicated for diabetic peripheral neuropathic pain. Potent inhibitor of neuronal serotonin and norepinephrine reuptake.

Dosing

Adult

60 mg PO qd; may initiate with lower dose in patient unable to tolerate 60 mg/d

Pediatric

Not established

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)

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

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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.
• 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 in the Medication section do not lead to complete symptom relief. Clinical trials are underway to help find new ways to treat symptoms and delay disease progression.

Patient Education

Patient education should begin in the primary care office. The following outline reviews some common questions and answers that can serve as a springboard for discussion. 

• What is diabetic neuropathy?
  • Diabetic neuropathy is nerve damage caused by diabetes. In the United States, diabetes is one of the most common causes of nerve damage, also known as peripheral neuropathy. Diabetic neuropathy can affect nerves that supply feeling and movement in the arms and legs. It can also affect the nerves that regulate unconscious vital functions such as heart rate and digestion.
• How does diabetic neuropathy occur?
  • Doctors have been studying this problem for many years, but they do not yet understand exactly how diabetes damages nerves. 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
    • 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 following steps may help to prevent or slow the worsening of diabetic neuropathy.
    • 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.
• 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.

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.

Miscellaneous

Medicolegal 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.

References

1. Boulton AJ, Malik RA. Diabetic neuropathy. Med Clin North Am. Jul 1998;82(4):909-29. [Medline].

2. Diabetes control and complications trial research group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. Sep 30 1993;329(14):977-86. [Medline].

3. Harati Y. Diabetes and the nervous system. Endocrinol Metab Clin North Am. Jun 1996;25(2):325-59. [Medline].

4. Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology. Aug 11 1999;53(3):580-91. [Medline].

5. Ryle C, Donaghy M. Non-enzymatic glycation of peripheral nerve proteins in human diabetics. J Neurol Sci. Mar 1995;129(1):62-8. [Medline].

6. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. Nov 2006;29(11):2365-70. [Medline].

7. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. Apr 1993;43(4):817-24. [Medline].

8. Perkins BA, Olaleye D, Bril V. Carpal tunnel syndrome in patients with diabetic polyneuropathy. Diabetes Care. Mar 2002;25(3):565-9. [Medline].

9. 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.

10. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. Feb 1993;36(2):150-4. [Medline].

11. Aaberg ML, Burch DM, Hud ZR, Zacharias MP. Gender differences in the onset of diabetic neuropathy. J Diabetes Complications. Mar-Apr 2008;22(2):83-7. [Medline].

12. Lozeron P, Nahum L, Lacroix C, Ropert A, Guglielmi JM, Said G. Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients. J Neurol. May 2002;249(5):569-75. [Medline].

13. 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. Jul 1998;21(7):1071-5. [Medline].

14. All About Diabetes. American Diabetes Association. Available at http://www.diabetes.org/about-diabetes.jsp. Accessed October 30, 2008.

15. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: A report of the World Health Organization and International Diabetes Federation. Geneva, Switzerland: WHO Press; 2006.

16. Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. Jun 2006;29(6):1294-9. [Medline].

17. Llewelyn JG, Tomlinson DR, Thomas PK. Dyck PJ and Thomas PK. Diabetic Neuropathies in Peripheral Neuropathy. Philadelphia: Elsevier Saunders; 2005:1951-91.

18. Slovenkai MP. Foot problems in diabetes. Med Clin North Am. Jul 1998;82(4):949-71. [Medline].

19. O'Brien SP, Schwedler M, Kerstein MD. Peripheral neuropathies in diabetes. Surg Clin North Am. Jun 1998;78(3):393-408. [Medline].

20. Skyler JS. Diabetic complications. The importance of glucose control. Endocrinol Metab Clin North Am. Jun 1996;25(2):243-54. [Medline].

21. Ziegler D. Treatment of diabetic neuropathy and neuropathic pain: how far have we come?. Diabetes Care. Feb 2008;31 Suppl 2:S255-61. [Medline].

22. [Best Evidence] Chou R, Carson S, Chan BK. Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: discrepancies between direct and indirect meta-analyses of randomized controlled trials. J Gen Intern Med. Feb 2009;24(2):178-88. [Medline].

23. Ahn AC, Bennani T, Freeman R, Hamdy O, Kaptchuk TJ. Two styles of acupuncture for treating painful diabetic neuropathy--a pilot randomised control trial. Acupunct Med. Jun 2007;25(1-2):11-7. [Medline].

24. Kawai T, Takei I, Tokui M, Funae O, Miyamoto K, Tabata M, et al. Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of N(varepsilon)-carboxymethyl lysine. J Diabetes Complications. Aug 26 2009;[Medline].

25. Schemmel KE, Padiyara RS, D'Souza JJ. Aldose reductase inhibitors in the treatment of diabetic peripheral neuropathy: a review. J Diabetes Complications. Sep 10 2009;[Medline].

26. [Best Evidence] Ziegler D, Movsesyan L, Mankovsky B, Gurieva I, Abylaiuly Z, Strokov I. Treatment of symptomatic polyneuropathy with actovegin in type 2 diabetic patients. Diabetes Care. Aug 2009;32(8):1479-84. [Medline].

27. Apfel SC. Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med. Aug 30 1999;107(2B):34S-42S. [Medline].

28. Apfel SC, Kessler JA, Adornato BT, et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology. Sep 1998;51(3):695-702. [Medline].

29. 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.

30. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. Apr 2005;28(4):956-62. [Medline].

31. Bromberg MB. Peripheral neurotoxic disorders. Neurol Clin. Aug 2000;18(3):681-94. [Medline].

32. Figueroa-Romero C, Sadidi M, Feldman EL. Mechanisms of disease: The oxidative stress theory of diabetic neuropathy. Rev Endocr Metab Disord. Dec 2008;9(4):301-14. [Medline].

33. Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract. Feb 2000;47(2):123-8. [Medline].

34. Goetz CG, Pappert EJ. Textbook of Clinical Neurology. Philadelphia: WB Saunders Co; 1999.

35. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. Jun 1998;50(6):1842-6. [Medline].

36. Krendel DA, Zacharias A, Younger DS. Autoimmune diabetic neuropathy. Neurol Clin. Nov 1997;15(4):959-71. [Medline].

37. Martin CL, Albers J, Herman WH, et al. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care. Feb 2006;29(2):340-4. [Medline].

38. Meijer JW, van Sonderen E, Blaauwwiekel EE, et al. Diabetic neuropathy examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care. Jun 2000;23(6):750-3. [Medline].

39. Miller RD. Anesthesia. 5^th ed. New York: Churchill Livingstone; 2000.

40. Pourmand R. Diabetic neuropathy. Neurol Clin. Aug 1997;15(3):569-76. [Medline].

41. Sugimoto K, Murakawa Y, Sima AA. Diabetic neuropathy--a continuing enigma. Diabetes Metab Res Rev. Nov-Dec 2000;16(6):408-33. [Medline].

42. Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. Jan 14 2003;60(1):108-11. [Medline].

43. Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia. Aug 2000;43(8):957-73. [Medline].

44. Waldman SD. Diabetic neuropathy: diagnosis and treatment for the pain management specialist. Curr Rev Pain. 2000;4(5):383-7. [Medline].

45. Wilson JD. Williams Textbook of Endocrinology. 9^th ed. Philadelphia: WB Saunders Co; 1998.

46. 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].

47. Zochodne DW. Diabetic polyneuropathy: an update. Curr Opin Neurol. Oct 2008;21(5):527-33. [Medline].

Keywords

diabetic polyneuropathy, diabetic amyotrophy, proximal diabetic neuropathy, mononeuropathy multiplex, diabetic autonomic neuropathy, distal symmetric sensorimotor polyneuropathy, painful diabetic neuropathy, generalized sensorimotor polyneuropathy of diabetes mellitus, diabetic peripheral neuropathy, peripheral neuropathies, chronic hyperglycemia, entrapment neuropathies, diabetic neuropathy, carpal tunnel syndrome, numbness, feeling of wearing gloves, lossof balance, electric shocklike feelings, hypersensitivity to touch, foot slapping, toe scuffing, postural lightheadedness, fainting, urinary urgency, urinary dribbling, urinary incontinence, nocturnal diarrhea, constipation

erectile impotence, ejaculatory failure, nighttime painful paresthesias, impaired proprioception, impaired vibratory perception, sensory ataxia, anhidrosis, bladder atony, unreactive pupils, painless electric tingling, snug bandlike sensation around ankles, snug bandlike sensation around feet, absent ankle jerk reflexes, proprioceptive sensory impairment, gait instability, orthostatic hypotension, resting tachycardia, loss of sinus arrhythmia, sluggish light reflex

diabetic neuropathic cachexia, median neuropathy of the wrist, MNW, ulnar neuropathy of the elbow, UNE, single somatic mononeuropathies, multiple somatic mononeuropathies, single monoradiculopathies, multiple monoradiculopathies, diabetic lumbosacral radiculoplexoneuropathy, DLSRPN, diabetic thoracolumbar radiculoneuropathy, DTLRN, diabetic autonomia, cranial mononeuropathy, anterior ischemic optic neuropathy, diabetic oculomotor cranial mononeuropathies, acute periorbital pain, facial neuropathy, mononeuritis multiplex

diabetic polyradiculopathy, thoracoabdominal neuropathy, lumbosacral radiculoplexopathy, thoracolumbar neuropathy, thoracoabdominal radiculopathy, thoracic radiculopathy, truncal neuropathy, asymmetric proximal motorneuropathy, diabetic femoral neuropathy, femorosciatic neuropathy, diabetic myelopathy, Bruhn-Garland syndrome, poorly controlled diabetes, acute painful neuropathy, chronic inflammatory demyelinating polyneuropathy, CIDP, diabetes mellitus-CIDP, demyelinating neuropathy, diabetic neuropathy

Contributor Information and Disclosures

Author

Dianna Quan, MD, Associate Professor of Neurology, Director, Electromyography Laboratory, University of Colorado Health Sciences Center
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
Disclosure: e-medicine Honoraria Other

Medical Editor

Milind J Kothari, DO, Professor and Vice-Chair, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Penn State Milton S Hershey Medical Center
Milind J Kothari, DO is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside
Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Emad Soliman, MD and Charles Gellido, MD to the development and writing of this article.

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