AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Neuropathies are the most common complication of diabetes mellitus (DM). Neuropathies related to DM affect up to 50% of patients both with type 1 and type 2 DM. Neuropathies also cause great morbidity because the symptoms severely decrease patients' quality of life (QOL). While the primary symptoms of neuropathy may be highly unpleasant, the secondary complications such as falls, foot ulcers, cardiac arrhythmias, and ileus are even more serious and can lead to fractures, amputations, and even death in patients with DM. Increasing evidence indicates that electrophysiologic, quantitative, and clinical measures of neuropathy can predict endpoints of morbidity.

Diabetic neuropathies are heterogeneous in type; thus, several classifications of diabetic neuropathy were created and recognized. A classification system by Thomas combines both anatomy and pathophysiology, is the most intuitive, and is presented below with a few modifications:

• Hyperglycemic neuropathy (acute)

• Generalized symmetric polyneuropathies
  • Sensory

  • Sensorimotor (chronic, symmetric)

  • Autonomic
    • Cardiovascular autonomic neuropathy

    • Gastrointestinal neuropathy

    • Genitourinary neuropathy

    • Sudomotor neuropathy

• Focal and multifocal neuropathies
  • Cranial

  • Proximal motor (amyotrophy)

  • Thoracic or lumbar radiculopathies

  • Focal limb (entrapment neuropathies)

• Superimposed chronic inflammatory demyelinating polyneuropathy (CIDP)

Understanding of the classifications becomes easier with a review of the anatomy of the peripheral nervous system. Peripheral neurons can be categorized broadly as motor, sensory, or autonomic.

• Motor neurons originate in the central nervous system (CNS) and then go to the anterior horn of the spinal cord. From the anterior horn, they exit the spinal cord (via ventral roots) and combine with other fibers to go through the brachial or lumbar plexuses and innervate their target organs through peripheral nerves.

• Sensory neurons originate at the dorsal root ganglia (which lie outside the spinal cord) and follow a similar course with motor neurons. Sensory neurons are subdivided into categories according to the sensory modality they convey (see the Table).

• Autonomic neurons consist of sympathetic and parasympathetic types. In the periphery, preganglionic fibers leave the CNS and synapse on postganglionic neurons in the sympathetic chain or in sympathetic ganglia.

Subdivisions of Sensory Neurons

Sensory neuropathy usually is insidious in onset and shows a stocking and glove distribution in the distal extremities. Sensorimotor neuropathy involves both sensory and motor function; pain, numbness, and paresthesias occur along with decreased strength and atrophy in the lower limb muscles. The feet of patients with DM often become insensate and are highly susceptible, not only to ulcers, but also to the Charcot foot (ie, a foot that loses its structure secondary to trauma and acute arthropathy, see Charcot-Marie-Tooth Disease) from frequent and multiple traumas. Autonomic neuropathy involves the cardiovascular system, gastrointestinal system, and the genitourinary system.

Diabetic amyotrophy affects the proximal lower extremities and leads to muscle atrophy and weakness. The focal and multifocal neuropathies can be separated into ischemic (presumed) and entrapment neuropathies. The ischemic focal neuropathies can occur after a single acute event of ischemia to a single blood vessel or group of blood vessels that serve a single nerve or group of nerves. Cranial nerve palsies, such as oculomotor neuritis and Bell palsy, are sudden and asymmetric and generally are self-limited.

Diabetic amyotrophy also can be classified under focal neuropathy because primarily the femoral nerve or upper lumbar plexus is affected. Entrapment neuropathies are more gradual in onset and usually are asymmetric. These disorders occur more frequently in the diabetic population than in the general population. Entrapment neuropathies include carpal and cubital tunnel syndromes and meralgia paresthetica. The Table above demonstrates that the smaller fibers are affected first in DM, and with continued exposure to hyperglycemia, the larger fibers become affected.

Pathophysiology

The cause of diabetic neuropathy continues to be studied in both basic and clinical sciences. Thus far, diabetic neuropathy is known to be multifactorial and there is a large basis for prevention. Both basic science research and large prospective clinical studies, such as the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetic Study (UKPDS) have shown that tight glucose control and euglycemia (or near euglycemia) can prevent the onset or slow progression of diabetic neuropathy.

Currently, the factors recognized in the pathogenesis of diabetic neuropathy are metabolism, vascular insufficiency, loss of growth factor trophism, and autoimmune destruction of small unmyelinated nerves (C fibers) in a visceral and cutaneous distribution. The 2 main features that explain symptoms and complications of diabetic neuropathy are believed to be the degeneration of nerve fibers and grossly diseased blood vessels that supply those nerve fibers. Proper circulation determines whether or not nerve fibers repair themselves or proceed to total degeneration.

Metabolic failure can affect several pathways, greatly contributing to diabetic neuropathy. Hyperglycemia causes several biological changes, including an increase in the production of advanced glycosylated end products, a defect in the polyol pathway and involvement of aldose reductase enzyme, and impaired resistance to oxidative stress. All the above biological changes are closely related and work together to initiate the neuropathic complications.

Glucose is converted to sorbitol in cells by the aldose reductase enzyme. In hyperglycemia, sorbitol accumulates and results in the swelling of cells and increased activity of protein kinase C, which is implicated in the damage of blood vessels related to increasing basement membrane synthesis and vascular permeability. This sorbitol accumulation also results in a decrease in the intracellular levels of myoinositol (an important membrane component) and taurine to the extreme that they become rate limiting for intracellular metabolism. Nonspecific glycosylation of axon and microvessel proteins may cause reduction of endoneural blood flow and nerve ischemia, causing nerve and ganglia hypoxia and oxidative stress.

Derangement of the polyol pathway and vascular ischemia converge through oxidative stress. The conversion of glucose to sorbitol and sorbitol to fructose results in the depletion of reduced nicotinamide adenine dinucleotide (NADPH) and oxidized nicotinamide adenine dinucleotide (NAD⁺) stores in the cell, making the cell more vulnerable to reactive stresses. Ischemia induces reactive oxygen species, so the increase in these and the increase in vulnerability cause nerve injury. These processes are the basis of antioxidant therapy.

Another factor involved in the pathogenesis of diabetic neuropathy is the need for nerve regeneration after injury. Recent studies have suggested that loss of neurotrophic support contributes to the pathogenesis. Neurotrophic factors are proteins that promote the development, survival, and maintenance of specific neuronal populations. Sensory neuropathy involves the smallest nerve fibers (ie, C fibers). These small nerve fibers are supported by neurotrophic factor and nerve growth factor (NGF); hence, there is active research on this factor. Several studies have demonstrated that levels of NGF are reduced significantly and its action is impaired.

Other factors implicated in diabetic neuropathy are neurotrophin-3 and insulin growth factors. Autoimmune damage has been postulated, and one study demonstrated that serum autoantibodies against sulfatide and phospholipid in patients with type 2 DM were higher in patients with documented neuropathy than in those with no neuropathy. In summary, the etiology of neuropathy is multifactorial. Therapy for patients with diabetic neuropathy needs to encompass these factors to increase the yield of a successful treatment.

Frequency

United States

Diabetic neuropathy occurs in 10-20% of patients newly diagnosed with DM, and its prevalence is up to 50% in elderly patients with DM. Most studies agree that the overall prevalence of symptomatic diabetic neuropathy is approximately 30% of all patients with DM. The incidence of diabetic neuropathy is 2% of the general population. Diabetic neuropathy is more common in smokers, people older than 40 years, and those who have uncontrolled DM.

International

Diabetic neuropathy is found around the world in 20-30% of individuals with type 2 DM. This number depends on the type of fiber that is being sensed and the sensitivity of the measure. Individuals with type 1 DM usually develop neuropathy after more than 10 years of living with DM.

Mortality/Morbidity

Mortality increases in people with cardiovascular autonomic neuropathy (CAN). The overall mortality rate over periods up to 10 years was 27% in patients with DM and CAN detected, compared to a 5% mortality rate in those without evidence of CAN. Morbidity results from foot ulceration and lower extremity amputation. These 2 complications are the most common causes of hospitalization among people with DM in Western countries. Severe pain, dizziness, diarrhea, and impotence are common symptoms that decrease the QOL of a patient with DM.

Race

Members of minority groups (eg, Hispanics, African Americans) have more secondary complications from diabetic neuropathy, such as lower extremity amputations, than whites. They also have more hospitalizations for neuropathic complications.

Sex

DM affects men and women with equal frequency. Neuropathic pain causes more morbidity in females than in males.

Age

Diabetic neuropathy is more common in elderly patients. Up to 50% of patients with type 2 DM have peripheral neuropathy.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Diabetic neuropathy is more common in patients with a longer duration of DM. Symptoms can vary significantly based on the type of neuropathy.

• Patients with the most common neuropathy, generalized sensorimotor peripheral neuropathy, most often report symptoms related to altered sensation in the distal feet or hands. The most common words used to describe the symptoms are pain, numbness, and pins and needles (ie, paresthesia). The distribution of symptoms is stronger distally and less proximally and is termed a glove-stocking distribution. The symptoms include the following:
• • Dysesthetic pain in the hands and feet
    • Burning sensations

    • Skin tingling

    • Allodynia - Painful sensation on contact with something that typically would not hurt (eg, bed sheets)

    • Hyperalgesia - Abnormally exaggerated response to painful stimuli
  • Paresthetic pain
    • Sensation of pins and needles

    • Electric shock–like sensation

    • Numbness and aching

    • Knifelike pain

    • Sensation like feet have been in ice water

    • Shooting and lancinating pain
  • Muscular pain (much less common)
    • Dull ache

    • Night cramps

    • Bandlike sensation

    • Drawing sensation

    • Deep aches

    • Spasms

    • Toothachelike pain

• Patients with generalized autonomic neuropathies may report ataxia, gait instability, or near syncope/syncope. Also, autonomic neuropathies have further symptoms that relate to the anatomic site of nerve damage.
• • Gastrointestinal neuropathy
    • Dysphagia

    • Abdominal pain

    • Nausea/vomiting

    • Malabsorption

    • Fecal incontinence

    • Diarrhea

    • Constipation
  • Cardiovascular autonomic neuropathy
    • Persistent sinus tachycardia

    • Orthostatic hypotension

    • Sinus arrhythmia

    • Decreased heart variability in response to deep breathing

    • Valsalva maneuver

    • Near syncope upon changing positions from supine to standing
  • Bladder neuropathy (must differentiate from prostate or spine disorders)
    • Poor urinary stream

    • Feeling of incomplete bladder emptying

    • Straining to void
  • Sudomotor neuropathy
    • Heat intolerance

    • Heavy sweating of head, neck, and trunk with anhidrosis of lower trunk and extremities

    • Gustatory sweating

• Mononeuropathy may involve the following:
• • Cranial nerves III (oculomotor), VI (abducens), and IV (trochlear)
  • Diplopia and eye pain
  • Third nerve palsy (pupil usually spared when secondary to diabetic neuropathy)
  • Seventh nerve palsy
  • Bell palsy

Physical

Physical examination of patients with suspected distal sensory motor or focal (ie, entrapment or noncompressive) neuropathies should include at least the following:

• Peripheral neuropathy
• • Gross light touch and pinprick sensation
  • Distal proprioception
  • Reflexes (ankle)
  • Vibratory sense (128-Hz tuning fork) at base of great toenail and monofilament (5.07) to test larger sensory fibers: Inability to perceive the 128-Hz tuning fork or to feel a 10-g (5.07) monofilament on the plantar surfaces of the foot identifies patients who are at increased risk (ie, 60% in next 3 y) of developing a foot ulcer. The 2 tests should be performed at least every year.
  • Dorsal pedal and posterior tibial pulses
  • Skin examination for dryness, tinea pedis, cracks, onychomycoses, foot deformities, acute erythema and tenderness, and fluctuance under calluses
  • Tinel testing
  • Strength testing and examination for distal intrinsic extremity muscle atrophy
  • Cranial nerve testing
  • Heel-toe walk

• Autonomic neuropathies: In 2001, Perkins et al described a number of simple screening tests in outpatient clinics and validated a scoring system to document and monitor neuropathy in the clinic. In 2002, Dyck et al described case report forms for recording symptoms and signs of neuropathy that might be useful in longitudinal follow-up of individual patients.
• • Blood pressure and heart rate: Measure blood pressure and heart rate while the patient is supine and standing.
  • Sinus arrhythmia (SA) ratio: Have the patient breathe 6 times per minute while monitoring the heart rate in a continuous strip. Measure the longest R-R interval during expiration and the shortest R-R interval during inspiration. Take the average of 6 breaths. The SA ratio is R-R expiration/R-R inspiration. The normal response is 1:2.
  • Romberg sign testing
  • Gait analysis

Causes

Risk factors that are associated with more severe symptoms include the following:

Poor glycemic control

• Advanced age
• Hypertension
• Long duration of DM
• Dyslipidemia
• Smoking
• Heavy alcohol intake
• HLA-DR3/4 phenotype
• Tall height

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Peripheral neuropathy

Pernicious anemia
Vitamin B-6 intoxication
Alcoholism
Uremia
Chemical toxins
Nerve entrapment and compression of benign etiology
Hepatitis
Idiopathic
Congenital (various hereditary sensory motor neuropathies)
Paraneoplastic syndrome
Syphilis
HIV/AIDS
Medication (chemotherapy, eg, isoniazid)
Spine disease (eg, radiculopathy, stenosis, arteriovenous [AV] fistula)

Cardiovascular autonomic neuropathy (in addition to some listed above)

Myocardial infarction
Neuropathic arrhythmias (eg, Wolfe-Parkinson–White syndrome, sick sinus syndrome)
Volume depletion
Drugs

Gastrointestinal neuropathy

Gastrointestinal malignancy
Peptic ulcer disease
Postsurgical vagotomy
Electrolyte imbalance

Bladder dysfunction

Bladder outlet obstruction
Prostate cancer
Spinal cauda equine syndrome

Mononeuropathies

Vasculitides
Acromegaly
Coagulopathies
Hypothyroidism

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Fasting plasma glucose and hemoglobin A1c - Represent the most important screening tools; the follow-up is glycemic control
• Three-hour glucose tolerance test - May be more sensitive in borderline cases
• Complete blood cell count
• Hematology screen to check for anemia
• Sequential multiple analysis-7 (SMA7) to check renal function and electrolyte imbalances
• Screening examinations to rule out other etiologies - Antinuclear antibodies (ANA), rheumatoid factor (RF), C-reactive protein (CRP), serum protein electrophoresis (SPEP), rapid plasma reagin (RPR), vitamin B-12, folate, thyrotropin, genetic screens

Imaging Studies

• Imaging studies rarely help the physician diagnose or manage diabetic neuropathy. The following studies can be considered:
• Scintigraphic techniques
• • Scintigraphic techniques are used to detect and quantify CAN (for research purposes).
  • Techniques include radiolabeled analogs of norepinephrine, 123I-metaiodobenzylguanidine (MIBG), and 11C-hydroxyephedrine.
  • Adrenergic nerve terminals of the heart actively take up these compounds. Combining this technique with single-photon emission computed tomography (SPECT) scanning allows detection of decreased innervation of the heart.

• Laser Doppler: Skin blood flow is measured by continuous laser Doppler assessment in response to several stimuli.
• Microdialysis: Probes are inserted into the dermis (with an ISO-NO Mark II oxide meter, a microsensor that measures nitric oxide release from single cells).

Other Tests

• Nerve conduction studies (NCS) and electromyography (EMG) can document the characteristics of the neuropathy (eg, axonal, demyelinating) and the localization (eg, mononeuropathy versus radiculopathy or distal neuropathy) and, possibly, the severity and even prognosis for morbidity.
• • Multiple consensus panels recommend the inclusion of electrophysiologic testing in the evaluation of diabetic neuropathy.
  • These same panels recommend the use of nerve conduction velocity (NCV)/EMG procedures in clinical research studies.
  • An appropriate array of electrodiagnostic tests includes both nerve conduction testing and needle EMG of the most distal muscles usually affected.
    • Conventional NCV testing includes measurement of the speed of both motor and sensory conduction. The amplitude of the distal response is also measured. The proximal component of conduction can be investigated with H-reflex (S1 root) or F-wave (motor pathways only) response.

    • Needle EMG is performed in the distal muscles in cases of generalized neuropathy and entrapment, in the proximal limb muscles in amyotrophy, and in the paraspinal and limb muscles in suspected radiculopathy. The examiner searches for abnormal spontaneous potentials, voluntary motor unit recruitment, and motor unit configuration. Often, the recruitment characteristics can help distinguish a neuropathic from a myopathic process in weak patients.
  • Some studies have proposed that the severity of electrophysiologic abnormalities not only correlates with symptoms but also predicts the level of morbidity related to DM. Most authors suggest the NCV results to be stable or worsening over time; however, in 1998, Tkac found that the NCV levels could improve with glycemic control.
  • Quantitative sensory testing (QST) may be performed for pure autonomic neuropathies using Semmes-Weinstein monofilament. In the diabetic population, vibration, thermal, and pain thresholds have proven valuable in the detection of subclinical neuropathy, in tracking the progression of neuropathy in clinical studies, and in predicting patients at risk for foot ulceration.

• Electrocardiography may reveal prolongation of the QT interval. This is secondary to imbalance between right and left sympathetic innervation. This abnormality is thought to increase risk of arrhythmias.

Procedures

• A nerve biopsy can be obtained, typically of the sural nerve, to confirm and help diagnose the neuropathic stage (ie, mild, moderate, severe). However, this is an invasive procedure and carries the risk of producing a chronic neuropathic pain syndrome of pain, numbness, and cold insensitivity in the distribution of the sural nerve. Thus, with NCV/EMG and QST available, the sural nerve biopsy is rarely needed for diagnostic purposes any longer.
• A skin biopsy can be obtained for research purposes only.
• • Immunohistochemistry is used to quantify the cutaneous nerves to provide a morphologic assessment of diabetic neuropathies.
  • This tool is new for clinical research, and it is used as an endpoint in diabetic neuropathy.
  • The procedure only requires a 3-cm skin biopsy and enables a direct study of small nerve fibers (ie, C-fibers) that produce pain and temperature sensation.

Histologic Findings

Biopsy rarely is recommended for clinical purposes. This study is performed primarily when the etiology of the neuropathy is in question or in research settings. Several studies have looked at biopsies, mainly of the sural nerve in humans. These studies were performed in advanced neuropathy, and vessels were found to be thickened, and nerves were found to have undergone severe damage. Indications of nerve regrowth were small and weak.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Rehabilitation Program

Physical Therapy

Physical therapy may be a useful adjunct to other therapy, especially when muscular pain and weakness are a manifestation of the patient's neuropathy. The physical therapist can instruct the patient in a general exercise program to maintain his or her mobility and strength.

The patient also should be educated on independent pain management and relaxation strategies to assist with pain control. Transcutaneous electrical nerve stimulation (TENS) may be a recommended modality for patients with neuropathic pain, and the physical therapist can be helpful in teaching and monitoring the patient in its use. In a 1999 case report, Somers and Somers found that application of TENS to the skin of the lumbar region was an effective treatment for the pain of diabetic neuropathy, but there are no controlled studies to confirm this finding.

In cases of foot ulcers, physical therapy may be indicated for wound care. Treatments may consist of whirlpool, Unna boots (if necessary, although not commonly used), and debridement.

For patients with autonomic neuropathy, balance training and fall prevention education is paramount.

An aquatic therapist can also be helpful.

Brace assessment and orthotic or prosthetic training is useful when appropriate.

Walking aid assessment and implementation may be necessary.

Occupational Therapy

Occupational therapy may be necessary in cases where there is severe loss of functional status. When the lower limbs are involved only, patients may need home modifications and equipment

When the upper limbs are involved, patients may need more extensive functional restoration and adaptive equipment.

When a person loses a limb because of secondary complications even more intensive functional retraining is required.

Speech Therapy

Involvement of a speech therapist rarely is indicated, but professionals from this discipline can help with patients affected by gastroparesis or dysphagia.

Recreational Therapy

A recreational therapist may help the patient with performance of community activities. Many patients with chronic disease, especially elderly patients, become isolated and are at risk for comorbid conditions such as depression.

Medical Issues/Complications

Important secondary complications of diabetic neuropathy are foot ulcers and leg amputations. When a foot ulcer shows signs of infection (eg, thick yellow drainage, erythema around the wound, fever, necrotic tissue), the patient often fares much better by being admitted to a hospital, having the extent of infection assessed (eg, with MRI), and receiving IV antibiotics and foot debridement (if necessary). Intravenous antibiotics should have broad coverage for aerobic bacteria, and if the foot ulcer is chronic or recurrent, coverage should include anaerobes as well.

Surgical Intervention

Surgery is indicated in the following cases:

• In cases where infection is not controlled in foot ulcers, either an aggressive debridement or an amputation may be necessary if signs of necrosis or infection do not improve with IV antibiotics.
• In cases of intractable gastroparesis (ie, severe nausea and vomiting, severe weight loss), a jejunostomy may be performed to feed the patient nutrients by bypassing the paralytic stomach.
• When impotence is a continual problem, the patient may pursue the option of a penile prosthesis.
• A Charcot joint occurs when the denervated joint becomes deformed when surrounding bone develops osteoporosis. Treatment consists of bracing, placing the joint in a boot, and if necessary, surgery to correct the deformity.

Consultations

• Physical medicine and rehabilitation physicians provide a functional-based comprehensive evaluation and treatment program for patients with diabetic neuropathy.
• Ulcer management may warrant consultation with a specialist at a wound clinic or perhaps a vascular surgeon.
• Consultation with a neurologist should be recommended for any neuropathy that is not managed quickly by the primary care physician. Additionally, particularly complex cases should be referred for in-depth laboratory testing (often genetic testing).
• A cardiologist should monitor patients who have electrocardiographic abnormalities and/or suggestion of CAN.
• A gastroenterologist can monitor patients with intractable GI problems, such as gastroparesis and diarrhea, as well as in the following instances:
• • A question remains relative to the diagnosis.

  • The patient does not tolerate first-line medications.

  • Even with glycemic control, the patient continues to experience severe neuropathy.

Other Treatment

Most often, further treatment depends on the severity of pain symptoms the patient presents with. Simple injections are typically of no benefit. Some case reports suggest that neuromodulation may be an option in particularly refractory cases.

Many health care professionals have produced testimonials that various unproven treatments such as laser or vibratory stimulator treatments are helpful, but controlled studies are necessary.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Diabetic neuropathy can be grouped into 3 specific categories (ie, painful peripheral neuropathy, cardiovascular autonomic neuropathy, diabetic enteropathy) to simplify treatment. Based on the category, an appropriate treatment regimen can be implemented.

In painful peripheral neuropathy, the acute phase typically occurs in people with intermediate duration of DM. The condition has an acute onset and has a duration of less than 12 months. This acute phase usually is self-limited.

The first line of therapy for this type of neuropathy is tight glucose control and simple analgesics (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen).

Chronic painful neuropathy typically occurs in people with intermediate duration of DM. However, in these cases of neuropathic pain, simple analgesics are typically not effective. More often, neuropathic pain requires treatment with off-label medications. The primary approved uses for these medications include antidepressants, anticonvulsants, and antiarrhythmics.

Identifying the type of pain can direct the course of therapy. Dysesthetic pain (refer to symptoms in Clinical) can be relieved with capsaicin cream applied qid. The problem with this cream is that it may cause pain during the initial few applications; patients need to be made aware of this potential effect. Additionally, few patients comply with the frequent dosing, and the cream is messy on socks and shoes. Gabapentin also has been reported to work in the treatment of dysesthetic pain.

The next type of pain is paresthetic pain. Tricyclic antidepressants, such as imipramine and amitriptyline, have been shown to be efficacious in randomized controlled trials. Mexiletine, an orally active local anesthetic agent structurally related to lidocaine, also has been used with fair success in this kind of painful neuropathy. Carbamazepine and selective serotonin reuptake inhibitors (SSRIs) also have been used, but SSRIs seem to work only in patients with depression.

For patients with muscular pain, simple stretching exercises and proper footwear can help relieve pain. Occasionally, muscle relaxants may be of benefit in the first 2 weeks of therapy.

Each type of pain or a combination of pain types should be treated. Reevaluation of the painful neuropathy should be performed every 6 weeks. Every effort should be made to taper and eventually to stop therapies. Therapies may need to be reinstated at later dates if symptoms flare up.

The most important treatment is glucose control and achieving a near-euglycemic state. However, this state may be difficult to achieve in elderly patients.

Patients with autonomic dysfunction of the gastrointestinal tract are taught to eat very small meals several times a day. In severe cases, reducing the dietary fiber to near zero may improve symptoms. Medications for gastroparesis are Reglan and erythromycin.

Diabetic diarrhea is a diagnosis of exclusion and can be difficult to control. A high-fiber diet, along with diphenoxylate (Lomotil), loperamide (Imodium), or clonidine, can be helpful. Small bowel stasis contributes to bacterial overgrowth, causing diarrhea. Antibiotic treatment is recommended for a period of 2 weeks. Bacterial overgrowth does not have to be proven; it is prudent to treat the condition empirically. Doxycycline, amoxicillin, metronidazole, and ciprofloxacin are choices for the treatment of diabetic diarrhea secondary to bacterial overgrowth of the small intestine.

In cases of neurogenic bladder, voiding every 3-4 h, combined with bethanechol 10-50 mg tid/qid may relieve symptoms.

Symptomatic orthostatic hypotension can be troubling in patients with diabetic neuropathy. Increasing the patient's salt intake, along with use of compression stockings, may help. If these modalities do not improve symptoms, then fludrocortisone may help.

For diabetic impotence, several modalities may be used for treatment. Despite the choices, it is a very difficult condition to treat. All other causes of impotence must be excluded. Once the diagnosis has been confirmed, then drugs such sildenafil (Viagra) can be used (if not contraindicated in the patient), or older methods such as vacuum devices or intracavernosal papaverine injections may be tried. Referral to a urologist is suggested.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

For use in the acute phase of painful neuropathy, along with glucose control, or for use as first-line therapy of painful peripheral neuropathy.

Drug Category: Tricyclic antidepressants (TCAs)

TCAs are effective for paresthetic pain, such as the feeling of pins and needles, electricity, numbness, and achy knifelike shooting pains.

Drug Category: Antiepileptic drugs (AEDs)

The use of AEDs for the control of painful peripheral neuropathy has generated great interest as a potential therapy. These drugs have been found to have analgesic effects to neuropathic pain. The pharmacology of these drugs involves blocking channels and inhibiting specific neuronic components.

Drug Category: Selective serotonin reuptake inhibitors (SSRIs)

Recently Duloxetine became the first medication of any kind to be approved specifically for the treatment of diabetic neuropathy.

Serotoninergic antidepressants have had mixed reviews in the literature. Paroxetine and citalopram are reported to relieve painful sensory symptoms. Fluoxetine was found to relieve symptoms only in depressed patients.

Drug Category: Antiarrhythmic agents

Mexiletine and lidocaine have been used in this drug class. Some intractable neuropathic pain states have been shown to improve with administration of these agents.

Drug Category: Synthetic adrenocortical steroids

Florinef is used in severely symptomatic orthostatic hypotension. Use if salt tablets and pressure stockings fail to alleviate hypotension.

Drug Category: Prokinetic agents

Erythromycin, cisapride, and metoclopramide are used to treat diabetic gastroparesis. Additionally, MiraLAX (polyethylene glycol 3350) is gaining increasing popularity as the first-line agent for severe constipation and lower motor unit bowel.

Although a newer agent, tegaserod (Zelnorm), may be helpful in patients with chronic ileus, tegaserod was withdrawn from the US market on March 30, 2007. The withdrawal was prompted by an excess number of serious adverse cardiovascular events, including angina, heart attack, and stroke, in patients taking tegaserod, compared with those taking a placebo.
 
The market withdrawal came following analysis of safety data pooled from 29 clinical trials, involving more than 18,000 patients. In each study, patients were assigned at random to either tegaserod or a placebo. Tegaserod was taken by 11,614 patients, and a placebo, by 7,031 patients. The average age of patients in these studies was 43 years, and most patients (ie, 88%) were women. Thirteen patients treated with tegaserod (0.1%) had serious and life-threatening adverse cardiovascular effects; among these, 4 patients had a heart attack (1 died), 6 had unstable angina, and 3 had a stroke. Among the patients taking a placebo, only 1 (0.01%) had symptoms suggesting the beginning of a stroke, but these went away without complication. For more information, see the FDA MedWatch Product Safety Alert and Medscape Alerts: Marketing of Zelnorm Suspended.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit patients for an infected diabetic foot ulcer or gangrene.
• Admit for severe nausea or vomiting as a result of gastroparesis.

Further Outpatient Care

• Patients should be monitored every 4 weeks to 3 months to try to assess whether therapy is working to decrease pain or nausea or vomiting and also to taper off medications for painful peripheral neuropathy.
• Monitoring patients closely for their glycemic control is essential.
• Assess the patient's feet with monofilament and tuning fork on every visit when the patient comes in for his or her DM care.
• Objective measures of function and improvement should be taken at every visit.

In/Out Patient Meds

• Medications include NSAIDs, TCAs, AEDs, and serotonin-norepinephrine reuptake inhibitors (SNRIs) for painful diabetic neuropathy. The symptomatology should be assessed every 6 weeks so that side effects can be monitored if possible. Decrease or increase drug dose if indicated.
• Patients on Florinef should have their blood pressure monitored. Florinef can cause increases in blood pressure and edema from salt retention.
• Research is currently ongoing into not only medications that treat the painful symptoms of diabetes but also medications that can alter the progression of the disease. One such medication is epalrestat, a carboxylic acid derivative that inhibits aldose reductase, an enzyme of the sorbitol (polyol) pathway. Under hyperglycemic conditions, epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity and vibration threshold compared with baseline and placebo in patients with diabetic neuropathy. Subjective symptoms, including pain, numbness, hyperesthesia, coldness in the extremities, muscular weakness, dizziness, and orthostatic fainting, were also improved (Hotta, 2006).
• Pain medicine specialists have been experimenting with spinal cord stimulator implants in severely painful cases. One such study of 10 patients showed that median background and peak pain scores at the end of the study were, respectively, 77 and 81 with the stimulator off and 23 and 20 with the stimulator on. Exercise tolerance significantly improved at 3 months (n = 7, median % increase 85) and at 6 months. Further study is necessary (Daousi, 2005).

Deterrence

• Prevention of diabetic neuropathy is potentially best achieved by having near-euglycemic control from the onset of DM. Even with symptoms of diabetic neuropathy, controlling blood glucose to euglycemic levels reduces pain significantly. When a person has poor control and becomes euglycemic quickly, pain may be exacerbated (possibly an insulin effect), but this pain disappears in a few days.
• The bottom line for patients is that the medications are imperfect. Many result in no pain relief for certain patients. However, glucose control is something that the patient can achieve that may reduce pain.
• Controlling diet and nutrition are paramount to improving the secondary complications of diabetes, including neuropathy. Vitamin supplementation is being studied to see if that can have an impact. One study of zinc sulfide showed improvement in glycemic control in 60 patients. Certain B vitamins are often prescribed in an attempt to reduce paresthesias.

Complications

• Cardiovascular autonomic neuropathy can cause death.
• Peripheral neuropathy can lead to foot ulcers and leg amputations.
• Autonomic neuropathy is associated with dizziness and falling with associated injuries, nausea and vomiting, severe diarrhea, and dehydration, all of which can lead to hyperosmolar nonketotic diabetic coma or diabetic ketoacidosis and, hence, to death.

Prognosis

• In patients with diabetic peripheral neuropathy, the prognosis is good, but the patient's QOL is reduced.
• With cardiovascular autonomic neuropathy, there is a 27% increase in sudden death. The prognosis is not favorable.

Patient Education

• Patients with diabetic neuropathy need to be educated on all aspects of their condition, and they need to know that it is very much affected by poor glycemic control.
• Patients need to be taught proper foot care by a foot care specialist.
• For excellent patient education resources, see eMedicine's Diabetes Center and the patient education article Diabetic Foot Care.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Medicolegal pitfalls can arise from a clinician's failure to examine a patient's feet, to support good glycemic management, and to keep the patient informed of potential complications of diabetic neuropathy. Cases are in court currently in which physicians did not examine patients' feet and missed a sore/ulcer, and the patient lost a limb. Physicians are liable for missing such a complication, even if it is not reported by the patient. A physician should examine the feet of every patient with DM on every visit. Orthostatic blood pressure measurements should be performed in patients with chronic DM (ie, >10 y). An ECG should be performed, especially by the primary care physician, in patients with a long history of DM.
• Many of the medications physicians use for neuropathic pain are off-label. Many are in the news for questionable side effects and mood effects. They were approved by the Food and Drug Administration for one use and are being used for another. Multiple clinical studies show benefit for the use of these medications in the treatment of neuropathic pain. Use of these medications is well within the standard of care in most medical communities.
• Nonwhite and elderly populations are more susceptible to complications of diabetic neuropathy, so the physician should be more careful not to overlook anything in these groups of patients.

Special Concerns

• During pregnancy, prescribing medicine for pain control is difficult. The best hope for pain control in rare cases of young women with severe neuropathy is to control their blood glucose diligently and try to control pain with acetaminophen. Once the pregnancy lasts 9 months, the physician can prescribe Elavil, gabapentin, and other medications as indicated if the benefit clearly outweighs the risk to the fetus. Physical therapy may be effective in these patients by increasing their circulation.
• Diabetic neuropathy is rare in the pediatric population, but NSAIDs can be used in appropriate doses.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ando H, Takamura T, Nagai Y, et al. Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy. J Diabetes Complications. Nov-Dec 2006;20(6):367-70.
• Apfel SC. Diabetic polyneuropathy. Diabetes and Endocrinology Clinical Management. 1999.
• Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. Apr 2006;81(4 Suppl):S12-25.
• Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. Dec 2 1998;280(21):1831-6. [Medline].
• Bennett GJ, Dworkin RH, Nicholson B. Anticonvulsant Therapy in the Treatment of Neuropathic Pain. Neurology Treatment Update. 2000.
• Biaggioni I. Postural hypotension. In: Therapy for Diabetes Mellitus. American Diabetes Association;1998: 423-30.
• Bomholt SF, Mikkelsen JD, Blackburn-Munro G. Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain. Neuropharmacology. Feb 2005;48(2):252-63.
• Boulton A. Current and Emerging Treatments for Diabetic Neuropathies. Diabetes Reviews. 1999;7:379-86.
• Bril V. Electrophysiologic testing. In: Gries FA, Cameron NE, Low PA, Ziegler D, eds. Textbook of Diabetic Neuropathy. Struttgart, Germany:. Thieme Medical Publishers;2003:177-84.
• Calcutt NA, Dunn JS. Pain: Nociceptive and Neuropathic Mechanisms. Anesthesiology Clinics of North America. 1997.
• Carrington AL, Litchfield JE. The aldose reductase pathway and nonenzymatic glycation in the pathogenesis of diabetic neuropathy: a critical review for the end of the 20th century. Diabetes Reviews. 7:275-99.
• Coppini DV, Wellmer A, Weng C, et al. The natural history of diabetic peripheral neuropathy determined by a 12 year prospective study using vibration perception thresholds. J Clin Neurosci. Nov 2001;8(6):520-4. [Medline].
• Crouch J. Charcot's joint and bilateral foot neuropathy. Adv Nurse Pract. Mar 2005;13(3):18. [Medline].
• Daousi C, Benbow SJ, MacFarlane IA. Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabet Med. Apr 2005;22(4):393-8.
• Davidson MB. In: Diabetes Mellitus: Diagnosis and Treatment. 4th ed. 1998:297-307.