AUTHOR INFORMATION

Section 1 of 11

Authored by Fernando Dangond, MD, Associate Neurologist, Brigham and Women's Hospital; Assistant Professor, Department of Neurology, Harvard Medical School

Coauthored by Luis Carlos Sanin, MD, Professor, Department of Neurology, Universidad Javeriana Bogota, Colombia

Fernando Dangond, MD, is a member of the following medical societies: American Academy of Neurology, American Association for the Advancement of Science, American Association of Immunologists, and American Medical Association

Edited by Milind J Kothari, DO, Professor and Vice-Chair for Education and Training, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Hershey Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCar; Consulting Staff, Barnes Jewish Hospital; Selim R Benbadis, MD, Professor of Neurology, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine, Tampa General Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Fernando Dangond, MD
Editor's Email:	Milind J Kothari, DO

eMedicine Journal, April 10 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 11

Background: The term metabolic neuropathy includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders, among others. The common hallmark of these diseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation.

Diabetic mellitus is the most common cause of metabolic neuropathy, followed by uremia. Recognizing that some disorders involving peripheral nerves also affect muscles is important. This article reviews the general aspects of metabolic neuropathy; the reader is referred to other eMedicine articles on nutritional and diabetic neuropathy for more detailed information (see Differentials). This article mentions some aspects of diabetic neuropathy but does not discuss nutritional neuropathy.

Pathophysiology: Little is known about the mechanisms underlying metabolic peripheral neuropathy. As stated above, metabolic impairment causes demyelination or axonal degeneration.

Diabetic polyneuropathy

Although controversial, most studies suggest that diabetic polyneuropathy has a multifactorial etiology. Results from the Diabetes Control and Complications Trial (DCCT) demonstrated that hyperglycemia and insulin deficiency contribute to the development of diabetic neuropathy and that glycemia reduction lowers the risk of developing diabetic neuropathy by 60% over 5 years (Tamborlane and Ahern, 1997). Decreased bioavailability of systemic insulin in diabetes may contribute to more severe axonal atrophy or loss. Different levels of involvement of peripheral nerve are found in type 1 and type 2 diabetes, with milder compromise in type 2.

Studies in rats have demonstrated involvement of the polyol pathway. Myoinositol and taurine depletion have been associated with reduced Na⁺/K⁺-ATPase activity and decreased nerve conduction velocities (NCVs), all of which are corrected by aldose reductase inhibitors in rat studies. Recent studies have suggested that aldose reductase inhibitors may also improve NCVs and protect small sensory fibers from degeneration. Unfortunately, treatment with these agents so far has failed to show any significant benefits in humans.

Sural nerve biopsies from patients with diabetes have demonstrated changes suggestive of microvascular insufficiency, including membrane basement thickening, endothelial cell proliferation, and vessel occlusions. Rats with diabetes have been shown to have reduced blood flow to the nerves. Ischemia from vascular disease induces oxidative stress and injury to nerves via an increase in the production of reactive oxygen species. Some studies have suggested that antioxidant therapy may improve NCVs in diabetic neuropathy. These findings suggest that the metabolic and vascular hypotheses may be linked mechanistically.

Another mechanism in diabetic neuropathy is impaired neurotrophic support. Nerve growth factor (NGF) and other grow factors, such as NT3, IGF-I, and IGF-II, may be decreased in tissues affected by diabetic neuropathy. Other factors such as abnormalities in vasoactive substances and nonenzymatic glycation have demonstrated possible involvement in diabetic neuropathy development.

A glycoprotein called laminin promotes neurite extension in cultured neurons. Lack of expression of the laminin beta2 gene may contribute to the pathogenesis of diabetic neuropathy.

Recent studies suggest that microvasculitis and ischemia may play significant roles in development of diabetic lumbosacral radiculoplexoneuropathy.

A role for hypoglycemia has also been demonstrated; peripheral nerve damage has been demonstrated in insulinoma and in animal models of insulin-induced hypoglycemia.

Uremic polyneuropathy

In uremic polyneuropathy, conduction velocity slowing is believed to result from inhibition of axolemma-bound Na⁺/K⁺-ATPase by uremic toxins, leading to intracellular sodium accumulation and altered resting membrane potentials. Eventually, this results in axonal degeneration with secondary segmental demyelination.

Thyroid neuropathy

Little is known about thyroid neuropathy, but studies have shown microvascular and endoneurial ischemic involvement like that in diabetes. In rats with hypothyroidism, no significant changes of NCVs occurred 5 months after onset, but alterations in latencies in brainstem evoked potentials have been demonstrated. The earliest observation was the deposit of mucopolysaccharide-protein complexes within the endoneurium and perineurium, but these studies await confirmation. Reductions in myelinated fibers, mostly of large diameter, and Renaut bodies have been noted; other studies have shown axonal degeneration.

Rarely, hyperthyroidism may be associated with polyneuropathy.

Frequency:

• In the US: Diabetic neuropathy is the most common metabolic peripheral neuropathy. Because of differences in definition of diabetic peripheral neuropathy, epidemiologic studies reviewing an absence of symptoms have shown different results, varying from 5% to as high as 60-100%. In a large prospective study done by Pirart, the prevalence rose from 7.5% at the time of diagnosis to 50% after 25 years. Many patients with diabetes may have asymptomatic peripheral neuropathy; thus, the early use of neurophysiologic tests may help in clarifying the true incidence.

  The second most common metabolic neuropathy is that associated with uremia, with studies showing ranges of peripheral neuropathy prevalence of 10-80%. However, because uremia often presents in the setting of other systemic diseases associated with peripheral neuropathy, such as diabetes, prevalence studies are difficult to perform and interpret.

  Most peripheral neuropathies have in common greater severity with poorer control of the underlying disease. When the underlying disease is controlled properly, other causes of peripheral neuropathy, unrelated to the metabolic condition, must be considered.

Mortality/Morbidity: Metabolic neuropathies cause autonomic involvement, which can be so severe as to lead to sudden death. In patients with diabetes, it has been called the “death in bed syndrome,” but its real prevalence is not known. Another complication in diabetic neuropathy is the development of foot ulcers, and some reports have estimated that this occurs in approximately 2.5% of patients with diabetes.

Race: No significant differences in the incidence of metabolic neuropathy have been attributed to race.

Sex: Uremic neuropathy is more frequent in males than in females.

Age:

• Diabetic neuropathy may be more common in elderly patients. Milder diabetic neuropathy has been reported in type 2 diabetes, which most commonly affects the elderly population.

• Rarely, metabolic neuropathies are associated with congenital and hereditary causes and are more common in childhood (ie, inherited metabolic disorders, mitochondrial diseases).

CLINICAL

Section 3 of 11

History: Symptoms in metabolic neuropathy can reflect sensory, motor, or autonomic involvement.

• Patients usually complain of tingling and numbness (ie, paresthesias) and painful dysesthesias, worse at night. Motor and autonomic complaints are less common. Classifying the involvement of peripheral nerves is useful. Classification of metabolic neuropathy by topographic involvement, modified from Thomas and Tomlinson, is as follows:


• • Symmetric polyneuropathies
    • Sensory or sensorimotor polyneuropathy

    • Autonomic neuropathy
  
  
  
  • Focal and multifocal neuropathies
    • Entrapment neuropathies

    • Cranial neuropathy

    • Radiculopathy/plexopathy

    • Asymmetric lower limb motor neuropathy
  
  
  
  • Mixed forms
  
  
  
  • Symptoms of metabolic neuropathy according to this classification are as follows:
    • In symmetric polyneuropathy, initial symptoms begin insidiously and are most prominent distally in the lower extremities. Sensory disturbances exhibit a typical “length related pattern,” with involvement of the toes that advances to the feet and legs.

    • The upper limbs are affected more rarely; however, when upper limbs are involved, symptoms develop in the same pattern, with involvement of the fingers spreading to the hands and forearms in a glovelike pattern.

    • In advanced stages, sensory symptoms may involve the anterior part of abdomen and trunk (hence the term “trunk neuropathy”), leading sometimes to the erroneous diagnosis of myelopathy. In extreme cases, the vertex of the head may be affected.
  
  
  
• Sensory symptoms


• • Symptoms in most patients are mild in severity. However, when pain becomes severe, it presents with lancinating paresthesias and burning sensations that are typically worse at night.
  
  
  
  • Involvement of nerves by entrapment is common in metabolic neuropathies. Sensory symptoms such as pain and paresthesias along the distribution of the nerve and worsening at night are typical manifestations. The nerves most commonly involved are the median nerve (carpal tunnel syndrome [CTS]), ulnar nerve, and median and lateral plantar nerves (tarsal tunnel syndrome [TTS]). Multifocal sensory symptoms also suggest mononeuritis multiplex.
  
  
  
  • Pain described as “aching of the whole arm” is not uncommon in CTS. In TTS, paresthesias in the feet and pain are worse when walking. The presence of an entrapment neuropathy in children younger than 10 years is almost always suggestive of a rare metabolic disorder such as mucopolysaccharidosis or mucolipidosis or of hereditary neuropathy with liability to pressure palsy.
  
  
  
  • Metabolic neuropathy can cause injury to both large and small nerve fibers. Involvement of large fibers can cause alteration in vibration and proprioception and a sensory ataxia. Involvement of small fibers produces alteration in temperature perception or autonomic function. Small-fiber involvement can cause alteration in pain and temperature, leading to the so-called “pseudosyringomyelia.”
  
  
  
• Motor symptoms


• • Mild distal weakness is a common complaint, but patients also may experience proximal leg weakness, which is often asymmetric.
  
  
  
  • Asymmetric motor involvement in lower limbs is more common in patients with diabetes and is termed “amyotrophy.”
  
  
  
  • Motor weakness can be asymmetric and focal, suggesting the diagnosis of plexopathy; when painful, it suggests the presence of radiculoplexopathy.
  
  
  
  • Involvement of cranial nerves can cause signs and symptoms such as diplopia, facial drooping, lacrimation, dysgeusia, and facial pain.
  
  
  
• Autonomic symptoms: Clinical manifestations of autonomic neuropathy, modified from Thomas and Tomlinson, are as follows:


• • Pupillary and lacrimal gland dysfunction
    • Miosis

    • Disturbance of dilatation

    • Argyll Robertson pupil
  
  
  
  • Cardiovascular disturbances
    • Tachyarrhythmias and bradyarrhythmias

    • Postural hypotension

    • Asymptomatic myocardial infarction

    • Sudden death
  
  
  
  • Thermoregulatory disorders
    • Distal anhydrosis

    • Gustatory sweating

    • Abnormal vasomotor responses to temperature changes
  
  
  
  • Alimentary tract disorders
    • Esophageal atony

    • Gastric and duodenal atony

    • Gallbladder atony

    • Diarrhea, constipation

    • Colonic atony

    • Anal sphincter weakness

  • Genitourinary disturbances
    • Bladder atony

    • Retrograde ejaculation

    • Impotence

    • Female sexual dysfunction

    • Disturbances of respiratory control
  
  
  

Physical: In the general examination, checking for signs of autonomic dysfunction as described above is important if metabolic diseases are present. Also, determination of skin color changes is key; look for signs of adrenal insufficiency or the syndrome of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS). For signs of diabetic neuropathy, refer to the article Diabetic Neuropathy.

• Sensory findings


• • Symmetric distal sensory loss suggests polyneuropathy.
  
  
  
  • Asymmetric hypoesthesia in distal territories of multiple nerves suggests mononeuritis multiplex.
  
  
  
  • Allodynia is the perception that a sensory stimulus is painful.
  
  
  
  • Signs of entrapment include Tinel sign, in which percussion around the site of the median nerve in the wrist produces paresthesias in the first 4 digits, and Phalen sign, in which sustained flexion of the wrist causes paresthesias in the digits. These signs also may be triggered with percussion of the ulnar nerve at the wrist or elbow, at the fibular head (peroneal nerve entrapment), or at the posterior part of the internal malleolus (tibial nerve entrapment).
  
  
  
  • Altered perception of pain and temperature with a pseudosyringomyelia state suggests involvement of small fibers. Some patients experience loss of visceral pain sensation, which may manifest as painless myocardial infarction or loss of testicular sensation.
  
  
  
  • Foot ulceration is one of the most severe complications of diabetic neuropathy; it can lead to gangrene and result in the need for amputation.
  
  
  
  • Damage to large sensory fibers leads to loss of touch-pressure sensitivity, vibration and joint position sense, and tendon reflexes, with a resulting sensory ataxia. Patients may have postural instability, with sensory ataxia that is more prominent in lower limbs and with eyes closed (Romberg sign).
  
  
  
• Motor findings
  • Mild distal weakness may be noted in patients with sensory polyneuropathy. If any metabolic condition is accompanied by moderately severe to severe subacute weakness, consider other diagnoses, including chronic inflammatory demyelinating polyneuropathy (CIDP). This entity is more common in patients with diabetes than in the general population.

  • Asymmetric motor neuropathy, which is subacute painful asymmetric lower limb (rarely upper limb) weakness, is another motor abnormality that has received several names, including motor neuropathy, diabetic myelopathy, diabetic amyotrophy, femoral neuropathy, Burns-Garland syndrome, diabetic polyradiculopathy, proximal diabetic neuropathy and, perhaps the most adequate, diabetic lumbosacral plexus neuropathy.

  • Double-crush phenomenon: Simultaneous compromise of nerve roots and peripheral nerves by entrapment can be found in metabolic diseases.



• Cranial neuropathies: The most common finding in patients with diabetes is an isolated third nerve palsy without pupillary involvement. Less common is compromise of the sixth or seventh cranial nerve. These neuropathies are usually not painful and occur most commonly in elderly patients. Diabetes may involve the optic nerve and retina, causing diabetic retinopathy, which leads to blindness.



• The following table summarizes symptoms and signs of peripheral neuropathies.

  Symptoms and Signs of Neuropathy*
  
  

  Small-Fiber Sensory	Large-Fiber Sensory	Autonomic
  Burning pain	Loss of vibration	Heart rate changes
  Cutaneous allodynia	Proprioception loss	Postural blood pressure change
  Paresthesias	Loss of reflexes	Abnormal sweating
  Lancinating pain	Slowed NCVs	Gastroparesis
  Loss pain/temperature	Sensory ataxia	Impotence
  Foot ulcers	Weakness	Abnormal ejaculation
  Visceral pain loss

  
  

  * Modified from Apfel, 1999




• Uremia
  • Uremic polyneuropathy is usually subacute, sensorimotor, distal, and more prominent in the lower extremities. It commonly is associated with muscle cramps and the restless leg syndrome.

  • The earliest finding in uremic neuropathy is loss of ankle jerks or elevation of the vibratory sensation threshold. Assessing neuropathic changes in uremia is challenging because they also may be related to other factors, such as diabetes, vasculitis, or nutritional impairment.

  • The most common mononeuropathy in chronic renal failure is CTS, but mononeuropathies of ulnar or femoral nerves may be caused by compression by fistulas or dialysis catheters. Multiple cranial nerve neuropathies also have been reported in uremia.



• Thyroid neuropathy
  • Entrapment neuropathy of the median nerve is the most common neuropathy associated with hypothyroidism. Compromise of the eighth nerve causing deafness is not uncommon. Multiple cranial nerve involvement is rare.

  • Polyneuropathy is usually subacute, sensory, and occurs in 31-65% of patients. Subclinical hypothyroidism also may present with peripheral nerve involvement.

  • Sensory complaints include painful dysesthesias in the hands and feet and radiating lancinating pains, occasionally suggesting nerve root compression. Examination findings may reveal distal glove-and-stocking sensory loss and ataxia.

  • Weakness is a common complaint, but it usually is related to myopathic involvement.

  • Hyporeflexia and delayed relaxation phase of the ankle jerk are common. Transient swelling on percussion of the skin (mounding phenomenon) may be observed.

  • Occasionally, hyperthyroidism may be associated with polyneuropathy.



• Neuropathy in chronic liver disease


• • Nonalcoholic chronic liver disease may be associated with an asymptomatic or mild sensory-motor demyelinating polyneuropathy in approximately 45-50% of patients.

  • Peripheral neuropathy also has been reported in primary biliary cirrhosis and following acute viral hepatitis.

  • Acute motor peripheral neuropathy similar to that of Guillain-Barré syndrome and associated with liver disease also has been documented.
  
  
  
• Polyneuropathy in chronic obstructive pulmonary disease (COPD): Several controversial reports describe mild polyneuropathy associated with COPD. Treatment of patients who have COPD with drugs that may affect peripheral nerves secondarily may help explain this association.



• Miscellaneous: Acromegaly and amyloidosis are associated more often with entrapment neuropathies and less commonly with peripheral neuropathy. Monoclonal gammopathies, such as cryoglobulinemia, monoclonal gammopathy of undetermined significance (MGUS), and myelin-associated glycoprotein (MAG)–associated gammopathy, can present with peripheral neuropathy.


• • Clinical features of MGUS
    • It is associated with the presence of monoclonal proteins in the serum.

    • Amyloidosis, osteosclerotic myeloma, or related disorders are absent.

    • MGUS presents as a symmetric sensorimotor polyneuropathy that begins insidiously and progresses slowly over months or years.

    • It occurs especially in the fifth, sixth, and seventh decades of life.

    • Males are affected more commonly than females.

    • Paresthesias, ataxia, and pain may be prominent.

    • Cranial nerves are not affected.
  
  
  
  • Amyloid neuropathy (nonfamilial)
    • Progressive involvement of small-diameter fibers with loss of pain and temperature sensation is typical of amyloid neuropathy, but occasionally patients can develop large-fiber neuropathy as well.

    • It presents commonly as CTS or as a painful peripheral neuropathy. Initial symptoms of neuropathy are sensory, with more extensive involvement of the lower extremities. With time, motor symptoms develop and are more prominent in the lower limbs.

    • Occasionally, amyloid neuropathy may manifest as autonomic dysfunction with severe orthostatic hypotension, syncopal episodes, or sexual impotence.

    • In patients whose amyloidosis begins with neuropathy, the clue to the diagnosis may be involvement of the heart, bowel, or kidneys.
  
  
  
  • Porphyric neuropathy
    • Disorders of porphyrin metabolism are a rare cause of peripheral neuropathy. Only hepatic porphyrias are associated with neurologic disease.

    • Acute intermittent porphyria may be associated with attacks of acute motor neuropathy with mild sensory symptoms very similar to Guillain-Barré syndrome.

    • Attacks are precipitated by drugs like phenytoin and phenobarbital and may be accompanied by abdominal pain, confusion, and seizures.

  • Diabetic neuropathy and nutritional neuropathy are discussed in detail in the following articles: Diabetic Neuropathy and Nutritional Neuropathy.
  
  
  

Causes:

• Common causes of metabolic neuropathy include the following:


• • Diabetes
  
  
  
  • Uremia
  
  
  
  • Chronic liver disease
  
  
  
  • Polycythemia
  
  
  
  • COPD
  
  
  
  • Amyloidosis
  
  
  
  • Acromegaly
  
  
  
  • Monoclonal gammopathies
  
  
  
  • Hypothyroidism
  
  
  
• Rare causes of metabolic neuropathy include the following:


• • Hyperthyroidism
  
  
  
  • Porphyria
  
  
  
  • Mitochondrial disorders
  
  
  
  • Adrenal insufficiency (rare reports of autonomic involvement)
  
  
  
  • Disorders of lipid or glycolipid metabolism (eg, Refsum disease, Fabry disease, abetalipoproteinemia, hypobetalipoproteinemia, Tangier disease)
  
  
  
  • Leukodystrophies with peripheral nerve involvement (adrenomyeloneuropathy, adrenoleukodystrophy, Krabbe disease)
  
  
  
• Risk factors for metabolic neuropathy include the following:


• • Uncontrolled metabolic status
  
  
  
  • Hypertension, obesity, and smoking (for diabetic neuropathy)
  
  
  

DIFFERENTIALS

Section 4 of 11

Acute Inflammatory Demyelinating Polyradiculoneuropathy
Alcohol (Ethanol) Related Neuropathy
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Diabetic Neuropathy
HIV-1 Associated Acute/Chronic Inflammatory Demyelinating Polyneuropathy
HIV-1 Associated Distal Painful Sensorimotor Polyneuropathy
Meralgia Paresthetica
Neuronal Ceroid Lipofuscinoses
Neuropathy of Friedreich Ataxia
Neuropathy of Leprosy
Neurosarcoidosis
Neurosyphilis
Nutritional Neuropathy
Peroneal Mononeuropathy
Polyarteritis Nodosa
Postherpetic Neuralgia
Radiation Necrosis
Sarcoidosis and Neuropathy
Toxic Neuropathy
Varicella Zoster
Vasculitic Neuropathy

Other Problems to be Considered:

Rare causes of metabolic diseases (eg, inherited disorders of metabolism, mitochondrial diseases) - In childhood and adolescence, these disorders may present with peripheral neuropathy.

Myelopathy: Especially in patients with diabetes, sensory symptoms may mimic myelopathy.

Hereditary motor and sensory neuropathies

WORKUP

Section 5 of 11

Lab Studies:

• General laboratory tests for metabolic neuropathy


• • Blood glucose, glucose tolerance test and glycosylated hemoglobin levels, vitamin B-12, folate, vitamin E, cryoglobulins, hepatitis profile, and antibodies to antinuclear antigen (ANA), extractable nuclear antigen (ENA), and sulfatide
  
  
  
  • Creatinine
  
  
  
  • Thyroid function tests
  
  
  
  • Liver function tests
  
  
  
  • Serum protein electrophoresis or serum immunofixation, anti-MAG antibodies
  
  
  
• Suggested studies for disorders of carbohydrate metabolism (when metabolic myopathy is being ruled out)


• • Ischemic forearm exercise test
  
  
  
  • Serum lactate, ammonia, and pyruvate
  
  
  
  • Urine myoglobin
  
  
  
  • Muscle histochemistry
  
  
  
  • Enzyme assays of muscle, blood, and fibroblast
  
  
  
  • Leukocyte glycogen levels to detect acid maltase deficiency
  
  
  
  • Leukocyte, DNA analyses (McArdle disease)
  
  
  
• Suggested investigations for mitochondrial disorders


• • Resting lactate and pyruvate level

  • Muscle histochemistry and electron microscopy

  • Serum mitochondrial DNA deletion and mutation

  • Enzyme assays of muscle, platelets, liver, and fibroblasts

  • Muscle cytochrome oxidase analysis
  
  
  
• Other suggested studies


• • Biotinidase levels
  
  
  
  • Aminolevulinic acid synthase in urine (porphyria)
  
  
  
  • Arylsulfatase A and B (leukodystrophies)

  • Hexosaminidases

  • Urine oxalate levels to rule out primary hyperoxaluria, which in patients who are undergoing hemodialysis may present with peripheral neuropathy (direct deposition of oxalate crystals on Schwann cells)
  
  
  

Imaging Studies:

• Peripheral nerve imaging: Magnetic resonance techniques have demonstrated increased water content in peripheral nerves of patients with diabetes. Its utility remains under investigation.



• When metabolic myopathy is being ruled out, phosphorus magnetic resonance spectroscopy of muscle may be useful for the investigation of carbohydrate metabolism (McArdle disease, phosphofructokinase deficiency) and mitochondrial disorders.



• MRI of the brain is suggested for patients in whom leukodystrophies are suspected.

Other Tests:

• Nerve conduction studies (NCS) and electromyography (EMG) are essential to classify and determine the severity of any neuropathy


• • NCS abnormalities in axonal sensory or sensory motor polyneuropathies consist of small or absent sensory nerve action potentials and compound motor action potentials, but NCS findings may be normal in mild cases or in small-fiber neuropathies. NCS abnormalities in demyelinating polyneuropathies can include prolonged distal and F-wave latencies, decreased conduction velocities, and conduction block.
  
  
  
  • EMG abnormalities are more common in axonal neuropathies and consist of signs of denervation (fibrillations and positive sharp waves and reduced recruitment patterns) and reinnervation (large-amplitude, broad-duration polyphasic motor unit potentials).
  
  
  
• Quantitative sensory testing (QST): Perform QST to evaluate involvement of small nerve fibers. QST holds promise in metabolic neuropathies as a technique to assess perceptual thresholds to pain, temperature, or vibration.



• Quantitative sudomotor axonal reflex testing (Q-SART) is very useful to identify autonomic involvement and help in establishing the prognosis.

Procedures:

• Sural nerve biopsy in diabetic neuropathy may reveal a histologic pattern suggestive of nerve ischemia (selective fascicular involvement, diffuse loss of myelinated fibers). However, sural nerve biopsy rarely is performed now unless evidence is being sought of vasculitic, demyelinating, hereditary, or infectious origin for the neuropathy. Muscle biopsy should always be done with nerve biopsy to increase the diagnostic yield for vasculitic and amyloid neuropathies.



• Punch skin biopsy and immunohistochemical staining for peripheral nerve axons can be performed.


• • Advances in immunohistochemical techniques, specifically the development of antibodies to human protein gene product 9.5 (PGP 9.5), an antigen present in peripheral nerve fibers of all calibers, allow assessment of the effect of diseases on peripheral nerve density.
  
  
  
  • Fiber density can be quantified with an interobserver agreement of 96%. Reports exist of excellent correlation between reductions in intradermal nerve fiber density and severity of symptoms in a wide range of neuropathies.
  
  
  

TREATMENT

Section 6 of 11

Medical Care: The best medical care for patients with metabolic neuropathy is control of the underlying metabolic condition, which results in better control of the neuropathy.

• Diabetic neuropathy: No pharmacologic treatment exists for moderately severe to severe diabetic peripheral neuropathy or other metabolic neuropathies. Only symptomatic treatments exist for pain and other conditions such as gastroparesis. However, control of hyperglycemia has been demonstrated to decrease progression of diabetic neuropathy. This section discusses recent and ongoing studies, followed by a discussion of symptomatic treatment.


• • Insulin pump: Continuous infusion of insulin has been demonstrated to improve results of NCS. This treatment seems to benefit only patients with mild peripheral neuropathy associated with diabetes. Exercise caution to prevent severe hypoglycemic episodes.

  • Aldose reductase inhibitors: Recent meta-analysis of randomized controlled trials of aldose reductase inhibitors indicates that benefits of treatment have not been demonstrated conclusively in diabetic neuropathy.

  • Neurotrophic factors: Neurotrophic factors have been tested in animal models of diabetic neuropathy. Insulin growth factor (IGF) and NGF have yielded encouraging results in animal studies. However, in humans, only recombinant NGF has been tested in phase II clinical trials, and the initial results did not demonstrate major benefits.

  • Gangliosides: Gangliosides have been shown to promote improvement in sensation without changes in NCVs. A moratorium has been placed on their development because of significant adverse effects.

  • Linoleic acid: In patients with diabetes, conversion of linolic acid or its metabolite gamma linoleic acid (GLA) is impaired. A recent multicenter study using GLA for 1 year demonstrated clinical and neurophysiologic improvement.

  • Advanced glycosylation end products (AGE): AGE inhibitors have shown some value in treatment of peripheral neuropathy in rats. Human trials are pending.

  • Human intravenous immunoglobulin: Small open-label studies have demonstrated improvement in diabetic peripheral neuropathy, especially in neuropathies with asymmetric involvement (eg, diabetic lumbosacral radiculoplexopathy) with intravenous immunoglobulin. Further studies are necessary to draw definitive conclusions.
  
  
  
• Symptomatic treatment of diabetic neuropathy


• • Gastroparesis: The first step is to attempt multiple small feedings. The amount of dietary fat should be decreased. Metoclopramide, which sensitizes tissue to the action of acetylcholine, stimulates the motility of the upper gastrointestinal tract. Cisapride, a prokinetic drug, is effective in some patients. If medications fail, jejunostomy may help.

  • Enteropathy: Stasis of bowel contents with bacterial overgrowth may contribute to diarrhea. Treatment with broad-spectrum antibiotics such as ampicillin or tetracycline is the initial therapy. Metronidazole may also be given. Anticholinergics may help in controlling diarrhea. Patients with poor digestion may benefit from a gluten-free diet.

  • Cystopathy: Patients with neurogenic bladder may not perceive when the bladder is full. Manual downward pressure of the bladder can help. Parasympathomimetic agents such as bethanechol also may be of help.
  
  
  
• Treatment of painful neuropathy: The FDA has approved duloxetine hydrochloride, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), for the treatment of diabetic peripheral neuropathic pain. A recent study concerning neuropathic pain using the NNT approach (number of patients needed to treat to get a beneficial response) was published recently by Sindrup and Jensen. This section reviews the drugs most often used to treat pain in peripheral neuropathies based on their approach.


• • Tricyclic antidepressants: Tricyclic antidepressants have been shown to be effective in treating painful diabetic neuropathy. Tricyclics act on the central nervous system, preventing the reuptake of norepinephrine and serotonin at synapses involved in pain inhibition. Benefits are unrelated to relief of depression. Amitriptyline and nortriptyline are used most commonly.

  • Selective antidepressants: Selective serotonin reuptake inhibitors (SSRIs) specifically inhibit presynaptic reuptake of serotonin but not noradrenaline. Paroxetine has been effective in painful diabetic neuropathy.

  • Ion channel blockers
    • Lidocaine: Lidocaine is a nonspecific sodium channel blocker. It relieves painful diabetic neuropathy in severe cases but is not convenient to administer since no oral form is available.

    • Mexiletine: Mexiletine is an oral analogue of lidocaine. It has been used at a dosage of 10 mg/kg, but clinical trials so far have shown equivocal results.

    • Phenytoin: Phenytoin blocks sodium channels nonspecifically and therefore reduces neuronal excitability in sensitized C-nociceptors. It has been demonstrated to be effective in neuropathic pain, but it suppresses insulin secretion and may precipitate hyperosmolar coma in patients with diabetes.

    • Carbamazepine: Carbamazepine is another nonspecific sodium channel blocker that has been effective in the treatment of painful diabetic neuropathy, but it is more useful in trigeminal neuralgia.

    • Gabapentin: Gabapentin is a novel anticonvulsant with an unknown mechanism of action, but it is believed to antagonize glutamate excitotoxicity. It has demonstrated effectiveness in neuropathic pain, but doses in clinical trials were as high as 3600 mg.

    • Lamotrigine: Lamotrigine is a new anticonvulsant acting as a stabilizer in the slow inactivated conformation of a subtype of sodium channels, indirectly suppressing the neuronal release of glutamate. Studies in trigeminal neuralgia favor its use, but no studies have been reported in other neuropathic pain syndromes.

  • N-methyl-D-aspartate (NMDA) antagonists: Aspartate, an excitatory neurotransmitter, has been shown to play a role in the development of neuropathic pain. Its receptor is NMDA. NMDA antagonists have shown effectiveness when given intravenously for neuropathic pain (eg, ketamine). Other studies with another NMDA antagonist, dextromethorphan, have shown efficacy for neuropathic pain.

  • Opioids: Until recently, high controversy surrounded opioid use in neuropathic pain. However, recent studies have demonstrated its efficacy in different types of neuropathic pain. Tramadol is an analgesic drug probably acting over both monoaminergic and opioid mechanisms. The monoaminergic effect is shared with tricyclic antidepressants. Tolerance and dependence appear to be uncommon. Doses of 100-400 mg have been shown to be effective in diabetic neuropathic pain. Oxycodone and morphine have been tried in other neuropathic pain syndromes with good results. Risk of dependence remains an issue to consider, and these agents should not be given to individuals at risk of addiction.

  • Levodopa: Dopamine agonists inhibit noxious input to the spinal cord. Levodopa also has actions over noradrenergic receptors. One recent study showed benefit in polyneuropathic pain with 300 mg/d of levodopa.

  • Capsaicin: Capsaicin is an alkaloid substance derived from chilies. It depletes substance P from sensory nerves, causing chemodenervation. It has demonstrated effectiveness in several studies of diabetic neuropathic pain and in other types of neuropathic pain as well. It must be applied topically every 4 hours over the entire pain area. It causes a burning sensation, and applying it with gloves is advisable.

  • Miscellaneous: Several still unproven medical treatments are proposed for mitochondrial respiratory chain disorders, including drugs such as coenzyme Q10, menadione, vitamin E, ascorbic acid, N-acetylcysteine, riboflavin, succinate, L-carnitine, and dichloroacetate.
  
  
  

Surgical Care:

• Surgical release of entrapment neuropathy (CTS, ulnar neuropathy at the elbow, TTS)



• Specialized surgical care of diabetic foot and foot ulcers, including vascular and plastic surgery evaluation



• Jejunostomy for severe gastroparesis



• Pancreatic islet transplants have been reported to improve diabetic neuropathy and pancreas-kidney transplantation in patients with diabetes and renal failure



• Liver transplantation (may improve familial amyloid neuropathy)



• Renal transplantation (may improve uremic neuropathy)

Consultations:

• Nutrition or genetics consults, especially for patients with diabetes or metabolic neuropathies in childhood



• General surgery for patients in whom transplant is considered



• Plastic or vascular surgery for patients with diabetic foot ulceration or necrosis

Diet:

• Low-calorie diet in patients with diabetes



• Modified lipid-intake diets for inherited conditions associated with alteration in lipid metabolism



• Low-protein intake in chronic renal failure and in hepatic failure

Activity: No restrictions in activity are recommended for most of the metabolic neuropathies. However, some neuropathies in childhood can be triggered by exercise.

MEDICATION

Section 7 of 11

See Medical Care for a full discussion of recent and ongoing studies and symptomatic treatment.

Drug Category: Gastrointestinal agents -- These agents increase peristalsis of upper GI tract.

Drug Name	Metoclopramide (Clopra, Reglan, Maxolon) -- Sensitizes tissue to action of acetylcholine and stimulates motility of upper GI tract; indicated for gastroparesis. In severe gastroparesis, is not absorbed and should be given IV.
Adult Dose	10 mg PO qd ac 5-20 mg IV bid prn
Pediatric Dose	<6 years: 0.1 mg/kg PO 6-14 years: 2.5-5 mg PO >14 years: 10 mg PO
Contraindications	Documented hypersensitivity; pheochromocytoma; GI hemorrhage, obstruction, or perforation; history of seizure disorders
Interactions	Anticholinergics may decrease efficacy; opiate analgesics may increase toxicity in CNS
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in history of mental illness or Parkinson disease

Drug Category: Broad-spectrum antibiotics -- Therapy must be comprehensive and cover all likely pathogens in the context of neuropathic enteropathy.

Drug Name	Ampicillin (Omnipen, Marcillin, Polycillin, Principen) -- Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication orally.
Adult Dose	250 mg PO q8h
Pediatric Dose	<7 days, <2000 g: 50 mg/kg/d IV/IM divided bid (q12h) <7 days, >2000 g: 75 mg/kg/d IV/IM divided tid (q8h) >7 days, <1200 g: 50 mg/kg/d IV/IM divided bid (q12h) >7 days, 1200-2000 g: 75 mg/kg/d IV/IM divided tid (q8h) >7 days, >2000 g: 100 mg/kg/d divided qid (q6h) Infants/children: 100-200 mg/kg/d IV/IM divided q4-6h; not to exceed 2-3 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid and disulfiram elevate levels; allopurinol decreases effects and has additive effects on ampicillin rash; may decrease effects of oral contraceptives
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction

Drug Name	Tetracycline (Sumycin) -- Treats gram-positive and gram-negative organisms as well as mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).
Adult Dose	250 mg PO q8h
Pediatric Dose	>8 years: 25-50 mg/kg PO divided q6h; not to exceed 3 g/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate decrease availability; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risks during pregnancy; can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; if used during tooth development (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Metronidazole (Flagyl, Protostat) -- Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis).
Adult Dose	500 mg PO q6h
Pediatric Dose	<7 days, >1200 g: 7.5-15 mg/kg PO/IV qd or divided q12h (bid) >7 days, >1200 g: 15-30 mg/kg PO/IV qd divided q12h (bid) Infants and children: 30 mg/kg PO/IV qd divided q6h (qid); not to exceed 4 g/d
Contraindications	Documented hypersensitivity
Interactions	May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity; disulfiram reaction may occur with orally ingested ethanol
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy

Drug Category: Cholinergic agents -- These agents increase peristalsis and secretions in the intestine. They also increase contraction and relaxation of the sphincter of the bladder. They may help in treatment of cystopathy.

Drug Name	Bethanechol (Urecholine, Duvoid, Myotonachol) -- Used for selective stimulation of bladder to produce contraction to initiate micturition and empty bladder. Most useful in patients who have bladder hypocontractility, provided they have functional and coordinated sphincters. Rarely used because of difficulty in timing effect and because of GI stimulation.
Adult Dose	5-10 mg PO initially; not to exceed 50 mg; total dose should continue at 6-h intervals
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; peptic ulcer disease, obstructive pulmonary disease, bradycardia, vasomotor instability, hypotension, atrioventricular conduction defects, hyperthyroidism, epilepsy, mechanically obstructed GI or GU tract
Interactions	Ganglion-blocking compounds may cause drop of blood pressure to critical levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Urinary retention secondary to possible reflux of urine into kidneys may occur

Drug Category: Tricyclic antidepressants -- These agents have been shown to be effective in treating painful diabetic neuropathy. They act on CNS, preventing reuptake of norepinephrine and serotonin at synapses involved in pain inhibition. Benefits are unrelated to relief of depression.

Drug Name	Amitriptyline (Elavil) -- Analgesic for certain types of chronic and neuropathic pain.
Adult Dose	10-25 mg PO hs initial, gradually increase to 50-100 mg
Pediatric Dose	<9 years: Not established 9-12 years: 1-3 mg/kg PO qd divided q8h; not to exceed 200 mg/d >12 years: 25-100 mg PO qd divided qd/tid; not to exceed 200 mg/d
Contraindications	Documented hypersensitivity; MAOIs in past 14 d; history of seizures, cardiac arrhythmias, glaucoma, or urinary retention
Interactions	Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (eg, cimetidine, quinidine) may increase levels; inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in cardiac conduction disturbances and history of hyperthyroidism, renal or hepatic impairment; avoid using in elderly; adverse effects include blurred vision, constipation, sleepiness, dry mouth, and dysautonomia

Drug Name	Nortriptyline (Aventyl HCl, Pamelor) -- Has demonstrated effectiveness in treatment of chronic pain. By inhibiting reuptake of serotonin and/or norepinephrine by presynaptic neuronal membrane, this drug increases synaptic concentration of these neurotransmitters in CNS. Pharmacodynamic effects such as desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors also appear to play roles in its mechanisms of action.
Adult Dose	10-25 mg PO hs initial, gradually increase to 50-100 mg
Pediatric Dose	<6 years: Not established 6-7 years: 10 mg PO qhs 7-11 years: 10-20 mg PO qhs >11 years: 25-35 mg PO qhs
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; MAOIs in past 14 d
Interactions	Cimetidine may increase levels; may increase PT in patients stabilized with warfarin
Pregnancy	D - Unsafe in pregnancy
Precautions	Adverse effects include blurred vision, constipation, sleepiness, dry mouth, and dysautonomia; caution in cardiac conduction disturbances and history of hyperthyroidism, renal or hepatic impairment; because of pronounced effects in cardiovascular system, best to avoid in elderly

Drug Category: Selective serotonin reuptake inhibitors -- These agents specifically inhibit presynaptic reuptake of serotonin but not noradrenaline.

Drug Name	Paroxetine (Paxil) -- Effective in painful diabetic neuropathy.
Adult Dose	10-60 mg PO qd
Pediatric Dose	<8 years: Not established >8 years: 10-30 mg PO qd; start with 5-10 mg PO qd and advance gradually by 5 mg/d qwk
Contraindications	Documented hypersensitivity; history of seizures; MAOIs in past 14 days; impaired liver or renal function; elderly subjects; suicidal thoughts
Interactions	Triptans (5-HT1 agonists), buspirone, or lithium may increase risk of serotonin syndrome; may inhibit hepatic metabolism into active form of hydrocodone; may inhibit hepatic metabolism of flecainide and increase risk of toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Patients may be advised not to operate heavy machinery or perform tasks that may imply high risk of personal injury during early stages of treatment, as it may cause excessive somnolence, blurred vision, and asthenia in some patients

Drug Category: Anticonvulsants -- Use of certain anti-epileptic drugs, such as the GABA analogue gabapentin, has proven helpful in some cases of neuropathic pain. Thus, a trial of such an agent might provide analgesia for symptomatic neuropathy.

Drug Name	Phenytoin (Dilantin) -- Blocks sodium channels nonspecifically and therefore reduces neuronal excitability in sensitized C-nociceptors. Has been demonstrated effective in neuropathic pain but suppresses insulin secretion and may precipitate hyperosmolar coma in patients with diabetes.
Adult Dose	300 mg PO qhs
Pediatric Dose	Infants/children: 5-10 mg/kg/d PO/IV divided bid/tid
Contraindications	Documented hypersensitivity; sino-atrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
Interactions	Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity Barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate may decrease effects May decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if skin rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood glucose); discontinue use if hepatic dysfunction occurs

Drug Name	Carbamazepine (Tegretol) -- Nonspecific sodium channel blocker that has been effective in treatment of painful diabetic neuropathy; more useful in trigeminal neuralgia.
Adult Dose	400-1000 mg PO bid
Pediatric Dose	<6 years: Not established >6 years: 10 mg/kg PO qd
Contraindications	Documented hypersensitivity; history of bone marrow depression; MAOIs within last 14 d
Interactions	Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels)
Pregnancy	D - Unsafe in pregnancy
Precautions	Do not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBC and serum iron baseline prior to treatment, during first 2 months, and yearly or every other year thereafter to monitor for aplastic anemia; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Drug Name	Gabapentin (Neurontin) -- Novel anticonvulsant with unknown mechanism of action; believed to antagonize glutamate excitotoxicity. Has demonstrated effectiveness in neuropathic pain, but doses in clinical trials were as high as 3600 mg.
Adult Dose	300 mg/d PO initial; gradually increase; mean dose is 2400 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Antacids may significantly reduce bioavailability (administer at least 2 h following antacids); may increase norethindrone levels significantly
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe renal disease; adverse effects include somnolence, dizziness, and diarrhea

Drug Category: Analgesics -- Recent studies have demonstrated efficacy in different types of neuropathic pain.

Drug Name	Tramadol (Ultram) -- Analgesic probably acting over both monoaminergic and opioid mechanisms. Monoaminergic effect shared with TCAs. Tolerance and dependence appear to be uncommon.
Adult Dose	100-400 mg PO qd shown to be effective in diabetic neuropathic pain
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; opioid dependency; MAOIs within 14 days; use of SSRIs, TCAs, opioids; acute alcohol intoxication
Interactions	Decreases carbamazepine effects significantly; cimetidine increases toxicity; antidepressants increase risk of serotonin syndrome
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Can cause dizziness, nausea, constipation, sweating, pruritus; additive sedation with alcohol and TCAs; abrupt discontinuation can precipitate opioid withdrawal symptoms; adjust dose in liver disease, myxedema, hypothyroidism, hypoadrenalism; pregnancy, breastfeeding; seizure; development of tolerance or dependency with extended use

Drug Category: Dopamine agonists -- In order for a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. The role of other dopamine receptor subtypes is currently unclear. They inhibit noxious input to spinal cord.

Drug Name	Levodopa (Depar, Larodopa) -- Has actions over noradrenergic receptors.
Adult Dose	300 mg/d PO shown recently to benefit in polyneuropathic pain
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; MAOI therapy; melanomas or undiagnosed skin lesions
Interactions	Phenothiazines, hydantoins, pyridoxine, and hypotensive agents may decrease effects; MAOIs may cause hypertensive reactions
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Common adverse effects include nausea, vomiting, hypertension, dyskinesias, and postural hypotension; caution in arrhythmias, asthma, wide-angle glaucoma, myocardial infarction, peptic ulcer disease

Drug Category: Topical analgesics -- Studies have demonstrated efficacy in different types of neuropathic pain. Capsaicin has been shown to have efficacy in treatment of painful diabetic neuropathy and postherpetic neuralgia.

Drug Name	Capsaicin (Dolorac, Zostrix) -- Derived from chili peppers; depletes substance P from sensory nerves, causing chemodenervation. Has demonstrated effectiveness in several studies of diabetic neuropathic pain and in other types of neuropathic pain.
Adult Dose	0.075% preparation applied topically q4h over entire pain area Also available in 0.025% preparation
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; broken or irritated skin
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Main adverse effects are burning and/or stinging sensations at site of application, particularly first wk of therapy For external use only; avoid contact with eyes; do not use tight bandage; discontinue use if condition worsens or symptoms persist for 14-28 d

Drug Category: Selective serotonin and norepinephrine reuptake inhibitors (SSNRI) -- SSNRIs have antidepressant and central pain inhibitory actions.

Drug Name	Duloxetine hydrochloride (Cymbalta) -- The efficacy of duloxetine in the treatment of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 large, randomized, placebo-controlled trials in adult patients. These studies led to duloxetine becoming the first FDA-approved agent for the treatment of diabetic neuropathic pain. Action is believed to involve inhibition of central pain mechanisms at the recommended dose of 60 mg/d PO.
Adult Dose	60 mg PO qd (120 mg PO qd is also considered safe and effective, but somewhat less tolerated)
Pediatric Dose	Not established; drug package insert contains warning of risk of suicidality in children receiving antidepressants; anyone considering use of Cymbalta in this population must balance risk with clinical need
Contraindications	Documented hypersensitivity; uncontrolled narrow-angle glaucoma; within 14 d of stopping MAO inhibitor use (do not initiate MAO inhibitors within 5 d of stopping duloxetine)
Interactions	Metabolized by CYP1A2 and CYP2D6; coadministration with drugs that inhibit CYP1A2 (eg, fluvoxamine, cimetidine, ciprofloxacin, enoxacin) may increase duloxetine blood levels and toxicity; coadministration with drugs that inhibit CYP2D6 (eg, paroxetine, fluoxetine, quinidine) may increase duloxetine blood levels and toxicity; duloxetine moderately inhibits CYP2D6 and may decrease elimination of CYP2D6 substrates (eg, tricyclic antidepressants, phenothiazines {eg, thioridazine], type 1C antiarrhythmics [eg, propafenone, flecainide]); coadministration with MAO inhibitors may cause serious, sometimes fatal reactions that include hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes including extreme agitation, delirium, and coma (see Contraindications)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Observe closely for clinical worsening and suicidality when initiating treatment or following dosage change; gradually decrease dose when discontinuing, do not abruptly discontinue; caution with hepatic impairment or end-stage renal disease; recommended not to prescribe to patients with substantial alcohol use or evidence of chronic liver disease; may cause slight blood pressure increase; may activate mania or hypomania; common adverse effects include nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Inpatient care of complications of the metabolic disorder (hyperosmolar state, silent myocardial infarction, arrhythmias) is required.



• Local treatment of ulcerated diabetic foot and surgical procedures to alleviate pain or impending infection are best performed in the hospital setting.

Further Outpatient Care:

• Provide close outpatient follow-up care to patients with metabolic neuropathy to treat the primary metabolic condition and to assess treatment results and adverse effects.

In/Out Patient Meds:

• Patients should keep a calendar with all medications and their adverse effects.

Transfer:

• Transfer patients to an inpatient facility whenever complications develop.

Complications:

• Patients with metabolic neuropathy can develop autonomic dysfunction and are at high risk to develop asymptomatic myocardial infarction and sudden death.



• Patients with diabetes who have neuropathy can develop foot ulcers.

Prognosis:

• Prognosis depends on the control of the primary metabolic condition. If the metabolic condition is controlled, usually the neuropathy also is reasonably well controlled.



• Autonomic involvement has a worse prognosis than other neuropathies because of the risk of asymptomatic myocardial infarction.

Patient Education:

• Provide patients with education about the disease and methods of preventing complications.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• The fact that patients have a systemic, metabolic illness that may explain their neuropathy does not preclude investigations of other possible causes. Patients with peripheral neuropathies may have other underlying systemic illnesses, including cancer, or neuropathies due to toxicity with heavy metals. Early diagnosis is therefore very important. Thallium toxicity neuropathy and others can be caused by malicious administration by individuals interested in poisoning the patient. The physician must keep a high index of suspicion to detect these cases and report them to authorities. Arsenic poisoning, which causes a glove-stocking symmetric sensory polyneuropathy followed by motor involvement, also should be suspected, especially when the patient manifests with subungual transverse white bands (Aldrich-Mees lines). Ingestion of illicit whiskey (moonshine) is a source of arsenic and has resulted in poisoning.

TEST QUESTIONS

Section 10 of 11

CME Question 1: What is the most common peripheral nerve involvement in hypothyroidism?

A: Polyneuropathy
B: Multiple mononeuropathy
C: Entrapment neuropathy
D: Optic nerve involvement
E: Cranial neuropathy

The correct answer is C: Entrapment neuropathy manifesting as carpal tunnel syndrome is the most common peripheral nerve complication found in patients with hypothyroidism. Replacement with thyroid hormone tends to relieve the symptoms.

CME Question 2: What is the most effective treatment for diabetic neuropathy?

A: Gangliosides
B: Nerve growth factor
C: Aldose reductase inhibitors
D: Control of hyperglycemia
E: Tricyclic antidepressants

The correct answer is D: Optimal control of high glucose levels remains the cornerstone of treatment for diabetic neuropathy. Current data on the use of recombinant human nerve growth factor to treat diabetic neuropathy are inconclusive; tricyclic agents are used for symptomatic pain control.

Pearl Question 1 (T/F): Autonomic involvement is not frequent in metabolic neuropathies.

The correct answer is False: Although most polyneuropathies are associated with some degree of mixed sensorimotor involvement or autonomic dysfunction, the latter most often is observed in metabolic neuropathies.

Pearl Question 2 (T/F): Neuropathies in childhood frequently are caused by inherited disorders.

The correct answer is True: Hereditary neuropathies are common disorders and usually are detected during childhood; assessment of skeletal abnormalities including hammer toes or high arches, investigation of a family history, and neurologic examinations of relatives may help uncover hereditary neuropathies. These include nonmetabolic disorders such as Charcot-Marie-Tooth disease or, less commonly, metabolic disorders such as the leukodystrophies.

Pearl Question 3 (T/F): Chronic inflammatory demyelinating polyneuropathy (CIDP) is a common manifestation of diabetic peripheral neuropathy.

The correct answer is False: Diabetic neuropathies can be symmetric or asymmetric. Symmetric diabetic neuropathies can involve large or small fibers or the autonomic system and can have a distal sensory or sensorimotor distribution. Asymmetric neuropathies can involve single or multiple nerves, presenting with concomitant root or plexus involvement or as an entrapment neuropathy. CIDP is not a manifestation of diabetes, although it is more common in patients with diabetes than in the general population.

Pearl Question 4 (T/F): Renal transplant may improve uremic peripheral neuropathy.

The correct answer is True: Both renal transplant or regular hemodialysis may improve the clinical symptoms of uremic peripheral neuropathy, even in patients in whom no improvement in conduction velocities is noted.

BIBLIOGRAPHY

Section 11 of 11

• Apfel SC: Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med 1999 Aug 30; 107(2B): 34S-42S[Medline].
• Arezzo JC: New developments in the diagnosis of diabetic neuropathy. Am J Med 1999 Aug 30; 107(2B): 9S-16S[Medline].
• Azoulay D, Samuel D, Castaing D, et al: Domino liver transplants for metabolic disorders: experience with familial amyloidotic polyneuropathy. J Am Coll Surg 1999 Dec; 189(6): 584-93[Medline].
• Burn DJ, Bates D: Neurology and the kidney. J Neurol Neurosurg Psychiatry 1998 Dec; 65(6): 810-21[Medline].
• Chalk CH: Acquired peripheral neuropathy. Neurol Clin 1997 Aug; 15(3): 501-28[Medline].
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• Dick PJ, Thomas PK, eds: Peripheral Neuropathy. 3rd ed. Philadelphia: WB Saunders Co; 1993.
• Dyck PJ, Norell JE, Dyck PJ: Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999 Dec 10; 53(9): 2113-21[Medline].
• Greene DA, Stevens MJ, Feldman EL: Diabetic neuropathy: scope of the syndrome. Am J Med 1999 Aug 30; 107(2B): 2S-8S[Medline].
• Harati Y: Frequently asked questions about diabetic peripheral neuropathies. Neurol Clin 1992 Aug; 10(3): 783-807[Medline].
• Kaminski HJ, Ruff RL: Neurologic complications of endocrine diseases. Neurol Clin 1989 Aug; 7(3): 489-508[Medline].
• Kyle RA: Monoclonal proteins in neuropathy. Neurol Clin 1992 Aug; 10(3): 713-34[Medline].
• Lagueny A: [Metabolic and nutritional neuropathies]. Rev Prat 2000 Apr 1; 50(7): 731-5[Medline].
• Misiunas A, Niepomniszcze H, Ravera B, et al: Peripheral neuropathy in subclinical hypothyroidism. Thyroid 1995 Aug; 5(4): 283-6[Medline].
• Parry GJ: Management of diabetic neuropathy. Am J Med 1999 Aug 30; 107(2B): 27S-33S[Medline].
• Pirart J: [Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 (3rd and last part) (author's transl)]. Diabete Metab 1977 Dec; 3(4): 245-56[Medline].
• Sindrup SH, Jensen TS: Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999 Dec; 83(3): 389-400[Medline].
• Tamborlane WV, Ahern J: Implications and results of the Diabetes Control and Complications Trial. Pediatr Clin North Am 1997 Apr; 44(2): 285-300[Medline].
• Thomas PK, Tomlinson DR: Diabetic and hypoglycemic neuropathy. In: Dick PJ, Thomas PK, eds. Peripheral Neuropathy. Philadelphia: WB Saunders Co; 1993: 1221.

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