Metabolic Neuropathy

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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 Medscape Reference 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

Diabetic polyneuropathy is a small fiber neuropathy, which involves the sensory A≏ and C fibers. Nearly 7% of the general population suffer chronic neuropathic pain responsible for severe quality-of-life impairments. The main causes consist chiefly of metabolic diseases (diabetes mellitus, glucose intolerance), dysimmunity syndromes (Sjögren's syndrome, sarcoidosis, monoclonal gammopathy), and genetic abnormalities (familial amyloidosis due to a transthyretin mutation, Fabry disease, sodium channel diseases), among others. Sène suggests that the most informative diagnostic tests are epidermal nerve fiber density in a skin biopsy, laser-evoked potentials, heat- and cold-detection thresholds, and electrochemical skin conductance.[1]

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.[2, 3] 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.[4, 5]

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.[6] 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.[7]

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.

Epidemiology

Frequency

United States

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%.[8] In a large prospective study done by Pirart, the prevalence rose from 7.5% at the time of diagnosis to 50% after 25 years.[9] Many patients with diabetes may have asymptomatic peripheral neuropathy; thus, the early use of neurophysiologic tests may help in clarifying the true incidence.[10]

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.[11, 12]

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.[13]

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

See the list below:

History

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

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.

Peripheral neuropathies

Table 1. Symptoms and Signs of Peripheral Neuropathy*



View Table

See Table

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.[16]

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.[17]

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

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

Causes

See the list below:

Laboratory Studies

See the list below:

Imaging Studies

See the list below:

Other Tests

See the list below:

Procedures

See the list below:

Histologic Findings

Loss of myelinated fibers, epineurial periarteriolar lymphocytic infiltrates, and selective involvement of fascicles can be observed in diabetic radiculoplexopathy or other vasculitic neuropathies. Amyloid birefringent deposits (under polarized light) within the endoneurium are revealed in amyloid neuropathy.

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.[22] This section discusses recent and ongoing studies, followed by a discussion of symptomatic treatment.

Symptomatic treatment of diabetic neuropathy

See the list below:

Surgical Care

See the list below:

Consultations

See the list below:

Diet

See the list below:

Activity

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

Medication Summary

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

Metoclopramide (Clopra, Reglan, Maxolon)

Clinical Context:  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.

Class Summary

These agents increase peristalsis of upper GI tract.

Ampicillin (Omnipen, Marcillin, Polycillin, Principen)

Clinical Context:  Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication orally.

Tetracycline (Sumycin)

Clinical Context:  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).

Metronidazole (Flagyl, Protostat)

Clinical Context:  Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis).

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of neuropathic enteropathy.

Bethanechol (Urecholine, Duvoid, Myotonachol)

Clinical Context:  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.

Class Summary

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.

Amitriptyline (Elavil)

Clinical Context:  Analgesic for certain types of chronic and neuropathic pain.

Nortriptyline (Aventyl HCl, Pamelor)

Clinical Context:  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.

Class Summary

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.

Paroxetine (Paxil)

Clinical Context:  Effective in painful diabetic neuropathy.

Class Summary

These agents specifically inhibit presynaptic reuptake of serotonin but not noradrenaline.

Phenytoin (Dilantin)

Clinical Context:  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.

Carbamazepine (Tegretol)

Clinical Context:  Nonspecific sodium channel blocker that has been effective in treatment of painful diabetic neuropathy; more useful in trigeminal neuralgia.

Gabapentin (Neurontin)

Clinical Context:  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.

Class Summary

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.

Tramadol (Ultram)

Clinical Context:  Analgesic probably acting over both monoaminergic and opioid mechanisms. Monoaminergic effect shared with TCAs. Tolerance and dependence appear to be uncommon.

Class Summary

Recent studies have demonstrated efficacy in different types of neuropathic pain.

Levodopa (Depar, Larodopa)

Clinical Context:  Has actions over noradrenergic receptors.

Class Summary

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.

Capsaicin (Dolorac, Zostrix)

Clinical Context:  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.

Class Summary

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.

Duloxetine hydrochloride (Cymbalta)

Clinical Context:  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.

Class Summary

SSNRIs have antidepressant and central pain inhibitory actions.

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.

Further Inpatient Care

See the list below:

Inpatient & Outpatient Medications

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

Transfer

Transfer patients to an inpatient facility whenever complications develop.

Complications

See the list below:

Prognosis

See the list below:

Patient Education

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

What is metabolic neuropathy?What is the pathophysiology of metabolic neuropathy?What is the pathophysiology of diabetic polyneuropathy?What is the pathophysiology of uremic polyneuropathy?What is the pathophysiology of thyroid neuropathy?What is the prevalence of metabolic neuropathy in the US?What is the mortality and morbidity associated with metabolic neuropathy?What are the racial predilections of metabolic neuropathy?What are the sexual predilections of metabolic neuropathy?Which age groups have the highest prevalence of metabolic neuropathy?How are metabolic neuropathies classified?What are the sensory symptoms of metabolic neuropathy?What are the motor symptoms of metabolic neuropathy?What are the autonomic symptoms of metabolic neuropathy?What is included in the physical exam to evaluate metabolic neuropathy?Which sensory findings are characteristic of metabolic neuropathy?Which motor findings are characteristic of metabolic neuropathy?Which physical findings are characteristic of cranial neuropathies?What are the signs and symptoms of peripheral neuropathies?Which physical findings are characteristic of uremia in metabolic neuropathy?Which physical findings are characteristic of thyroid neuropathy?Which physical findings are characteristic of metabolic neuropathy in chronic liver disease?Which physical findings are characteristic of metabolic neuropathy in COPD?Which physical findings are characteristic of MGUS?Which physical findings are characteristic of amyloid neuropathy (nonfamilial)?Which physical findings are characteristic of porphyric neuropathy?What are the common causes of metabolic neuropathy?What are rare causes of metabolic neuropathy?What are risk factors for metabolic neuropathy?What are the differential diagnoses for Metabolic Neuropathy?Which lab tests are performed in the workup of metabolic neuropathy?What is the role of imaging studies in the workup of metabolic neuropathy?What is the role of NCS in the workup of metabolic neuropathy?What is the role of quantitative sensory testing (QST) in the workup of metabolic neuropathy?What is the role of quantitative sudomotor axonal reflex testing (Q-SART) in the workup of metabolic neuropathy?What is the role of nerve excitability measurement in the workup of metabolic neuropathy?What is the role biopsy in the workup of metabolic neuropathy?Which histologic findings are characteristic of metabolic neuropathy?How is metabolic neuropathy treated?How is diabetic neuropathy treated?How is gastroparesis treated in diabetic neuropathy?How is enteropathy treated in diabetic neuropathy?How is cystopathy treated in diabetic neuropathy?How is diabetic peripheral neuropathic pain treated?What is the role of surgery in the treatment of metabolic neuropathy?Which specialist consultations are beneficial to patients with metabolic neuropathy?Which dietary modifications are used in the treatment of metabolic neuropathy?Which activity modifications are used in the treatment of metabolic neuropathy?What is included in the long-term monitoring of metabolic neuropathy?When is inpatient care of metabolic neuropathy indicated?What instructions should be given to patients regarding medications for metabolic neuropathy?When is patient transfer considered in the treatment of metabolic neuropathy?What are the possible complications of metabolic neuropathy?What is the prognosis of metabolic neuropathy?What is included in patient education about metabolic neuropathy?Which medications in the drug class Selective serotonin and norepinephrine reuptake inhibitors (SSNRI) are used in the treatment of Metabolic Neuropathy?Which medications in the drug class Topical analgesics are used in the treatment of Metabolic Neuropathy?Which medications in the drug class Dopamine agonists are used in the treatment of Metabolic Neuropathy?Which medications in the drug class Analgesics are used in the treatment of Metabolic Neuropathy?Which medications in the drug class Anticonvulsants are used in the treatment of Metabolic Neuropathy?Which medications in the drug class Selective serotonin reuptake inhibitors are used in the treatment of Metabolic Neuropathy?Which medications in the drug class Tricyclic antidepressants are used in the treatment of Metabolic Neuropathy?Which medications in the drug class Cholinergic agents are used in the treatment of Metabolic Neuropathy?Which medications in the drug class Broad-spectrum antibiotics are used in the treatment of Metabolic Neuropathy?Which medications in the drug class Gastrointestinal agents are used in the treatment of Metabolic Neuropathy?

Author

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS, Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE, Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc; Chief Strategy Officer, Discourse LLC

Disclosure: Nothing to disclose.

Additional Contributors

Milind J Kothari, DO, Professor, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Penn State Milton S Hershey Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Fernando Dangond, MD, and Luis Carlos Sanin, MD, to the development and writing of this article.

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Small-Fiber Sensory Large-Fiber Sensory Autonomic
Burning painLoss of vibrationHeart rate changes
Cutaneous allodyniaProprioception lossPostural blood pressure change
ParesthesiasLoss of reflexesAbnormal sweating
Lancinating painSlowed NCVsGastroparesis
Loss pain/temperatureSensory ataxiaImpotence
Foot ulcersWeaknessAbnormal ejaculation
Visceral pain loss  
* Modified from Apfel, 1999.[15]