Metabolic Neuropathy

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.

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.

Frequency

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 prevalence of diabetic neuropathy changes with disease duration. In the Danish Addition study, the patient with newly diagnosed screen-detected type 2 diabetes had a prevalence of diabetic neuropathy of 13% at study entry with cumulative incidence of 10% over a 13-year cumulative followup period in a cohort with very mild type 2 diabetes that adhered to good metabolic control. On the other hand, in a large cohort of patients with more advanced type 2 diabetes and confirmed coronary artery disease participating in the BARI 2D trial, 50% had confirmed diabetic neuropathy at baseline and 4-year cumulative incidence was 66%–72% in those with no neuropathy at baseline.[11]

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. In uremic neuropathy, neurological symptoms increase steadily with rising serum creatinine.[12]

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.[13, 14]

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.[15]

Diabetic neuropathy significantly impairs quality of life (QOL). QOL is lower in patients with neuropathy and difference start years before and continued years after diagnosis of neuropathy. The high prevalence of pain due to diabetic neuropathy with substantial sleep impairment and mood disorders was reported in a study conducted in India.[11]

Demographics

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

Uremic neuropathy is more frequent in males than in females.

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).

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.

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

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,[16]  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[16] , 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

    • Charcot's neuroarthropathy[17]

    • Neuroendocrine dysfunction[18]

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* (Open Table in a new window)

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. Pardoxical heat sensation seems to be a common and early sign in uremic sensory neuropathy.[20]

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.[21]

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. A study done in 2010 compared COPD patients and healthy controls. All study participants were evaluated with standard motor and sensory nerve conduction studies. Peripheral neuropathy was found in 15% of COPD patients.[22]

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.[23]

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.

See the list below:

• 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)

  • Thalidomide has been found useful in treating multiple myeloma, whether in refractory forms, in first diagnosis patients,[24] during the induced-remission phase before autologous transplantation, or as maintenance therapy for responders. However, the most feared side effect is peripheral neuropathy, which inevitably causes even effective therapy to be suspended.

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.

See the list below:

• 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)

Magnetic resonance techniques have demonstrated increased water content in peripheral nerves of patients with diabetes. Its utility remains under investigation. Magnetic resonance imaging and ultrasound can be used in peripheral nerve imaging to demonstrate extrinsic compressive lesions, focal neural lesions such as neural edema and swelling, focal neural scarring (posttraumatic neuroma in continuity) and intraneural ganglia. Ultrasound can be particularly useful in assessing for intrinsic lesions in small peripheral nerves because of the superior spatial resolution of ultrasound in assessing superficial structures. Plain radiography (and sometimes computed tomography scanning) may show significant bone changes and should be the initial imaging modality.[25]

Acute or subacute denervation results in prolonged T2 relaxation time, producing increased signal in skeletal muscle on short tau inversion-recovery and fat-suppressed T2-weighted images. Chronic denervation produces fatty atrophy of skeletal muscles, resulting in increased muscle signal on T1-weighted images.[26]

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.

See the list below:

• 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.

• Measurement of nerve excitability by threshold tracking provides complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during the process of impulse conduction. This review highlights recent clinical excitability studies that have suggested mechanisms for nerve involvement in a range of metabolic and toxic neuropathies. While there is growing evidence of their utility to provide novel insights into the pathophysiological mechanisms involved in a variety of neuropathic disturbances, it is too early to know whether they have diagnostic value.[27]

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.

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.

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.[28] 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: A 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

See the list below:

• 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 AAN guideline for treatment of painful diabetic neuropathy (PDN) from 2011 established pregabaline as effective treatment (Level A Evidence).[29] Venalafaxine, duloxetine, amitriptline, capsaicin, gabapentin, valproate, opioids (morphine sulfate, tramadol and oxycodone controlled release) are probably effective for treatment of PDN (Level B Evidence). The FDA has approved duloxetine hydrochloride, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), pregabalin, and capsaicin patches 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.[30] 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.

    • Pregabalin: Pregabalin binds to calcium channels and modulates calcium influx at nerve terminals. A randomized, double-blind, placebo-controlled, parallel group, multicenter trial done in 2004 showed that pregabalin produced significant improvement in pain score and sleep. The pain relief and sleep improvement began in week 1 of the study and effect remained significant through the study length. It was also effective in improving mood and quality of life. There was greater incidence of dizziness and somnolence as compared to placebo, but the adverse effects were mild to moderate and did not result in withdrawal from study.[31] Another randomized, double-blind clinical trial compared pregabalin and amitriptyline. There was no significant difference in improvement in both groups and improvement was seen from the first week. There were more reported adverse effects with amitriptyline (65.4%) as compared to pregabalin (25%).[32]

    • 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. Freeman et al performed a meta-analysis of 7 randomized, placebo-controlled trials that evaluated the efficacy and safety of pregabalin treatment of painful diabetic peripheral neuropathy.[33] Daily doses included 150, 300, and 600 mg/d, with dosing intervals of 2 or 3 times per day. Pregabalin was found to be effective for painful diabetic peripheral neuropathy at all doses and intervals, with the greatest and most rapid pain reduction seen in patients receiving pregabalin 600 mg/d divided into 2 or 3 doses.

    • 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.

    • The SYDNEY-2 trial provided evidence that oral treatment with alpha lipoic acid for 5 weeks improved symptoms in patients with distal sensory polyneuropathy. A daily oral dose of 600 mg was found to have optimum risk-benefit ratio.[34]

    • A systematic review conducted in 2013 to determine role of acupuncture in management of diabetic peripheral neuropathy showed that manual acupuncture had better effect on global symptom improvement as compared to mecobalamin, Vitamin B1, Vitamin B12 and no treatment. The combination of manual acupuncture and mecobalamin had better effects on global symptom improvement than mecobalamin alone. Assymetric funnel plot suggested publication bias so more high-quality studies are needed for effects of acupuncture.[35]

  • Kiviniemi et al., based on their study, conclude that low cardiorespiratory fitness (CRF) was a more important determinant of cardiac autonomic function than moderate-to-vigorous physical activity (MVPA) and body fat. Furthermore, MVPA but not body fat was independently associated with cardiac autonomicfunction in both men and women.[36]

See the list below:

• 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)

See the list below:

• 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

See the list below:

• 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

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

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

Class Summary

These agents increase peristalsis of upper GI tract.

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.

Class Summary

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

Ampicillin (Omnipen, Marcillin, Polycillin, Principen)

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

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).

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).

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.

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.

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.

Amitriptyline (Elavil)

Analgesic for certain types of chronic and neuropathic pain.

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.

Class Summary

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

Paroxetine (Paxil)

Effective in painful diabetic neuropathy.

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.

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.

Carbamazepine (Tegretol)

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

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.

Class Summary

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

Tramadol (Ultram)

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

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.

Levodopa (Depar, Larodopa)

Has actions over noradrenergic receptors.

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.

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.

Class Summary

SSNRIs have antidepressant and central pain inhibitory actions.

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.

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.

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.

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

Transfer patients to an inpatient facility whenever complications develop.