• The five-step approach to classify neuropathies based on fiber type, pattern of distribution, temporal course, pathology, and key features allows a tailored diagnostic evaluation.
• Electrodiagnostic testing provides a useful adjunct to the clinical evaluation.
• The cause of neuropathy might not be found in 20% of patients, but there are treatments for several known etiologies, as well as specific medications to treat neuropathic pain.
Disorders of the peripheral nerve system (PNS) include pathology affecting the spinal cord roots (radiculopathies), the dorsal root ganglia (neuronopathies), the brachial, lumbar, and sacral plexuses (plexopathies), and the terminal nerve (mononeuropathies) or nerves (polyneuropathies). They are among the most common and challenging problems in medical practice, with literally hundreds of conceivable causes. An organized diagnostic approach consists of first categorizing the neuropathy based on clinical and electrophysiologic assessments and then performing a tailored diagnostic evaluation.
However astute the diagnostician, the cause of a neuropathy might not found in up to 20% of patients.
Four types of fibers are found in the PNS: motor, large fiber sensory, small fiber sensory, and autonomic. Motor fibers extend peripherally to the neuromuscular junction of their respective muscles and have their cell bodies in motor neurons located in the spinal cord.
Conversely, sensory fibers receive information from peripheral sensory receptors and transfer this to cell bodies in the dorsal root ganglia, located near, but outside, the spinal cord. Large, myelinated sensory fibers supply information regarding position and vibration. Small myelinated axons, composed of autonomic and sensory fibers, are responsible for light touch, pain, temperature, and parasympathetic and sympathetic information.
Damage can occur to the cell bodies (neuronopathy), nerve fibers (axonopathy), or to the surrounding myelin sheath (myelinopathy). Myelinopathies principally affect only the coating around the nerve, and an axonopathy results in degeneration of both the axon and myelin. The most distal segments usually degenerate first, in a process termed Wallerian degeneration, resulting in a dying-back neuropathy and a stocking and glove clinical pattern. Neuronopathies affect either the motor neuron or dorsal root ganglion and result in degeneration of both peripheral and central processes.
Five-Step Approach to Neuropathies
When evaluating neuropathy, the differential diagnosis can be limited by asking five key questions:
• What is the fiber type involved (motor, large sensory, small sensory, autonomic, combination)?
• What is the pattern of distribution (distal or proximal, symmetric or asymmetric)?
• What is the temporal course (acute, chronic, progressive, stepwise, relapsing–remitting)?
• Are there any key features pointing to a specific etiology?
• What is the pathology (axonal, demyelinating)?
The PNS produces symptomatology in only two ways: negative symptoms (weakness, numbness), which reflect loss of nerve signaling, or positive symptoms (tingling, burning) due to inappropriate spontaneous nerve activity. Box 1 lists symptoms and signs that suggest localization to the peripheral nerves and point specifically to motor, sensory, or autonomic involvement. When inquiring about symptoms, it is important to ask the patient to be as specific as possible. Many patients simply describe an area as numb when, in fact, they are experiencing tingling or even weakness.
|Signs and Symptoms of Peripheral Nervous System Disease by Fiber Type|
• Muscle atrophy
• Pes cavus
Large Fiber Sensory
• Decreased vibration and position
• Pins and needles
• Unsteady gait, especially at night or with eyes closed
Small Fiber Sensory
• Decreased pain sensation
• Decreased temperature sensation
• Decreased or increased sweating
• Heat intolerance
• Postural hypotension
• Urinary retention
A detailed motor examination should include inspection for atrophy, particularly in the distal extensor digitorum brevis and first dorsal interosseous muscles, and for fasciculations (visible twitches of muscle), which are best seen using tangential light. Strength should be tested against resistance, as well as with active maneuvers such as walking on the heels and toes to assess distal strength and rising from a squatting position to examine proximal muscles. Facial muscles should also be tested. When assessing deep tendon reflexes, ensure the reflex is truly absent by asking the patient to concurrently perform a Jendrassic maneuver (pulling against interlocking fingers) or clench the jaw. Note that the reflex arc consists of large-diameter afferent sensory input as well as motor nerve output, so that dysfunction of either can impair reflexes. Tone is sometimes reduced in peripheral nerve diseases.
On sensory examination, sensation should be tested with a pin and a 128-Hz vibratory tuning fork, beginning at the big toe level and moving progressively more proximal. Likewise, position testing should begin distally, with fingers placed on the lateral sides of the big toe and progressively smaller movements tested. Severe loss of position sense can result in athetoid movements of the fingers when the eyes are closed (pseudoathetosis) or a positive Romberg’s sign.
Temperature can be tested informally by placing a cold tuning fork on the skin. Foot injuries may be apparent with severe sensory loss.
Other important signs include high arches and hammertoe deformities, which suggest a long-standing neuropathy causing differences in muscular force. Demyelinating neuropathies, amyloidosis, and leprosy can cause nerve thickening, which is felt best in the dorsal cutaneous nerve of the foot or the great auricular nerve.
Superficial nerves, such as the ulnar nerve at the elbow, can be palpated when appropriate. Postural blood pressure should be assessed for a blood pressure drop more than 20 mm Hg systolic or more than 10 mm Hg diastolic, following 5 minutes of supine rest at a minimum, to test autonomic functioning.
Several other levels of the nervous system can mimic symptoms of PNS disease. Myelopathy and motor neuron disease can manifest with weakness similar to motor neuropathies, although upper motor neuron features such as spasticity and increased reflexes are clues.
Myopathies can also cause weakness, but usually more proximal than distal and without any sensory impairment. Isolated sensory involvement should be a red flag that the dorsal root ganglia may be the site of involvement rather than the peripheral nerve; this is particularly important because neuronopathies have a limited differential.
Pattern of Distribution
The pattern of distribution should be classified in two ways: symmetric or asymmetric and distal or proximal. Putting this together with the fiber type, six patterns of PNS disorders can be appreciated, with specific differentials (Table 1).
Causes of Neuropathy by Pattern Type
Abbreviations:ANA = antinuclear antibodies; ANCA = antineutrophilic cytoplasmic antibodies; bx = biopsy; CBC = complete blood count; CIDP = chronic inflammatory demyelinating polyneuropathy; CMT = Charcot-Marie-Tooth disease; CSF = cerebrospinal fluid; EMG/NCS = electromyography/nerve conduction studies; ESR = erythrocyte sedimentation rate; GBS = Guillain-Barré syndrome; HIV = human immunodeficiency virus; HNPP = hereditary neuropathy with liability to pressure palsies; IF = immunofixation; LFT = liver function tests; MGUS = monoclonal gammopathy of unknown significance; MMNCB = multifocal motor neuropathy with conduction blocks; OGTT = oral glucose tolerance test; RF = rheumatoid factor; SPE = serum protein electrophoresis; TSH = thyroid-stimulating hormone.
The symmetric distal sensorimotor neuropathy (pattern 1) manifests in a stocking-and-glove distribution and is the most common type of polyneuropathy. Once the level of the upper calves is reached, fibers of the same length in the fingertips begin to be affected. Sensorimotor polyneuropathies that affect both the distal and proximal nerves (pattern 2) should alert the physician to think of inflammatory neuropathies, such as Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP).
Asymmetric patterns (pattern 3) are often a result of trauma or compression, such as that seen in mononeuropathies, radiculopathies, and plexopathies. A pattern that affects multiple anatomically separated nerves is termed mononeuritis multiplex and is usually the result of a more diffuse process, such as diabetes or vasculitis.
Predominant motor neuropathies (pattern 4) are often proximal, such as diabetic amyotrophy. An exception is lead neuropathy, which affects motor fibers in a distal radial and peroneal distribution. Pure sensory neuropathies (pattern 5) are more likely to be distal, with the exception of a rare few such as Tangier disease, which manifests with a bathing-suit pattern. Neuropathies with autonomic impairment have a limited differential (pattern 6).
Additionally, involvement of the cranial nerves is only seen in a few causes of neuropathy. GBS, CIDP, Lyme disease, sarcoidosis, HIV- associated neuropathy, and Tangier disease are examples.
Acute neuropathies are relatively rare and suggest an etiology such as GBS, acute intermittent porphyria, ischemia, toxins (thallium toxicity), drugs, or infections (diphtheric neuropathy). Subacute onset (>8 weeks) is seen in nutritional deficiencies, metabolic neuropathies, paraneoplastic syndromes, and CIDP. A chronic course is typical of hereditary neuropathies, a stepwise pattern can be seen in mononeuropathy multiplex, and a relapsing-remitting course occurs with intermittent exposure to a toxin or drug and in CIDP.
Sometimes, there is a key classic feature on history or examination that significantly narrows the differential immediately. Box 2 includes a checklist of items for inquiry and observation during assessment of neuropathy.
|Key Diagnostic Features|
• Connective tissue disease
• Renal disease
• Thyroid disease
Surgical History, Trauma
• Compression neuropathies
• Drug-induced neuropathy
Family History, High Arches
• Inherited neuropathy
Nutrition, Alcohol Use
• Alcoholic neuropathy
• Vitamin deficiency
• Toxic neuropathy
History of Weight Loss
Recent Infection, Travel
• Guillain-Barré syndrome
• Lyme disease
Dry Eyes and Mouth
• Guillain-Barré syndrome
• Anesthetic patches (leprosy)
• Bullous lesions (porphyria)
• Hyperpigmentation (osteosclerotic myeloma)
• Mee’s lines (arsenic or thallium poisoning)
• Orange tonsils (Tangier disease)
• Angiokeratomas (Fabry’s disease)
Pathology and the Role of Neurophysiology
Nerve conduction studies (NCSs) and electromyography (EMG) are highly specialized tests that are performed principally by neurologists. NCSs electrically activate peripheral nerves at particular sites and then assess for abnormal transmission from the stimulation point to the final muscle response. EMG involves placing a small needle into the muscle to observe both the sound and appearance of the muscle at rest and with motor units firing. Because NCSs can only be performed at points where the nerve is superficial (most often distal), EMG is needed to assess for more proximal damage such as radiculopathy. EMG can also rule out other mimics of PNS disease, such as myopathy.
For the general physician, the most important thing is being able to interpret the results of these tests. Often, a report will be received back such as: “There is evidence of a symmetric distal axonal sensorimotor neuropathy.” An NCS/EMG study should be able to specify the distribution and if motor or sensory fibers are involved. Autonomic and small sensory fibers are not tested well by EMG, so the diagnosis of these types of neuropathies is often clinical or requires more specialized testing. Thus, a normal NCS/EMG does not rule out neuropathy.
A further feature that electrophysiology can add is whether the pathology is demyelinating or axonal. Demyelination is characterized by slowed conduction velocity, temporal dispersion of the muscle action potential, and conduction block. Hereditary demyelinating neuropathies, such as Charcot-Marie-Tooth disease, do not show the latter two features, which are only seen in acquired neuropathies.
Axonal disease is characterized by modest slowing of velocities and more marked reduction in the amplitudes of the muscle and sensory action potentials. On EMG, there are fibrillations within 3 weeks of the neuropathic injury, indicating spontaneous firing of denervated muscle. Enlarged and prolonged motor unit potentials indicate subsequent regeneration, which occurs after several weeks to months.
Demyelination has a limited differential (Box 3) and often a better prognosis, because myelin can start to regenerate within a few days. Axonal regeneration proceeds at a far slower rate of 1 to 3 µm/day, and nerves with proximal lesions must go a long distance to reinnervate their muscle and might never reach their goal.
|• Charcot-Marie-Tooth disease
• Hereditary neuropathy with liability to pressure palsies
• Inflammatory neuropathies
• Monoclonal gammopathies and paraproteinemias
• Multifocal motor neuropathy with conduction block
• Neuropathies caused by drugs such as amiodarone (Cordarone) and suramin2
• Neuropathies caused by infections (diphtheria) or toxins (arsenic)
|2 Not available in the United States.|
Once the neuropathy has been subclassified, investigations for the specific causes in that pattern class should be undertaken (see Table 1). Several recent papers suggest that 2-hour oral glucose tolerance testing (OGTT) is the best test for glucose intolerance due to the relatively low sensitivity of serum glucose levels and glycosylated hemoglobin (HbA1c). Likewise, vitamin B12 levels have a low sensitivity, and serum metabolites methylmalonic acid (MMA) and homocysteine (Hcy) should be measured in patients with a result less than 300 pg/mL to improve diagnostic accuracy. These metabolites can be falsely increased with hypovolemia, renal insufficiency, hypothyroidism, and increased age, but a return to normal levels 1 to 2 weeks after beginning replacement therapy indicates this is the cause. The combination of elevated gastrin and anti–parietal cell antibodies may be used to diagnose pernicious anemia. The yield of general testing for other vitamin deficiencies in polyneuropathy is relatively low.
Antinuclear antibodies (ANA) probably are usually only significant in the context of suggestive features (abrupt onset, mononeuropathy multiplex pattern, arthralgia or arthritis, fevers, rash, or renal abnormalities) because they are positive in about 3% of normal patients. However, referral to a rheumatologist should be considered with a very high titer (>1:1280).
The erythyrocyte sedimentation rate (ESR) is often elevated, especially in older patients. Rates greater than 70 mm/hour tend to be more meaningful, particularly with a mononeuritis multiplex pattern.
Serum protein electrophoresis lacks sensitivity, and immunofixation should be ordered if there is high suspicion of a paraproteinemia. If an elevated monoclonal antibody is found, a 24-hour urine test for Bence Jones proteinuria, skeletal survey, CBC, renal function tests, and serum calcium should be ordered. If the M protein is greater than 2.5 g/dL or if abnormalities are detected on these tests, referral to a hematologist for bone marrow aspiration is required. Polyclonal antibodies are not associated with neuropathy.
If there is suspicion of amyloidosis, a rectal, abdominal fat, or sensory nerve biopsy can be undertaken. Sural nerve biopsy is reserved for difficult diagnostic situations because it causes a permanent area of numbness with possible dysesthesias over the biopsied area. Suspicion of vasculitis is the most common indication, but pathology can also be seen in leprosy and with tumor infiltrate.
In approximately 20% of patients, an underlying cause of neuropathy is not found. These patients are said to have a cryptogenic sensory or sensorimotor neuropathy. A distinct clinical picture has emerged, most commonly of a patient in the sixth or seventh decade manifesting with distal dysesthesias and possibly with mild weakness and sensory ataxia. These patients tend not to develop significant disability, and treatment is mainly for neuropathic pain.
The most common cause of mononeuropathy is nerve compression, and surgical treatment is often a consideration for these patients. The four most common locations are median neuropathy at the wrist (carpal tunnel syndrome), ulnar neuropathy at the elbow, peroneal neuropathy at the fibular head, and facial nerve palsy (Bell’s palsy).
Carpal tunnel syndrome manifests with pain and numbness principally in the first three digits, although it is often poorly localized. Classic features include pain at night and shaking out the hand to relieve pain. For milder symptoms, a nighttime splint, which prevents wrist flexion and high pressure in the carpal tunnel, is often helpful. Local corticosteroid injections can provide relief, and surgical decompression has a very high success rate.
Ulnar neuropathy manifests with numbness of the fourth and fifth digits and wasting of the interosseous muscles, often with pain localized to the elbow. Peroneal neuropathies manifest with foot drop and numbness on the dorsum of the foot. In both cases, avoidance of pressure over the nerve often leads to improvement. Surgery might improve symptoms, but less reliably so than carpal tunnel surgery.
Bell’s palsy is an inflammatory rather than compressive process, presumably due to a viral etiology. Treatment is controversial, but early (within 14 days) use of prednisone1 60 mg daily, decreasing by 10 mg steps every 2 days, along with acyclovir (Zovirax)1 800 mg five times daily for 7 days has been advocated. About 15% of patients have residual facial weakness.
GBS often begins following gastroenteritis with Campylobacter jejuni, or an upper respiratory tract infection, due to a presumed autoimmune response directed against myelin. The incidence is 1 or 2 per 100,000 persons per year. Characteristic features are ascending weakness, areflexia, and sensory and autonomic symptoms progressing over a few days up to 4 weeks. Facial diplegia and pain can occur. Electrophysiology shows acute demyelination with conduction blocks, and cerebrospinal fluid (CSF) reveals an increase in protein with a cell count of fewer than 5 white blood cells (cytoalbuminologic dissociation) in more than 80% of patients after 2 weeks. A CSF pleocytosis of more than 10 lymphocytes/mm3 should alert the physician to another cause such as sarcoidosis, Lyme disease, or early HIV.
The Miller-Fisher variant is characterized by specific clinical features of sensory ataxia, areflexia, and ophthalmolplegia. C. jejuni infection has been correlated with more severe variants, such as acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAM), which damage axons in addition to myelin. C. jejuni–related GBS correlates with anti-GM1 antibodies, although they are not prognostic or specific. Recovery can take months to years. Only 20% of patients are left without residual deficit. About 5% to 10% have significant persistent disability, and the mortality rate is 5%.
During early treatment, patients might require admission to intensive care, with close monitoring of pulmonary function tests for respiratory compromise. Diaphragmatic weakness correlates with neck flexion and extension and shoulder abduction. The patient should be intubated when the forced vital capacity (FVC) declines to less than 15 mL/kg or when negative inspiratory flow (NIF) is less than −20 to −30. Monitoring of the cardiac rhythm is important due to dysautonomia.
The preferred treatment is intravenous immunoglobulin (IVIg)1 at a dose of 0.4 g/kg/day for 5 days. This is generally well tolerated, and adverse side effects such as myalgia, headache, or flu-like symptoms often resolve with a reduced infusion rate. If IVIg is contraindicated (renal failure, IgA deficiency), plasmapheresis can be initiated with four alternate-day exchanges over 7 to 10 days for a total of 200 to 250 mL/kg. Both plasmapheresis and IVIg continue to work for several weeks after the treatment period, but if patients experience a secondary worsening after successful treatment, a second dose may be initiated. Steroids were reviewed recently by a Cochrane systematic review and were not found to be of benefit in GBS.
Chronic Inflammatory Demyelinating Polyneuropathy
This neuropathy is pathologically similar to GBS, but progression is longer than 8 weeks, often with a relapsing-remitting course.
Symmetric distal and proximal weakness and sensory impairment, hyporeflexia, and cytoalbuminergic dissociation in the CSF is the classic presentation, although there are variants.
Treatment is either IVIg1 or prednisone. IVIg is given initially at 1.4 g/kg/day for 5 days, and then the dose and frequency are reduced over time. Prednisone is given 1 mg/kg/day until improvement, followed by a slow tapering of 5 mg every 2 to 3 weeks over a period of months. Response is usually seen within 4 weeks. Refractory patients have been treated with repeated plasmapheresis treatments or immunosuppressive therapy with cyclosporine (Sandimmune).1
Multifocal Motor Neuropathy
Multifocal motor neuropathy (MMN) is not a common disorder but is important not to mistake for motor neuron disease because it has a very different prognosis and treatment. Patients present with progressive asymmetric distal weakness, often of the arm, without sensory loss and with less atrophy than would be expected for the degree of weakness. Unlike motor neuron disease, there are no upper motor neuron signs. It is different from multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), an asymmetric variant of CIDP, in that loss of reflexes and weakness involves only the affected limb, there is a relatively normal CSF protein concentration, and sensory nerve conduction studies are normal. Diagnosis is supported by finding conduction blocks in sites not usually associated with compression. The GM1 antibody is elevated in 60% of cases. Repeated treatments with IVIg1 or cyclophosphamide (Cytoxan)1 are common choices. Rituximab (Rituxan),1 a monoclonal antibody, has also been used. Prednisone classically worsens the condition.
Diabetes is one of the most common causes of neuropathy. Patients can present with a symmetric distal neuropathy, autonomic proximal diabetic neuropathy, mononeuritis multiplex, compressive and cranial neuropathies, and trunk polyradiculopathies.
The distal symmetric sensory polyneuropathy (DSPN) correlates with the duration of the diabetes, control of hyperglycemia, and presence of retinopathy and nephropathy. The exact etiology is unknown, but theories include a metabolic process involving aldose reductase, ischemic damage, or an immunologic disorder. Typical symptoms include lancinating pains or burning, worse at night, and possible dysautonomia. Atrophy may be noted in the foot muscles, but severe weakness is atypical. NCS may be normal because small fibers are primarily affected. Treatment includes blood sugar control to limit progression and symptom control for neuropathic pain.
Gabapentin (Neurontin)1 and tricyclic antidepressants are common choices (see later). Drugs such as QR-333, a topical compound that contains quercetin, a flavonoid with aldose reductase–inhibitor effects, are being investigated specifically for diabetic neuropathy.
Autonomic neuropathy is treated symptomatically, with fludrocortisone (Florinef)1 0.1 mg/day for orthostatic hypotension, meto-clopramide (Reglan) 10 mg before meals for gastroparesis, and sildenafil (Viagra) 25 mg 1 hour before sexual intercourse for impotence.
Proximal diabetic neuropathy (diabetic amyotrophy) manifests typically with unilateral pain in the anterior thigh followed by step- wise progression over weeks to months of quadriceps weakness, atrophy of the proximal leg muscles, and a reduced knee reflex, with occasional contralateral leg involvement. The ESR may be elevated and CSF protein mildly increased (120 mg/dL on average). NCS and EMG reflect multifocal active axonal damage (fibrillations) to the lumbar plexus and roots. Small retrospective studies have reported that IVIg1 and other forms of immunosuppressive therapy are effective in treating patients with proximal diabetic neuropathy. A short course of corticosteroids (prednisone1 50 mg/day for 1 week, then tapering by 10 mg/week) can be used to ease pain in severe cases, with close monitoring of the glucose level, but overall prognosis is quite good, ranging from 1 to 18 months of recovery phase (mean of 6 months) and partial or complete restoration of strength in approximately 70% of patients.
Multiple myeloma, Waldenström’s macroglobulinemia, cryoglobulinemia, osteosclerotic myeloma (POEMS syndrome), and monoclonal gammopathy of unknown significance (MGUS) are associated with monoclonal antibodies directed at PNS components, such as myelin-associated glycoprotein (MAG). Neuropathies associated with an immunoglobulin (Ig)M monoclonal protein (approximately 60%) are typically distal, demyelinating, and symmetric, whereas IgG (30%) and IgA (10%) gammopathies can be axonal or demyelinating. In terms of treatment, the distal demyelinating neuropathy of IgM paraproteinemias tends to be treatment refractory. IgG and IgA gammopathies can mimic the demyelination pattern seen in CIDP, and patients with any antibody and this pattern should receive immunotherapy as recommended for CIDP (see earlier). Axonal neuropathies and IgM, IgG, or IgA gammopathies have a less clear relationship and are typically not responsive to treatment.
Charcot-Marie-Tooth (CMT) disease is among the most common of genetic neuromuscular disorders, and more than 30 genes have been identified. Clues are a history of difficulty running in childhood, high arches, hammertoes, ankle weakness, and nerve hypertrophy developing in teenage years. Depending on the subtype, the neuropathy may be axonal or demyelinating, but the most common type (CMT-1) is caused by an autosomal dominant gene encoding peripheral myelin protein 22 and is easily diagnosed by the relatively uniform slowing on nerve conduction velocities (<25% of lower limits of normal). Patients have a mild course and remain ambulatory throughout life in most cases.
Hereditary neuropathy with liability to pressure palsies (HNPP) is another dominantly inherited neuropathy in which patients have recurrent episodes of isolated mononeuropathies, typically affecting, in order of decreasing frequency, the common peroneal, ulnar, radial, and median nerves. Most attacks are sudden onset, painless, and followed by complete recovery. There is no treatment other than preventive measures.
Toxic and Nutritional Neuropathies
Treatment of toxic and nutritional neuropathies involves detection and removal of the underlying cause. A thorough review of medications, occupational exposures, and nutritional risk factors is essential (Box 4). Drug toxicity is much more common than environmental toxicity. Incidence of neuropathy does not always correlate with the dosage and duration of exposure. For instance, amiodarone neuropathy has been reported with dosages as low as 200 mg/day and durations as short as 1 month. Symptoms might not improve, or might even worsen, for several weeks after the drug is stopped before improvement starts, a phenomenon known as coasting.
|Causes of Toxic and Nutritional Neuropathies|
• Nitrous oxide
• Amiodarone (Cordarone)
• Chloroquine (Aralen)
• Cisplatin (Platinol-AQ)
• Pyridoxine (vitamin B6)
• Thalidomide (Thalomid)
• Acrylamide (plastics)
• Allyl chloride (insecticides)
• Carbon disulfide (cellophanes)
• Ethylene glycol (antifreeze)
• Ethylene oxide (sterilizer)
• Hexacarbons (glue)
• Methyl bromide (fumigant)
• Organophosphates (insecticides)
• Thallium (pesticides)
• Trichloroethylene (drycleaning)
• Vacor (rodenticide)
• B1 (alcoholism)
• B3 (alcoholism)
• B6 (isoniazid use)
• B12 (vegans, pernicious anemia)
• E (cholestasis and abetalipoproteinemia)
2 Not available in the United States.
Cisplatin can cause a neuropathy that overlaps in symptomatology with paraneoplastic sensory neuronopathy, and dapsone is associated with a motor axonopathy. Gold neuropathy can have prominent myokymia and can mimic GBS.
Specific treatments for drug-induced neuropathies include cyano- cobalamin (vitamin B12)1 for nitrous oxide neuropathy and pyridoxine (vitamin B6)1 for hydralazine and isoniazid neuropathies. Excessive vitamin B6 can also cause a neuropathy. Glutamine7 and vitamin E1 300 mg twice a day has shown promise for paclitaxel neuropathy, and neuroprotective agents such as nerve growth factor are being investigated for cisplatin-induced neuropathy. Tacrolimus can cause a CIDP-like neuropathy that responds to IVIg1 or plasmapheresis.
One of the most common nutritional neuropathies is caused by thiamine deficiency and is associated with alcohol consumption of at least 100 g per day. Patients present with burning feet, and early alcohol abstinence and treatment with thiamine denotes better chance of recovery. Vitamin B12 deficiency is vital not to miss and can manifest with a subacute combined degeneration, whereby patients have a superimposed myelopathy and neuropathy (spasticity but reduced reflexes). Sudden-onset symptoms, particularly in the feet and hands simultaneously, are also suggestive.
Metabolic and Infectious Neuropathies
Peripheral neuropathy can complicate renal failure, hypothyroidism, biliary cirrhosis, porphyria, Tangier disease, Fabry’s disease, and mitochondrial diseases.
Early in the course, HIV can manifest as a GBS-like syndrome, although with CSF pleocytosis. This typically responds to IVIg1 and plasmapheresis. In later stages, patients might develop a distal symmetric polyneuropathy, although it is important to determine if this might be due to nucleoside reverse transcriptase inhibitors, nutritional deficiency, or infection. Cranial neuropathies, sensory neuronopathy, lumbosacral polyradiculopathies, and mononeuritis multiplex also occur.
Leprosy is the most common treatable neuropathy worldwide.
Tuberculoid leprosy leads to hypopigmented patches with loss of pain and temperature sensation. Lepromatous leprosy, a more severe form seen in immunosuppressed persons, can cause ulnar, common peroneal, and facial neuropathies. Treatment involves a long-term multidrug regimen of dapsone and rifampin (Rifadin).1
Herpes zoster can cause a postherpetic neuralgia, defined as pain persisting for more than 6 weeks after the rash appears. Early treatment with acyclovir (Zovirax) (800 mg five times daily for 7 days) can reduce the duration of the acute phase. Chronic discomfort is treated with medications for neuropathic pain (see later).
Lyme disease, caused by Borrelia burgdorferi, begins with erythema migrans, followed by multifocal peripheral and cranial neuropathies, particularly facial diplegia. CSF lymphocytic pleocytosis plus serologic demonstration of B. burgdorferi infection on serum or CSF are the diagnostic features. Early stages are treated with a 3-week course of doxycycline1 100 mg twice daily, and intravenous penicillin G1 should be given in the late stages.
Tumors can cause neuropathy by compression, metastatic spread, paraneoplastic antibodies, hemorrhage, and treatment with chemotherapy or radiation therapy. A distal sensorimotor neuropathy is associated with many different tumors and seldom precedes tumor diagnosis. Pathogenesis can include toxic, nutritional, and immunologic causes. A sensory neuronopathy is less common, but often precedes tumor diagnosis, thus warranting a careful work-up.
Lung, breast, ovary, and gastrointestinal tract cancers are the most likely associated types. Imaging and paraneoplastic antibodies (particularly anti-Hu and anti-CV2, most commonly associated with lung cancer) may help in making the diagnosis. Treatment focuses on the underlying neoplasm.
Vasculitis can be primary (polyarteritis nodosa, Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangitis) or secondary (connective tissue diseases, systemic infections, drug reactions). It classically manifests with a painful mononeuritis multiplex with asymmetric patchy features, reflecting multifocal ischemic damage. If the patient’s vasculitis is restricted to the PNS, serologic testing for these disorders is often negative. In this case, a sural nerve biopsy might reveal fibrinoid necrosis and perivascular inflammation.
Treatment needs to be carefully undertaken with intravenous methylprednisolone (Solu-Medrol)1 for 3 days followed by oral prednisone. In many cases, other immunosuppressive drugs are eventually used.
Often pain is the most predominant and distressing feature of neuropathy. Several classes of medications can be tried (Table 2), although it is important to counsel the patient that complete abolition of pain is unlikely. A trial period should be undertaken for at least 6 to 8 weeks before concluding that the patient does not respond. A combination of agents with different mechanisms can have an advantage over monotherapy for the nonresponsive patient.
Select Neuropathic Pain Medications
|Amitriptyline (Elavil)1||10 mg/d, increasing weekly by 10 mg, up to 150 mg/d||Dry mouth, sedation, urinary retention, cardiac arrhythmias, orthostatic hypotension, constipation, weight gain
Contraindications: cardiac arrhythmias, CHF, recent MI, narrow angle glaucoma, urinary retention
|Capsaicin (Zostrix)||0.075% cream applied tid to qid||Sneezing, coughing, rash, skin irritation|
|Carbamazepine (Tegretol)1||100 mg bid, increasing by 100 mg weekly
Max: 1200 mg/d
|Somnolence, dizziness, nausea, gait changes, urticaria, hyponatremia, pancytopenia, hepatic dysfunction
Obtain baseline and 6-wk CBC and LFT
|Gabapentin (Neurontin)1||300 mg on day 1, 600 mg on day 2,
900 mg on day 3
Max: 3600 mg/d
|Sedation, fatigue, dizziness, confusion, tremor, weight gain, peripheral edema, headache
Reduce dose in renal insufficiency
|Lamotrigine (Lamictal)1||25 mg at night for 2 wk, increasing weekly by 25–50 mg
Max: 400 mg/d
|Severe rash (especially if increased too quickly), dizziness, unsteadiness, drowsiness, diplopia|
|Tramadol (Ultram)||50 mg bid
Titrate 50 mg every 3–7 d, using a tid or qid schedule
Max: 100 mg qid
|Constipation, headache, nausea
Risk of seizures with neuroleptics and antidepressants Reduce dose with hepatic or renal dysfunction
Abbreviations: CBC = complete blood count; CHF = congestive heart failure; LFT = liver function test; max = maximum; MI = myocardial infarction.
1 Not FDA approved for this indication.
First-line treatment is generally with tricyclic antidepressants.
Serotonin and noradrenaline reuptake inhibitors such as amitriptyline1 (Elavil), imipramine1 (Tofranil), and clomipramine1 (Anafranil) may be marginally more effective than those with relatively selective noradrenergic effects such as desipramine and nortriptyline. However, nortriptyline and desipramine are less sedating. Selective serotonin reuptake inhibitors appear to be less effective. Second-line antidepressants include venlafaxine1 (Effexor), bupropion1 (Wellbutrin), and the recently approved duloxetine (Cymbalta), which have the advantage of better tolerability due to less muscarinic, histaminergic, and α-adrenergic affinity.
The typical next class of medications to try is the antiepileptics. Gabapentin1 is a common choice and is generally well tolerated. Pregabalin (Lyrica) is a newer related agent that, unlike gabapentin, exhibits linear pharmacokinetics and can be initiated at a therapeutic dose without a long titration. Second-line choices include lamotrigine1 (Lamictal), carbamazepine1 (Tegretol), and topiramate1 (Topamax).
Valproate1 (Depacon) and zonisamide1 (Zonegran) have limited evidence, and phenytoin1 (Dilantin) can cause neuropathy.
Oxcarbazepine1 (Trileptal), like carbamazepine, slows the recovery rate of voltage-activated sodium channels, but it also inhibits high- threshold N-type and P/Q-type calcium channels and reduces glutamatergic transmission. As a result, it can modulate both peripheral and central neuropathic pain pathways, and several studies into its efficacy are under way.
Topical creams, such as capsaicin (Zostrix), an extract of chili, can be tried. Capsaicin works by depleting substance P and can temporarily worsen pain by causing a burning sensation. Lidocaine1 (Xylocaine) can be also used topically.
Other agents for severe neuropathies include opioid agents, such as tramadol (Ultram), which has low-affinity binding for µ-opioid receptors coupled with mild inhibition of norepinephrine and serotonin reuptake. Slow-release opioids, such as oxycodone (OxyContin) 30 to 60 mg/day, can help, and risk of addiction is low in this population. Glutamate antagonists, such as dextromethorphan1 (Delsym), have shown benefit in some studies, as has mexiletine1 (Mexitil), a class IB antiarrhythmic agent and oral analogue of lidocaine. Nonpharmacologic therapies, such as transcutaneous electrical nerve stimulation (TENS) and acupuncture, might also provide adjunctive relief.
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2. Dworkin R.H., Backonja M., Rowbotham M.C., et al. Advances in neuropathic pain: Diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60:1524–1534.
3. Grant I., Benstead T.J. Differential diagnosis of peripheral neuropathy. In: Dyck P.J., Thomas P.K., eds. Peripheral Neuropathy. Philadelphia: Saunders; 2005.
4. Poncelet A.N. An algorithm for the evaluation of peripheral neuropathy. Am Fam Physician. 1997;57(4):755–764.
5. Stewart J.D. Focal peripheral neuropathies. New York: Raven Press; 1993.
1 Not FDA approved for this indication.
7 Available as a dietary supplement.