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Peripheral Neuropathy guidelines

most of neuropathy is really CIDP.

Article URL: http://merck.micromedex.com/index.asp?page=bpm_brief&article_id=BPM01NE12

Peripheral Neuropathy

by Frisso A Potts, MD, Best Practice of Medicine. April 2001.

Last modified November 14, 2001.

History

a complete current medical history, past medical history, occupational history, family history, and review of systems.

Try to determine whether presenting symptoms are motor, sensory, or both
Inquire about autonomic symptoms: e.g., fainting spells, orthostatic hypotension (lightheadedness when upright), abnormal sweating, gastrointestinal symptoms (early satiation, bloating, nausea), urinary symptoms (frequency, incontinence), and erectile dysfunction.
Ask the patient about the order in which the body parts became affected.
Inquire about the temporal course of signs and symptoms: i.e., are they acute, subacute, chronic, progressive, relapsing, or remitting?
Ask about a family history of nervous system or muscular diseases, or bone deformities, especially if an acquired generalized neuropathy is suspected.
Try to determine whether PN symptoms are related to an underlying infection or systemic illness.
Ask about potential occupational exposures to toxins [Table 6], and try to determine whether symptoms are related to occupational exposure(s).
Inquire about the use of any medications, both nonprescription and prescription.
Ask about dietary habits, vitamin intake, and use of alcohol.

Physical Examination

Perform a complete physical and neurological examination.
Assess the presence and distribution of weakness [Table 7] [Table 8] [Table 9].
Examine muscles for (bilateral) symmetry, bulk, tone, and fasciculations.
Determine the response, reproducibility, and symmetry of deep tendon reflexes.
Test pain, light touch, vibratory, and proprioceptive senses.
Palpate pertinent peripheral-nerve trunks to detect sites of compression or entrapment.

Testing > Office and Laboratory

Consider a basic battery of laboratory tests to rule out an underlying systemic disease, especially in the patient who presents with distal symmetrical sensorimotor neuropathy of uncertain cause [Table 10].
If after the initial clinical and laboratory evaluation the diagnosis is still unclear, request electrodiagnostic studies to confirm the presence of a neuropathy, to differentiate axonal from demyelinating conditions, and to differentiate myogenic from neurogenic causes of weakness [Table 11] [Table 12] [Table 13] [Table 14].

Testing > Radiologic

Consider MRI studies if nerve compression is suspected.
Order chest radiographs in an older patient with unexplained sensory PN and a long history of cigarette smoking.

Differential Diagnosis

Determine if the symptoms and signs are consistent with peripheral [Table 5] or central nervous-system disorders.
Determine the pattern of weakness and/or sensory loss.
Differentiate lower-motor-neuron (peripheral-nerve) disorders from neuromuscular junction or muscle disorders [Table 15].
If a single nerve is involved (mononeuropathy), suspected a peripheral-nerve entrapment syndrome.
Rule out systemic disease, toxic-metabolic processes, and psychiatric syndromes as the cause of weakness.

Diagnostic Criteria

First, determine whether the patient actually has peripheral neuropathy.
Second, determine the pattern of peripheral-nerve involvement [Table 7].
Third, determine the underlying cause. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies for further details.

Treatment

Acute Care/Hospitalization

Hospitalize patients presenting with symptoms indicative of Guillain-Barr� syndrome (GBS).
Hospitalize patients if there is clinical suspicion of tetrodon (puffer fish) poisoning, black widow spider bites, or rat poisoning.
Hospitalize patients with suspected chronic exposure to a toxin to avoid further exposure until the agent is identified.

Lifestyle Measures

Recommend a basically healthy lifestyle.

Medical Therapy

If identified and relevant, first treat the underlying disorder.
Direct symptomatic therapy toward pain control [Table 16]. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies for further details concerning treatment of specific disorders.

Invasive Procedures

Consider surgical treatment of entrapment mononeuropathies.

Complications

Neuropathic complications are specific to a particular condition. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies.

When to Consult or Refer

If the diagnosis is uncertain, refer the patient to a neurologist.
Refer patients with foot-related symptomatology to a podiatrist.

Prognosis

The prognosis depends on the diagnosis. See the neurology contents page for details on specific neuropathies.

Patient Education

General Information

Use appropriate measures to make movement easier and compensate for any type of sensory loss. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies for details.

Self-care Instructions

See General Advice.

Follow-up

Dependent on the specific condition. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies for details.

Prevention and Screening

Consider screening for PN in patients who are at increased risk.

Management Highlights

�	Determine patterns based on whether symptoms are acute or chronic, mononeuropathic or polyneuropathic, and motor or sensory. Use the time course to narrow the differential diagnosis, e.g., rapid onset suggests Guillain-Barr� syndrome, porphyric neuropathy, and some acute toxic neuropathies (e.g., insecticides or acrylamide). A stepwise or relapsing course can be found with inflammatory, hereditary, and vasculitic neuropathies, and with repeated exposure to toxins. A slow, progressive course is more typical of diabetic and alcoholic neuropathies, and of neuropathies due to chronic exposure to toxic substances (e.g., lead and some industrial solvents).
�	Recall that mononeuropathies are disorders of a single nerve that cause focal motor, sensory, or reflex changes and usually result from trauma or entrapment. Mononeuropathy multiplex is a focal involvement of two or more nerves that usually results from a generalized disorder such as diabetes or vasculitis. Generalized neuropathies involve multiple nerves and typically interrupt neural function predominantly in the distal extremities, and can be caused by diabetes, hereditary diseases, inflammatory/autoimmune disorders, toxic/metabolic/infectious etiologies (e.g., HIV, Lyme disease, alcoholism, or uremia) or be cancer related [Table 7]. Most peripheral neuropathies will have some sensory component; pure motor deficiencies suggest myopathy, motor-neuron disease, or a neuromuscular junction disease.
�	Look for autonomic dysfunction (e.g., erectile dysfunction or urinary, gastrointestinal, and orthostatic symptoms) as a clue to specific neuropathies such as diabetes, Guillain-Barr� syndrome, porphyria, HIV-related autonomic neuropathy, and some toxic neuropathies.
�	Base laboratory testing on history and exam findings [Table 10 ]. Consider testing for common causes with complete blood count, erythrocyte sedimentation rate, urinalysis, glycohemoglobin, glucose, BUN, creatinine, serum vitamin B12 level, serum protein electrophoresis, and TSH.
�	Order an MRI if nerve compression is suspected, particularly if a single nerve or root is involved or the pattern of weakness or sensory loss suggests a single location in the central nervous system.
�	Consider nerve conduction and electromyography studies to confirm the presence of neuropathy and differentiate among myogenic, axonal, and demyelinating conditions. Refer to a neurologist if the diagnosis remains uncertain.
�	In general, avoid potent narcotics in treating chronic neuropathic pain. Start with simple, non-narcotic analgesics such as nonsteroidal anti-inflammatory agents or tramadol hydrochloride up to 50 mg PO t.i.d. in treating mild neuropathic pain [Table 16].

Background

Overview

Primary care physician frequently managed the most common underlying diseases (i.e., diabetes mellitus, alcoholism). The term peripheral neuropathy refers to a variety of syndromes that result from lesions of the peripheral nerves [1]. The peripheral nervous system is comprised of the cranial nerves (except I and II) and the spinal nerves (sensory, motor, autonomic, and mixed). Fortunately, patterns of signs and symptoms facilitate diagnosis, as they generally reflect anatomical localization of the peripheral lesions. Mononeuropathies are disorders of a single nerve that usually result from trauma or entrapment. Any focal, motor, sensory, or reflex changes are restricted to the regions innervated by the specific nerve [1]. Mononeuropathy multiplex is a focal involvement of two or more nerves that usually results from a generalized disorder such as diabetes or vasculitis [1]. Generalized neuropathies involve multiple nerves and typically interrupt neural function predominantly in the distal extremities [Table 1].

Table 1. Mono- and Generalized Neuropathies Commonly Encountered in Clinical Practice

Mononeuropathies

Generalized neuropathies

Cranial neuropathies:

Trigeminal neuralgia
Bells palsy
Diabetic cranial neuropathies

Carpal tunnel syndrome (median nerve)
Cubital tunnel syndrome (ulnar nerve) Sciatic nerve damage following hip replacement
Diabetic mononeuropathy/mononeuropathy multiplex
Amyloidosis

Diabetic neuropathies:

Generalized sensorimotor polyneuropathy
Autonomic neuropathy
Polyradiculopathy

Hereditary neuropathies:

Charcot-Marie-Tooth disease
Amyloid polyneuropathy
Dejerine-Sottas disease
Refsums disease

Inflammatory/autoimmune neuropathies:

Guillain-Barr� syndrome (GBS)
Chronic inflammatory demyelinating polyneuropathy (CIDP)

Toxic/metabolic/infectious diseases:

Various toxin-induced neuropathies
Alcoholic neuropathy
HIV neuropathy
Lyme neuropathy
Uremia
Porphyria

Systemic/malignancy-related neuropathies:

Paraneoplastic
Dysproteinemia

Etiology/Pathophysiology

Normal nerve integrity and function rely on the proper functioning of four components of peripheral nerves: (1) the cell body, where protein manufacturing and the majority of metabolic processes occur; (2) the axon, whose plasma membrane conducts the nerve action potential, and in which axoplasmic transport carries structural and metabolic substances from the cell body to where they are needed, and toxins and metabolic by-products to the cell body for processing; (3) the myelin sheath, which facilitates the conduction of nerve impulses; and (4) connective tissue, which provides mechanical protection and blood supply. Interruption or impairment of any of these structures can lead to transient or permanent nerve injury. Various insults to peripheral nerves can lead to (1) neuronopathy, (2) axonal degeneration (

dying-back

neuropathy), (3) segmental demyelination, and/or (4) Wallerian degeneration

Figure 1. Main pathologic events of a distal axonal degeneration or axonopathy

The jagged lines indicate that either a toxin or a metabolic insult is acting at multiple sites along motor and sensory axons in the peripheral nervous system (PNS) and central nervous system (CNS). Axonal degeneration begins at the most distal part of the nerve fiber and progresses proximally by the late stage. Recovery occurs by axonal regeneration but is impeded by astroglial proliferation in the CNS.

From Schaumburg [4]

Figure 2. Main pathologic events of a sensory neuronopathy

A toxin, identified by the jagged lines, produces destruction of dorsal root ganglion neurons, which is accompanied by degeneration of their peripheral-central axonal processes. Recovery is poor, as no axonal regeneration can take place.

From Schaumburg [4]

Figure 3. Main pathologic events of primary segmental demyelination in immune-mediated inflammatory polyneuropathies

The attack by inflammatory cells causes multifocal demyelination along the entire length of nerve fibers but spares their axons. Recovery occurs by remyelination. The demyelinated segments become invested by several Schwann cells, resulting in a decrease in the internodal length of those areas.

From Schaumburg [4]

Table 2. Pathologic Events Affecting the Peripheral Nerves

Event

Description

Classification and Examples

Prognosis

Axonal degeneration^a

Distal breakdown of the myelin sheath and axon that progresses toward the nerve body^b

Axonal polyneuropathies

Most toxic/metabolic neuropathies

Recovery is delayed and often incomplete

Wallerian degeneration

Degeneration of axons and their myelin sheaths distal to the point of trauma

Any mechanical injury: e.g., focal nerve trauma

Ischemic nerve injury

Recovery depends on the extent of the Schwann cell-basal lamina tube/nerve sheath destruction, distance to injury site, patient age

Neuronopathy

Primary loss/destruction of nerve cell bodies accompanied by degeneration of their peripheral and central axons

Inherited disorders: e.g., spinal muscular atrophies, amyloidosis

Toxic: cadmium poisoning

Degenerative disorder of neuron cell body with no possibility of recovery

Segmental demyelination

Breakdown (acquired) or improper manufacture (congenital) of myelin sheaths with relative sparing of axons

Immune-mediated acquired demyelinating neuropathies: e.g.,
Guillain-Barr� syndrome

Hereditary disorders of Schwann cell-myelin metabolism: e.g., metachromatic leukodystrophy, Dejerine-Sottas disease

Compression or entrapment mononeuropathies

Recovery does not occur in congenital disorders

In acquired disorders, recovery is dependent on remyelination of demyelinated segments, which can take from days to several months

^a Most common pathologic peripheral-nerve reaction; often coexists with segmental demyelination.
^b Hence the term ?dying-back? neuropathy.
^c Clinically, may be difficult to distinguish from axonopathy.

Based on Bosch [2], Raynor [3].

Demographics/Epidemiology

The numbers of people affected by PN vary by specific type of neuropathy. However, age appears to have a significant influence on the distribution of neuropathies in the general population [Table 3]. This may relate to specific clinical, histologic, and physiologic age-related changes in the peripheral nervous system [Table 4].

Table 3. Distribution of Neuropathies by Age and in General Population
Subcategory^a	Age <49	Age >50	Overall population
Mononeuropathy
	35%	50%	30%
Generalized neuropathies
Toxic/metabolic	60%	55%	69%^a
Hereditary	5%	<1%	30%^a
Malignancy	2%	10%	5%
Idiopathic	8%	5%	5%
^a Categories coexist in up to one-third of cases.

Table 4. Age-Related Changes in the Peripheral Nervous System

Type

Changes

Clinical

Decreased vibratory sense
Decreased threshold response to tactile stimuli, but normal threshold response to pain
No change in position sense
Decreased muscle bulk and strength

Histologic

Reduction in number of nerve fibers
Preferential loss of large-diameter fibers
Reduction in muscle-fiber size
Decline in number of motor units (distal muscles)
Evidence of denervation and reinnervation with advancing age

Physiologic

Decline in motor- and sensory-nerve conduction velocity (MCV)
Decreased amplitude in sensory-nerve action potential (SNAP)
Increased amplitude and duration of voluntary motor units suggesting denervation and reinnervation

Diagnosis

History

Obtain a complete current medical history, past medical history, occupational history, family history, and review of systems.
Because peripheral neuropathy can be caused by a plethora of injuries, toxins, drugs, and diseases, determining the etiology of a PN can be difficult [5]. Nevertheless, a systematic review of onset, duration, and evolution of symptoms, as well as of associated disease, family history, and occupational factors, often yields important clues to the specific cause of the presenting complaints. Because the role of the history in identifying the underlying cause of PN (e.g., trauma, metabolic, infectious, inflammatory, ischemic, and paraneoplastic disorders) is well known to primary care physicians, the following information focuses on aspects on the history that are particularly pertinent to diagnosing PN per se.

Try to determine whether presenting symptoms are motor, sensory, or both [Table 5].
The nature of a patient's symptoms usually reveals the type of fiber (i.e., motor, sensory, autonomic) affected. Fiber dysfunction creates certain signs and symptoms that can be delineated by a lack of function (i.e.,

negative

) or by extra or abnormal function (i.e.,

positive

). Notably, sensory involvement is an important diagnostic key. Most peripheral neuropathies cause some degree of sensory pathology, even if it is only detected upon careful neurologic examination. Generalized neuropathies (e.g., Guillain-Barr� syndrome, chronic inflammatory demyelinating polyneuropathy, lead intoxication, and diabetic and alcoholic neuropathy) commonly present with sensory symptoms. Weakness without a sensory component suggests myopathy, motor-neuron disease, or a neuromuscular junction disease [6] [Table 5]. An important exception is multifocal motor neuropathy, which presents with weakness and a normal sensory examination [7].

Inquire about autonomic symptoms: e.g., fainting spells, orthostatic hypotension (lightheadedness when upright), abnormal sweating, gastrointestinal symptoms (early satiation, bloating, nausea), urinary symptoms (frequency, incontinence), and erectile dysfunction.
Autonomic symptoms can be important diagnostic clues, because certain causes of PN typically present with significant concurrent autonomic nervous system dysfunction [6]. Examples include diabetes mellitus, familial amyloidosis, Guillain-Barr� syndrome, porphyria, HIV-related autonomic neuropathy, some toxic neuropathies, and idiopathic pandysautonomia [6].

Ask specific questions about the nature/character of the sensory and/or motor involvement.
The nature or character of symptoms can reveal important information about which fibers (i.e., motor, sensory, autonomic) are involved [Table 5]. Inquire about the types of activities or movements the patient finds difficult. Interestingly, involvement of a particular muscle group (e.g., proximal upper extremity or distal lower extremity) tends to elicit similar reports of symptoms from most patients. For example, difficulties with combing hair or shaving are indicative of proximal upper-extremity muscle weakness, while difficulty in getting out of a chair or the bath are indicative of proximal lower-extremity muscle weakness.

Ask the patient about the order in which the body parts became affected.
The answers can help differentiate symmetric vs. asymmetric evolution [5]. Sensory disturbances, which originate in the feet and then ascend to the knees, or originate in the fingertips and then ascend to the forearms, demonstrate the so-called

dying-back

pattern, and are characteristic of acquired neuropathies [5]. If the history indicates an asymmetric evolution of symptoms, this may help identify cumulative multifocal deficits, which on physical examination sometimes appear to be symmetrical [5]. Because the way that a patient describes his or her symptoms may be inexact, specific questioning may be needed to obtain meaningful information. [8]. For example, patients often have trouble distinguishing between dyesthesia (unpleasant, abnormal sensations in response to ordinarily painless stimulus), paresthesias (unpleasant sensations arising spontaneously and apparently without stimulus), and allodynia (the perception of nonpainful stimuli as painful) [6]. Similarly, a complaint of

weakness

may indicate sensory perception rather than true motor dysfunction.

Inquire about the temporal course of signs and symptoms: i.e., are they acute, subacute, chronic, progressive, relapsing, or remitting?
Temporal characteristics of symptoms can help narrow the differential diagnosis. For example, Guillain-Barr� syndrome, porphyric neuropathy, and some acute toxic neuropathies (e.g., insecticides or acrylamide) have rapid presentations with a time to nadir (maximum deficits) of only days or weeks [2] [5]. A stepwise or relapsing course can be found with chronic inflammatory demyelinating polyradiculoneuropathy, Refsum

s disease, hereditary neuropathy with liability to pressure palsies, familial brachial plexus neuropathy, repeated exposure to toxins, and vasculitic neuropathies. A slow, progressive course is more typical of diabetic and alcoholic neuropathies, and of neuropathies due to chronic exposure to toxic substances (e.g., lead and some industrial solvents) [2].

Ask about a family history of nervous system or muscular diseases, or bone deformities, especially if an acquired generalized neuropathy is suspected.
Inherited generalized neuropathy is typically characterized by an insidious progression that goes unrecognized by the patient and family members alike. If there is no history of a diagnosed PN, a family history of slowly progressive weakness or bony deformities (e.g., pes cavus, clawed toes, scoliosis) may be the initial diagnostic clue. Systematically inquire about the medical history of the patient

s first- and second-degree blood relatives. If the patient is uncertain, obtain permission to contact relatives and/or take advantage of the opportunity to quickly examine any relatives who accompanied the patient. Many of the same clinical exercises used with the patient (i.e., walking on toes and heels, rising from a seated position, etc.) can be used with relatives, even if interviewed over the telephone. Notably, inherited neuropathy typically involves few positive sensory phenomena and family members may sometimes have demonstrable polyneuropathy when examined, even if asymptomatic [5]. Also, a symmetric distal symptom pattern is characteristic of familial neuropathies, while asymmetric presentation or proximal involvement are not [9] [Table 5].

Try to determine whether PN symptoms are related to an underlying infection or systemic illness.
In Western societies, diabetes is the most common source of both generalized neuropathy and mononeuropathy [5]. Other systemic endocrine diseases associated with PN include hypothyroidism, acromegaly, and adrenoleukodystrophy [9]. Common infectious etiologies include Borrelia burgdorferi (Lyme disease), HIV, herpes simplex, and herpes zoster. Certain malignancies - e.g., osteosclerotic myeloma and small-cell bronchogenic carcinoma - are also associated with PN.

Ask about potential occupational exposures to toxins [Table 6], and try to determine whether symptoms are related to occupational exposure(s).
The patient

s exposure history can often be unclear, either due to a similarity to other peripheral neuropathies or because the etiologic agent is no longer detectable (because of the lag time between exposure and examination) [10]. When considering a potential toxic PN, it is important to (1) determine if the clinical manifestations are consistent with neurotoxic disease and (2) to know the potential neurotoxicity of a particular compound. Notably, neurotoxin-induced PN rarely presents with focal or asymmetric symptoms; it usually presents as symmetrical distal axonopathy [10].

Next, ascertain if a dose-response relationship exists between exposure and the onset and severity of symptoms. Symptoms generally coincide with or shortly follow exposure, and rarely occur months to years afterwards [10]. Additionally, the degree of symptomatology is usually related to the length or degree of exposure. Ask about individual habits, such as the use of protective devices and clothing at work, sanitary habits (washing hands before eating), waxing and waning of symptoms (at work vs. other places), recent use of pesticides, and subsequent illnesses in neighbors, pets, and children [10].

Inquire about the use of any medications, both nonprescription and prescription.
Medications that frequently cause neuropathy include amiodarone, isoniazid, platinum antineoplastic drugs, pyridoxine, thalidomide, and vinca alkaloids [12]; those that occasionally cause PN include nitrofurantoin, vincristine, cisplatin, disulfiram, chloramphenicol, chloroquine, phenytoin, aurothioglucose, metronidazole, and gold salts [12] [Table 6]. Other often-overlooked but important culprits are herbal medicines. Chinese herbals in particular are sometimes rich in mercury and arsenic. Remarkably, unlike toxin-related PNs, drug-related PNs rarely are associated with a distinctive symptom pattern [12]. Hence, a thorough drug history is important whatever the pattern of PN.

Ask about dietary habits, vitamin intake, and use of alcohol.
Alcoholic neuropathy may be related to both nutritional deficiencies (chiefly, of thiamine [B₁] and other B-group vitamins) and the toxic effect of alcohol on nerves [12]. Patients typically present with a characteristic pattern of distal muscle wasting and weakness with prominent positive sensory symptoms (e.g., hypersensitivity and burning soles, calf tenderness). This pattern is also observed in thiamine, pantothenic acid, and niacin deficiencies. Like patients with other B-vitamin deficiencies, patients with pyridoxine (B₆) deficiency typically present with glossitis, cheilosis, weakness, and irritability. However, pyridoxine taken in megadoses (usually >2 g/day) can also cause a sensory neuropathy. Unlike other nutritionally related neuropathies, patients with vitamin B₁₂ deficiency classically present with sensory ataxia and a loss of vibration and joint position sense in the lower limbs. However, the distal sensory polyneuropathy may go unnoticed, because it is overshadowed by the CNS manifestations such as intellectual changes, myelopathy, and optic neuropathy.

Table 5. Signs and Symptoms of Peripheral-Nerve Disorders

System

Positive

Negative

Motor^a

Cramps
Fasciculations
Myokymia (quivering)
Restless legs
Tightness

Weakness
Fatigability
Hypotonia
Areflexia
Deformities (pes cavus, claw hand)

Sensory (large fiber)^b

Paresthesias
Tingling

Loss of vibration sense
Loss of joint position sense
Areflexia
Sensory ataxia (positive Romberg test)
Hypotonia

Sensory (small fiber)^c

Burning, jabbing pain (dysesthesias)

Loss of pain sense
Loss of temperature sense

Autonomic^d

Hyperhidrosis
Excess saliva

Orthostasis
Erectile dysfunction
Bowel and/or bladder dysfunction
Anhidrosis

^a All motor fibers are large fibers.
^b Mediate vibration, proprioception, touch.
^c Mediate pain, temperature sensations.
^d All autonomic fibers are small fibers.

Table 6. Drugs and Toxins Causing Peripheral Neuropathy

Drug

Special features

Antibiotics

Chloramphenicol

Distal, primarily sensory neuropathy, optic neuritis during prolonged high-dose use

Dapsone

Predominantly motor neuropathy

Dideoxycytidine, dideoxyinosine,
Dideoxythmidine

Painful sensory neuropathy

Ethambutol

Optic neuritis

Isoniazid

Distal axonal neuropathy, paresthesiae are prominent. Prevented by vitamin B₆

Metronidazole

Distal sensory neuropathy

Nitrofurantoin

Distal sensorimotor neuropathy; occurs in renal failure

Suramin

Distal sensorimotor and demyelinating neuropathy

Antineoplastics

Cisplatin

Sensory ataxia

Cytarabine

Sensorimotor neuropathy; rare

Misonidazole

Painful sensory neuropathy

Procarbazine

Distal paresthesias

Paclitaxel

Distal sensorimotor neuropathy

Vinca alkaloids: vincristine, vinblastine, vindesine, vinorelbine

Distal sensorimotor neuropathy

Antirheumatics

Chloroquine

Neuromyopathy

Chlochicine

Mild sensory neuropathy, myopathy

Organic gold

Demyelinating sensorimotor neuropathy

Penicillamine

Demyelinating sensorimotor neuropathy

Other pharmaceuticals

Amiodarone

Mild sensorimotor neuropathy

Disulfiram

Distal sensorimotor neuropathy

Ergots

Distal paresthesiae and dysesthesiae

FK 506

Axonal neuropathy

Hydralazine

Prevented by vitamin B₆

Nitrous oxide

Associated with myelopathy

Perhexiline

Demyelinating neuropathy

Phenytoin

Mild distal sensory loss

Procainamide

Demyelinating neuropathy; rare

Pyridoxine

Sensory ataxia

Thalidomide

Painful axonal neuropathy, primarily sensory

L-Tryptophan

Associated eosinophilia, fasciitis

Nonpharmaceutical toxic agents

Acrylamide

Excessive sweating

Allyl chloride

Distal numbness

Arsenic

Elevated hair, urine, and fingernail levels

Buckthorn

Motor neuron syndrome causing bulbar and limb paralysis

Cadmium

Sensory neuronopathy

Propionitriles (e.g., dimethylaminopropionitrile)

Urinary hesitancy, sexual dysfunction

Ethylene oxide

Associated cognitive impairment

Hexacarbons (n-hexane, methyl n-butyl ketone)

Distal axonopathy

Lead

Predominantly motor; associated anemia

Mercury

Associated central nervous system manifestations

Methyl bromide

Calf-muscle tenderness

Organophosphorus esters

Diarrhea, sweating, fasciculations

Polychlorinated biphenyls

Acne, brown-pigmented nails

Thallium

Gastrointestinal symptoms, delayed alopecia

Trichlorethylene

Facial numbness

Vacor

Acute diabetes mellitus

Based on Lynn and Mendell [11].

Physical Examination

Perform a complete physical and neurological examination.
The purpose of the general physical examination is to identify potential systemic causes of neuropathies. For example, the presence of skin lesions, lymphadenopathy, hepatomegaly, or splenomegaly suggests that the neuropathy is caused by a systemic disorder. Orthostatic hypotension without a compensatory increase in pulse rate suggests autonomic system involvement. The funduscopic examination may reveal optic pallor, which suggests vitamin B12 deficiency. Pale transverse lines in the nail beds (Mees

lines) suggest arsenic poisoning [Figure 4]. Both pes cavus (characterized by a high-arched sole and foreshortened foot) [Figure 5] and hammertoes may indicate the presence of a long-standing hereditary neuropathy.

Assess the presence and distribution of weakness [Table 7] [Table 8] [Table 9].
Identification of the distribution of weakness is a key element in the differential diagnosis [6]. The main goals are to determine whether weakness is basically distal, proximal, both distal and proximal, or if it is asymmetric or symmetric [6] [Table 7].

Examine muscles for (bilateral) symmetry, bulk, tone, and fasciculations.
Pay particular attention to the tongue, neck, deltoid and intraosseus hand muscles, extensor digitorum brevis muscles of the feet, the calf, and the tibialis anterior and quadriceps muscles [5]. Subtle weaknesses in leg muscles (e.g., the hip abductors and ankle plantar flexors) can be detected by asking patients to stand on one foot or to walk on tiptoes. Other naturally weaker muscles, such as those of the feet or wrist, can be evaluated through confrontational muscle testing. This assessment uses a scale of 0 to 5, where 5 = normal, 4 = weak, 3 = able to overcome gravity, 2 = movement with gravity eliminated, 1 = flicker of movement, and 0 = paralysis.

Test limb muscles along a proximal to distal axis in the following order: (1) shoulder, elbow, wrist, intrinsic hand, and (2) hip girdle, knee, ankle, and intrinsic foot. Notably, most distal polyneuropathies show atrophy of the extensor digitorum brevis (a small muscle on the dorsum of the foot) early in their course.

Determine the response, reproducibility, and symmetry of deep tendon reflexes.
A loss or reduction of deep tendon reflexes is frequently a sign of peripheral neuropathy [15]. Responsivity, reproducibility, and symmetry should be tested at the biceps, brachioradialis, triceps, finger flexors, knees, and ankles, as well as the jaw. The latter is especially useful since it is the only deep tendon reflex that gives us information about cranial nerves (V and VII) [16]. Record reflexes on a 0 to 4 scale (0 = absent, 1-2 = within normal range, though 1 can be abnormal in Guillain-Barr� syndrome [GBS], 3 = hyperreflexic, and 4 = hyperreflexic with clonus). In most

dying-back

neuropathies, the ankle reflex is blunted. GBS in particular often presents with generalized areflexia (the diagnosis should be questioned if reflexes are preserved). Importantly, only acute CNS lesions can lead to decreased or absent reflexes, while chronic or subacute CNS pathology typically causes hyperreflexia. Hence, be mindful that acute cord compression or transection, cerebral infarcts, and other acute CNS insults can initially present with diminished reflexes.

Test pain, light touch, vibratory, and proprioceptive senses.
Sensory testing is generally conducted at the end of the neurologic examination. If a neuropathic disorder is suspected, assess pain, light touch, vibratory, and proprioceptive senses. When examining potential deficits, begin in the dysfunctional area and move toward the normal. Charting results on an outline of the body facilitates localization and follow-up comparisons [17].

Pain sense is typically assessed with the tip of an unused, sterile safety pin held between the thumb and index finger. It is applied with light pressure to the skin without penetration but with a constant stimulus and with an irregular rhythm [8] [18]. Note that certain areas naturally have increased sensitivity (chiefly the axillae, around the lips, and in the groin area). To minimize errors during assessment, consider the following:

1. A too-rapid series of pinpricks can provide a false sensation-loss pattern at the fading border of peripheral neuropathies, because the patient may still be responding to the previous pinpricks.

2. Sensory thresholds may be increased (i.e., sensitivity reduced) in the

cooler

areas distal to the trunk.

3. The patient may respond to the sharpness rather than the pain sensation elicited by the pinprick [18].

To ensure that patients are actually reporting pain; watch their facial expressions during the examination. Also, check that they are keeping their eyes closed throughout the sensory examinations.

To examine for light touch sense, touching the skin lightly with a fingertip or a cotton swab, in a manner similar to that described for pain-sensibility testing, is usually sufficient.

For vibration sense assessment, a 120 Hz tuning fork is struck (to obtain maximal vibratory stimulus) and then the handle is applied to the interphalangeal joint of the great toe and to other bony prominences. Evaluate how long a patient is able to perceive the vibration. Notably, vibratory sense declines naturally with age. Then ask the patient to compare the strength of the stimulus between distal and proximal points (i.e., the foot and the patella or anterior iliac crest). Under normal circumstances, it is about the same, while in distal neuropathies, it is perceived as weaker distally. Also, place the tuning fork distally until the patient stops feeling it, and then move it to a more proximal site. If the vibrations are still perceived, a distal defect is likely.

Test the patient

s proprioceptive sense by grasping the sides of the finger or toe and asking the patient (with eyes closed) whether the digit is being moved up or down. A loss of balance (particularly in the dark), a lack of coordination in the limbs, and disequilibrium symptoms should raise clinical suspicion [6]. Observe the patient

s gait - step height is often increased in PN to compensate for foot drop, and the sole of the foot may slap onto the floor in order to use pressure or pain to compensate for proprioceptive loss [18].

Temperature sense can be tested using test tubes filled with water of varying temperatures. Normal persons can detect differences of just a few degrees. Unfortunately, temperature-sense testing is more cumbersome than other sensory tests and the patient

s subjective responses may be harder to verify.

Palpate pertinent peripheral-nerve trunks to detect sites of compression or entrapment.
Especially in mononeuropathies, palpate the entire course of the nerve trunk to detect focal thickening and point tenderness. Also, examine for Tinels sign (tapping of nerve trunk elicits tingling sensation in the area of the sensory nerve) and for increased sensitivity (pain) when the nerve is stretched. Notably, enlarged nerves may be present in leprosy, neurofibromatosis, localized hypertrophic neuropathy, Charcot-Marie-Tooth disease types 1 and 3, and Refsum

s disease [19].

Figure 4. Mees

lines

These pale transverse white nail bands may occur in patients with peripheral neuropathy caused by arsenic or thallium poisoning.

From Lynn and Mendell [11].

Figure 5. Pes cavus

High-arched foot results from a chronic imbalance of intrinsic foot muscles in Charcot-Marie-Tooth disease.

From Lynn and Mendell [11].

Table 7. Key Findings from History and Physical Examination: Pattern Recognition for Generalized Neuropathies

Pattern

Classification/possible diagnoses

Comments

Symmetric proximal and distal weakness with sensory loss

Inflammatory demyelinating polyneuropathy
Guillain-Barr� syndrome (GBS)
Chronic inflammatory demyelinating polyneuropathy

Patient complaints include: difficulty raising arms to brush teeth and comb hair, problems climbing stairs, difficulty rising from a seated position, sensory loss, and sensory ataxia

Symmetric distal weakness with sensory loss

Metabolic disorders (e.g., amyloidosis, diabetes, Sj�gren

s syndrome)
Drugs (amitriptyline, chloroquine, dapsone) and toxins
Hereditary neuropathies (Charcot-Marie-Tooth disease, amyloidosis)

Underlying conditions may be axonal or demyelinating;
therefore, laboratory investigations (e.g., fasting blood sugar, hemoglobin
A_1C, vitamin B₁₂ levels, molecular genetic blood tests) are recommended based on initial suspicions

Asymmetric distal weakness with sensory loss

Vasculitis
Hereditary neuropathy with predisposition to pressure palsies
Infectious diseases (leprosy, Lyme, HIV)
Sarcoidosis
Compression and entrapment neuropathies

Vasculitis is the most common diagnosis when multiple nerves not normally subject to compression are involved. Compressive mononeuropathy, radiculopathy should be considered with single nerve/region involvement.

Asymmetric distal weakness without sensory loss

Upper-motor-neuron disease
Generalized: multifocal motor neuropathy (MMP)

Bulbar findings (i.e., slurred or nasal speech, drooling, nasal regurgitation of liquids, difficulty whistling, swallowing), fasciculations,and hyperreflexia suggest upper-motor-neuron disease, and are rare with MMP

Asymmetric proximal and distal weakness with sensory loss

Polyradiculopathy
Plexopathy (brachial or lumbar)
Meningeal carcinomatosis or lymphomatosis

In diabetic plexopathy, pain typically precedes weakness

Symmetric sensory loss without weakness

Cryptogenic sensory polyneuropathy (CSPN)
Metabolic derangements (diabetes, alcohol), drugs, toxins

CSPN is primarily observed in older adults. Diabetic and alcoholic neuropathies may present with few or no motor signs.

Asymmetric proprioceptive sensory loss without weakness

Sensory neuropathy (ganglionopathy)
Paraneoplastic syndrome
Sj�gren

s syndrome
Idiopathic sensory neuropathy
Drug (e.g., cisplatin and its analogues) or vitamin B₆ toxicity
HIV sensory neuropathy

Primarily affects large fibers. May warrant a cancer workup.

Autonomic symptoms

Generalized - diseases affecting small fibers: e.g., acute dysautonomia, familial/ primary amyloidosis, GBS, diabetes, Chagas

disease, porphyria, HIV-related autonomic neuropathy, idiopathic pandysautonomia

Typically associated with other types of neuropathy. Conduct autonomic testing (e.g., Valsalva heart rate response to pressure changes). May be an early or sole presentation of alcoholic or diabetic neuropathy.

Based on Barohn [6], Kowalske [13].

Table 8. Assessment of Muscle-Group Weakness

Symptoms

Likely source of weakness

Slurred/nasal speech
Drooling
Nasal regurgitation of liquids
Difficulty whistling, smiling
Difficulty swallowing, weight loss

Bulbar muscles

Diplopia
Ptosis

Extraocular muscles

Trouble reaching
Difficulty holding razor, comb, hair dryer
Difficulty placing things in high cabinets

Proximal upper-extremity muscles

Difficulty opening jars, doors, using keys, silverware
Trouble buttoning clothing

Distal upper-extremity muscles

Trouble rising from chairs, sofas
Trouble getting out of car, bath, or off toilet
Difficulty climbing stairs

Proximal lower-extremity muscles

Tripping
Sprained ankles

Distal lower-extremity muscles

Table 9. Principal Motor Innervation of Peripheral Nerves: Localizing Muscle Weakness

Nerves

Muscles

Action

Axillary

Deltoid

Shoulder abduction

Musculocutaneous

Biceps, brachialis

Flexion of elbow

Median

Flexor carpi radialis

Radial flexion of wrist

Flexor digitorum sublimis

Flexion of middle phalanges (digiti II-V)

Flexor digitorum profundus (lateral half)

Flexion of distal phalanges (digiti II, III)

Pronator teres, pronator quadratus

Pronation of forearm

Abductor pollicis brevis

Abduction of thumb

Opponens pollicis brevis

Opposition of thumb

Flexor pollicis longus

Flexion of distal phalanx of thumb

Flexor pollicis brevis

Flexion of proximal phalanx of thumb

Ulnar

Flexor carpi ulnaris

Ulnar flexion of wrist

Flexor digitorum profundus (medial half)

Flexion of distal phalanges (digiti IV, V)

Abductor digiti minimi

Abduction of digiti V

All other intrinsics of hand

Finger abduction/adduction

Radial

Triceps

Extension at elbow

Brachioradialis

Flexion of forearm

Extensor carpi radialis/ulnaris

Extension at wrist with radial/ulnar deviation

Supinator

Supination of forearm

Extensor pollicis brevis

Extension of thumb (proximal)

Extensor pollicis longus

Extension of thumb (distal)

Extensor indicis proprius

Extension of index (proximal)

Extensor digiti V proprius

Extension of little finger (proximal)

Extensor digiti communis

Extension of digits (II-V, proximal)

Femoral

Iliopsoas

Flexion of thigh at hip

Quadriceps

Extension of leg at knee

Obturator

Adductor longus, adductor brevis, adductor magnus

Adduction of thigh at hip

Superior gluteal

Gluteus medius, gluteus minimus, gluteus maximus

Abduction of thigh at hip

Sciatic

Biceps femoris, semitendinosus, semimembranosus

Flexion of leg at knee

Sciatic branches: fibular (deep)

Tibialis anterior

Dorsiflexion of foot

Extensor digitorum longus

Extension of toes

Extensor hallucis longus

Extension of great toe

Sciatic branches: fibular (superficial)

Peroneus

Everts foot

Tibial

Gastrocnemius, soleus

Plantar flexion of foot

Flexor digitorum longus

Flexion of distal phalanges (II-IV)

Flexor hallucis longus

Flexion of distal phalanges (I)

Flexor digitorum brevis

Flexion of middle phalanges (II-V)

Flexor hallucis brevis

Flexion of middle phalanges (I)

Pudendal

Perineal and sphincters

Closure of sphincters, contraction of pelvic floor

From Ronthal [14].

Testing

Testing > Office and Laboratory

Consider a basic battery of laboratory tests to rule out an underlying systemic disease, especially in the patient who presents with distal symmetrical sensorimotor neuropathy of uncertain cause [Table 10].
Although there is no universally accepted basic set of laboratory tests, many authorities recommend most or all of the following tests: complete blood count, erythrocyte sedimentation rate, urinalysis, hemoglobin A1C level, standard blood chemistries (especially fasting blood sugar, blood urea nitrogen, and serum creatinine), serum vitamin B12 level, serum protein electrophoresis, and thyrotropin-stimulating hormone (TSH) level. Further studies are guided by the likely diagnostic possibilities [Table 10].

If after the initial clinical and laboratory evaluation the diagnosis is still unclear, request electrodiagnostic studies to confirm the presence of a neuropathy, to differentiate axonal from demyelinating conditions, and to differentiate myogenic from neurogenic causes of weakness [Table 11] [Table 12] [Table 13] [Table 14].
Electrodiagnostic studies, which include nerve conduction and electromyography (EMG), play a key role in clarifying localization of weakness/dysfunction, the severity and chronicity of a lesion, and the underlying type of pathology, i.e., axonal or demyelinating. Nerve-conduction assessment focuses on the motor and sensory responses to electrical stimulation. Motor-conduction studies record this response from the muscle supplied by the nerve. Sensory studies record the response of the nerve itself. Evaluation is conducted in one arm and leg (usually on the affected side of the body if the presentation is asymmetric) [20]. Details of important electrodiagnostic measurements can be found in Table 11 and Table 12.

In addition to velocity, nerve-conduction studies also measure the amplitude of the response from a nerve or muscle to the electrical stimulus. This helps to quantitate fiber loss, as the fewer fibers a peripheral nerve contains, the smaller the resulting response. Notably, axonal or

dying-back

neuropathies demonstrate normal or nearly normal conduction velocity, but reduced response amplitude.

The needle-electrode examination (NEE) is also part of the electrodiagnostic evaluation. NEE, which represents a recording of the electrical activity in muscle-fiber membranes, is used to determine if the axonal supply to the nerve has been damaged (i.e., neuropathy), or if there is evidence of muscle-fiber pathology (i.e., myopathy) [3] [11]. Of note, NEE is most effective in assessing generalized polyneuropathies (in which the distal extremity muscles are affected first) [20].

Table 10. Tests to Consider for Patients with Suspected Peripheral Neuropathy

Test

Indications

Interpretation

Laboratory

CBC, erythrocyte sedimentation rate

Conduct in most patients

Commonly abnormal in systemic disease. Erythroblastic anemia suggests vitamin B₁₂ or folate deficiency; erythrocyte stippling suggests lead toxicity.

Blood sugar, hemoglobin A_1C

Suspected diabetic PN
Undiagnosed PN

Symptoms of neuropathy may be the first presentation of diabetes mellitus

Blood chemistry battery (e.g., SMA 20)

Conduct in most patients

Detects renal insufficiency and other metabolic disorders

Vitamin B₁₂ levels

Conduct in most patients
Suspected nutritional PN

CNS and posterior-column manifestations may obscure PN; folate treatment normalizes CBC, but does not prevent progressive neurologic injury

Serum protein electrophoresis

Conduct in most patients

If a paraprotein is identified, request a bone survey and consider bone biopsy to rule out multiple myeloma or osteosclerotic myeloma.

Serum creatinine kinase (CK)

Suspected motor-neuron disease (MND)

Moderate CK elevation is often supportive of MND diagnosis [6]

Serologic testing for syphilis, HIV, Lyme disease; tuberculin skin test; antinuclear antibodies; urine tests for aminolevulinic acid, porphobilinogen; urine immunoelectrophoresis; 24-hr urine test for heavy metals (Pb, TI, As)

In selected patients with suggestive clinical indications

Yield is very low in the absence of specific clinical indications

Cerebral spinal fluid examination

May be particularly helpful in patients with predominant sensory neuropathy, with or without corticospinal findings, and in paraneoplastic neuropathies [5]

CSF protein will be elevated in >90% of patients with acute and chronic inflammatory demyelinating polyneuropathy; it is also frequently elevated in paraneoplastic sensory neuropathy [21]. Elevated total protein with <5 cells/mm³ suggest Gullain-Barr� syndrome or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Radiologic

MRI

Suspected nerve compression (e.g., carpal tunnel syndrome)

Used primarily to confirm peripheral-nerve entrapments/compressions or root disease

Invasive

Nerve biopsy

Considered when there is a specific diagnosis in mind or when no etiology is evident from serologic and electrodiagnostic tests

Diagnostic abnormalities present in [2]:
Vasculitis
Amyloidosis
Sarcoidosis
Leprosy
Hereditary neuropathy with liability to pressure palsies
Giant axonal neuropathy
Metachromatic leukodystrophy
Paraproteinemic neuropathy
Tumor infiltration

Based on Bosch [2], Logigian [5], Barohn [6].

Table 11. Electrodiagnostic Studies: Key Measurements

Study

Key measurement

Nerves measured

Important parameters

Motor conduction

Compound muscle action potential (CMAP)

Ulnar
Median
Peroneal
Posterior tibial

Latency
Amplitude
Conduction velocity
F wave
H reflex

Sensory conduction

Sensory-nerve action potential (SNAP)

Ulnar
Median
Radial
Sural

Latency
Amplitude

Needle electromyography

Configuration and size of individual motor unit potentials

Not relevant

Spontaneous activity
Firing pattern

Table 12. Electrodiagnostic Studies: Terminology

Parameter

Definition

Amplitude

In motor-conduction studies: height in millivolts of CMAP from baseline to peak, i.e., number of muscle fibers activated by stimulus at a particular site

In sensory-conduction studies: height in microvolts of SNAP from baseline to peak

CMAP

Summation of all muscle-fiber action potentials activated by motor nerve stimulation

Conduction velocity

Speed in meters per second of nerve impulse conduction

F wave

Assesses conduction along the proximal portion of the motor nerve; most commonly used in evaluating demyelinating neuropathies

Firing pattern

The number, size, and shape of motor units that initially fire and then recruit other motor units to fire, following voluntary muscle contraction

H reflex

Analogous to the ankle-jerk reflex but reflex is stimulated by a submaximal electrical current that selectively activates IA afferent sensory fibers (to cause a motor reflex)

Latency

In motor-conduction studies: time in milliseconds for conduction of a stimulus along the length of the nerve, transmission of the neurotransmitter-mediated signal across the neuromuscular junction, and depolarization of the muscle-fiber membrane
In sensory-conduction studies: conduction time of the fastest-conducting fibers along a given segment

SNAP

Summation of individual action potentials of all the fibers activated

Spontaneous activity

Measures endplate muscle activity when a needle is placed near the neuromuscular junction (including spontaneous discharges - i.e., fibrillations and fasciculations - of muscle activity at rest)

CMAP, compound muscle action potential; SNAP, sensory nerve action potential.

Based on Raynor [3], Lynn and Mendell [11].

Table 13. Electrophysiologic Findings of Axonal vs. Demyelinating Peripheral Neuropathies

Study

Axonal degeneration

Segmental demyelination

Motor-nerve conduction studies

CMAP^a amplitude

Decreased

Normal^b

Distal latency

Normal

Prolonged

Conduction velocity

Normal

Slow

Conduction block

Absent

Present

Temporal dispersion

Absent

Present

F wave

Normal

Prolonged or absent

H reflex

Normal

Prolonged or absent

Sensory-nerve conduction studies

SNAP amplitude
Distal latency
Conduction velocity

Decreased
Normal
Normal

Normal
Prolonged
Slow

Needle electromyography (spontaneous activity)

Fibrillations

Present

Absent

Fasciculations

Present

Absent

Recruitment

Number of motor units

Decreased

^a Compound motor action potential.
^b Except with conduction block.

Reprinted with permission from Barohn R: Approach to peripheral neuropathy and neuronopathy. Semin Neurol. 1998;18(1):7-18.

Table 14. Categorical Classification of Selected Peripheral Neuropathies

Axonal

Demyelinating

Mononeuropathies

Diabetes

Entrapments

Generalized neuropathies

Diabetes
Alcohol
Carcinoma
Vitamin deficiencies
Toxic/metabolic neuropathies [Table 6], including heavy metals, industrial solvents and hydrocarbons, and medications
Hereditary peroneal muscular atrophy
Familial amyloidosis
Porphyria
Whipple

s disease
Leprosy

Guillain-Barr� syndrome
Leprosy
Hereditary peroneal muscular atrophy/Dejerine-Sottas disease
Diphtheria
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Toxic neuropathies

Testing > Radiologic

Consider MRI studies if nerve compression is suspected.
The inability to distinguish certain peripheral nerves (e.g., posterior interosseous, distal radial nerves) from background soft tissue limits the utility of MRI studies in patients with suspected PN [22]. Nevertheless, it is of particular value in confirming the presence of compression mononeuropathies, such as carpal tunnel syndrome or ulnar nerve compression at the elbow.

Order chest radiographs in an older patient with unexplained sensory PN and a long history of cigarette smoking.
In general, PN is not associated with carcinoma or sarcoma [9]. However, small-cell bronchogenic carcinoma is a known cause of sensory neuropathy. Suspected tuberculosis also warrants chest radiographs.

Testing > Invasive

Consider a nerve biopsy if diagnosis remains uncertain following electrodiagnostic testing.
If the conditions listed in Table 14 are suspected, a nerve biopsy may be warranted. Nerve biopsy may be particularly helpful in recognizing inflammation, infection, or unique tissue reactions [9]. In general, nerve biopsy is most useful in suspected nerve vasculitis, because the diagnosis can be confirmed histologically and vasculitis is relatively treatable [6]. In such cases, either the sural (the most common) or the superficial peroneal sensory nerve can be biopsied; adjacent muscle should also be biopsied to increase the likelihood of identifying vasculitis [6]. The advantage to targeting the superficial peroneal sensory nerve is that it allows simultaneous access to the peroneus brevis muscle through one incision [2]. Of note, tissue should be sent to a laboratory that has the technology to perform plastic embedding of nerve tissue and teased-nerve fiber analysis, in addition to routine frozen and paraffin studies [2].

Differential Diagnosis

Determine if the symptoms and signs are consistent with peripheral [Table 5] or central nervous-system disorders.
CNS disorders (e.g., spinal-cord tumors, stroke, seizure with sensory symptoms, or multiple sclerosis) can mimic PN, particularly if weakness is a chief complaint. Symptoms suggestive of CNS dysfunction include diplopia, dysphagia, ataxia, seizures, spasticity, or hemiparesis [15]. If sensory alteration occurs in an ipsilateral arm and leg, it is probably due to an underlying cord or cortex disorder [8]. In contrast, PN is usually characterized by a slow, progressive deterioration compared to central lesions, which are commonly acute or subacute [15]. In most cases, hyporeflexia, hypotonia, and muscle wasting are indications of a peripheral-nerve problem [8] [23].

Determine the pattern of weakness and/or sensory loss.
Determining the pattern of weakness or sensory loss (e.g., symmetric or asymmetric, distal or proximal, confined to a specific nerve, plexus, or root level) helps narrow the differential diagnosis [Figure 6]. For example, neuropathies that present with asymmetric (or focal) weakness and subacute or acute sensory and motor symptoms in one arm or leg include cervical and lumbosacral radiculopathies, plexopathies, vasculitis, compressive mononeuropathy, or hereditary neuropathy with predisposition to pressure palsy [6]. In contrast, patients who present with symmetric proximal and distal weakness and sensory symptoms are likely to have a potentially treatable acquired demyelinating neuropathy [6]. Alternatively, patients who present with symmetric distal weakness and sensory symptoms generally have a primary axonal peripheral neuropathy that is not as treatable [6].

Differentiate lower-motor-neuron (peripheral-nerve) disorders from neuromuscular junction or muscle disorders [Table 15].
The absence of sensory and autonomic symptoms in the presence of weakness is suggestive of a pure motor disease: i.e., motor-neuron disease, myopathy, or a neuromuscular-junction disorder (NMJD). Various key findings separate muscle from nerve disease [Table 15]. In general, spasticity and increased deep tendon reflexes suggest an upper-motor-neuron disorder; flaccidity, fasciculations, and lack of reflexes suggest a lower-motor-neuron disorder; and preserved tendon reflexes, elevated muscle enzymes, and normal sensation suggests muscle disease [23]. Notably, proximal and oculopharyngeal muscles are commonly affected in patients with NMJD (e.g., myasthenia gravis), and patients are often easily fatigued.

If a single nerve is involved (mononeuropathy), suspected a peripheral-nerve entrapment syndrome.
Focal involvement of a single nerve implies a local cause, usually direct trauma, entrapment, or compression. However, patients should be screened for an underlying systemic cause such as hypothyroidism, diabetes mellitus, amyloidosis, or rheumatoid arthritis.

Rule out systemic disease, toxic-metabolic processes, and psychiatric syndromes as the cause of weakness.
Before embarking on a broadly based investigation for underlying diseases, it is essential that such a search be focused on diseases likely to cause the neuropathy under investigation (see the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies for further details). For example, while the association between osteosclerotic myeloma (which has a very low incidence in the general population) and peripheral neuropathy is close to 100%, lung cancer, which occurs more frequently, does not often lead to neuropathy [9]. It may be more prudent to look for specific patterns of disease to assess the need for further investigation. For example, a patient who presents with hyperpigmentation and neuropathic symptoms may have adrenal insufficiency. Likewise, a patient with significant weight loss may be suffering from neuropathy due to nutritional deficiency or malignancy.

In addition to the multitude of systemic illnesses that manifest, in part, with weakness, various drugs (e.g., quinidine, adrenocorticotropic hormone [ACTH], chloroquine, lithium) can similarly induce neuromuscular blockade and related symptoms. Individuals who are especially susceptible include elderly patients with underlying muscle disease, patients with electrolyte disorders, patients who are immunocompromised, and patients who have overdosed [15]. Certain psychiatric illnesses also include weakness as a chief complaint (most frequently, depression, the somatoform disorders, anxiety states, sleep disorders, and malingering) [15].

Figure 6. Approach to the differential diagnosis of peripheral neuropathy

CMT, Charcot-Marie-Tooth disease. From Lynn and Mendell [11].

Table 15. Differential Diagnosis of Nerve and Muscle Disease

Parameter

Peripheral nerve

Neuromuscular junction

Muscle

Weakness

Distal

Generalized

Proximal

Pain

Present

Absent

May be present or absent

Reflexes

Decreased

Normal

Autonomic abnormalities

May be present

Absent

Diurnal variation

Rare

Common

Rare

Motor-nerve conduction

Often abnormal

Normal

Sensory-nerve conduction

Abnormal

Normal

Repetitive stimulation

Not diagnostic

Diagnostic

Not diagnostic

Electromyography

Often abnormal

Always abnormal

Muscle enzymes

Normal

Abnormal

Diagnostic Criteria

First, determine whether the patient actually has peripheral neuropathy.
Peripheral neuropathy (PN) is a general term that applies to peripheral-nerve disorders of any cause. Peripheral-nerve disorders are manifested as sensory, motor, and/or autonomic symptoms and signs. Peripheral-nerve disorders must be differentiated from central nervous system disorders, which also affect sensory, motor, and autonomic functions. Additionally, peripheral-nerve disorders must be differentiated from disorders of the target organs (e.g., myopathies). The diagnosis of PN per se is usually based on the clinical history and neurological examination findings and confirmed, if necessary, by electrodiagnostic studies.

Second, determine the pattern of peripheral-nerve involvement [Table 7].
Based on clinical information and electrodiagnostic studies, if needed, PN can be classified according to speed of onset (acute, subacute, chronic), pattern of nerves affected (mononeuropathy, polyneuropathy, multiple mononeuropathy), population of neurons affected (sensory, motor, autonomic, large or small diameter), level of neuron involvement (proximal, distal, or both), major pathology (axonal degeneration or demyelination), etc. Determining the pattern of PN helps focus the differential diagnosis and limit the number of ancillary examinations required.

Third, determine the underlying cause. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies for further details.
Although PN can be caused by a large variety of entrapment syndromes, trauma, metabolic disorders, toxins, drugs, infections, nutritional deficiencies, etc., it is usually possible to diagnose the underlying disorder. The single most important diagnostic tool is a thorough medical history [9]. The physical examination and laboratory studies largely serve to corroborate or rule out the underlying disorder(s) that are suspected based on the medical history.

Treatment

Acute Care/Hospitalization

Hospitalize patients presenting with symptoms indicative of Guillain-Barr� syndrome (GBS).
GBS, a demyelinating generalized neuropathy, is the most common cause of acute generalized paralysis in the Western world [24] [25]. Classically, GBS presents with dysesthesias and paresthesias in the lower extremities that progress to ataxia and, within a few days, to weakness; eventually, involvement extends to the upper extremities (

ascending paralysis

) [25]. Reflexes are typically absent early in the disease, and motor weakness may be present without sensory symptoms. Cranial-nerve involvement occurs in roughly 50% of patients. Notably, although weakness and hyporeflexia are the hallmarks of GBS, a subgroup of patients may present with only ataxia in the early stages. In 90% of patients, maximum deficits are reached within 4 weeks after symptom onset. Yet due to the vague progressive nature of GBS, it is often initially misdiagnosed as viral syndrome, anxiety, or sciatica [24].

The most ominous aspect of GBS is respiratory failure, which occurs in up to 20% of patients. Satisfactory outcomes can be expected in 80% to 85% of patients, but only with optimal supportive management. Autonomic impairment (characterized by tachycardia and blood pressure instability) can also be problematic. Hence, hospitalization is necessary as soon as GBS is suspected.

Hospitalize patients if there is clinical suspicion of tetrodon (puffer fish) poisoning, black widow spider bites, or rat poisoning.
Poisoning from ingestion of puffer fish and certain other large, carnivorous tropical fish can result in acute gastroenteritis and an acute demyelinating neuropathy, with painful paresthesias [15]. However, unlike ciguatoxin poisoning (which comes from mahi-mahi and some other species and is typically self limiting), tetrodon poisoning (from ingestion of puffer fish) can result in ascending paralysis and associated respiratory failure. A key diagnostic clue is significant oral paresthesias. As there is no known antidote, treatment is supportive.

Most neurotoxic spider bites derive from the black widow spider. Although the bite is often painless or feels like a pinprick, it can result in cramping pain and muscle rigidity (especially in the abdomen and jaw) within a few hours [26]. These symptoms resolve within 1 to 2 days, although weakness and lethargy can persist for up to a month. Severe symptoms warrant hospitalization for further management.

Intoxication from rodenticides that contain thallium salts can produce a painful polyneuropathy. Massive acute exposure is characterized by severe gastrointestinal distress that includes diarrhea, abdominal pain, and vomiting. Patients will typically complain of severe burning paresthesias and intense joint pain; sensory symptoms may also manifest in the hands and trunk with both small- and large-fiber involvement [10]. Weakness, though not a predominant complaint, is evident on physical examination. Severe intoxication can result in lethargy, cardiac and respiratory failure, seizures, coma, and death.

Hospitalize patients with suspected chronic exposure to a toxin to avoid further exposure until the agent is identified.
Exposure to toxic substances can cause dysfunction in both the central nervous system (CNS) and peripheral nervous system (PNS). Toxins known to cause acute or dramatic PNS include arsenic, lead, and triorthocresyl phosphate. The symptomatology is usually related to the length or degree of exposure.

Neurotoxic reactions to arsenic can have a subacute or a chronic course (e.g., occupational exposure). Importantly, while acute manifestations tend to involve neuropathic and bone marrow abnormalities, chronic manifestations tend to involve the skin (e.g., hyperkeratosis, hyperpigmentation, Mees' lines, pitting edema of the distal extremities, and mucosal irritation) [10]. Weakness, malaise, and vomiting are also early symptoms, with an overt stocking-glove neuropathy (i.e., prominent numbness and burning of hands and feet) developing over time. Subacute exposure can result in abdominal pain, diarrhea, tachycardia, hypotension, vasomotor collapse, and sometimes mortality within a day.

Lead and arsenic toxicity may be seen as a result of occupational exposure or accidental ingestion(smelting factories, battery manufacturing, demolition work, and automobile radiator repair). Unlike arsenic poisoning, PN develops with prolonged exposure, and by the time it becomes obvious a number of systemic features (e.g., weight loss, anorexia, fatigue, constipation, and episodic abdominal pain) are present. Lead neuropathy is predominantly characterized by motor symptoms; the most common neuropathic expression is progressive, symmetric axonopathy with weakness, areflexia, and fasciculations [10].

Lifestyle Measures

Recommend a basically healthy lifestyle.
A basically healthy lifestyle that includes avoidance of excessive alcohol intake, weight control, good nutrition, avoidance of unnecessary use of drugs, practicing safe sex, and following occupational safety recommendations reduces the risk for some of the underlying causes of peripheral neuropathy. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies.

Medical Therapy

If identified and relevant, first treat the underlying disorder.
Treatment of an underlying metabolic, nutritional, infectious, or endocrine disorder helps preserve nerve function and may ameliorate the neuropathy. Some underlying disorders, such as hypothyroidism, are easily treated; other disorders, such as diabetes mellitus or HIV infection, require complex regimens.

Direct symptomatic therapy toward pain control [Table 16]. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies for further details concerning treatment of specific disorders.
In general, potent narcotic analgesics should be avoided for treatment of chronic neuropathic pain [11]. Poorly localized burning pain may be treated with tricyclic antidepressants, such as amitriptyline or nortriptyline. Carbamazepine is useful for chronic sharp pain. Despite the lack of controlled studies, the anticonvulsant gabapentin is gaining favor for the treatment of painful neuropathy [28]. It is important to emphasize to patients that the beneficial effects of these medications may not be apparent for several weeks, and that side effects often resolve with time.

Table 16. Management of Neuropathic Pain

Symptom

Treatment

Mild neuropathic pain

Simple non-narcotic analgesics such as nonsteroidal anti-inflammatory agents or tramadol hydrochloride up to 50 mg PO t.i.d. may be helpful for all types of pain

Diffuse, poorly localized pain

Amitriptyline, 10-150 mg/day, in gradually increasing dosages (contraindicated in heart block, urinary tract obstruction, or narrow-angle glaucoma)
If orthostatic hypotension is problematic: Other tricyclic depressants, including nortriptyline

Sharp, well-localized pain

Carbamazepine: initial dose, 100 mg b.i.d.; gradually increasing to 400-1,200 mg/day as tolerated
If carbamazepine is not tolerated:
Phenytoin, in gradually increasing doses beginning with 300 mg/day
Gabapentin, beginning with 100-300 mg/day and titrating up to 600 mg t.i.d. or more
Capsaicin, 0.075% topical ointment, applied q.i.d.
For both diffuse and sharp pains: Mexiletine, up to 10 mg/kg/day

Lancinating pains

Clonazepam, 0.5-10.0 mg/day

Nocturnal leg pain, cramping

Clonidine, 0.1-0.5 mg q.h.s., quinine sulfate 200-400mg at bedtime

b.i.d., twice daily; q.h.s., before bedtime; q.i.d., 4 times a day; PO, orally; t.i.d., 3 times a day.

Modified from Lynn and Mendell [11].

Invasive Procedures

Consider surgical treatment of entrapment mononeuropathies.
Factors favoring surgical management include chronicity and worsening neurological deficit on examination (particularly if motor), failure to respond to non-surgical management, and electrodiagnostic evidence of Wallerian degeneration [27]. Factors favoring conservative management include sudden onset (without a history of trauma), no motor deficit, no or few sensory findings (despite pain or sensory symptoms), and no evidence of axonal degeneration on electrodiagnostic testing.

Complications

Neuropathic complications are specific to a particular condition. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies.

When to Consult or Refer

If the diagnosis is uncertain, refer the patient to a neurologist.
Patients with PN typically present first to a primary care physician. The generalist has important roles in both the early recognition of PN and in the diagnosis of any potential underlying disorder. In many cases, a primary care physician can diagnose PN and initiate treatment while nerve dysfunction is still reversible. However, if the initial clinical evaluation does not reveal a clear diagnosis, or if the neuropathy is acute and progressive, referral to a neurologist is warranted.

Refer patients with foot-related symptomatology to a podiatrist.
Neuropathic foot pain and sensory symptoms can lead to trouble with balance and gait. In fact, in most neuropathies, distal limb weakness with paralysis of the intrinsic foot muscles is quite common [1]. Although foot problems are easily misdiagnosed as orthopedic abnormalities, referral to a foot specialist is warranted if the pathology appears related to PN. The podiatrist can also help the patient learn to protect insensitive feet from trauma and infections, such as those related to improperly fitting shoes or inadequate hygiene.

Prognosis

The prognosis depends on the diagnosis. See the neurology contents page for details on specific neuropathies.

Patient Education

General Information

Use appropriate measures to make movement easier and compensate for any type of sensory loss. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies for details.
An ankle-foot orthosis compensates for footdrop by stabilizing the ankle and overcoming the tendency of toes to catch on edges of curbs and carpets [25]. A brace that keeps the wrists and fingers in a neutral position may help patients with weakness of wrist and finger extensors. In general, soft-soled, loose-fitting shoes with thick socks are helpful. Nightly foot soaking (e.g., 15 to 20 minutes in cold tap water without ice) often helps relieve foot pain. In patients with neuropathy involving the feet, learning to inspect their feet daily for undetected injuries is important.

Self-care Instructions

See General Advice.

Follow-up

Dependent on the specific condition. See the related Best Practice of Medicine articles on mononeuropathies and generalized neuropathies for details.

Prevention and Screening

Consider screening for PN in patients who are at increased risk.
Routine screening for PN is currently recommended for patients with diabetes, and may to be useful for other patients who are at increased risk for PN, such as those with chronic renal disease, alcoholism, nutritional deficiency, or HIV infection.

For diabetes mellitus, tight glucose control has been shown to markedly delay the onset and slow the progression of diabetic polyneuropathy [28]. Recent evidence suggests that improved glucose control has a similar beneficial effect on patients with type 2 diabetes.

Key References

Key References include the latest guidelines and reviews, plus noteworthy papers selected by the author (highlighted with **).

	Barohn RJ : Approach to peripheral neuropathy and neuronopathy. .Sem Neurol . 1998: 18(1): 7- 18.
		This excellent review describes key clinical and laboratory evaluations to assist with differential diagnosis of peripheral neuropathy.
	Dyck PJ, Dyck PJB, Grant IA, Fealey RD : Ten steps in characterizing and diagnosing patients with peripheral neuropathy. .Neurology .1996:47(1):10-7.
		This detailed review summarizes a 10-step approach for placing PN into the correct anatomic-pathologic patterns to facilitate accurate diagnosis.
	Elvey RL : Physical evaluation of the peripheral nervous system in disorders of pain and dysfunction. .J Hand Ther .1997:10:122-29.
		This article presents an in-depth summary of tests that facilitate the physical examination of the patient with possible neurologic pain; includes a case analysis to illustrate key points.
	Krivickas LS : Electrodiagnosis in neuromuscular diseases. .Phys Med Rehab Clin N Am .1998:9(1):83-114.
		This review presents an organized approach to electrodiagnostic studies in the neuromuscular patient to assist the clinician in differential diagnosis of peripheral neuropathy, myopathy, and neuromuscular junction transmission disorders.

Literature Cited

Papers of particular interest are highlighted with **.

1.	Latov N : Merritt?s Textbook of Neurology, edn. 9. Edited by Rowland LP. Philadelphia: Lippincott Williams&Wilkins; 1995:648-50
2.	Bosch EP, Mitsumoto H : Neurology in Clinical Practice, edn. 2 . Edited by Bradley WG, Daroff RB, Fenichel GM, Marsden CD. Woburn, MA: Buttersworth-Heinemann; 1996:1881-92
3.	Raynor EM, Preston DC : Merritt?s Textbook of Neurology, edn. 9. Edited by Rowland LP. Philadelphia: Lippincott Williams&Wilkins; 1995:168-78
4.	Schaumburg HH, Spencer PS, Thomas PK : Disorders of Peripheral Nerves. Philadelphia: Davis; 1983
5.	Logigian EL :Publication Information Not Available
6.	** Barohn R : Approach to peripheral neuropathy and neuronopathy. Semin Neurol. 1998;18(1):7-18 [PubMed abstract] [Related articles]
7.	Katz JS, Wolfe GI, Bryan WW, Jackson CE, Amato AA, Barohn RJ : Electrophysiologic findings in multifocal motor neuropathy. Neurology. 1997 Mar;48(3):700-7 [PubMed abstract] [Related articles]
8.	Huff J : New-onset sensory loss or alteration. Emerg Med Clin North Am. 1998 Nov;16(4):811-24 vi-vii [PubMed abstract] [Related articles]
9.	** Dyck PJ, Dyck PJ, Grant IA, Fealey RD : Ten steps in characterizing and diagnosing patients with peripheral neuropathy. Neurology. 1996 Jul;47(1):10-7 [PubMed abstract] [Related articles]
10.	Berger AR : Merritt?s Textbook of Neurology, edn. 9 . Edited by Rowland LP. Philadelphia: Lippincott Williams&Wilkins; 1995:534-40
11.	Lynn DJ, Mendell JR : Peripheral neuropathy. Curr Pract Med. 1999;2(5):819-30
12.	McManis P :Publication Information Not Available
13.	Kowalske KJ, Agre JC : Neuromuscular rehabilitation and electrodiagnosis. 3. Generalized peripheral neuropathy. Arch Phys Med Rehabil. 2000 Mar;81(3 Suppl 1):S20-6; quiz S36-44 [PubMed abstract] [Related articles]
14.	Ronthal M : Merritt?s Textbook of Neurology, edn. 9 . Edited by Rowland LP. Philadelphia: Lippincott Williams&Wilkins; 1995:9-13
15.	LoVecchio F, Jacobson S : Approach to generalized weakness and peripheral neuromuscular disease. Emerg Med Clin North Am . 1997 Aug;15(3):605-23 [PubMed abstract] [Related articles]
16.	Feske S : Merritt?s Textbook of Neurology, edn. 9 . Edited by Rowland LP. Philadelphia: Lippincott Williams&Wilkins; 1995:2-9
17.	Sabin RD, Dawson DM : Merritt?s Textbook of Neurology, edn. 9 . Edited by Rowland LP. Philadelphia: Lippincott Williams&Wilkins; 1995:30-6
18.	Sudarsky R : Merritt?s Textbook of Neurology, edn. 9 . Edited by Rowland LP. Philadelphia: Lippincott Williams&Wilkins; 1995:26-30
19.	** Elvey R : Physical evaluation of the peripheral nervous system in disorders of pain and dysfunction. J Hand Ther. 1997 Apr-Jun;10(2):122-9 [PubMed abstract] [Related articles]
20.	** Krivickas L : Electrodiagnosis in neuromuscular disease. Phys Med Rehabil Clin N Am . 1998 Feb;9(1):83-114 vi [PubMed abstract] [Related articles]
21.	Chalk CH, Windebank AJ, Kimmel DW, McManis PG : The distinctive clinical features of paraneoplastic sensory neuronopathy. Can J Neurol Sci. 1992 Aug;19(3):346-51 [PubMed abstract] [Related articles]
22.	Aagaard BD, Maravilla KR, Kliot M : MR neurography. MR imaging of peripheral nerves. Magn Reson Imaging Clin N Am. 1998 Feb;6(1):179-94 [PubMed abstract] [Related articles]
23.	Logigian EL : Internal Medicine, edn. 3 . Edited by Stein JH. New York: Little Brown&Company; 1993:1975-82
24.	Ropper AH : The Guillain-Barr� syndrome. N Engl J Med. 1992;326(17):1130-36
25.	Chalk CH, Dyck PJ :Publication Information Not Available
26.	Pickett J : Merritt?s Textbook of Neurology, edn. 9 . Edited by Rowland LP. Philadelphia: Lippincott Williams&Wilkins; 1995:571-7
27.	Asbury AK : Harrison?s Principles of Internal Medicine, edn. 14 . Edited by Fauci AS, Braunwalk E, Iselbacher KJ, et al. New York: McGraw-Hill; 1998:2457-69
28.	Vaillancourt PD, Langevin HM : Painful peripheral neuropathies. Med Clin North Am. 1999 May;83(3):627-42 vi [PubMed abstract] [Related articles]

What Your Patients Are Asking

What causes peripheral neuropathy?
	The peripheral nervous system consists of nerves that connect the brain and spinal cord (the central nervous system) to the muscles, skin, glands, and internal organs. When peripheral nerves are damaged, inflamed, or diseased, this can cause a disorder called a peripheral neuropathy (PN). Various factors can cause PN, including diabetes, vitamin or dietary deficiencies, alcoholism, certain medications, environmental toxins, and some inherited diseases. Common symptoms include numbness, tingling, pain, and muscle weakness. It's important to know that, even with extensive evaluation, the cause of a patient?s neuropathy sometimes cannot be diagnosed.
What's the likelihood that I won't fully recover from my condition?
	Recovery depends on the type and extent of nerve damage and the underlying cause of the neuropathy. The timeliness of diagnosing your condition may affect your recovery. Fortunately, in many patients, full recovery can be expected.
I've been having pain in my feet when I walk and stand, as well as pain in my lower back. How do I know that it's PN and not just an orthopedic condition?
	Your physician will conduct a detailed examination that includes your medical history, a physical exam, and, if needed, laboratory and electrical nerve tests. Together, this information can help him or her diagnose the cause of your symptoms. Keep in mind that foot and back pain are common symptoms of many types of neuropathies, and not just orthopedic or muscle disorders.

MDAlert 04/15/03

Study offers guidance on use of opioids for treating chronic neuropathic pain

In Brief

Apr 15, 2003 Opioids are effective for treating refractory chronic neuropathic pain, but there is a tradeoff between pain reduction and adverse effects when choosing a dose, according to a randomized double-blind trial in the New England Journal of Medicine. The trial found that higher doses produce a greater reduction in pain intensity than lower doses do, but also lead to more adverse effects.
     Researchers at the University of California, San Francisco, studied 81 patients with chronic peripheral or central neuropathic pain that had not responded to other therapies. For 8 weeks, the patients were treated with high-strength (0.75 milligrams [mg]) or low-strength (0.15 mg) capsules of levorphanol up to a maximum of 21 capsules per day.
     The reported reduction in pain intensity was significantly greater in patients taking high-strength capsules than in those taking low-strength capsules (36% vs 21%).
      When patients were grouped according to the cause of pain, the greater reduction in pain intensity at the higher strength was most pronounced in patients with postherpetic neuralgia, spinal cord injury, and multiple sclerosis. Patients with central neuropathic pain after stroke had the smallest reductions in pain intensity during treatment.
     Patients in the high-strength group took fewer capsules per day (12 vs 18) and had a higher total daily dose of levorphanol (9 mg vs 3 mg).
     Patients in both groups had reduced affective distress and interference of pain with functioning and improvements in ability to get sufficient sleep. There were no significant differences between the two groups in these end points.
     Twenty-seven percent of patients withdrew from the study. Among patients withdrawing, the main reason cited was adverse effects of the opioid, and this reason was given by more of the withdrawing patients in the high-strength group. In addition, certain adverse effects, such as anger and generalized confusion, were reported only in the high-strength group.
     Higher doses of opioids achieve a greater reduction in pain intensity, but adverse effects are more problematic at such doses, the investigators concluded. They caution, "On the basis of our findings, it is clear that not all patients will benefit from opioids, and some will have worsening of mood and function without relief of pain."

Our Recommendations

Recommended by Barry D. Weiss, MD, Professor of Clinical Family and Community Medicine, Department of Family and Community Medicine, University of Arizona College of Medicine, Deputy Editor of Best Practice of Medicine.

Consider opioid therapy as an adjunct for treating patients who have chronic peripheral neuropathic pain - especially those who have not had adequate relief from standard treatments such as tricyclic antidepressants (eg, amitriptyline) and anticonvulsants (eg, gabapentin or valproic acid).
When treating chronic peripheral neuropathic pain with opioids, consider using the opioids that have the most activity against neuropathic pain - levorphanol and methadone.
Use high-strength doses by titration to control peripheral neuropathic pain, as high-strength doses result in better pain relief than lower doses. Be aware that higher doses are associated with a higher risk of adverse effects.
Consider rotating opioids (ie, change from levorphanol to methadone or vice versa) if patients develop tolerance to the anti-neuropathic pain effects of these drugs, as clinical experience suggests that a change in drug may improve pain control.
Be aware that the neuropathic conditions for which opioids have been shown most effective are peripheral neuropathy, focal peripheral nerve injury, and post-herpetic neuralgia. There is less clear benefit from opioids when neuropathic pain is caused by a central nervous system condition (eg, multiple sclerosis, stroke, spinal cord injury).

References and Links

Rowbotham MC, Twilling L, Davies PS, et al. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med. 2003;348:1223-32. [Pubmed abstract][Related articles]
Foley KM. Opioids and chronic neuropathic pain. N Engl J Med. 2003;348(13):1279-81. No abstract available. [Pubmed abstract][Related articles]
Dellemijn P. Are opioids effective in relieving neuropathic pain? Pain. 1999;80(3):453-62. Review. [Pubmed abstract][Related articles]

MDNews

06/12/01 - Carpal tunnel not increased in frequent computer users

NEW YORK, June 12 (Praxis Press) A prospective study published in the journal Neurology determined that using a computer does not appear to increase the risk for carpal tunnel syndrome (CTS)--a result that surprised even the researchers.
      Researchers from Department of Neurology at the Mayo Clinic, Scottsdale, AZ sent questionnaires to 314 employee computer users asking if they experienced any pins and needles or numbness in their hands. Those indicating paresthesias were then asked to complete a CTS symptom questionnaire (i.e., awakened by paresthesias, hand goes to sleep while driving and/or reading, and relief by shaking hand) and undergo nerve conduction studies to confirm the presence and severity of CTS.
      Seventy-six employees reported paresthesias. Of the 70 available for further testing, 10.5% (27 patients, 39 hands) were classified as having CTS. Nine (3.5%) of CTS classified cases were confirmed by nerve conduction studies--an incidence that previous studies have shown to be similar to that found in the general population. Most of the employees classified as having "possible CTS" had mild symptoms and had not previously consulted their physicians. The researchers could find no specific characteristics of employees with and without CTS that might implicate computer use as a causative factor, and noted that both groups had similar occupations and years/time spent using computer each day.
      From these results, it appears that the rate of CTS in computer users is the same as that in the general population.

References:
Stevens JC, Witt JC, Smith BE, Weaver AL: The frequency of carpal tunnel syndrome in computer users at a medical facility. Neurology. 2001;56:1568-70. [http://neurology.org/cgi/content/abstract/56/11/1568]

[ICD-9-CM code 337.0, 337.1, 354, 355, 356, 356.1, 356.2, 356.3, 356.4, 356.8, 356.9, 357.2, 782]

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