Toxic Neuropathy

Updated: Dec 01, 2022
Author: Jonathan S Rutchik, MD, MPH, FACOEM; Chief Editor: Jasvinder Chawla, MD, MBA 


Practice Essentials

Toxic neuropathy refers to neuropathy caused by drug ingestion, drug or chemical abuse, or industrial chemical exposure from the workplace or the environment. Distal axonopathy, causing dying-back axonal degeneration, is the most common form.

Signs and symptoms

Patients with neuropathy typically present with symptoms of pain, tingling, or numbness in their feet, consistent with dysfunction affecting the longest and largest fibers of the peripheral nervous system (PNS). Other manifestations of neurologic dysfunction that may be present include the following:

  • Hypohidrosis or hyperhidrosis

  • Diarrhea or constipation

  • Urinary incontinence or retention

  • Gastroparesis

  • Sicca syndrome

  • Blurry vision

  • Facial flushes

  • Orthostatic intolerance

  • Sexual dysfunction

  • Cramping

  • Tachycardia

  • Rapid alterations in blood pressure

During physical examination, the following symptoms of polyneuropathy may be found:

  • Sensory loss in a stocking-glove distribution

  • Distal to proximal progression: Consistent with the commencement of axonal degeneration

  • Early loss of symmetrical ankle jerk

  • Motor dysfunction (eg, abnormal gait and foot drop): In severe cases

Central nervous system (CNS) disease can manifest as follows:

  • Corticospinal tract disease: Hyperreflexia, Babinski responses, and stiff-leg ataxic gait

  • Dorsal column degeneration: Diffusely decreased proprioceptive and vibratory sensations and gait ataxia

The following examples list the neuropathic signs and symptoms associated with specific toxins:

  • Thallium: Acute intoxication leads to pain and paresthesias in the distal extremities followed by weakness and eventual atrophy; autonomic dysfunction also may be part of the clinical syndrome; peripheral reflexes are preserved

  • Dimethylaminopropionitrile (DMAP): Industrial exposure has led to prominent urinary and sexual dysfunction, as well as to distal sensory neuropathy

  • Alcohol: Ataxia and other systemic symptoms may accompany dysesthesia and weakness of the lower extremities

  • Carbon disulfide: Reduced or absent sensory nerve action potentials (SNAPs) are common; conduction velocities are usually normal, but they may be borderline low owing to selective involvement of large fibers

  • Ethylene oxide (EtO): Symptoms suggestive of neuropathy, such as numbness and weakness of extremities, leg cramps, and gait difficulties, are reported mostly after long-term EtO exposures

  • Mercury: Reportedly causes reduced strength and coordination, tremor, impaired sensation, and higher prevalence of Babinski and snout reflexes

  • Lead: Acute, high-level exposure can reportedly cause motor neuropathy with minimal sensory involvement and, in rare cases, wrist drop; chronic, lower-level exposures cause axonal dying back neuropathies that appear similar to neuropathies from diabetes or alcohol

See Clinical Presentation for more detail.


Take a thorough medical history, including the patient’s occupational and environmental history, to consider all sources of exposure to all possible agents. List details of all jobs and specific tasks within these jobs, as well as when various symptoms and medical problems began for the patient.

Quantitative sensory testing in the diagnosis of neuropathy includes the following:

  • Vibration threshold

  • Thermal threshold

  • Portable motor and sensory latency

  • Current perception threshold (CPT)

Other studies that help to prove the presence of neuropathy include the following:

  • Intraepidermal nerve fiber density (IENF)

  • Sympathetic skin reflex

  • Electromyography (EMG)

  • Nerve conduction

Laboratory studies in patients with neuropathy can include the following:

  • Glucose tolerance

  • Serum, urine, or blood

  • Vitamin B-12

  • Monoclonal gammopathy of unknown significance

  • Axonal neuropathy

  • Cryoglobins and hepatitis C evaluation

  • Immunofixation (for paraneoplastic neuropathy)

  • Cerebrospinal fluid (CSF) protein level: Usually normal in toxic neuropathy

See Workup for more detail.


In addition to advising the patient to avoid the causative drug or occupational or environmental toxin, management of toxic neuropathy can include the following:

  • Nonpharmacologic measures: Cool soaks, heat, massage, elevation or lowering of the limbs, and/or exercise

  • Tricyclic antidepressants

  • Anticonvulsants

  • Opiates

  • Topical capsaicin cream

Consistent follow-up care with a neurologist is necessary to monitor the progress of neurologic findings. Follow-up with an occupational medicine specialist may be important to assist with return to work and reduction of exposure.

See Treatment for more detail.


Lewis P. Rowland, in Merritt's Textbook of Neurology, defines the terms peripheral neuropathy and polyneuropathy as describing "the clinical syndrome of weakness, sensory loss and impairment of reflexes caused by diffuse lesions of peripheral nerves." The diagnosis most often is based on the clinical picture and is confirmed with electrodiagnostic techniques, most commonly electromyography (EMG) and nerve conduction studies. Facial nerve and blink reflex testing also are used commonly. Apparatuses, such as the neurometer, vibrometer, and sensory nerve perception threshold-testing device, often are used in research settings or to evaluate clusters of patients.

Patients with toxic etiologies for neuropathy are less common than patients with other neuropathies such as those due to hereditary, metabolic, or inflammatory causes. Drug-related neuropathies are among the most common toxic neuropathies. Neuropathies from industrial agents (either from occupational or environmental sources), presenting after either limited or long-term exposure, are insidious. Patients may present with subtle pain or weakness. Subclinical abnormalities found on electrodiagnostic testing may herald a progressive neuropathy if exposure continues at a similar dose. Attributing neuropathy to such an exposure often is difficult. In some patients, extensive search for an etiology may fail to uncover the exact cause of neuropathy.

Many chemicals are known to cause neuropathy in laboratory animals. Some of these have been associated with neuropathy in clinical epidemiologic studies, confirming their ability to injure the human peripheral nervous system (PNS). Other chemicals have been reported to be associated with PNS dysfunction and neuropathy on the basis of retrospective and cross-sectional epidemiologic studies. Designs for many of these studies have been criticized. Other associations have been made from many case reports and case series.

Human studies infrequently have associated exposure to environmental sources with peripheral neuropathy. As compared to nonexposed controls, exposed individuals have statistically significant differences in nerve conduction velocity (NCV) and EMG findings. Exposures have been estimated for duration and intensity based on point source extrapolation, a common method of environmental risk assessment. When reviewing the literature, a critical analysis of study designs and electrodiagnostic techniques is important.

An algorithm to assess patients with suspected neurotoxic illness is detailed in Medical/Legal Pitfalls. It describes occupational and environmental history as an important aspect of the medical history. In cases of positive occupational or environmental exposure, estimating dose and duration of exposure and level of protection afforded by personal protective equipment is emphasized. Government and professional organizations publish exposure limits for workers using various chemicals. Physicians may use this information to compare with industrial hygiene data. These are outlined in Table 1.

Table 1. Exposure Limits, Common Organic Solvents and Metals (Open Table in a new window)




ppm (mg/m3)


TWA: ppm (mg/m3),



ppm (mg/m3) TLV,




(0.03), 60 Ca


Arsenic, inorganic


C (0.002)

(0.01), -

Arsenic, organic

0.5 mg/m3



Carbon disulfide

20, 30, 100 for 30 min

1 (3),

10 STEL (30),


10 (31)

Ethylene oxide


1 < 0.1,

< 0.18, 5 C,


1 (1.8)

n -hexane

500 (1800)

50 (180), 1100

50, (176)


0.05 mg/m3

0.100 mg/m3

(0.05), -

Mercury, inorganic

C 0.1 mg/m3

0.05 mg/m3,

C 0.01 mg/m3,

10 mg/m3

0.025 mg/m3

Mercury, organic

0.01 mg/m3,

C 0.04 mg/m3

0.01 mg/m3,

ST 0.03 mg/m3,

2 mg/m3

0.01 mg/m3,

0.03 mg/m3

Methyl n -butyl


100 (410)


5 (20)


100, 200 C,

300 for 5 min

in 3 h

150 Ca

25 (170),

100 (685)


100, 200 C,

600 for 5 min

in 3 h

50 (215),

100 ST (425), 700

50 (213),

100 (428)


0.1 mg/m3 skin

0.1 mg/m3,

15 mg/m3

0.1 mg/m3


200, 300, 500 for 10 min

100 (375),

150 ST (560),


50 (188)



(methyl chloroform)

350 (1900)

C 350(1900)

for 15 min,


350 (1910),

450 (2460)


100, 200 C,

300 for 5 min

in 2 h

1000 Ca

50 (269),

100 (1070)

Vinyl chloride

1, 5 for 15 min




100 (435)

100 (435),

150 ST (655)

100 (434),

150 (651)

Abbreviations: OSHA - Occupational Safety and Health Association; NIOSH - National Institute of Occupational Safety and Health; ACGIH - American Congress of Governmental Industrial Hygienists; TWA - time-weighted average; TLV - threshold limit value; PEL - permissible exposure limit; REL - recommended exposure limit; ppm - parts per million; STEL - short-term exposure limit; Ca - level for carcinogenicity; C - ceiling, should never be exceeded; ND - not determined

Utilizing neurophysiologic testing, neuropsychological testing, and neuroimaging to support a clinical suspicion is encouraged. When the exposure has ended, retesting also is appropriate after a period of time. Perform biological testing of serum and urine to assess absorbed dose. Values have been published for these data. These are outlined in Table 2.

Table 2. Agency for Toxic Substances and Disease Registry Biological Exposure Indices (Open Table in a new window)













Inorganic arsenic: end of work week, 50 µg/g

monomethyl-arsonic acid, cacodylic acid (days)



Hair (ingestion chronic)

Carbon disulfide

2-TTCA* 5 mg/g

Carbon disulfide

Carbon disulfide


Ethylene oxide





n -hexane

2-5 hexanediol: end of shift, 5 mg/g

2 hexanol, total metabolites

n -hexane

n -hexane




Lead 30 μg/100 mL


Erythrocyte protopor-phyrin

Mercury, inorganic

Mercury: start of shift, 35 µg/g

Mercury: end of shift at end of work week, 15 µg/L



Methyl n -butyl ketone


2,5 hexane dione




Perchloro-ethylene, trichloroacetic acid

Perchloroethylene 1 mg/L

Perchloro-ethylene: before last shift of week, 10 ppm†



Mandelic acid: start of shift, 300 mg/g; end of shift, 800 mg/g

Phenylglyoxylic acid: start of shift, 100 mg/g; end of shift, 240 mg/g

Styrene: start of shift, 0.02 mg/L; end of shift, 0.55 mg/L









Hippuric acid




1,1,1 Trichloroethane (methyl chloroform)

Trichloroacetic acid: end of work week, 10 mg/L

total trichloroethanol: end of shift at end of work week, 30 mg/L

Total trichloroethanol

1 mg/L

Methyl chloroform: prior to last shift of work week, 40 ppm†



Trichloroethylene, trichloroacetic acid: end of work week, 100 mg/g or trichloroacetic acid plus trichloroethanol, 300 mg/g

Trichloroethylene: end of work week, 4 mg/L




Vinyl chloride






Methylhippuric acid: end of shift, 1.5 mg/g




*2-TTCA - 2-thiothiazolidine-4-carboxylic acid

† ppm - parts per million

Use of the medical literature to associate an agent with an abnormality is important. Ascertain existence of supporting evidence that suggests exposure at a specific dose and duration that can cause such dysfunction and whether animal data are helpful to extrapolate an estimated dose that may lead to a health effect in humans.


Neuropathy may be categorized by presentation (ie, motor or sensory symptoms), electrodiagnostic features, and neuroanatomical location within the peripheral nerve (ie, demyelinating or axonal, neuronopathy, ion channel neuropathy, neuromuscular transmission) or location (ie, cranial or peripheral). Toxic neuropathy refers to those presentations that are caused by drug ingestion, drug or chemical abuse, or industrial chemical exposure from the workplace or from the environment.

Kimura mentions that these may be divided into the following 3 groups based on the presumed site of cellular involvement:

  • Neuropathy affecting the cell body, especially those of the dorsal root ganglion

  • Myelinopathy or schwannopathy with primary segmental demyelination

  • Distal axonopathy causing dying back axonal degeneration

Although distal axonopathy is the most common form, a few agents have been associated with the first 2 types. Antibiotic treatment or cisplatin or pyridoxine toxicity may cause sensory neuronopathy, and segmental demyelination may result from the cardiac medications perhexiline or amiodarone, tetanus toxoid or diphtheria toxin administration, or exposure to lead or arsenic.[1, 2]

Other types of neuropathy, such as sodium channel, neuromuscular transmission, or cranial neuropathies, also have toxic etiologies.

In North America, sodium channel dysfunction may be the result of ciguatera toxin from reef fish or saxitoxin from shellfish. This often presents as an acute or subacute illness. Puffer fish may be intoxicated with tetrodotoxin in Japan. Neuromuscular transmission dysfunction is associated most commonly with organophosphate intoxication; however, envenomation from snake bites or botulism may be as serious a culprit. Cranial neuropathies affecting isolated nerves are uncommon. Trichloroethylene (TCE) has been associated with trigeminal neuropathy, and ethylene glycol may affect the facial nerve. The existence of these syndromes has been revealed by facial nerve and blink electrophysiologic studies (see Causes).


In one study, 76% of 205 patients who presented with undiagnosed neuropathy had neuropathies that were classifiable. Thus, about 25% of all neuropathies have an unknown etiology. Environmental and occupational exposure may play a role in some of these undiagnosed neuropathies.


Each patient's prognosis depends on the severity of the neuropathy when exposure is ceased or reduced to levels that will not affect health negatively.

Patient Education

Inform patients about aspects of dose, diet, and nutrition that may increase risk of toxicity when taking a medication. Since many solvents are metabolized in the liver, concomitant use of medications with similar metabolism may lead to increased toxicity.

Workers, by law, need to be informed of chemicals in the workplace and their potential health hazards. Material safety data sheets (MSDS), per order of Occupational Safety and Health Administration (OSHA), are available to all workers in the workplace.

The Emergency Planning and Community Right to Know Act (EPCRA) requires that facilities using, storing, or manufacturing hazardous chemicals make public inventory and report every release to public officials and health personnel. These facilities must cooperate with health personnel who are treating victims of exposure.




Patients with neuropathy typically present with symptoms of pain, tingling, or numbness in their feet, consistent with dysfunction affecting the longest and largest fibers of the PNS. In some cases, they may have weakness (distal more than proximal) or difficulty with gait. In other cases, patients may also present with symptoms of pain. This may suggest a small fiber neuropathy, which exists when small myelinated and unmyelinated fibers are involved. Clinically, pain may be accompanied by restless leg syndrome, a condition in which disagreeable leg sensations and an irresistible urge to move occur prior to sleep onset.

Additionally, other forms of autonomic dysfunction may be present such as hypohidrosis or hyperhidrosis, diarrhea or constipation, urinary incontinence or retention, gastroparesis, sicca syndrome, blurry vision, facial flushes, orthostatic intolerance, or sexual dysfunction. Autonomic dysfunction may present as cramping. In these cases, the examination reveals normal proprioception, vibration, power or bulk, reflexes, and normal findings on electromyography (EMG) or nerve conduction studies (NCS).[3]

The clinician needs to exercise a high index of suspicion to uncover toxic etiologies. A patient beginning a new medication in the last few weeks or months should raise a red flag. Certainly, the search for an underlying chronic disease is the most common workup ordered; however, new medications are commonly a culprit.

Toxic neuropathy due to recreational drug or chemical abuse may be more difficult to uncover than occupational or environmental exposures, since direct questioning of the patient may lead to incorrect information. In some cases, a dramatic systemic reaction leads to an emergency department (ED) visit because of an acute alteration of consciousness, heralding the diagnosis of drug abuse. The challenge for the ED clinician at this point is to uncover the agent of ingestion or inhalation. Neuropathy, in these cases, may present over a few days to weeks since the dose is often higher than in prescribed-medication settings.

Occupationally induced neuropathies may be secondary to low-level, long-term exposures. The differential diagnosis may not include a work-related exposure, since physicians often are not trained to ask questions about patients' work practices or environment. The presentation may coincide with other lifestyle and medication changes and recent medical diagnoses. After a high-level acute exposure, an occupational etiology for toxic neuropathy may be easier to consider.

Environmental exposure–induced neuropathies follow the same pattern as those from occupational exposures; however, they are omitted even more commonly from the differential diagnosis. For example, a physician is even less likely to ask questions about the patient's use of groundwater, proximity to pesticides, or household use of organic solvents than about occupational exposures. As with occupational exposure, environmental exposures often are very low level, but they are long term and more intensive than occupational exposures, lasting longer than a 40-hour workweek for the duration of employment. Patients who have had high-concentration acute exposure from an environmental accident may present with more obvious clinical symptoms. A differential diagnosis ruling out more common causes of neuropathy is mandatory to establish the cause of neuropathy.[4, 5]

Prior to appearance of symptoms, subclinical findings on EMG or NCV studies may be apparent and consistent with axonal or demyelinating abnormalities. Occupational or environmental exposure at doses approaching regulatory levels for duration or intensity may warrant such an evaluation. Often these are performed in field studies with the use of portable apparatus. Dysfunction associated with environmental exposure to TCE, mainly subclinical, is revealed by electrodiagnostic techniques.

Pain or numbness in the distribution of the trigeminal nerve suggests a disorder of that nerve.


Kimura, in Electrodiagnosis in Diseases of Nerve and Muscle, notes that polyneuropathy presents clinically as a "triad of sensory changes in a glove and stocking distribution, distal weakness, and hyporeflexia." The sensory changes include sensory loss in a stocking-glove distribution. Often, progression is distal to proximal. This is consistent with the commencement of axonal degeneration. Early loss of symmetrical ankle jerk is noted. In severe cases, motor dysfunction such as abnormal gait and foot drop also may occur. In some patients with exclusively small fiber neuropathy, the motor and reflexes examination may be normal.

Spencer and Schaumberg emphasized a gradual insidious onset, as well as slow recovery. Recovery proceeds at a rate of 2 mm/day and may take months or several years, or may never be complete. Function is restored in reverse order to the sequence of loss. Coasting may be noted, that is, intensification may occur for weeks before improvement. This often reflects continued axonal degeneration and reconstitution.

Signs of CNS disease also may be present at examination. This occurs in some patients recovering from certain toxic neuropathies. Dorsal column or corticospinal tract degeneration may be present. These clinical signs of degeneration are not prominent early in the illness; however, the patient may manifest hyperreflexia, Babinski responses, and stiff-leg ataxic gait with corticospinal tract disease or diffusely decreased proprioceptive and vibratory sensations and gait ataxia with dorsal column degeneration.

Involvement of the autonomic nerves may lead to a different clinical presentation–miosis, anhydrosis, orthostatic hypotension, sphincter symptoms, impotence, and vasomotor abnormalities. These may occur with or without evidence of a peripheral neuropathy. Tachycardia, rapid alterations in blood pressure, flushing and sweating, and abnormalities in gastrointestinal motility may be present.

Spencer and Schaumberg reported the association of sensory ganglion cell loss in pyridoxine-associated sensory neuropathy with 9 clinical features; they are as follows:

  • Rapid or subacute onset may occur following massive intravenous administration.

  • Initial sensory loss may occur anywhere; the gasserian ganglion often is affected simultaneously with the dorsal root ganglion, and thus facial numbness may be noted.

  • Diffuse sensory loss with ataxia and preservation of motor power may be present. Proprioceptive deficit is noted to be greater than the loss of pain or temperature sensation.

  • Tendon reflexes may be absent.

  • NCV results usually are normal; sensory nerve potentials may be abnormal or absent. Recovery is variable, reflecting the death of nerve cell bodies and consequent permanent loss of axons. Collateral sprouting from surviving axons may account for the extent of recovery in these conditions.

  • No signs of CNS disease are present.

  • Cholinergic symptoms follow (see Organophosphates and disorders of neuromuscular transmission).


A variety of drugs and industrial chemicals cause distal axonopathy. In 1989, Kimura listed the following as potential causes of toxic neuropathy:[6, 7]

  • Amiodarone

  • Chloramphenicol

  • Dapsone

  • Disulfiram

  • Gold

  • Isoniazid

  • Lithium

  • Metronidazole

  • Nitrofurantoin

  • Nitrous oxide

  • Perhexiline maleate

  • Phenytoin

  • Thalidomide

  • Vincristine

In August 2013, the US Food and Drug Administration (FDA) announced that oral or injected fluoroquinolone antibiotics can cause permanent peripheral neuropathy and that labels on the drugs will be updated to reflect this finding. (Topical fluoroquinolones have not been associated with this condition.)[8, 9]

The change strengthens the FDA’s previous warning, first added to fluoroquinolone labels in 2004, that oral and injectable fluoroquinolones carry a risk of peripheral neuropathy. The 6 FDA-approved fluoroquinolone antibiotics on the market are ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin.[8, 9]

Industrial chemicals causing toxic axonal neuropathy also are listed by Kimura; they include the following:[6, 7]

  • Acrylamide

  • Carbon disulfide

  • Inorganic mercury

  • Methyl n -butyl ketone

  • Parathion

  • Polychlorinated biphenyl

  • Thallium

  • Triorthocresyl phosphate

  • Vinyl chloride

In 1999, Feldman added the heavy metals arsenic and lead, as well as the solvents n -hexane, perchloroethylene (PERC), and TCE to this list.[10] In 1995, Albers and Bromberg summarized the literature on toxic neuropathy caused by the solvents ethylene oxide (EtO), styrene, toluene, and mixed solvents.[11]

Spencer and Schaumberg listed agents that commonly are associated with peripheral neuropathy (see Table 2 in Schaumberg, 2000[12] ).

Toxic neuropathy may be the result of exposure to numerous agents and is related to dose and duration of exposures and to host factors. Most syndromes are subacute, progressing to chronic as already described. Chemicals such as thallium, dimethylaminopropionitrile (DMAP), and organophosphates (eg, parathion) produce specific syndromes associated with peripheral neuropathy; however, all of these may lead to systemic abnormalities as well.

Thallium is used in glass and in metal alloys. It had been used therapeutically to treat venereal disease, tuberculosis, and ringworm. It has also been used as a rodenticide. Accidental or homicidal abuse is a common reason for toxicity.

Acute thallium intoxication leads to pain and paresthesias in the distal extremities followed by weakness and eventual atrophy. Preservation of peripheral reflexes is a useful physical finding to differentiate thallium toxicity from Guillain-Barré syndrome. Alopecia is a clinical hallmark of thallium toxicity that may develop weeks after intoxication. Mee lines, nephropathy, anemia, and hepatotoxicity are systemic manifestations. Autonomic dysfunction also may be a part of the clinical syndrome. Thallium toxicity may be mistaken for porphyria, arsenic toxicity, or botulism. Serum thallium levels typically are elevated.

DMAP is used as a catalyst in the manufacture of polyurethane foam and in an acrylamide grouting compound. It is used as a waterproofing agent in tunnels and sewer lines. Industrial exposure has led to prominent urinary and sexual dysfunction as well as to distal sensory neuropathy.

Alcohol, by itself, is toxic to the PNS. Individuals who consume alcohol also may become nutritionally compromised. Studies have found that alcohol impairs axonal transport and that this can occur in the setting of normal nutrition. Since it may affect both the cerebellum and the autonomic nervous system, ataxia and other systemic symptoms may accompany symptoms of dysesthesia and weakness of the lower extremities. In the patient with occupational exposure to other peripheral neurotoxic agents, alcohol may act either to slow metabolism and increase toxicity or, in the case of a habitual alcohol user, promote metabolism and reduce toxicity from the agent. This is observed most clearly with toluene exposure.

A number of studies have attempted to address the type of neuropathy that occurs with alcohol exposure, as well as what amount of exposure is required before neuropathy occurs. A sensorimotor axonopathy with secondary demyelination that was not necessarily related to a deficit in thiamine was described by Mellion et al in 2011.[13] Ten ounces of whiskey per day in a 70-kg man for several years was mentioned to cause alcohol neuropathy.[14] Three liters of beer per day for 3 years was described as another threshold.[15] Wine in combination with other forms of ethanol was deemed worse, possibly due to impurities with lead.[16]

Other organic solvents have been associated with peripheral neuropathy on the basis of cross-sectional studies and animal data. Prospective data are unavailable. Solvent mixtures have been noted to be responsible for toxic neuropathies in many studies. Identifying the culpable agent has been difficult. Often, no chemical with a clear association with neuropathy is listed, suggesting that organic solvents themselves, either in mixture or individually, may cause neuropathy. Studies that have found subclinical abnormalities further support this hypothesis.

Often, study designs have been criticized for their definition of neuropathy. NCV and EMG findings in many of these studies are difficult to categorize. To ascertain whether a toxic etiology is a possibility for a patient, a clinician may need to search the literature for the agent as well as the industry. Many agents are used in many different industries. The industrial agents and some of the industries that utilize them are listed in Table 3. For information on toxic neuropathy caused by organophosphates, refer to the article Organophosphates.

Carbon disulfide and peripheral neuropathy

Carbon disulfide is an agent used in the viscose rayon industry. Refer to Table 3 for its other uses.

Carbon disulfide has been deemed a peripheral neurotoxin in both animals and humans by the Agency for Toxic Substances and Disease Registry (ATSDR). Consistency has been established for effect (ie, neurophysiological impairment and pathologic changes) but not for dose. The pathophysiology for toxic neuropathy is an axonal neuropathy in a distal dying back pattern. Reduced or absent sensory nerve action potentials (SNAPs) are common. Conduction velocities are usually normal, but they may be borderline low owing to selective involvement of large fibers. Metabolic abnormalities from coexisting diseases may be associated with reduced conduction velocities and may contribute to electrophysiologic abnormalities.

In humans, neurophysiological effects have been demonstrated at low levels of occupational exposure. In 1974, Seppalainen and Tolonen demonstrated a decrease in maximal motor NCV in the median, ulnar, peroneal, and posterior tibial nerves in 118 viscose rayon workers who had exposure to an average of 10-20 parts per million (ppm) of carbon disulfide for an average of 15 years. No improvement was noted after removal from exposure, but a follow-up study by these authors demonstrated that fewer workers who had retired 10-15 years prior had decreased NCVs than those who had been removed from their work 0-4 years prior to the study. (These abnormalities were in workers who had no subjective complaints.)[17]

In 1990 and 1993, Ruitjen et al demonstrated that 44 viscose rayon workers exposed to 1-30 ppm of carbon disulfide for at least 10 years had somewhat slower slow motor fiber conduction velocities than 31 controls, based on the antidromic collision technique. Symptoms of clinical neuropathy related to cumulative exposures were absent in the patients in this study. This study revealed that a decrease in the conduction velocity occurs at low levels of exposure to carbon disulfide. Extrapolation of these results suggests that small effects may occur after a mean cumulative exposure of 165 ppm-years, which would be equivalent to a concentration of 4 ppm over an 8-hour time-weighted average (TWA). At this exposure level over a lifetime of employment, the observed effects would be expected.

The authors explained that the significance of these effects on health would be that these observed changes might reduce reserve capacity to cope with other noxious influences. They concluded that these changes are undesirable until they are shown to be not detrimental to health in the long term.

The second study to verify these findings reexamined these workers 4 years later and found a statistically significant decrease in velocities in the slow as well as the fast motor nerve fibers of the peroneal nerve. Weighted cumulative exposures correlated less well with the peripheral nerve indices and revealed no evidence that the effects were reversible. The authors reiterated their concerns for the neurotoxic effects of carbon disulfide at these exposure levels.[18, 19]

In 1983, Johnson et al examined 189 workers from a viscose rayon plant; 245 workers in polyester-nylon filament and staple plants were used as controls.[20] Confounding exposures were hydrogen sulfide, tin oxide, zinc oxide and sulfate, sodium hydroxide, and sulfuric acid. At no point in time did hydrogen sulfide levels exceed 1 ppm.

Carbon disulfide exposure was divided into high (median >7.1 ppm), medium (median 3-7.1 ppm), and low (median < 3 ppm). Exclusion criteria were alcohol consumption >35 U, blood glucose >110 mg/dL, or blood lead >40 mcg/L. Mean duration of exposure for all exposed subjects was 12.1 years; for the high-exposure group it was 13.6 years; for the medium-exposure group it was 12.3 years; and for the low-exposure group it was 10.5 years. The average age of exposed individuals was 38.5 years and of controls, 33.9 years.

The study assessed NCV of motor (ie, peroneal, ulnar) and sensory (ie, sural) nerves. A reduction in peroneal nerve mean conduction velocity (MCV) was found to be related, in a dose-response sense, to cumulative exposure to carbon disulfide.

Ethylene oxide and peripheral neuropathy

EtO is a sterilizing agent with an epoxide structure often used in hospital settings. Refer to Table 3 to review other industrial uses of EtO. Symptoms suggestive of neuropathy, such as numbness and weakness of extremities, leg cramps, and gait difficulties, are reported mostly after long-term EtO exposures. In 1979, Gross et al reported 4 cases of peripheral neuropathy caused by EtO resulting from a large EtO sterilizer leak that was not noticed for 2 months.[21] These patients were working as sterilizer operators and had exposures of 3 weeks to 8 years. One operator was asymptomatic; 3 had headaches; and 2 developed fatigue, numbness, and muscle weakness in the extremities. In 1983, 5 of 6 sterilizer operators of a factory producing medical appliances were poisoned by EtO gas.

In 1986, Fukushima et al examined 4 operators who had exposures to the chemical ranging in duration from 20 days to 8 months. Gait disturbance was noted in all 4 operators. All 4 complained of numbness and muscle weakness in the feet and numbness of the fingers. Two operators had pain in the calf muscles and 3 had muscle weakness of the fingers. A 23-year-old man had been exposed 2-3 times a day for 5 months to high levels of EtO, up to 500 ppm, while working in a food and medical supply sterilization factory prior to his admission to a hospital. He complained of increasing weakness in his lower extremities.[22]

Schroder and Kuzuhara reported 2 patients with long-term EtO exposure. Both had difficulty in walking. One had been an operator of a sterilizer for 3 months before noting paresthesias and weakness in the distal limbs with staggering. After he returned to work, his symptoms worsened, and 3 months later he was admitted to a local hospital. His symptoms cleared entirely after 2 months. The second patient noted paresthesias in his feet 6 months after he had started to load and unload the sterilizers with medical supplies. Staggering followed the numbness and tingling of both hands and feet. Symptoms cleared 1 month later.[23, 24]

Finelli et al reported another case series of 3 males with toxicity from EtO. Two of these had been operators of sterilizers. One worked for a year and the other worked part-time for 1.5 years before developing symptoms. Both had difficulties with their gait after developing numbness and weakness in their lower extremities. One operator reported numbness in his feet and buckling of his right leg, and the other complained of cramps in his calf muscles. Both reported an odor; the part-time operator also reported headaches, burning eyes, and nausea.[25]

The third patient worked for 6 days a week at a plastic manufacturing company, where several times a day he worked in a sterilizing tank for about 40 minutes; he also unloaded materials in a decontamination area for half an hour each day. His chief complaints were leg cramps and a sense of heaviness of the feet. He first noted difficulty with sleeping, nervousness, and cramps in his hands and calf muscles. One month later, he noted poor balance and repeated stumbling. He also was aware of odd tingling sensations in both feet that had been present for longer than 3 months.

Two women workers developed symptoms referred to the PNS after chronic EtO exposure. Both had been part of a group of 12 sterilizer workers in a hospital in Italy who were tested 2 years after the commencement of this exposure. Four of these 12 women complained of paresthesias and fatigue. Two were found to have peripheral neuropathy. Complete remission of these symptoms was reported for most of these women approximately 6 months after removal from exposure.

Mercury (inorganic and organic) and peripheral neuropathy

Inorganic mercury is used in the chloralkali industry. Other uses are noted in Table 3. Neuropathy and PNS dysfunction, often motor more than sensory, were noted in the cases summarized here.

Albers et al reported 138 chloralkali plant workers with long-term exposure to inorganic mercury vapor who were found to have elevated urine mercury levels and reduced sensation on quantitative testing. Subjects exposed to mercury for 20-35 years who had urine mercury levels greater than 0.6 mg/L demonstrated significantly less strength, poorer coordination, more severe tremor, more impaired sensation, and higher prevalence of Babinski and snout reflexes than controls. Subjects with polyneuropathy had higher peak levels of mercury than healthy subjects.[11]

In another study by Andersen et al, chloralkali workers exposed to inorganic mercury vapor for an average of 12.3 years revealed a higher prevalence of reduced distal sensation, postural tremor, and impaired coordination than controls.[26] Barber reported 2 employees of a chloralkali plant who had findings suggestive of amyotrophic lateral sclerosis (ALS). Signs, symptoms, and laboratory findings returned to normal 3 months after withdrawal from exposure.[27] Adams et al reported a 54-year-old man with a brief but intense exposure to mercury vapor, which led to a syndrome resembling ALS that resolved as urinary mercury levels fell.[28] Ross reported that prolonged application of an ammoniated ointment to the skin was a cause of motor polyneuropathy, with cerebrospinal fluid (CSF) findings suggestive of Guillain-Barré syndrome.[29]

Warkany and Hubbard reported the association of acrodynia and symmetrical flaccid paralysis with mercury toxicity.[30]

Organic mercury was deemed the culprit in a number of historic environmental accidents. One noted catastrophe, reported by Yoshida et al, occurred in Minimata Bay, Japan, and involved organic mercury. The majority of Minimata patients with methylmercury intoxication had elevated pain thresholds but suffered from glove and stocking hyperesthesia in the extremities.[31]

Lead and neuropathy

A review of the literature reported that acute, high-level lead exposure has been described to cause motor neuropathy with minimal sensory involvement and rarely the textbook-described wrist drop. Chronic, lower-level exposures lead to axonal dying back neuropathies that appear similar to neuropathies from diabetes or alcohol. Chronic exposures, depending on the length of exposure, may have poorer prognoses but may present with a slower and more gradual onset. High–level, acute exposures are more likely to cause motor neuropathies, and recovery may be complete if termination of exposure is prompt. Because neuropathies have not seemed to correlate with blood lead levels, interference with porphyrin metabolism has been proposed as the etiology.[32]

Xylene and neuropathy

Xylene often is a component of paints and other industrial processes (see Table 3 for other uses of xylene). A literature search using Medline uncovered 11 epidemiologic studies of painters or other subjects with occupational exposure to organic solvents, including xylene, that found positive associations between exposure and PNS dysfunction. Two studies reported that vibration sensation was significantly less acute in 102 painters than in 102 age- and sex-matched controls. Four studies utilized quantitative sensory test (QST) methods.

In 1991, Bleecker found a correlation between increasing exposure dose and elevated vibration sensation thresholds in 187 workers from 2 paint-manufacturing plants.[33] A second study noted higher vibration thresholds in 80 exposed painters than in controls.[34] Demers et al noted statistically significant differences in vibrotactile measurements by QST of upper and lower extremities between 28 painters and 20 nonexposed controls.[35] In 1989, Bove et al compared 93 painters to a nonexposed control population of 105 construction workers.[36] Subjects were tested by 2 QST devices, a vibrometer and a temperature sensitivity tester. Painters had significantly higher temperature sensation thresholds, and exposure intensity and cumulative exposure over the past month and year were associated positively with vibration thresholds.

In 1989, Padilla et al performed an important animal study in which axonal transport was noted to be decreased by 30-50% in the rat optic nerve system immediately and 13 hours after inhalation exposure to xylene. Exposure was subacute; 800 and 1600 ppm for 6 hours/day, 5 days a week for 8 days led to these abnormalities. The authors concluded that the decreased supply of cellular materials to the axon and nerve-ending regions could initiate the neuronal malfunction reported in solvent-exposed animals and humans.[37] As axonal transport is a process common to all nerves, any perturbation in these processes may disrupt the structure and functional integrity of the neuron. This mechanism has been used to explain both the CNS and PNS toxicity from organic solvents.

Seven men aged 17-22 years developed severe distal symmetrical polyneuropathy after repeatedly inhaling a commercially available brand of lacquer thinner that was composed predominantly of xylene. All 7 were disabled permanently with motor weakness. One man died, 3 remained wheelchair bound, and 3 could walk but demonstrated varying degrees of weakness. Pathologic specimens revealed evidence of peripheral neuropathy.

Perchloroethylene and neuropathy

PERC is an agent used in the dry-cleaning industry. Its various other uses are listed in Table 3. Peripheral neuropathy is a clinical diagnosis that is listed as secondary to chronic PERC exposure by Feldman.[38, 39] Neither article refers to specific study results. Spencer and Schaumberg list neuropathy with a question mark as an effect of tetrachloroethylene (ie, perchloroethylene) toxicity. This article refers to 2 articles by Antti-Poika and Juntunen et al that reported sensory trigeminal (fifth cranial nerve) defects in those exposed to mixed solvents. A 1978 National Institute for Occupational Safety and Health (NIOSH) publication on PERC remarked that "various disturbances of the peripheral nervous system such as tremors and numbness have also been associated with exposure to tetrachloroethylene."

Juntunen et al studied 87 patients from Finland diagnosed as having chronic intoxication caused by exposure to a mixture of solvents or to TCE and PERC between 1970 and 1974. Of these, 14 had been exposed to TCE or PERC alone, 53 to solvent mixtures, and 13 to all of them. Disturbances of cutaneous sensation and the sense of vibration were encountered frequently as clinical signs.[40]

The Antti-Poika article of the same year (1982) discussed the EMG findings of this same group. Electroneuromyography ([ENMG], including NCV and EMG) revealed 64 patients with signs positive for PNS disease and 34 patients with subjective symptoms. Signs of polyneuropathy were reported in 13 subjects. In the discussion, the author remarked that the number of patients with clinical polyneuropathy was so small that a trend could not be evaluated definitively.[41]

A publication the following year (1983) by Seppalainen and Antti-Poika categorized the specific ENMG findings of each of the 3 groups in the previously mentioned 2 studies. Of 18 patients in the group exposed to either TCE or PERC alone, 9 (50%) were deemed to have neuropathy on the first ENMG examination. On the second ENMG, 15 of 21 (71%) patients had this diagnosis. For those exposed to TCE or PERC or a mixture, 10 of 11 (91%) patients and 11 of 13 (85%) patients had this diagnosis, as opposed to 26 of 44 (59%) and then 38 of 53 (72%) of those exposed only to a mixture excluding chlorinated hydrocarbons (ie, TCE or PERC). The authors concluded that those patients with exposure to a mixture of solvents and to TCE or PERC tended to have neuropathic findings more often than patients exposed to either TCE or PERC alone or to a solvent mixture that did not include TCE or PERC. Findings on ENMG in these patients suggested axonal changes rather than segmental demyelination.[42]

One toxicology text remarked that neuropathy may present following solvent exposures because the solvent (ie, PERC) often is mixed with amines, epoxides, and esters to protect it from moisture and light. Some of these compounds are known to cause neuropathy. Two European articles report PERC as being associated with neuropathy. In 1989, Herruzo-Perez et al described one case in which the authors suspected that a sensitive painful polyneuropathy probably was caused by poisoning with PERC.[43] In 1989, Muller et al found slight derangements in neural functions in 130 dry-cleaning workers with long-term exposure to PERC during a 5-year follow-up study.

Baker reported in a review from 1994 that recent studies suggested that mild subclinical disruption of PNS function does occur in workers exposed to solvent mixtures.[44] In 1988, Orbaek et al studied patients with long-term exposures to organic solvents and found evidence of PNS dysfunction and slowing of the median nerve that was more pronounced in follow-up testing 22-72 months later. Slowing in the peroneal nerve was observed only at the follow-up NCV examination. Sensory conduction studies showed substantially reduced amplitudes in median and sural nerves with a prolongation of the distal latency in comparison with a control group; sensory conduction velocity in the median nerve also was slowed in the follow-up examination.[45]

Whether this and other studies of mixed organic solvent exposures suggesting neuropathy with various neurophysiological tests can implicate PERC is not clear, since PERC, its metabolites, or chemicals of similar structure may or may not have been a component of the solvent mixture. Maizlish et al refer to chlorinated aliphatic and chlorinated hydrocarbon solvents as components of paint vehicles and glues to which their subject population was exposed[46] ; other authors do not specify the composition of the substances to which their subjects were exposed.

Trichloroethylene and neuropathy

TCE is used as degreaser in many industrial processes (refer to Table 3 above to review its other industrial uses). Bernad et al evaluated 22 persons in a cohort of Michigan residents exposed for 5-20 years to well water with a low level of TCE contamination; 8-14 ppm of TCE was measured in the well water. Questionnaire, examination, and computer current perception-threshold testing (CPT) was performed. Results revealed hyperesthesia in 21 of 22 persons by CPT. Fatigue, lack of energy, somnolence, numbness, and tingling were reported by all 10 adults.

Feldman et al evaluated 21 residents of a Massachusetts community with alleged long-term exposure to TCE through drinking water and laboratory controls. The wells in question had 256 and 111 parts per billion (ppb) mean concentrations of TCE (maximum contaminant level [MCL] recommended by the Environment Protection Agency [EPA] is 0.5 ppb) and 26 and 24 ppb mean concentrations of PERC; duration of exposures was less than 1 to 12 years. Blink reflexes revealed differences in conduction latency of the reflex for the exposed population versus the controls, suggesting a subclinical alteration in the function of the fifth cranial nerve.[47]

In 1994, Feldman et al published a study that compared this population to 2 other populations that had been exposed to environments contaminated with TCE and PERC and included more details of the population's neurologic examinations. The Massachusetts group was found to have sensory impairment and reflex abnormalities as evidence of peripheral neuropathy.

The second group was 12 residents from an Ohio community who had been exposed to well water contaminated by wastewater deposited in a nearby creek by a company that fabricated sheet metal and precision-formed metal tubes. Their exposure was 3.3-330 ppb of TCE for 5-17 years. PERC also was found in the contaminated water. Nerve conduction studies (including blink reflexes) were performed. Reflex abnormalities were the most prevalent examination finding. Abnormal ulnar sensory latencies were noted in 81% of the group.

The third group comprised 14 residents from a Minnesota community who had been exposed to well water contaminated by a nearby army ammunitions plant. Exposure to TCE was between 261 and 2440 ppb in wells. 1,1-dichloroethane (DCE), 1,2-DCE, and 1,2-trans -DCE were identified in some wells. Questionnaires, examinations, and nerve conduction studies (including blink reflexes) were performed. Reflex abnormalities were the most common finding on neurologic examination. Approximately 70.6% had abnormal ulnar sensory latency, while 21% had abnormal blink reflex studies.[47]

Table 3. Industrial Uses of Common Organic Solvents and Metals (Open Table in a new window)


Industrial Uses


Mining and tunneling, adhesives, waste treatment, ore processing, paper, pulp industry, photography, dyes


Pesticides, pigments, antifouling paint, electroplating, seafood, smelters, semiconductors, logging

Carbon disulfide

Viscose rayon, explosives, paints, preservatives, textiles, rubber cement, varnishes, electroplating

Ethylene oxide

Instrument sterilization, chemical precursor

n -hexane

Glues and vegetable extraction, components of naphtha, lacquers, metal-cleaning compounds


Solder, lead shot, illicit whiskey, insecticides, auto body shops, storage batteries, foundries, smelters, lead-based paint, lead stained glass, lead pipes


Scientific instruments, electrical equipment, amalgams, electroplating, photography, felt making, taxidermy, textiles, pigments, chloroalkali industry

Methyl n -butyl ketone

Paints, varnishes, quick-drying inks, lacquers, metal-cleaning compounds, paint removers






Dry cleaning, degreaser, textile industry


Fiberglass component, ship building, polyester resin


Rodenticides, fungicides, mercury and silver alloys, lens manufacturing, photoelectric cells, infrared optical instruments


Paint, fuel oil, cleaning agents, lacquers, paints and paint thinners


Trichloroethane (methyl chloroform)

Degreaser and propellant


Cleaning agent, paint component, decaffeination, rubber solvents, varnish

Vinyl chloride

Intermediate for polyvinyl chloride (PVC) resins for plastics, floor coverings, upholstery, appliances, packaging


Fixative for pathologic specimens, paint, lacquers, varnishes, inks, dyes, adhesives, cements





Laboratory Studies

See other Medscape Reference articles on neuropathy for workup to rule out common causes of neuropathy.

A differential diagnosis for peripheral neuropathy with appropriate lab testing is noted in Table 4.

Table 4. Differential Diagnosis of Peripheral Neuropathy With Selective Lab Testing (Recommended lab tests in bold.) (Open Table in a new window)


Metabolic and Nutritional

Infective and Granulo-matous


Neoplastic and Para-proteinemic

Drug-Induced and Toxic


Acute idiopathic polyneuro-pathy (Anti-Gm1, anti-Gd1a, anti-GQ1b)

Diabetes ( Fasting blood glucose, 2-hour glucose tolerance test)


Mixed CT disease (ESR)

Compression and infiltration ( chest radiograph)



Chronic inflammatory demyelin-ating polyneuro-pathy

Endocrino-pathies: hypo-thyroidism, acromegaly ( TSH, Electrolytes, GH)

Leprosy, syphilis ( RPR, FTA, MHA-TP)

Poly-arteritis nodosa

Paraneo-plastic syndromes (anti-Hu, anti-RII, etc; CBC)

See Table



Uremia ( BUN/CR)

Diphtheria, Lyme ( Serology)

Rheu-matoid arthritis ( RF)

Paraprotein-emias ( SPEP, immuno-fixation, anti-MAG, M protein)


Friedreich ataxia


Liver disease ( LFTs)

Sarcoidosis ( ACE)


Amyloidosis (nerve biopsy)


Familial amyloid (nerve biopsy)


Vitamin B-12 deficiency ( B12)

Sepsis and multi-organ failure ( ESR)




Porphyria (porphobil-inogen, amino-levulinic acid),

meta-chromatic leukodys-trophy, Krabbe, abetalipo-proteinemia, Tangier disease, Refsum disease, Fabry disease


Neuropathies with unusual features are listed in Table 5.

Table 5. Neuropathies With Unusual Features (Open Table in a new window)

Small Fiber Neuropathies

Facial Nerve Involvement

Autonomic Involvement

Sensory Ataxia

Pure Motor Involvement

Skin, Nail, or Hair Manifestation





Motor neuron disease

Vasculitis: purpura, livedo reticularis





Multifocal motor neuropathy

Cryoglo-binemia: purpura


Lyme disease


Sjögren syndrome


Fabry disease: angiokera-tomas

Hereditary sensory and autonomic neuropathy


Vincristine, vacor

Cisplatin analogs

Acute motor axonal neuropathy

Leprosy: skin hypopig-mentation

Fabry disease



Vitamin B-6 toxicity


Osteo-sclerotic myeloma: skin hyperpig-mentation

Tangier disease



GBS (Miller-Fisher variant)


Variegate porphyria: bullous lesions

Sjögren syndrome



IgM monoclonal gammopathy of undetermined significance

Osteosclerotic myeloma

Refsum disease: ichthyosis



Hereditary sensory and autonomic neuropathy


Diabetic lumbar radiculoplex-opathy

Arsenic or thallium intoxication: Mees lines





Hereditary motor sensory neuropathy (Charcot-Marie-Tooth)

Thallium intoxication: alopecia






Giant axonal neuropathy: curled hair


Quantitative sensory testing includes vibration threshold testing, thermal threshold testing, portable motor and sensory latency tests, and current perception threshold (CPT) testing. These tests are often portable gadgets useful in the field. Each has its limitations, but some may be able to measure functions pertaining to small fiber neuropathy, such as the CPT and thermal testing devices. Others are simple versions of the NCV. The vibration testing device measures large fiber function and may be useful if NCV is not available.

Other techniques that help prove the presence of neuropathy include skin biopsy and intraepidermal nerve fiber density (IENF) testing. This is well reviewed in the article by Smith et al (2005).[48]

The sympathetic skin reflex is performed with EMG machinery, where the absence of one side's testing suggests an abnormality. This test is technically difficult. A sural nerve biopsy is invasive but may be useful. Laser evoked potential and Quantitative Sudomotor Axon Reflex Test (QSART) have been useful in research. QSART measures sweat volume.

IENF testing is relatively easy since it is a small punch biopsy of skin (6 mm). It has a reliable method of measuring small fiber neuropathy and has good interrater reliability. It measures intraepidermal nerve fibers, crossing the dermal, epidermal junction. It is being used in clinical trials for pharmaceuticals.

For patients with cryptogenic neuropathies, glucose tolerance testing makes sense because impaired glucose tolerance is prevalent in 14% of those aged 50-65 years. This is well reviewed by Sumner et al (2003).[49] It is associated with a syndrome of insulin resistance, and 25-40% of patients progress to frank diabetes. An abnormal oral glucose tolerance test result is defined as a glucose level of 140-200, 2 hours after a 75-g anhydrous load. Clinically, 86% of patients had exclusively sensory symptoms with pain and one third had otherwise idiopathic neuropathy. Oral glucose tolerance testing is more sensitive than glycosylated hemoglobin HbA1C testing.

For cryptogenic neuropathy, the glucose tolerance test result is abnormal in 33-61% of patients. Other important laboratory tests to consider are tests for vitamin B-12, monoclonal gammopathy of unknown significance (3% of those >70 y), axonal neuropathy (1-5%), cryoglobins and hepatitis C evaluation, and immunofixation for paraneoplastic neuropathy.

CSF protein level in toxic neuropathy is usually normal.

Consider performing serum, urine, or blood testing to assess for evidence of absorption (see Table 2). If evaluating a patient weeks or months after the exposure ceased, biological data may not yield useful information. In the case of arsenic, for example, separating inorganic from organic arsenic is important, since organic arsenic is a component of seafood and may contaminate and confuse clinicians. Patients need to refrain from seafood for 24 hour prior to urine testing. Furthermore, labs need to be instructed to perform testing for inorganic, not organic, arsenic. Some agents do not have indices that can be tested. Most need to be performed relatively soon after exposure.

Other Tests

Electromyography (EMG) and nerve conduction study (NCV)

See the list below:

  • Using EMG and NCV, peripheral neuropathy may be separated into axonal and demyelinating forms.

  • Axonal neuropathies are more commonly the result of chronic low-level occupational or environmental toxicity.

  • Axonal neuropathies are characterized by sensory amplitude loss in the lower extremities, commonly the sural and or superficial peroneal nerves.

  • More severe axonal neuropathies may involve motor fibers and thus motor amplitudes may be small.

  • When motor fibers are involved, then fibrillation may be noted as evidence for acute denervation. For more chronic neuropathies, polyphasia and wave forms for large and long duration are evident. EMG needle assessment may then help classify duration of the neuropathy.

  • Demyelination-type neuropathies are characterized by sensory and motor slowing.

  • Some toxic neuropathies that are the result of high-level acute exposure may result in severe motor demyelinating neuropathies. However, these conditions are rare. “Ginger Jack leg” paralysis from ingestion of organophosphates is one example of this. NCV may reveal prolonged F waves initially, but then later, motor slowing.

  • EMG needle testing in these cases may be normal if the condition is purely demyelinating.

  • Characterizing a neuropathy into demyelinating or axonal may assist in identifying chemical agents responsible. (See Table 6.)

  • The differential diagnosis, however, must include inherited neuropathies as well as other common acquired neuropathies.

  • Patients with inherited demyelinating neuropathies are noted to have prolonged and symmetrical sensory and/or motor nerve conduction velocities.

  • Those with inherited axonal neuropathies may have small amplitudes that are out of proportion to their relatively minor sensory or motor findings.

  • These patients may also have high arches or other congenital physical ailments.

  • Patients with other acquired neuropathies, such as diabetes or thyroiditis, may have EMG and NCV findings that are inseparable from those with toxic neuropathy.

Table 6. Industrial Agents and Pharmaceuticals Associated With Peripheral Neuropathy (Open Table in a new window)

Almitrine (s)

“Spanish toxic oil”

Arsenic (s)(d)

2-t-Butylazo- 2- hydroxyl- 5 methylhexane



Carbamate pesticides (nm)

Allyl chloride

Carbon disulfide (m)(d)

Amiodarone (d)

Chloramphenicol (s)


Cimetidine (m)

Carbamates (nm)

Cisplatin (s)

Carbon monoxide






Dichloroacetic acid

Dapsone (m)

Disulfiram (m)

Dichloroacetylene (cr)


Didoxynucleosides (s) (ddC, ddI, d4T)

Ethyl alcohol


Ethylene glycol (cr)

Doxorubicin (m)

Ethylene oxide

Ethambutol (s)

Germanium dioxide

Etoposide (s)






Hydralazine (s)


Hyperinsulinemia/ hypoglycemia (m)


Imipramine (m)

Lincomycin (nm)

Interferon alpha (nm)


Lead (m)



Mercury, inorganic

Methyl n-butyl ketone (m)(d)

Mercury, organic

Metronidazole (s)


Misonidazole (s)

Methyl bromide


Methyl methacrylate

Nitrous Oxide (s)

N hexane (d)

Organophosphates (m)


Organophosphorus compounds (nm)

Nitrofurantoin (m)

Polychlorinated biphenyls (s)

Penicillamine (nm)

Polymyxin (nm)

Perhexiline (d)

Pyrethroids (ic)


Pyridoxine (s)




Succinylcholine (nm)

Quinine (nm)

Sulfonamides (m), sulfasalazine



Stilbamidine (cr)

Taxanes (paclitaxel, docetaxel) (s)


Thalidomide (s)


Thallium (s)

Tetracyclines (nm)

Trimethaphan (nm)



Tubocurarine (nm)

Vincristine (m)

Vincristine (m), Vinca alkaloids


Vinyl chloride

(s): Predominantly sensory

(m): Predominantly motor

(d): Possibly demyelination with conduction block

(cr): Associated with cranial neuropathy

(nm): Associated with neuromuscular transmission syndromes

(ic): Associated with axon ion channel syndromes

Bold: A rating for common or strong association

Unbolded: B rating for less common or less than strong association

Neurophysiologic abnormalities in workers exposed to ethylene oxide

See the list below:

  • In 1993, Ohnishi and Murai reviewed polyneuropathy cases caused by EtO. Needle EMG revealed neurogenic changes in 8 of 11 patients. Conduction studies of limb nerves were abnormal in 8 of 10 patients. Relatively mild decreases of motor and sensory NCVs with decreases in the amplitudes of nerve and muscle action potentials indicated axonal degeneration of both motor and sensory nerve fibers.[50]

  • In 1983, Kuzuhara et al reported 2 patients with occupationally induced EtO polyneuropathy and their EMG and NCV results. In one patient, EMG of the limb muscles was normal except for long-duration and high-amplitude units recorded from the triceps. Motor NCVs were relatively well preserved. In the second patient, only an EMG was performed, which revealed denervation patterns in distal limb muscles.[24]

  • Finelli et al reported electrophysiological findings in 3 patients with EtO-induced neuropathy; they demonstrated mild slowing of motor conduction with positive sharp waves and fibrillation potentials on EMG during the active disease state, indicating axonal neuropathy.[25]

    • In patient 1, nerve conduction studies showed no response to stimulation of the left peroneal nerve, slowing of motor conduction over the right peroneal and the right posterior tibial nerves, and absence of the right tibial H reflex and the right sural nerve sensory potential. The EMG showed scattered positive sharp waves and fibrillation potentials with increased polyphasic activity in the intrinsic foot muscles and, to a lesser extent, in the leg muscles. Repeated examinations 5 weeks and 7 months later showed return of normal conduction velocity and disappearance of denervation potentials and the recording of giant potentials as signs of reinnervation. The left H reflex remained suppressed.

    • In patient 2, the EMG initially showed positive sharp-wave fibrillation potentials and small-amplitude motor unit potentials in leg and foot muscles. Follow-up studies showed the disappearance of the denervation potentials and the appearance of giant potentials indicating reinnervation.

    • Patient 3 showed absent potentials from the extensor digitorum brevis muscle on stimulation of the right peroneal nerve. Right tibial conduction was slowed, and the tibial H reflex was absent on the right and delayed on the left. The right sural nerve sensory potential amplitude was normal but delayed. Leg and foot muscle EMG studies showed denervation potentials. Repeat studies 7 months later showed mild slowing and active denervation on EMG with some polyphasic giant potentials.

  • In 1979, Gross et al reported 4 patients with EtO neurotoxicity and results of their nerve conduction studies. One patient had acute CNS symptoms and normal NCV. Another 2 had milder CNS symptoms with symptoms of a generalized sensorimotor polyneuropathy with fibrillations in the intrinsic muscles of the feet and abnormal NCVs (patient 2), and decreased numbers and increased amplitude and duration of motor unit potentials in the distal muscles (patient 3). Patient 4 was asymptomatic. Patients 2, 3, and 4 had decreased amplitudes of motor action potentials, moderately decreased NCVs, and signs of denervation compatible with axonal degeneration as the cause of neuropathy.[21]

  • In 1985, Schroeder et al also reported a case of EtO-induced polyneuropathy. This patient had nerve conduction study findings that showed slowed NCVs; the mean tibial NCV was 26 m/s, with normal amplitudes, 2.5 mV.[23]

  • Fukushima et al reported a 19-year-old patient with 20 days of EtO exposure who had numbness and weakness of his extremities and was noted to have a steppage gait on examination at the time of admission 1 month later. Nerve conduction study findings were abnormal; mean peroneal and tibial NCVs were 37.7 and 37.1 m/s (no normals were included), respectively. No latency potential was demonstrable for the right peroneal nerve. Neurogenic changes were demonstrated on EMG in the anterior tibial muscles.[22]

  • Deschamps et al reported a case of persistent asthma after accidental EtO exposure. They performed EMG and NCVs after an examination of the patient's lower extremities revealed abnormal findings. EMG and NCV findings were normal, but maximum amplitudes of the right and left H reflex responses were reduced significantly (ie, 6% and 2% of the maximum amplitude elicited from the direct response) without a decrease in the proximal conduction velocity. These results suggested axonal neuropathy.[51]

Neurophysiologic abnormalities associated with mercury exposure (inorganic and organic)

See the list below:

  • Inorganic mercury is noted to produce a sensory or sensorimotor polyneuropathy similar to that produced by arsenic. Chloralkali plant workers (n=138) with long-term inorganic mercury vapor exposure were noted to have elevated urine mercury levels and reduced sensation on quantitative testing, prolonged distal latencies with reduced sensory-evoked response amplitudes, and increased likelihood of abnormal needle EMG findings. Factory workers exposed to elemental mercury vapor with elevated urine mercury concentrations had prolonged motor and sensory ulnar distal latencies. Slowing of the median motor NCV was found to correlate with both increased levels of mercury in blood and urine and with increased numbers of neurological symptoms. Sensory deficits found with short-term exposure to mercury vapor, whereas motor nerve impairment occurred with longer periods of exposure.

  • Chloralkali workers exposed to inorganic mercury vapors for an average of 12.3 years were found to have median motor and sensory NCVs that were slightly reduced among the highly exposed subjects. Seventeen thermometer factory workers had high urine and blood mercury levels but no symptoms; 88% had subclinical neuropathy, mainly distal and axonal neuropathy. In another study, a sensory polyneuropathy was found in 11% of workers exposed to inorganic mercury, while a sensorimotor polyneuropathy was found in 27% of workers.

  • Chloralkali workers who were exposed to inorganic mercury for an average of 7.9 years and had ceased working in that environment an average of 12.3 years prior to the study were found to have both median sensory NCV and amplitude of the sural nerve associated with measures of cumulative exposure to mercury. A study reviewing the relationship between exposure-related indices and neurological and neurophysiological effects in workers previously exposed to mercury vapor revealed that, of 298 dentists with long-term exposure to mercury amalgam vapor evaluated for peripheral neuropathy, 30% had polyneuropathies. Another paper reported that one dentist apparently had an unelicitable sensory superficial peroneal nerve action potential that returned to normal following penicillamine treatment.

  • Industrial workers with long-term exposure to mercury were found to have performance decrements in neuromuscular functions that were reversible and correlated with blood and urine mercury levels.

Neurophysiological abnormalities in workers exposed to xylene

See the list below:

  • Nerve conduction testing was utilized in 8 studies evaluating the PNS in workers with occupational exposure to mixed organic solvents including xylene. One of these noted a prolonged refractory period in lower extremity motor and sensory nerves of 28 exposed painters compared with age-matched controls. In 1980, Elofsson found a slight decrease in NCV in the distal sensory nerves of the lower extremities of an exposed population. He concluded that these findings were consistent with an axonal polyneuropathy.

  • In 1978, Seppalainen noted that 12 of 59 car painters had abnormally slow motor and sensory NCVs, while none of the controls had slowing.[52] In 1980, Seppalainen reported that at least one abnormally slow NCV was noted in 48 of 107 subjects with a diagnosis of solvent poisoning.[53] A third publication by the same author reported a different cross-sectional study and noted that 26 of 44 (59%) subjects with a diagnosis of organic solvent intoxication, who had been exposed exclusively to mixed solvents including dimethyl benzene, were diagnosed with peripheral neuropathy by EMG.[42] Follow-up questionnaires of all subjects of the previous study, including those with mixed solvent exposure, noted that 57 of 87 subjects had symptoms referred to the PNS.

  • EMG revealed sensorimotor neuropathy in 5 of 7 painters tested in a study by Linz. Four of these 5 painters had evidence of mild distal neuropathy with reduced 2-point discrimination on neurologic examination. Temporal dispersion noted in sural SNAPs was a statistically significant finding in 50 male painters compared with controls.[54]

Histologic Findings

Muscle and nerve pathology findings associated with ethylene oxide or mercury exposure include the following:

  • Muscle and nerve biopsies were carried out by Kuzuhara et al on 2 patients who developed distal symmetrical polyneuropathies after being exposed to EtO while working as employees of a factory that produced medical supplies. The nerve biopsies of both patients implied axonal degeneration and regeneration. Swollen Schwann cell processes with numerous filaments, myelin figures, debris, and vacuoles with and without granules were seen on the electromicrogram of the sural nerve of patient 1. Growth cones of damaged axons were seen on the sural nerve of patient 2.[24]

  • Muscle biopsies revealed smearing and distortion of the Z bands. Some revealed absence of mitochondria and target or targetoid structures. Transverse sections showed atrophic fibers, scattered or grouped with many target fibers. Enzyme histochemistry of muscle from patient 2 revealed atrophy of both type 1 and type 2 fibers in the myosin adenosine triphosphatase (ATPase) reaction and dark angulated fibers, target, targetoid, and moth-eaten fibers on nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR) reaction.

  • In 1993, Ohnishi and Murai reported that histologic studies of the sural nerves biopsied in 3 patients revealed decreased density of large myelinated fibers, reduction of the cross-sectional area of axons, reduction of axonal circularity, and presence of myelin ovoid and Bunger bands, which are compatible with a mild degree of axonal degeneration.[50]

  • Experimental EtO neuropathy was produced by Ohnishi in rats exposed to a one-time dose of 500 ppm for 6 hours or 5 doses of 250 ppm for 6 hours at a time over a week. In both experiments, distal axonal degeneration was found both in peripheral and central myelinated axons of lumbar primary sensory neurons of rats. In hind leg nerves and in the fasciculus gracilis, myelinated fibers showed axonal degeneration sparing the nerve cell body of the lumbar dorsal root ganglion and myelinated fibers of lumbar dorsal and ventral roots. The rats exposed to 250 ppm also showed a retardation of growth and maturation of myelinated fibers in the presence of mild axonal degeneration.

  • In a patient with EtO polyneuropathy after 5 months of exposure, Schroder et al performed a sural nerve biopsy that revealed nerve fiber degeneration of the wallerian type associated with reduction of axonal cross-sectional areas and some degree of nerve fiber regeneration. Conspicuous paranodal vesicular disintegration of individual myelin lamella also was present. Unusual cisternae with introverted hemidesmosomes were noted in endoneural fibroblasts.[23]

  • Nerve pathology was investigated in those exposed to organic mercury. Miyakawa et al reported selective swelling and degeneration of the Schwann cells, noticeable changes of both myelin sheaths and the axon. Pathologic changes began at the nodes of Ranvier. Primary site of damage was noted to be in the cell bodies of the sensory ganglion cells, with axonal degeneration occurring later in rats poisoned by methylmercury hydroxide. The largest myelinated fibers were affected to a greater extent than the smaller caliber fibers in the dorsal root.[55]

  • An autopsy performed on a descendant of a woman exposed to mercury at Minimata Bay demonstrated segmental demyelination of the PNS. In both humans and animals, the major pathologic effect of methylmercury appears to be on the dorsal root ganglion cells. Similar data are not available for inorganic or metallic mercury poisoning.



Medical Care

Advise removal from occupational or environmental exposure.

Advise discontinuation of medication or recreational drug habit. Also provide information regarding how alcohols affect those with exposures.

Acute care for those intoxicated with recreational, industrial, or other agents is discussed in other articles on this website.

Preventive care and supportive care should include consideration of life stressors, diet, and overall behavior modifications.

Treatment options also include the following:

  • Nonpharmacologic options include cool soaks, heat, massage, elevation or lowering of the limbs, shoe tightness, and/or exercise.

  • Pharmacological options include tricyclic antidepressants, anticonvulsants, opiates, or topical capsaicin cream. Other options include intravenous gamma globulin, aldose reductase inhibitors, nerve growth factor, anti–tumor necrosis factor-α; these are mainly research ideas. Three that may be helpful presently include lipoic acid, evening primrose, and vitamin E.

    • Alpha lipoic acid is well reviewed by Halat and Dennehy.[56] Thiolic acid is a free radical scavenger and chelator. It is approved for use in Germany for neuropathy. The best studies suggest parenteral use followed by oral use relieves symptoms and improves nerve blood flow. Oral preparations are available in United States. Two studies suggest increased nerve conduction (600/1200 mg for 2 y, oral) and reduced symptoms (1800 mg/d for 3 wk, oral). The mechanism of action includes chelation and, thus, a concern for mineral shortage exists. Monitoring iron levels is suggested, and persons with alcoholism need to take vitamin B.

    • Evening primrose is also well summarized by Halat and Dennehy.[56] It includes omega 6 essential fatty acids: gamma linoleic acid (GLA) and linoleic acid. It is an essential component of myelin and the neuronal cell membrane. Dosages ranging from 360-480 mg/d for 6 months to 1 year improved nerve function measurements. It has mild side effects including inhibition of platelet aggregation. Concern also exists for those with seizure disorders.

    • Vitamin E is discussed in the article Argyriou et al.[57] Vitamin E has been administered to patients on chemotherapy for prevention of neuropathy at doses of 600 mg/d during treatment and then for 3 months after treatment. A reduced peripheral neuropathy score has been noted. A neuroprotective effect has been described.


Consultation with an occupational therapist or environmental medicine specialist may be helpful.


Although diet does not play a specific role in reparation of the PNS, a balanced diet is important for various reasons related to general health. Since various B vitamins have been implicated in the development of neuropathies, some physicians suggest supplementation.

Long-Term Monitoring

Consistent follow-up care with a neurologist is necessary to monitor the progress of neurological findings.

Follow-up with an occupational medicine specialist may be important to assist with return to work and reduction of exposure. This clinician may be able to work with the company supervisors or management to improve the work environment. This may occur if the company chooses to substitute the neuropathy-causing agent with a less-toxic agent in the workplace, to change the schedules of workers so that their exposure is less during a period of time, or to promote safer personal protective equipment. Communication between health care provider and management is essential for this individual's health as well as his or her status for disability or ability return to work.


Questions & Answers


What causes toxic neuropathy?

What are the signs and symptoms of toxic neuropathy?

How is toxic neuropathy diagnosed?

Which medications are used in the treatment of toxic neuropathy?

What is toxic neuropathy?

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What is the prevalence of toxic neuropathy?


Which clinical history findings are characteristic of toxic neuropathy?

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Which drugs cause toxic neuropathy?

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What is the role of carbon disulfide in the etiology of toxic neuropathy?

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What is the role of mercury in the etiology of toxic neuropathy?

What is the role of lead in the etiology of toxic neuropathy?

What is the role of xylene in the etiology of toxic neuropathy?

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What are the differential diagnoses for Toxic Neuropathy?


What is the role of lab tests in the workup of toxic neuropathy?

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Which neurophysiologic findings are characteristic of ethylene-related toxic neuropathy?

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Which histologic findings are characteristic of toxic neuropathy?


How is toxic neuropathy treated?

Which specialist consultations are beneficial to patients with toxic neuropathy?

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