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.
In a randomized, double-blind trial of 353 colon cancer patients receiving adjuvant therapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), Loprinzi and colleagues found that intravenous infusions of calcium and magnesium (CaMg) did not prevent oxaliplatin-induced sensory neurotoxicity.[1, 2]
The researchers found no significant difference in the incidence of acute neuropathy in the 5 days following each dose of oxaliplatin among patients who received CaMg before and after oxaliplatin, those who received placebo before and after oxaliplatin, and those who received CaMg before and placebo after oxaliplatin. Through 12 cycles of FOLFOX treatment, these groups did not differ significantly in the incidence of sensory, motor, or autonomic neuropathy.[1, 2]
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:
During physical examination, the following symptoms of polyneuropathy may be found:
Central nervous system (CNS) disease can manifest as follows:
The following examples list the neuropathic signs and symptoms associated with specific toxins:
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:
Other studies that help to prove the presence of neuropathy include the following:
Laboratory studies in patients with neuropathy can include the following:
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:
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
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
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:
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.[3, 4]
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.
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).
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.[6, 7]
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:
A variety of drugs and industrial chemicals cause distal axonopathy. In 1989, Kimura listed the following as potential causes of toxic neuropathy[8, 9] :
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.)[10, 11]
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.[10, 11]
Industrial chemicals causing toxic axonal neuropathy also are listed by Kimura; they include the following[8, 9] :
In 1999, Feldman added the heavy metals arsenic and lead, as well as the solvents n -hexane, perchloroethylene (PERC), and TCE to this list. In 1995, Albers and Bromberg summarized the literature on toxic neuropathy caused by the solvents ethylene oxide (EtO), styrene, toluene, and mixed solvents.
Spencer and Schaumberg listed agents that commonly are associated with peripheral neuropathy (see Table 2 in Schaumberg, 2000 ).
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. Ten ounces of whiskey per day in a 70-kg man for several years was mentioned to cause alcohol neuropathy. Three liters of beer per day for 3 years was described as another threshold. Wine in combination with other forms of ethanol was deemed worse, possibly due to impurities with lead.
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 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.)
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.[20, 21]
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. 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.
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. 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.
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.[25, 26]
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.
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.
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.
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. 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. 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. 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.
Warkany and Hubbard reported the association of acrodynia and symmetrical flaccid paralysis with mercury toxicity.
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.
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.
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. A second study noted higher vibration thresholds in 80 exposed painters than in controls. Demers et al noted statistically significant differences in vibrotactile measurements by QST of upper and lower extremities between 28 painters and 20 nonexposed controls. In 1989, Bove et al compared 93 painters to a nonexposed control population of 105 construction workers. 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. 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.
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.[40, 41] 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.
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.
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.
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. 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. 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.
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 ; other authors do not specify the composition of the substances to which their subjects were exposed.
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.
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.
Table 3. Industrial Uses of Common Organic Solvents and Metals
Table 4. Differential Diagnosis of Peripheral Neuropathy With Selective Lab Testing (Recommended lab tests in bold.)
Table 5. Neuropathies With Unusual Features
Table 6. Industrial Agents and Pharmaceuticals Associated With Peripheral Neuropathy
Muscle and nerve pathology findings associated with ethylene oxide or mercury exposure include the following:
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.
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.
TWA: ppm (mg/m3),
ppm (mg/m3) TLV,
Acrylamide (0.3) (0.03), 60 Ca Arsenic, inorganic (0.01) 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) Lead 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,
0.025 mg/m3 Mercury, organic 0.01 mg/m3,
C 0.04 mg/m3
ST 0.03 mg/m3,
Methyl n -butyl
100 (410) 5 (20) Perchloroethylene 100, 200 C,
300 for 5 min
in 3 h
150 Ca 25 (170),
Styrene 100, 200 C,
600 for 5 min
in 3 h
100 ST (425), 700
Thallium 0.1 mg/m3 skin 0.1 mg/m3,
0.1 mg/m3 Toluene 200, 300, 500 for 10 min 100 (375),
150 ST (560),
50 (188) 1,1,1
350 (1900) C 350(1900)
for 15 min,
Trichloroethylene 100, 200 C,
300 for 5 min
in 2 h
1000 Ca 50 (269),
Vinyl chloride 1, 5 for 15 min ND Xylene 100 (435) 100 (435),
150 ST (655)
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
Compound Urine Blood Expired
Other Acrylamide Arsenic 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 Lead 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 Perchloro-ethylene, trichloroacetic acid Perchloroethylene 1 mg/L Perchloro-ethylene: before last shift of week, 10 ppm† Styrene 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 Thallium Thallium Toluene Hippuric acid Toluene Toluene 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
Methyl chloroform: prior to last shift of work week, 40 ppm† Trichloro-ethylene 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 Trichloro-
Vinyl chloride Xylene Methylhippuric acid: end of shift, 1.5 mg/g Xylene Xylene *2-TTCA - 2-thiothiazolidine-4-carboxylic acid
† ppm - parts per million
Compound Industrial Uses Acrylamide Mining and tunneling, adhesives, waste treatment, ore processing, paper, pulp industry, photography, dyes Arsenic 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 Lead Solder, lead shot, illicit whiskey, insecticides, auto body shops, storage batteries, foundries, smelters, lead-based paint, lead stained glass, lead pipes Mercury 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 Organochlorine Insecticides Organophosphates Insecticides Perchloroethylene Dry cleaning, degreaser, textile industry Styrene Fiberglass component, ship building, polyester resin Thallium Rodenticides, fungicides, mercury and silver alloys, lens manufacturing, photoelectric cells, infrared optical instruments Toluene Paint, fuel oil, cleaning agents, lacquers, paints and paint thinners 1,1,1
Trichloroethane (methyl chloroform)
Degreaser and propellant Trichloroethylene Cleaning agent, paint component, decaffeination, rubber solvents, varnish Vinyl chloride Intermediate for polyvinyl chloride (PVC) resins for plastics, floor coverings, upholstery, appliances, packaging Xylene Fixative for pathologic specimens, paint, lacquers, varnishes, inks, dyes, adhesives, cements
Inflam-matory Metabolic and Nutritional Infective and Granulo-matous Vasculitic Neoplastic and Para-proteinemic Drug-Induced and Toxic Hereditary Acute idiopathic polyneuro-pathy (Anti-Gm1, anti-Gd1a, anti-GQ1b) Diabetes ( Fasting blood glucose, 2-hour glucose tolerance test) AIDS ( HIV) Mixed CT disease (ESR) Compression and infiltration ( chest radiograph) Alcohol HMSN 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 HSN 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) SLE ( ANA) 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
Small Fiber Neuropathies Facial Nerve Involvement Autonomic Involvement Sensory Ataxia Pure Motor Involvement Skin, Nail, or Hair Manifestation Diabetes Guillain-Barré Paraneo-plastic Polyganglio-nopathies Motor neuron disease Vasculitis: purpura, livedo reticularis Amyloid CIDP GBS Paraneo-plastic Multifocal motor neuropathy Cryoglo-binemia: purpura HIV-associated Lyme disease Porphyria Sjögren syndrome GBs Fabry disease: angiokera-tomas Hereditary sensory and autonomic neuropathy Sarcoidosis Vincristine, vacor Cisplatin analogs Acute motor axonal neuropathy Leprosy: skin hypopig-mentation Fabry disease HIV Diabetes Vitamin B-6 toxicity Porphyria Osteo-sclerotic myeloma: skin hyperpig-mentation Tangier disease Tangier Amyloid GBS (Miller-Fisher variant) CIDP Variegate porphyria: bullous lesions Sjögren syndrome HIV 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 Lead Giant axonal neuropathy: curled hair
Almitrine (s) “Spanish toxic oil” Arsenic (s)(d) 2-t-Butylazo- 2- hydroxyl- 5 methylhexane Capsaicin Acrylamide Carbamate pesticides (nm) Allyl chloride Carbon disulfide (m)(d) Amiodarone (d) Chloramphenicol (s) Amitriptyline Cimetidine (m) Carbamates (nm) Cisplatin (s) Carbon monoxide Cyanate Chloroquine Cycloleucine Colchicine Cytarabine Dichloroacetic acid Dapsone (m) Disulfiram (m) Dichloroacetylene (cr) Ethionamide Didoxynucleosides (s) (ddC, ddI, d4T) Ethyl alcohol Dimethylaminopropionitrile Ethylene glycol (cr) Doxorubicin (m) Ethylene oxide Ethambutol (s) Germanium dioxide Etoposide (s) Gold Glutethimide Hexamethylmelamine Hexachlorophene Hydrazine Hydralazine (s) Indomethacin Hyperinsulinemia/ hypoglycemia (m) Isoniazid Imipramine (m) Lincomycin (nm) Interferon alpha (nm) Lithium Lead (m) L-Tryptophan Lidocaine Mercury, inorganic Methyl n-butyl ketone (m)(d) Mercury, organic Metronidazole (s) Methaqualone Misonidazole (s) Methyl bromide Muzolimine Methyl methacrylate Nitrous Oxide (s) N hexane (d) Organophosphates (m) Naproxen Organophosphorus compounds (nm) Nitrofurantoin (m) Polychlorinated biphenyls (s) Penicillamine (nm) Polymyxin (nm) Perhexiline (d) Pyrethroids (ic) Phenol Pyridoxine (s) Phenytoin Sarin Pyriminil Succinylcholine (nm) Quinine (nm) Sulfonamides (m), sulfasalazine Statins Tacrolimus Stilbamidine (cr) Taxanes (paclitaxel, docetaxel) (s) Suramin Thalidomide (s) Tetrachloroethane Thallium (s) Tetracyclines (nm) Trimethaphan (nm) Trithiozine Vidarabine Tubocurarine (nm) Vincristine (m) Vincristine (m), Vinca alkaloids Zimeldine 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