Toxic Neuropathy

Updated: Feb 03, 2016
  • Author: Jonathan S Rutchik, MD, MPH, FACOEM; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS  more...
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Overview

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.

Diagnosis

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.

Management

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.

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Background

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)

Compound OSHA



PEL TWA:



ppm (mg/m3)



NIOSH REL



TWA: ppm (mg/m3),



IDLH



ACGIH



ppm (mg/m3) TLV,



STEL



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),



500



10 (31)
Ethylene oxide   1 < 0.1,



< 0.18, 5 C,



800



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,



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



ketone



100 (410)   5 (20)
Perchloroethylene 100, 200 C,



300 for 5 min



in 3 h



150 Ca 25 (170),



100 (685)



Styrene 100, 200 C,



600 for 5 min



in 3 h



50 (215),



100 ST (425), 700



50 (213),



100 (428)



Thallium 0.1 mg/m3 skin 0.1 mg/m3,



15 mg/m3



0.1 mg/m3
Toluene 200, 300, 500 for 10 min 100 (375),



150 ST (560),



500



50 (188)
1,1,1



Trichloroethane



(methyl chloroform)



350 (1900) C 350(1900)



for 15 min,



700



350 (1910),



450 (2460)



Trichloroethylene 100, 200 C,



300 for 5 min



in 2 h



1000 Ca 50 (269),



100 (1070)



Vinyl chloride 1, 5 for 15 min ND  
Xylene 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)

Compound Urine Blood Expired



Air



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



Total trichloroethanol



1 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-



ethylene



 
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



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.

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Pathophysiology

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).

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Frequency

United States

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.

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