Toxic Neuropathy
- Author: Jonathan S Rutchik, MD, MPH; Chief Editor: Tarakad S Ramachandran, MBBS, FRCP(C), FACP more...
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 μ g/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.
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.
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).
Epidemiology
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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- Table 1. Exposure Limits, Common Organic Solvents and Metals
- Table 2. Agency for Toxic Substances and Disease Registry Biological Exposure Indices
- 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
| 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 | |||
| 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 μ g/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 | ||||
| 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) | Amiodaron e (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 | |
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