Toxic Neuropathy Workup

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

Amiodaron e (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.