Toxic peripheral neuropathies

Michael T Pulley MD PhD (

Dr. Pulley of the University of Florida, Jacksonville, received honorariums from Alexion, Bio Products Laboratories, CSL Behring, Catalyst, and Stealth BioTherapeutics for consulting work.

Alan R Berger MD (Dr. Berger of the University of Florida, Jacksonville, and Director of the Shands Jacksonville Neuroscience Institute has no relevant financial relationships to disclose.)
Louis H Weimer MD, editor. (

Dr. Weimer of Columbia University has received consulting fees from Roche.

Originally released September 21, 1999; last updated May 1, 2019; expires May 1, 2022


In this article, the authors discuss general principles regarding toxic peripheral neuropathy. This clinical entity is most commonly encountered as an adverse effect of medications, but environmental and occupational exposure can also result in toxic neuropathy. The authors give clues to help guide the process of evaluation in patients suspected of having toxic peripheral neuropathy.

Key points


• Toxic neuropathy should have a temporal and dose-response relationship between symptoms and exposure.


• There should be consistency of disease in those with similar exposures.


• Improvement (or at least stabilization) of neuropathic symptoms should occur when exposure ceases.

Historical note and terminology

Despite widespread media attention to their rare epidemic occurrence, toxic polyneuropathies are relatively infrequent in North America. Neurotoxic exposure may be due to: (1) pharmaceutical agents, either self or iatrogenically administered; (2) biological agents including animal, plant, and bacterial products; (3) chemical exposure in the workplace; (4) environmental chemical exposure at home or elsewhere; or (5) intoxications due to suicide, recreational abuse, or homicide. Most toxic polyneuropathies encountered in routine clinical practice are due to iatrogenic pharmaceutical intoxications; epidemic occupational exposure, as with large pharmaceutical companies, receives the media headlines but is unusual. The majority (and unfortunately the most difficult) of the cases of toxic polyneuropathies are individual intoxications due to small-scale, often chance, occupational exposure, and also due to intentional, suicidal ingestion. The exception to the above rule involves reports of endemic arsenic exposure due to ground water contamination in West Bengal, India (Mukherjee et al 2003).

The determination that a sporadic peripheral neuropathy has resulted from toxin exposure in the occupational setting is often made difficult by an unclear exposure history. Toxic polyneuropathies are usually distal axonopathies that clinically and electrophysiologically resemble neuropathies from metabolic abnormalities, nutritional deficiencies, or systemic illnesses. Clinically relevant and reliable toxicological tests are often not helpful, either because the necessary laboratory tests are not available or because the substance is undetectable due to the delay between exposure and examination. Consequently, when a naturally occurring medical cause is not readily apparent, there is an unfortunate tendency for many peripheral neuropathies to be misdiagnosed as toxic in nature.

The underlying pathology of many toxic polyneuropathies is the central-peripheral axonopathy (Schaumburg and Spencer 1979). Initial exposure results in degeneration of distal peripheral sensory and motor axons in the central nervous system and peripheral nervous system. Continuous neurotoxin exposure causes peripheral nervous system axonal degeneration to proceed proximally toward the nerve cell body. Cessation of exposure allows for regeneration from proximal to distal, along the distal Schwann cell tube to the appropriate terminal. Similar events occur in the distal ends of long central nervous system axons (dorsal column, corticospinal tract), although regeneration is poor. Initial clinical symptoms reflect dysfunction in peripheral axons. As the peripheral nerves recover, however, signs of central nervous system impairment such as spasticity, mild ataxia, and persistent sensory loss may be evident. These latter deficits result from the lack of regeneration in central sensory and motor tracts.

Our limited knowledge of the biochemical and pathophysiologic mechanisms of most neurotoxins has led to a simplistic classification system according to compound class (eg, solvents, metals). Such a classification is clinically of little help and potentially misleading. A compound cannot be presumed to be neurotoxic because of a superficial resemblance to a related known toxin of similar class; not all compounds within the same class are neurotoxic (eg, acrylamide monomer is capable of producing a devastating peripheral neuropathy, whereas the polymer is innocuous). Structure-toxicity relationships are clear for only a few classes of substances, such as organophosphates and hydrocarbons.

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