Identification of Toxic Neuropathies: Cardinal Tenets

Alan R Berger; Michael Pulley

Disclosures

Future Neurology. 2014;9(4):411-418. 

In This Article

Abstract and Introduction

Abstract

Human toxic peripheral neuropathies (TxPN) due to occupational chemical exposure are relatively rare compared with medically related peripheral neuropathies. They are however difficult to diagnose due to their clinical and electrophysiologic similarity to nontoxic peripheral neuropathy. Understanding the cardinal tenets of neurotoxicology, as it applies to TxPN, helps differentiate between the toxic and nontoxic peripheral neuropathy. These tenets include: strong dose–response relationship, consistency of clinical response, proximity of symptoms to exposure, correlation between severity of neuropathy and degree of exposure, and improvement of PNS signs and symptoms follows cessation of exposure. A thorough clinical and occupational history is essential in identifying the possibility of a TxPN.

Introduction

Compared to medically related neuropathies, toxic peripheral neuropathies (TxPN) are relatively infrequent. The most frequent neurotoxic exposures include: pharmaceutical agents, most often due to iatrogenic administration;[1] biological agents such as bacterial, plant and animal compounds;[2] workplace chemical exposures;[3] environmental chemical exposure;[4] or overdoses due to recreational use, suicides or homicide.[5] The most commonly encountered TxPN are medication related. Occupational exposure, either a single individual, or epidemic as with large pharmaceutical companies, is often newsworthy, but infrequent. It is very difficult to determine that a peripheral neuropathy (PN) is toxic in etiology when the cause is a small-scale occupational exposure. There are, however, occasional epidemic outbreaks of TxPN, as illustrated by the episode of arsenic exposure in West Bengal, India.[1]

The most difficult aspect in determining whether a PN has a neurotoxic etiology is an unclear exposure history. In part, this is often due to TxPN usually being clinically and electrophysiologically indistinguishable from the more frequently encountered nontoxic, medically related PN. In most cases, toxicological tests to document toxin exposure or determine body burden are often either not available, or the toxin is undetectable due to a delay between exposure and testing. The unfortunate consequence is that a PN without a readily apparent medical etiology is often misclassified as being toxic in nature.

The pathology of many TxPN is the central-peripheral axonopathy.[2,3] The initial pathologic response to toxin exposure is multifocal paranodal axonal swellings in distal nerve regions which result in eventual axonal degeneration. The initial morphologic evidence of degeneration can be seen in distal sensory and motor axons in the PNS and CNS. If neurotoxin exposure continues, there is a resultant proximal spread of axonal degeneration in the corticospinal tract and posterior columns of the CNS, and peripheral motor and sensory axons in the PNS, toward their nerve cell bodies. Discontinuation of toxin exposure allows PNS axonal regeneration, which proceeds proximal to distal via Schwann cell tubes to motor and sensory end organ terminals. In contrast to the greater regenerative capacity in the PNS, there is limited regeneration in damaged CNS axons. In most TxPN, the earliest clinical deficits relate to peripheral nerve dysfunction, but with recovery, underlying CNS dysfunction such as spasticity, mild ataxia and sensory loss become evident. These latter deficits are often persistent, reflecting the poor regenerative capacity of spinal cord sensory and motor tracts. In some TxPN, such as acrylamide, the earliest site of structural and functional disruption appears not to be the cell body or distal axon itself, but the nerve terminal, producing the so called terminalopathy, with initial synaptic dysfunction and subsequent axon degeneration.[4]

The current classification system for neurotoxins reflecting compound class (e.g., solvents, metals) is of limited clinical utility owing to our incomplete knowledge of the underlying pathophysiologic mechanisms of most neurotoxins. Such a classification system runs the risk of being misleading, falsely attributing neurotoxicity to innocuous compounds simply because they have a close structural relationship to a known toxin of similar class. An example of this potential confusion is acrylamide, in which the monomer causes a severe PN, whereas the polymer is innocuous. Since structure–toxicity relationships are known for only a few classes of substances (e.g., organophosphates and hydrocarbons), it is difficult to accurately predict toxicity potential by chemical structure alone.

A PN is most likely to be neurotoxic when:

  • Neurotoxin exposure is suspected by history, and confirmed by workplace or home examination, or clinical chemical analysis;

  • The temporal onset and intensity of symptoms reflect the level and duration of exposure;

  • In mild cases, improvement of clinical symptoms follows cessation of exposure;

  • The pattern of clinical and electrophysiologic deficits reflects those known to occur in previous cases involving the toxin.

The single most useful instrument in determining whether a PN is toxin related is an accurate history.

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