Toxic Neuropathies

Clinical Features

Toxins and drugs with the potential to damage the PNS of infants and children usually have similar but often better-defined deleterious effects in adults. Arsenic neuropathy is a good example. Some neurotoxins also have the potential to damage the PNS in utero (e.g. poisoning by organic mercury). As in adults, most toxic childhood polyneuropathies present with evidence of length-dependent axonopathy. Typically, these toxic substances affect both small- and large-fiber sensory modalities.

Some toxic compounds, however, specifically affect other types of nerve fibers or nerve cells, providing important exceptions to the general rule that toxins damage primarily sensory nerves. Pyridoxine (vitamin B6) and the platinum-containing anticancer drugs (e.g. cisplatin) are examples of toxins that exclusively damage dorsal root ganglion neurons, leading to large-fiber sensory loss and sensory ataxia. In contrast, N-hexane inhalation produces almost entirely motor deficits. An acute sensorimotor demyelinating polyneuropathy may be caused by the ingestion of buckthorn “fruit”; clinically, this is sometimes hard to distinguish from idiopathic Guillain-Barré syndrome. Children poisoned by thallium initially present with pain and autonomic dysfunction. An encephalopathy associated with autonomic dysfunction occurs in children poisoned by organophosphates. In both thallium and organophosphate poisoning, sensory polyneuropathy usually becomes evident only as these early encephalopathic symptoms abate.

Pathophysiology

An appealing hypothesis is that length-dependent toxic axonopathies are a direct consequence of impaired axoplasmic transport of essential molecules from the neuronal perikaryon distally, or of end organ-derived trophic molecules proximally. Colchicine, paclitaxel (Taxol), and the vinca alkaloids can all induce symmetrical distal polyneuropathy and are known to perturb turnover of microtubules, which are an essential factor in axoplasmic transport. Studies of neuropathies caused by acrylamide, hexane, and the rodenticide Vacor also suggest perturbation of axoplasmic flow. It remains unclear, however, whether the impairment of axoplasmic transport is caused by these various toxic agents or whether this occurs secondary to the axonal degeneration itself.

The similarities in clinical, electrophysiologic, and pathologic features of cisplatin and pyridoxine sensory neuronopathies suggest common underlying pathophysiologic mechanisms. In both instances, the toxin evidently penetrates the blood-nerve barrier to reach dorsal root ganglion neurons; this likely causes the death of large sensory neurons by chemical cross-linking of macromolecules (DNA in the case of cisplatin, probably proteins in the case of pyridoxine).

The neuropathies caused by chloroquine and amiodarone appear to result from the lipophilic nature and resistance to degradation of these molecules. These properties cause the drugs to accumulate within Schwann cells as membrane-bound inclusions. This may be the basis for the Schwann cell metabolic dysfunction, eventually leading to segmental demyelination.

Diagnosis

A comprehensive history is the most essential tool for correctly diagnosing children with toxic neuropathies. Which, if any, medications has the child been prescribed or did he or she have access to in the home? Is there a suggestion of inadvertent or voluntary hydrocarbon inhalation? Has an exterminator visited the home recently? Have friends or family members had similar symptoms? Recognition of a drug-induced neuropathy is frequently delayed by the presence of an intercurrent illness. For example, is the abrupt onset of a painful neuropathy in a child receiving treatment for human immunodeficiency virus caused by the virus per se , or is it secondary to the purine or pyrimidine analogue with which the child is being treated?

The general physical examination may also yield important clues, such as hair loss in thallium poisoning and transverse white Mee’s lines on the nails in either arsenic or thallium poisoning. The neurologic examination establishes the distribution of sensory deficits (e.g. stocking-glove versus asymmetrical) and the modalities affected (large or small sensory, motor, autonomic). Obtaining reliable results from a sensory examination is challenging in children but is of particular importance, given their inability to describe their symptoms precisely. It is often desirable in young children to test perception of cold, rather than pinprick, to detect abnormalities in small-fiber sensory perception. Electrophysiologic testing is helpful in documenting the distribution of involvement, detecting subclinical damage and muscle denervation, and demonstrating whether the disorder affects axons, myelin sheaths, or both through measurements of conduction velocity and action potential amplitude.

DNA studies are useful for diagnosing the genetic neuropathies. Occasionally one may find that both genetic and toxic mechanisms are active in the same patient. Identification of a genetic neuropathy therefore does not exclude the remote possibility of a superimposed toxic or inflammatory process leading to an acute exacerbation of the underlying genetic process. This has been particularly well defined with the combination of vincristine superimposed on children with occult Charcot-Marie-Tooth disease type 1. Blood, urine, and hair can be analyzed for heavy metals. Although nerve biopsy often shows axonal balloons in patients with hydrocarbon-induced neuropathy or membrane-bound bodies in endoneurial cells in neuropathies caused by Vacor, amiodarone, or chloroquine, useful information is seldom obtained from nerve biopsy in patients with toxic neuropathies.