Toxic Neuropathies

Keywords

Toxic neuropathy, cisplatin, vincristine, paclitaxel, chloroquine, metronidazole, nitrofurantoin, colchicine, thalidomide, pyridoxine, hexane, organophosphates, thallium, arsenic, buckthorn

Introduction

In a sense, all peripheral nervous system (PNS) disorders caused by toxic molecules are toxic neuropathies. Even normal PNS proteins can have deleterious effects if overexpressed. For example, Charcot-Marie-Tooth syndrome type 1A (hereditary motor and sensory neuropathy type 1A) results from excess synthesis by Schwann cells of the myelin protein PMP22, caused by inheritance of a duplicated chromosomal segment within which PMP22 is encoded. Excessive deposition in the PNS of proteins produced by neoplastic cells elsewhere in the body (e.g. immunoglobulin light chains) can also damage the PNS. Neuropathies caused by bacterial proteins, such as diphtheritic neuropathy, as well as cases of Guillain-Barré syndrome associated with immunologic responses to bacterial glycolipids, also fall within this broad definition of a toxic neuropathy. Traditionally, however, the term “toxic neuropathy” is limited to PNS disorders caused by exposure to exogenous poisons or neurotoxic drugs. Furthermore, toxic disorders that primarily injure the perikarya of motor neurons or perturb neurotransmitter release at neuromuscular junctions are not generally classified as toxic neuropathies. To avoid overlap with other chapters, the discussion in this chapter is limited to disorders caused by environmental toxins and drugs that affect primarily Schwann cells, axons, and sensory and autonomic neurons.

General Features of 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.

Treatment

The primary treatment for toxic neuropathies is withdrawal of the offending toxin. In most instances, this is sufficient to stop the progression of deficits, and recovery follows. However, the “coasting phenomenon,” in which the disease worsens for weeks after cessation of exposure, is well recognized, particularly in patients exposed to hydrocarbons, cisplatin, or pyridoxine. Protection of deafferented limbs from trauma, range-of-motion physical therapy, and motor and gait reconditioning are frequently useful, and adequate suppression of pain is also important. Specific therapies are available in a few cases (e.g. pyridoxine supplementation for children at risk of isoniazid neuropathy; chelation of arsenic with penicillamine or BAL; treatment with atropine and pyridine 2-aldoxime during the early stages of organophosphate poisoning).

Selected Toxic Neuropathies

Antineoplastic Agents

Cisplatin and Other Platin Compounds. These drugs are used for the treatment of solid tumors but often cause sensory neuronopathy. Patients present with paresthesias and evidence of impairment of large-fiber sensory modalities, including sensory ataxia. Diminished pain and temperature perception, if present, are generally mild. Distal muscle stretch reflexes are usually depressed, and generalized areflexia may occur. Autonomic disturbances are infrequent, and motor function is spared. Symptoms and signs may progress for months after cessation of therapy. Electrophysiologic studies show reduced or absent sensory nerve action potentials, normal motor potentials, and no evidence of muscle denervation.

Vincristine and Other Vinca Alkaloids. These drugs, which are included in several chemotherapy protocols for childhood cancer, interfere with microtubule assembly. Vincristine toxicity is the most common cause of neuropathy in children with malignancies. Many children receiving vinca alkaloids have reduced ankle reflexes and mild diminution in distal extremity sensation. Some may also show evidence of autonomic dysfunction, such as urinary retention or orthostatic hypotension. One clinical review of 96 survivors of vincristine-treated childhood malignancies demonstrated that 47 (49%) had areflexia associated with decreased motor and sensory amplitudes on nerve conduction studies (NCS), consistent with an axonopathy. Needle electromyogram (EMG) may show muscle denervation. Although symptoms and signs of the axonal neuropathy typically dissipate gradually after cessation of exposure, some children develop substantial persistent weakness, sometimes with bilateral facial paresis. This is especially of concern with vincristine toxicity if the child has an unsuspected hereditary neuropathy.

Paclitaxel. This drug is used occasionally to treat solid tumors in children. It is frequently associated with burning dysesthesias secondary to a dose-dependent, predominantly sensory, axonal polyneuropathy.

Antibacterial, Antiprotozoal, and Antiretroviral Drugs

Chloroquine. This drug is used for malaria prophylaxis and for treatment of connective tissue diseases. Neuropathy may appear months or years after institution of therapy and may be accompanied by proximal weakness. Electrophysiologic testing may show evidence of both segmental demyelination and axonopathy; in those with proximal weakness, there may be evidence of myopathy as well. Membrane-bound inclusions similar to those described in amiodarone toxicity are seen in nerve biopsies of patients with chloroquine neuropathy.

Metronidazole. This antibiotic is used to treat amebiasis and other protozoan diseases, and may also be useful in anaerobic bacterial infections. Children treated with metronidazole may develop a mild, reversible, predominantly sensory axonal polyneuropathy.

Isoniazid. Children treated for tuberculosis with isoniazid occasionally develop a mild distal sensory axonal polyneuropathy. Isoniazid is an inhibitor of pyridoxal phosphokinase, and isoniazid neuropathy can usually be prevented by supplementation with pyridoxine.

Dapsone. This drug is used to treat leprosy and dermatitis herpetiformis. Occasionally, patients develop clinical and electrophysiologic evidence of a primary motor polyneuropathy.

Nitrofurantoin. Polyneuropathy caused by this antibacterial drug can be acute in onset and is most apt to occur in children with impaired renal function. It affects both sensory and motor axons. Distinguishing the toxic effects of nitrofurantoin from those of uremic toxins can be difficult.

Antiretroviral drugs. Chronic administration of a variety of purine and pyrimidine analogues, including dideoxycytidine (ddC), didanosine (ddI), and zidovudine (ZDV), can elicit either a rapid or gradual onset of a painful, length-dependent, small-fiber polyneuropathy, typically without autonomic deficits. Electrophysiology shows diminished sensory action potentials and normal motor action potentials. Symptoms and signs may worsen for a month or more after cessation of therapy.

Miscellaneous Medications

Amiodarone. This medication is used for the treatment of arrhythmias. As many as 10% of those who take it for a year or more develop a primary sensory polyneuropathy. Electrophysiologic testing shows evidence of segmental demyelination, but there may also be muscle denervation, indicating an axonal component. Nerve biopsy shows accumulation of intracellular, osmiophilic, membrane-bound inclusions in Schwann cells, perineurium, and endoneurium.

Phenytoin. Children treated chronically with this anticonvulsant occasionally develop reduced muscle stretch reflexes in the legs, and some suggest that patients may rarely develop distal sensory impairment. However, they do not have a clinically relevant polyneuropathy.

Colchicine. This drug is occasionally used in children for the treatment of inflammatory disorders. Prolonged therapy may elicit an axonal sensory polyneuropathy. Patients may also develop proximal weakness and an elevated serum creatine kinase level; in such cases, muscle biopsy shows a vacuolar myopathy.

Thalidomide. Indications are increasing for the use of this drug to treat inflammatory and neoplastic diseases. When children receive thalidomide, it is reasonable to expect that some of them, like many adults, will develop a motor, sensory, and autonomic polyneuropathy, which in some cases may worsen even after discontinuation of treatment. At Boston Children’s Hospital, preliminary data from the EMG laboratory suggest that this medication may lead to a significant polyneuropathy in at least some treated children after approximately 2 to 3 years of therapy. In adults, serial electrophysiologic monitoring has proved valuable in monitoring therapy to prevent this complication.

Pyridoxine (Vitamin B6). Megadoses of pyridoxine (e.g. 25–50 mg/kg per day) are occasionally used in children with pyridoxine-dependent epilepsies, but this is uncommon now that pyridoxal-5-phosphate has largely superseded pyridoxine for these conditions. When given in very large doses, pyridoxine often elicits large-fiber sensory defects and sensory ataxia. Lower doses, as little as 200 mg/day in adults, may also cause sensory deficits after prolonged therapy. Electrophysiologic examination shows diminished or absent sensory nerve action potentials. The primary site of pyridoxine toxicity is the dorsal root ganglia. The considerable degree of eventual recovery in most patients after cessation of pyridoxine exposure suggests that this drug, like cisplatin, causes a reversible functional impairment of some sensory neurons, as well as death of others.

Dichloroacetate. Dichloroacetate is a potent lactate-lowering agent that inhibits the pyruvate dehydrogenase complex and has been shown to relieve symptoms in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) caused by 3243A>G mutants (also discussed in Chapter 41 ). A recent large, randomized, double-blind, placebo-controlled cross-over trial of dichloroacetate, however, was terminated because of peripheral nerve toxicity. All subjects treated with dichloroacetate had to be taken off treatment because of development or worsening of a length-dependent axonal neuropathy that was felt to overshadow assessment of any benefit from the medication.

Hexane and Methyl-N-Butyl Ketone. Exposure of children to these hydrocarbons is most commonly the result of voluntary inhalation, so-called glue sniffing (see Case Example 23.1 ). Glue-sniffing neuropathy is characterized by predominant proximal as well as distal weakness. Distal paresthesias may be the first evidence of toxicity. This adolescent addiction should be considered in the differential diagnosis of any subacute polyneuropathy, especially chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Weakness may continue to worsen for months following cessation of glue sniffing or other exposure to these solvents, but then gradually abates. Occasionally, glue or gasoline sniffing can give rise to a mononeuritis multiplex-like clinical picture. The N-hexane component of glue is also found in certain commercial settings, particularly the shoe industry, where this toxin is a component of cements, and occupational exposure can lead to development of generalized weakness with areflexia, nausea, anorexia, and weight loss.

Case Example 23.1

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