Description

Presentation and course

Establishment of a neurotoxic etiology in cases of peripheral neuropathy is most certain when the following criteria are satisfied:

	(1) The presence of a neurotoxin is confirmed by history and either environmental or clinical chemical analysis.
	(2) The intensity and temporal onset of symptoms reflect the level and duration of exposure.
	(3) In mild cases, improvement follows cessation of exposure.
	(4) The pattern of clinical and electrophysiologic deficit reflects that known to occur in previous cases.

The single most useful instrument in acute and chronic disorders is an accurate history.

Cardinal tenets of neurotoxic illness affecting the peripheral nervous system. The identification of a neurotoxic illness should satisfy, or at least not be inconsistent with, the following basic principles of neurotoxic disease. The key to correctly recognizing the presence of a toxic polyneuropathy is not in remembering the characteristics of the many potential neurotoxins, but in understanding and applying these basic tenets (11).

Strong dose-response relationship. Most neurotoxins produce a consistent pattern of disease, commensurate with the dose and duration of exposure. Neurotoxins rarely cause focal or asymmetric deficits. Because most neurotoxins cause diffuse myelin or neuronal dysfunction, their related symptoms and signs are usually widespread and symmetric. In the case of toxic polyneuropathies, this usually means a relatively symmetric distal axonopathy with initial symptoms in the feet and proximal progression with continued exposure. Only rarely does a toxin cause strikingly asymmetric or focal dysfunction (eg, trichloroethylene) (03), reflecting the direct metabolic pathogenesis of most neurotoxic conditions. Most neurotoxins do not produce dysfunction via immunologic mechanisms.

Consistency of response. All individuals with similar exposure to the same neurotoxin will invariably manifest similar signs and symptoms, if the chemical enters the circulation and if the agent (its metabolite or intermediate) has similar access to the nervous system. Although the same toxin may produce strikingly different clinical syndromes if the exposure dose or duration is different, a similar and consistent illness should result in patients with similar exposures. There is usually no individual susceptibility or idiosyncratic reactions if dose and duration of exposure are similar. A neuropathy is unlikely to be neurotoxic if it occurs in only 1 member of a group with similar exposure histories. Likewise, neurotoxicity should also be doubted when substantially different clinical manifestations occur in a group of individuals with identical chemical exposure.

Proximity of symptoms to exposure. Neurotoxic illness usually occurs concurrent with exposure or following a short latency. Neurologic symptoms do not begin months to years after exposure. The most common exceptions are the 2- to 6-week delay following exposure to organophosphates, the 2-month delay following methylmercury poisoning, and the occasional 2-month latency between cisplatin intoxication and neuropathic symptoms (10). Delayed neurotoxic effects are occasionally encountered when substances are stored in nonneural tissues and released slowly (chloroquine in the choroid of the eye) or precipitously (lead in bone) during illness or chelation therapy. Rare agents, such as ciguatoxin, may produce repeated symptoms because they persist in the body.

In addition, the extent and severity of neuropathy is usually commensurate with the degree of toxin exposure. It is unlikely that a single, brief, low-level exposure will result in a devastating peripheral neuropathy. Some lipid stored agents (eg, chlorinated hydrocarbons) are detectable in fat biopsies years following exposure. Although this provides a valuable marker of previous exposure, there is no evidence that this state is associated with risk for future neurotoxicity, and attempts at removal or mobilization of the body burden are unnecessary.

Improvement. Improvement usually follows cessation of exposure. Toxic polyneuropathies generally plateau, then gradually improve after removal of the neurotoxic agent (especially if symptoms are due to biochemical or neurophysiologic derangement), without structural changes to cells or their processes. A neuropathy that shows no improvement or continues to deteriorate, despite the cessation of exposure to a suspected neurotoxin, is unlikely to be neurotoxic in nature. The clinical picture may become somewhat murky, however, in certain toxic axonopathies wherein cessation of exposure may be followed by worsening of symptoms (known as “coasting”) for several weeks before recovery commences (02). Recovery may be severely delayed, incomplete, or absent when there has been substantial neuronal loss. Occasionally, emergence or exacerbation of prior clinical deficits may reflect age associated neuronal loss superimposed on toxin-induced neuronal injury.

Confusing aspects of neurotoxic illness.

Exposure levels. Multiple clinical syndromes may result from different levels of exposure to a single toxin. Different exposure levels to the same substance may produce dramatically different syndromes. Most confusing is the bizarre constellation of symptoms that may arise from intoxication with intermediate levels of the neurotoxin. Examples include the different clinical syndromes produced by acute high-level and intermediate-level acrylamide exposure and prolonged low-level exposure. Exposures to high-level acrylamide cause early central nervous system dysfunction with drowsiness, disorientation, hallucinations, seizures, and severe truncal ataxia, followed by neuropathy of variable severity. Prolonged, lower-level exposure causes little central nervous system dysfunction but a marked peripheral neuropathy. Exposure to intermediate levels of acrylamide causes hallucinations, mental confusion, and cognitive dysfunction, followed by sensory complaints affecting the distal limbs.

Another example is organophosphate poisoning, where there may be early, severe cholinergic symptoms resulting from excessive muscarinic receptor stimulation. Within 1 to 3 days, generalized paralysis with respiratory distress owing to nicotinic receptor blockage may occur. After a few weeks, a distal axonopathy may be evident.

In some instances, a single compound may produce similar clinical symptoms at both high-level and low-level exposures, although different anatomic structures are affected. High dose pyridoxine intoxication produces widespread sensory loss due to dorsal root ganglion dysfunction; low-level exposure produces similar symptoms, but these are due to a distal axonopathy.

Asymptomatic disease. Prolonged, low-level exposure may occasionally produce widespread subclinical dysfunction. Clinical deficits may go unnoticed by the patient unless they perform job that requires fine-motor control or intact sensibility. Insidiously developing subclinical toxic polyneuropathies may occur in individuals who deny any disability.

Enhancement by bystander chemicals. An agent without known neurotoxic activity may enhance the toxicity of a known neurotoxin that is present at a “no effect” level. This disquieting notion has raised the general public’s fear that the combined effects of multiple chemicals in hazardous waste disposal sites may be more toxic than their separate effects. Such sites may contain low, presumably harmless levels of neurotoxic solvents, metals, or pesticides, whose neurotoxic potency conceivably might be enhanced by other chemicals present. Neurotoxic potentiation is illustrated by the epidemic of peripheral neuropathy that occurred in German youths who abused paint thinner containing n-hexane. Initially, there were no instances of neuropathy, but when lowering the concentration of n-hexane and adding methyl ethyl ketone reformulated the paint thinner, there resulted an epidemic of severe distal axonopathy (12). Experimental evidence subsequently showed that although methyl ethyl ketone by itself was not neurotoxic, the compound dramatically potentiated the neurotoxic effects of n-hexane.

Neurotoxic potential. Chemical formula may not predict toxicity. The neurotoxic potential of a compound cannot usually be predicted by its chemical formula. This is especially important to consider when evaluating cases of potential occupational exposure to chemicals that superficially resemble a known neurotoxin. For example, some workers exposed to acrylamide polymer, an innocuous substance, have been needlessly alarmed by physicians familiar only with the effects of acrylamide monomer, a potent neurotoxin. Unpredictability exists because the underlying biochemical mechanisms and active metabolites of most neurotoxins are unknown.

Clinical presentation. Clinical presentation, including severity, may be modulated by age, preexisting conditions or genetic variation in metabolism. Examples are the increased vulnerability of the fetal nervous system to toxic exposure, and the lessened vulnerability of young children or adolescents to some forms of neurotoxic exposure (organophosphates). Recovery, as a rule, is earlier and more complete in young patients than the elderly. In addition, the elderly workers may develop earlier and more severe deficits when exposed to neurotoxins than a similarly exposed younger person. Patients with preexisting neuropathies, especially those genetic in nature, appear to have increased vulnerability to chemotherapeutic induced peripheral neuropathy. This principle has been confirmed (04).

Violations of the cardinal tenets. Over the past few years, the potential that fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, norfloxacin) might cause a toxic peripheral neuropathy has come to light (05). However, the cases described violate many of the above principles. For example, there does not seem to be a dose-response relationship to the toxicity, with some patients having severe symptoms after a single dose. There is also marked variability of response, with the vast majority of those exposed to even high doses or long duration of treatment having no neuropathy, but others developing severe neuropathic symptoms after brief, low-level exposures. Also, there is no improvement and, in some cases, continued progression after stopping exposure (06).

Prevention. Limiting exposure to toxic substances in the workplace is the primary method for prevention of occupational toxic neuropathy. This includes the use of protective clothing, adequate ventilation, use of gloves and respirators.

Multiple substances have been investigated for their ability to prevent peripheral nerve toxicity associated with chemotherapy administration. Although vitamin E proved beneficial in a small trial (01), a subsequent larger study failed to show any benefit (08). Intravenous calcium and magnesium have shown promise in prevention of cisplatin-induced neuropathy (07). Many other agents have been tested and have not shown benefit to date.

Clinical applications

Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.

Identification of toxic peripheral neuropathy. The presence of a toxic peripheral neuropathy is suggested by the following:

	(1) Suspicion is raised by history and reinforced by compatible findings on physical exam.
	(2) Lack of a naturally occurring alternative explanation.
	(3) Consistency with basic principles of neurotoxic disease.
	(4) Compatible electrodiagnosis.
	(5) Confirmation by demonstration of elevated body burdens if appropriate, or resolution of condition with removal of potential exposure.

The initial step is a suspicion raised by a thorough occupational history. Information regarding the type, method, and duration of neurotoxin exposure is critical. Unfortunately, because most toxic polyneuropathies are insidious in onset, many patients are unable to discern a relationship between their symptoms and chronic, low-level, toxin intoxication. Inquiry should focus on potential occupational, environmental, and iatrogenic exposures. The individual habits of a patient should be considered. Are protective devices worn and clothes changed before coming home? Do they eat in the workplace, and are hands washed prior to eating? What is the health of their peers? Do symptoms improve when they are away from the potential toxin, such as on weekends or holidays? Do workplace conditions (eg, ventilation and drainage) predispose one to an unacceptably high risk of toxin exposure? Answers may only be available after a visit to the home or workplace itself. In cases of suspected domestic poisoning or substance abuse, home visits may be necessary in order to examine hobby workshops, medicine cabinets, and food and water sources. Inquiry should be made about recent pesticide applications. Similar illnesses in neighbors may prove helpful in identifying a neurotoxin. Because neurotoxic and naturally occurring illness may be clinically indistinguishable, the medical history should also focus on the possibility of a nutritional, metabolic, endocrine, or hereditary degenerative condition. Traumatic nerve and spine injury may mimic a toxic distal axonopathy if bilateral and symmetric. A list of all current and recent medicines, including vitamins and nutritional supplements, is essential.

The nature of the suspected toxin should focus the physical examination to relevant deficits. Thus, a suspicion of mercury poisoning should prompt a careful examination for tremor and mild cerebellar dysfunction. The purpose of the neurologic exam is to demonstrate that neurologic deficits are in a pattern and of a severity that is consistent with neurotoxic illness. Because the clinical deficits resulting from a toxic polyneuropathy should be symmetric in distribution, the presence of multifocal deficits should suggest a diagnosis other than neurotoxic disease. In addition, because most toxic polyneuropathies affect mixed nerve function, finding a purely small-fiber neuropathy makes neurotoxic disease unlikely.

Occasionally, the nature of the neurologic deficit gives some clue to etiology, as Table 1 illustrates.

Table 1. Motor and Sensory Toxic Neuropathies

Motor > Sensory toxic neuropathies
	(1) dapsone (2) disulfiram (3) nitrofurantoin (4) organophosphates (5) lead (6) vincristine (7) arsenic (shortly after acute exposure) (8) amiodarone (9) carbon disulfide (10) methyl n-butyl ketone (11) n-hexane
Sensory > Motor toxic neuropathies
	(1) cisplatin (2) pyridoxine (3) thalidomide (4) thallium (5) arsenic (6) polychlorinated biphenyls (7) ethyl alcohol (8) metronidazole

Determination of body burdens. In the usual scenario, screening levels for heavy metals are not fruitful. Often this is because the toxin exposure was too remote, allowing time for the offending agent to be cleared from the serum. In cases of prolonged exposure, the neurotoxin may be sequestered in various tissues and, therefore, not available to laboratory identification. With some chemicals, the safe level has not been established.

Caution must be taken when interpreting body burden results. For example, arsenic levels are frequently of little clinical value and may be raised by recent shellfish ingestion. In some cases of prolonged exposures to toxins such as thallium or lead, finding elevated levels in slow growing tissues such as hair or nails, or in urine or serum after chelation is often diagnostic.

However, once again, one must exercise caution as some labs have very low thresholds for abnormal value, vastly different than most other labs. Also, values post chelation therapy have not been established. The ability of labs to reliably test certain samples such as hair or nails, which they may not routinely examine, needs to be taken into consideration.

Electrodiagnostic assessment. Electrophysiologic findings should be consistent with a distal axonopathy or mixed axonal demyelinating neuropathy. The most sensitive measure of neurotoxic induced axonal dysfunction is diminution or absence of sensory potentials. Nerve conduction velocities reflect the conductivity of the largest diameter fibers within a nerve, and combined with changes in action potential configuration (eg, temporal dispersion), are sensitive measures of peripheral nerve demyelination. Only a few rare neuropathies, such as those caused by n-hexane, perhexiline, amiodarone, and early arsenic poisoning, have predominant demyelinating features. The pattern of axonal dysfunction (eg, proximal vs. distal) may also be established; this is a critical determinant for the detection of neurotoxic disease as deficits are almost always initially distal.

Skin biopsy. Epidermal nerve fiber density determination by skin biopsy is a useful and increasingly available method of assessing small-diameter nerve involvement and establishing whether the pattern is length dependent or non-length dependent.

Systemic features suggestive of neurotoxic disease. The neuropathies resulting from most neurotoxins are remarkably similar in both their clinical and electrophysiologic characteristics. Occasionally, there may be systemic complaints or signs that suggest the nature of the neurotoxic insult. Usually these symptoms and signs are apparent with either acute high-level, or chronic low-level intoxication. See Table 2 below for clinical characteristics that are identifying features suggestive of a possible toxic polyneuropathy.

Table 2. Clinical Characteristics of Various Toxins

Toxin	Clinical characteristics
Acrylamide	Dermal contact is associated with contact dermatitis, excessive sweating of hands and feet.
Carbon disulfide	Chronic low-level exposure is associated with a variety of behavioral and psychiatric abnormalities and peripheral neuropathy.
Ethyl oxide	Cognitive impairment and neuropathy is associated with prolonged low-level exposure.
Hexacarbons	Acute, high-level exposure may mimic acute inflammatory demyelinating polyneuropathy with prominent autonomic dysfunction.
Lead	Exposure is associated with Mee’s lines, blood abnormalities (basophilic stippling, anemia), gastrointestinal abnormalities, and a predominantly motor neuropathy.
Mercury	Exposure is associated with tremor and ataxia with a predominantly sensory neuropathy.
Methyl bromide	Exposure is associated with corticospinal and cerebellar dysfunction in addition to an axonal neuropathy.
Organophosphate intoxication	Exposure is associated with early cholinergic symptoms. There may be an intermediate syndrome preceding the neuropathy, and there may be a late emergence of corticospinal tract dysfunction as the peripheral neuropathy resolves.
Polychlorinated biphenyls	Exposure is associated with a symmetric sensory neuropathy associated with brown acneiform skin eruption and brown-pigmented nails.
Thallium	High-level exposure is associated with prominent gastrointestinal distress. Alopecia, Mee’s lines, and hyperkeratosis are associated with prolonged exposure. Sensory neuropathy is more likely than motor neuropathy.

Treatment. Treatment of toxic neuropathy is primarily symptomatic. The primary management to prevent disease progression and allow for recovery is removal from exposure (when possible). Symptomatic management has traditionally been based on management of other forms of neuropathy. As such, gabapentin, pregabalin, duloxetine, amitriptyline, and some topical agents have all been used. Evidence for the use of any particular treatment for pain relief in toxic neuropathy is lacking.

Prognosis. The degree of recovery in a toxic peripheral neuropathy depends on the degree of impairment at the time exposure is stopped. All toxic neuropathies should stop progressing when exposure ceases except, in rare instances, when there may be transient worsening known as coasting. If there is severe weakness or sensory loss related to axonal damage, there may be significant residual deficits.