Clinical manifestations of acrylamide toxicity depend on the severity of exposure. Acute high-dose exposure results in confusion, hallucinations, reduced attention span, drowsiness, and other encephalopathic changes. A peripheral neuropathy of variable severity may occur after acute high-dose or prolonged low-level exposure. The neuropathy is a length-dependent axonopathy involving both sensory and motor fibers; some studies suggest that terminal degeneration precedes axonopathy and is the primary site of involvement, leading to a defect in neurotransmitter release (LoPachin, 2005). Hyperhidrosis and dermatitis may develop before the neuropathy is evident clinically in those with repeated skin exposure. Ataxia from cerebellar dysfunction also occurs and relates to degeneration of afferent and efferent cerebellar fibers and Purkinje cells. Neurological examination reveals distal sensorimotor deficits and early loss of all tendon reflexes rather than simply the Achilles reflex, which is usually affected first in most length-dependent neuropathies. Autonomic abnormalities other than hyperhidrosis are uncommon. Gait and limb ataxia are usually greater than can be accounted for by the sensory loss. With discontinuation of exposure, the neuropathy “coasts,” arrests, and may then slowly reverse, but residual neurological deficits are common. These consist particularly of spasticity and cerebellar ataxia; the peripheral neuropathy usually remits because regeneration occurs in the peripheral nervous system. No specific treatment exists. Studies in rats have shown that administration of FK506 to increase Hsp-70 expression may exert a neuroprotective effect and have therefore suggested that compounds eliciting a heat shock response may be useful for treating the neuropathy in humans (Gold et al., 2004).

Electrodiagnostic studies provide evidence of an axonal sensorimotor polyneuropathy. Workers exposed to acrylamide may be monitored electrophysiologically by recording sensory nerve action potentials, which are attenuated early in the course of the disorder, or by measuring the vibration threshold. Histopathological studies show accumulation of neurofilaments in axons, especially distally, and distal degeneration of peripheral and central axons. The role of neurofilament accumulation in the generation of axonal degeneration has been questioned (Stone et al., 2001). The large myelinated axons are involved first. The affected central pathways include the ascending sensory fibers in the posterior columns, the spinocerebellar tracts, and the descending corticospinal pathways. Involvement of postganglionic sympathetic efferent nerve fibers accounts for the sudomotor dysfunction. Measurement of hemoglobin-acrylamide adducts may be useful in predicting the development of peripheral neuropathy.

Allyl Chloride

Allyl chloride is used for manufacturing epoxy resins, certain insecticides, and polyacrylonitrile. Exposure leads to a mixed sensorimotor distal axonopathy. Cessation of exposure is followed by recovery of variable degree. Intraaxonal accumulation of neurofilaments occurs multifocally before axonal degeneration in animals exposed to this compound. Similar changes may occur also in the posterolateral columns of the spinal cord.

Carbon Disulfide

Carbon disulfide is used as a solvent or soil fumigant, in perfume production, in certain varnishes and insecticides, in the cold vulcanization of rubber, and in manufacturing viscose rayon and cellophane films. Toxicity occurs primarily from inhalation or ingestion but also may occur transdermally. The pathogenetic mechanism is uncertain but may involve an essential metal-chelating effect of carbon disulfide metabolites, direct inhibition of certain enzymes, or the release of free radicals following cleavage of the carbon-sulfur bond. Most reported cases have been from Europe and Japan.

Acute inhalation of concentrations exceeding 300 to 400 ppm leads to an encephalopathy, with symptoms that vary from mild behavioral disturbances to drowsiness and, ultimately, to respiratory failure. Behavioral disturbances may include explosive behavior, mood swings, mania or depression, confusion, and other psychiatric disturbances. Long-term exposure to concentrations between 40 and 50 ppm may produce similar disturbances. Minor affective or cognitive disturbances may be revealed only by neuropsychological testing.

Long-term exposure to carbon disulfide may lead also to extrapyramidal (parkinsonian) or pyramidal deficits, impaired vision, absent pupillary and corneal reflexes, optic neuropathy, and a characteristic retinopathy. A small-vessel vasculopathy may be responsible (Huang, 2004). Neuroimaging may reveal cortical—especially frontal—atrophy, as well as lesions in the globus pallidus and putamen. A clinical or subclinical polyneuropathy develops after exposure to levels of 100 to 150 ppm for several months or to lesser levels for longer periods and is characterized histologically by focal axonal swellings and neurofilamentary accumulations.

No specific treatment exists other than the avoidance of further exposure. Recovery from the peripheral neuropathy generally follows the discontinuation of exposure, but some central deficits may persist.

Carbon Monoxide

Occupational exposure to carbon monoxide occurs mainly in miners, gas workers, and garage employees. Other modes of exposure include poorly ventilated home heating systems, stoves, and suicide attempts. The neurotoxic effects of carbon monoxide relate to intracellular hypoxia. Carbon monoxide binds to hemoglobin with high affinity to form carboxyhemoglobin; it also limits the dissociation of oxyhemoglobin and binds to various enzymes. Acute toxicity leads to headache (Hampson and Hampson, 2002), disturbances of consciousness, and a variety of other behavioral changes. Motor abnormalities include the development of pyramidal and extrapyramidal deficits. Seizures may occur, and focal cortical deficits sometimes develop. Treatment involves prevention of further exposure to carbon monoxide and administration of pure or hyperbaric oxygen, although the evidence is conflicting regarding the utility of hyperbaric oxygen in this setting (Buckley et al., 2005). Seizures may complicate hyperbaric oxygen therapy (Sanders et al., 2009). Neurological deterioration may occur several weeks after partial or apparently full recovery from the acute effects of carbon monoxide exposure, with recurrence of motor and behavioral abnormalities. The degree of recovery from this delayed deterioration is variable; full or near-full recovery occurs in some instances, but other patients lapse into a persistent vegetative state or severe parkinsonism. Neuroimaging may show lesions in the globus pallidus and elsewhere.

Pathological examination shows hypoxic and ischemic damage in the cerebral cortex as well as in the hippocampus, cerebellar cortex, and basal ganglia. Lesions are also present diffusely in the cerebral white matter. The delayed deterioration has been related to a diffuse subcortical leukoencephalopathy, but its pathogenesis is uncertain.

Ethylene Oxide

Ethylene oxide is used to sterilize heat-sensitive medical equipment and as an alkylating agent in industrial chemical synthesis. A byproduct, ethylene chlorohydrin, is highly toxic. Operators of sterilization equipment should wear protective ventilatory apparatus to prevent occupational exposure. Acute exposure to high levels produces headache, nausea, and a severe, reversible encephalopathy. Long-term exposure to ethylene oxide or ethylene chlorohydrin—as can occur, for example, in operating-room nurses and sterilizer workers—may lead to a peripheral sensorimotor axonopathy and mild cognitive changes. Recovery generally follows cessation of exposure. Neuropathy may be produced in rats by exposure to ethylene oxide, and the residual ethylene oxide in sterilized dialysis tubing may contribute to the polyneuropathy occurring in patients undergoing chronic hemodialysis.

Hexacarbon Solvents

The hexacarbon solvents, n-hexane and methyl n-butyl ketone, are both metabolized to 2,5-hexanedione, which targets proteins required for the maintenance of neuronal integrity (Spencer et al., 2002) and is responsible in large part for their neurotoxicity. This neurotoxicity is potentiated by methyl ethyl ketone, which is used in paints, lacquers, printer’s ink, and certain glues. n-Hexane is used as a solvent in paints, lacquers, and printing inks and is used especially in the rubber industry and in certain glues. Workers involved in the manufacturing of footwear, laminating processes, and cabinetry, especially in confined, unventilated spaces, may be exposed to excessive concentrations of these substances. Methyl n-butyl ketone is used in the manufacture of vinyl and acrylic coatings and adhesives and in the printing industry. Exposure to either of these chemicals by inhalation or skin contact leads to a progressive distal sensorimotor axonal polyneuropathy; partial conduction block may also occur (Pastore et al., 2002). Optic neuropathy or maculopathy and facial numbness also have followed n-hexane exposure. The neuropathy is related to a disturbance of axonal transport, and histopathological studies reveal giant multifocal axonal swelling and accumulation of axonal neurofilaments, with distal degeneration in peripheral and central axons. Myelin retraction and focal demyelination are found at the giant axonal swellings.

Acute inhalation exposure may produce feelings of euphoria associated with hallucinations, headache, unsteadiness, and mild narcosis. This has led to the inhalation of certain glues for recreational purposes, which causes pleasurable feelings of euphoria in the short term but may lead to a progressive, predominantly motor neuropathy and symptoms of dysautonomia after high-dose exposure and a more insidious sensorimotor polyneuropathy following chronic use.

Electrophysiological findings include increased distal motor latency and marked slowing of maximal motor conduction velocity, as well as small or absent sensory nerve action potentials and electromyographic (EMG) signs of denervation in affected muscles. The conduction slowing relates to demyelinating changes and is unusual in other toxic neuropathies. A reduction in the size of sensory nerve action potentials may occur in the absence of clinical or other electrophysiological evidence of nerve involvement. Central involvement may result in abnormalities of sensory evoked potentials. The cerebrospinal fluid (CSF) is usually normal, but a mildly elevated protein concentration is sometimes found. Despite cessation of exposure, progression of the neurological deficit may continue for several weeks or rarely months (coasting) before the downhill course is arrested and recovery begins. Severe involvement is followed by incomplete recovery of the peripheral neuropathy. When the polyneuropathy does resolve, previously masked signs of central dysfunction, such as spasticity, may become evident.

Methyl Bromide

Methyl bromide has been used as a refrigerant, insecticide, fumigant, and fire extinguisher. Its high volatility may lead to work-area concentrations sufficient to cause neurotoxicity from inhalation. Following acute high-level exposure, an interval of several hours or more may elapse before the onset of symptoms. Because methyl bromide is odorless and colorless, subjects may not even be aware that exposure has occurred, so chloropicrin, a conjunctival and mucosal irritant, is commonly added to methyl bromide to warn of inhalation exposure. Acute methyl bromide intoxication leads to an encephalopathy with convulsions, delirium, hyperpyrexia, coma, pulmonary edema, and death. Acute exposure to lower concentrations may result in conspicuous mental changes including confusion, psychosis or affective disturbances, headache, nausea, dysarthria, tremulousness, myoclonus, ataxia, visual disturbances, and seizures.

Long-term low-level exposure may lead to a polyneuropathy in the absence of systemic symptoms. Distal paresthesias are followed by sensory and motor deficits, loss of tendon reflexes, and an ataxic gait. Visual disturbances, optic atrophy, and upper motor neuron deficits may occur also. Calf tenderness is sometimes conspicuous. The CSF is unremarkable. Electrodiagnostic study results reveal both sensory and motor involvement. Gradual improvement occurs with cessation of exposure.

Treatment is symptomatic and supportive. Hemodialysis may also be helpful in removing bromide from the blood (Yamano et al., 2001). Chelating agents are of uncertain utility.

Organochlorine Pesticides

The organochlorine pesticides include aldrin, dieldrin, and lindane as well as the once popular insecticide, dichlorodiphenyl-trichloroethylene, commonly called DDT. Exposure is typically through inhalation or ingestion. Tremor, convulsions, and coma may follow acute high-level exposure, but the effects of chronic low-level exposure are uncertain. Chlordecone, which belongs to this group, may produce a neurological disorder characterized by “nervousness,” tremor, clumsiness of the hands, gait ataxia, and opsoclonus. Minor cognitive changes and benign intracranial hypertension may occur. The pathophysiology of the disorder has not been established.

Organophosphates

Organophosphates are used mainly as pesticides and herbicides but are also used as petroleum additives, lubricants, antioxidants, flame retardants, and plastic modifiers. Most cases of organophosphate toxicity result from exposure in an agricultural setting, not only among those mixing or spraying the pesticide or herbicide but also among workers returning prematurely to sprayed fields. Absorption may occur through the skin, by inhalation, or through the gastrointestinal tract. Organophosphates inhibit acetylcholinesterase by phosphorylation, with resultant acute cholinergic symptoms, with both central and neuromuscular manifestations. Symptoms include nausea, salivation, lacrimation, headache, weakness, and bronchospasm in mild instances and bradycardia, tremor, chest pain, diarrhea, pulmonary edema, cyanosis, convulsions, and even coma in more severe cases. Death may result from respiratory or heart failure. Treatment involves intravenous (IV) administration of pralidoxime (1 g) together with atropine (1 mg) given subcutaneously every 30 minutes until sweating and salivation are controlled. Pralidoxime accelerates reactivation of the inhibited acetylcholinesterase, and atropine is effective in counteracting muscarinic effects, although it has no effect on the nicotinic effects, such as neuromuscular cholinergic blockade with weakness or respiratory depression. It is important to ensure adequate ventilatory support before atropine is given. The dose of pralidoxime can be repeated if no obvious benefit occurs, but in refractory cases it may need to be given by IV infusion, the dose being titrated against clinical response. Functional recovery may take approximately 1 week, although acetylcholinesterase levels take longer to reach normal levels. Measurement of paraoxonase status may be worthwhile as a biomarker of susceptibility to acute organophosphate toxicity; this liver and serum enzyme hydrolyzes a number of organophosphate compounds and may have a role in modulating their toxicity (Costa et al., 2005).

Carbamate insecticides also inhibit cholinesterases but have a shorter duration of action than organophosphate compounds. The symptoms of toxicity are similar to those described for organophosphates but are generally milder. Treatment with atropine is usually sufficient.

Certain organophosphates cause a delayed polyneuropathy that occurs approximately 2 to 3 weeks after acute exposure even in the absence of cholinergic toxicity. In the past, contamination of illicit alcohol with triorthocresyl phosphate (“Jake”) led to large numbers of such cases. There is no evidence that peripheral nerve dysfunction follows prolonged low-level exposure to organophosphates (Lotti, 2002). Paresthesias in the feet and cramps in the calf muscles are followed by progressive weakness that typically begins distally in the limbs and then spreads to involve more proximal muscles. The maximal deficit usually develops within 2 weeks. Quadriplegia occurs in severe cases. Although sensory complaints are typically inconspicuous, clinical examination shows sensory deficits. The Achilles reflex is typically lost, and other tendon reflexes may be depressed also; however, in some instances, evidence of central involvement is manifested by brisk tendon reflexes. Cranial nerve function is typically spared. With time, there may be improvement in the peripheral neuropathy, but upper motor neuron involvement then becomes unmasked and often determines the prognosis for functional recovery. There is no specific treatment to arrest progression or hasten recovery. Electrodiagnostic studies reveal an axonopathy with partial denervation of affected muscles and small compound muscle action potentials but normal or only minimally reduced maximal motor conduction velocity.

The delayed syndrome follows exposure only to certain organophosphates such as triorthocresyl phosphate, leptophos, trichlorfon, and mipafox. The neurological disturbance relates in some way to phosphorylation and inhibition of the enzyme, neuropathy target esterase (NTE), which is present in essentially all neurons and has an uncertain role in the nervous system (Lotti and Moretto, 2005). In addition, “aging” of the inhibited NTE (loss of a group attached to the phosphorus, leaving a negatively charged phosphoryl group attached to the protein) must occur for the neuropathy to develop. The precise cause of the neuropathy is uncertain, however. No specific treatment exists to prevent occurrence of the neuropathy following exposure, but measurement of lymphocyte NTE has been used to monitor occupational exposure and predict the occurrence of neuropathy. Moreover, the ability of any particular organophosphate to inhibit NTE in hens may predict its neurotoxicity in humans.

Three other syndromes related to organophosphate exposure require brief comment. The intermediate syndrome occurs in the interval between the acute cholinergic crisis and the development of delayed neuropathy, typically becoming manifest within 4 days of exposure and resolving in 2 to 3 weeks (Guadarrama-Naveda et al., 2001). It reflects excessive cholinergic stimulation of nicotinic receptors and is characterized clinically by respiratory and bulbar symptoms as well as proximal limb weakness. Symptoms relate to the severity of poisoning and to prolonged inhibition of acetylcholinesterase activity but not to the development of delayed neuropathy. The syndrome of dipper’s flu refers to the development of transient symptoms such as headache, rhinitis, pharyngitis, myalgia, and other flulike symptoms in farmers exposed to organophosphate sheep dips. Vague sensory complaints (but no objective abnormalities on sensory threshold tests) may also occur (Pilkington et al., 2001). Whether these complaints relate to mild organophosphate toxicity is uncertain. Similarly uncertain is whether chronic effects (persisting behavioral and neurological dysfunction) may follow acute exposure to organophosphates. The occurrence of chronic symptoms in the absence of any episode of acute toxicity is unlikely. Evaluation of reports is hampered by incomplete documentation and the variety of agents to which exposure has often occurred. Carefully controlled studies may clarify this issue in the future.

Pyrethroids

Pyrethroids are synthetic insecticides that affect voltage-sensitive sodium channels. Type II (α-cyano) pyrethroids, which have enhanced insecticidal activity, also affect voltage-dependent chloride channels and, at high concentrations, γ-aminobutyric acid (GABA)-gated chloride channels (Bradberry et al., 2005). Occupational or residential exposure is increasing, is mainly through the skin but may also occur through inhalation, and has led to paresthesias that have been attributed to repetitive activity in sensory fibers as a result of abnormal prolongation of the sodium current during membrane excitation. The paresthesias affect the face most commonly and are exacerbated by sensory stimulation such as scratching; they typically resolve within a day. Treatment is purely supportive. Coma and convulsions may result if substantial amounts of pyrethroids are ingested (Proudfoot, 2005).

In laboratory animals, two syndromes relating to neurotoxicity have been described, but these are poorly defined in humans. The first syndrome (type I) is characterized by reflex hyperexcitability and fine tremor, whereas the second (type II) consists of choreoathetosis, salivation, and seizures.

Pyriminil

Exposure to pyriminil (Vacor), a rodenticide, has led to severe autonomic dysfunction accompanied by a usually milder sensorimotor axonopathy following its ingestion. The mechanism by which this develops is unclear, but it may relate to an impairment of fast anterograde axonal transport. Acute diabetes mellitus also results from necrosis of the beta islet cells of the pancreas.

Solvent Mixtures

In the 1970s, a number of reports from Scandinavia suggested that house painters, in particular, developed a disturbance of cognitive function that related to exposure to mixtures of organic solvents. However, further studies (including cases previously diagnosed with the disorder) have failed to validate the earlier reports, which in many instances were methodologically flawed. Furthermore, workers performing the same basic tasks in different companies have highly variable levels of solvent exposure, complicating the interpretation of published studies (Horstman et al., 2001). Because of these factors, the existence of so-called painter’s encephalopathy in those exposed to low levels of organic solvents for a prolonged period remains uncertain.

Styrene

Styrene is used for manufacturing reinforced plastic and certain resins. Occupational exposure occurs by the dermal or inhalation routes and is typically associated with exposure to a variety of other chemicals, thereby making it difficult to define the syndrome that occurs from styrene exposure itself. Exposure (inhalation or dermal) occurs particularly among those working in industries manufacturing or using styrene, those exposed to automobile exhaust or cigarette smoke, and those using photocopiers. Styrene may also be ingested in drinking water or certain foods. Further details and allowable limits are provided by the Agency for Toxic Substances and Disease Registry (2007). Acute exposure to high concentrations of styrene has led to cognitive, behavioral, and attentional disturbances. Less clear are the consequences of exposure to chronic low levels of styrene. Abnormalities in psychomotor performance have been reported, but there is little compelling evidence of persisting neurological sequelae in this circumstance. Visual abnormalities (impaired color vision and reduced contrast sensitivity) also occur.

Toluene

Toluene is used in a variety of occupational settings. It is a solvent for paints and glues and is used to synthesize benzene, nitrotoluene, and other compounds. Exposure, usually by inhalation or transdermally, occurs among workers laying linoleum, spraying paint, and working in the printing industry, particularly in poorly ventilated locations. Chronic high exposure may lead to cognitive disturbances and to central neurological deficits with upper motor neuron, cerebellar, brainstem, and cranial nerve signs and tremor (Filley et al., 2004). An optic neuropathy may occur, as may ocular dysmetria and opsoclonus. Disturbances of memory and attention characterize the cognitive abnormalities, and subjects may exhibit a flattened affect. Magnetic resonance imaging (MRI) shows cerebral atrophy and diffuse abnormalities of the cerebral white matter; symmetrical lesions may be present in the basal ganglia and thalamus and the cingulate gyri. Thalamotomy may ameliorate the tremor if it is severe. Lower levels of exposure lead to minor neurobehavioral disturbances.

Trichloroethylene

Trichloroethylene is an industrial solvent and degreaser that is used in dry cleaning and the manufacture of rubber. It also has anesthetic properties. Recreational abuse has occurred because it may induce feelings of euphoria. Acute low-level exposure may lead to headache and nausea, but claims that an encephalopathy follows chronic low-level exposure are unsubstantiated. Higher levels of exposure lead to dysfunction of the trigeminal nerve, with progressive impairment of sensation that starts in the snout area and then spreads outward. This has been particularly associated with rebreathing anesthetic circuits where the trichloroethylene is heated by the carbon dioxide absorbent. With increasing exposure, facial and buccal numbness is followed by weakness of the muscles of mastication and facial expression. Ptosis, extraocular palsies, vocal cord paralysis, and dysphagia may occur also, as may signs of parkinsonism (Gash et al., 2008) or an encephalopathy, but occurrence of a peripheral neuropathy is uncertain. The clinical deficit relates to neuronal loss in the cranial nerve nuclei and nigrostriatal dopaminergic system and degeneration in related tracts. With discontinuation of exposure, the clinical deficit generally resolves, sometimes over 1 to 2 years, but occasional patients are left with residual facial numbness or dysphagia.

Occupational Exposure to Metals

Aluminum

Aluminum exposure is responsible for dialysis encephalopathy, which is characterized by speech disturbances, cognitive decline, seizures, and myoclonus. Some reports suggest that workers exposed to aluminum dust or aluminum-containing welding fumes may develop mild cognitive dysfunction, but whether this relates to the occupational exposure is unclear; individual studies are difficult to interpret because of methodological and other issues.

Arsenic

Arsenic poisoning can result from ingestion of the trivalent arsenite in murder or suicide attempts. Large numbers of persons in areas of India, Pakistan, and certain other countries are chronically poisoned from naturally occurring arsenic in ground water (Vahidnia et al., 2007). Traditional Chinese medicinal herbal preparations may contain arsenic sulfide and mercury and are a source of chronic poisoning. Uncommon sources of accidental exposure include burning preservative-impregnated wood and storing food in antique copper kettles. Exposure to inorganic arsenic occurs in workers involved in smelting copper and lead ores.

With acute or subacute exposure, nausea, vomiting, abdominal pain, diarrhea, hypotension, tachycardia, and vasomotor collapse occur and may lead to death. Obtundation is common, and an acute confusional state may develop. Arsenic neuropathy takes the form of a distal axonopathy, although a demyelinating neuropathy is found soon after acute exposure. The neuropathy usually develops within 2 to 3 weeks of acute or subacute exposure, although the latent period may be as long as 1 to 2 months. Symptoms may worsen over a few weeks despite lack of further exposure, but they eventually stabilize. With low-dose chronic exposure, the latent period is more difficult to determine. In either circumstance, systemic symptoms are also conspicuous. With chronic exposure, similar but less severe gastrointestinal disturbances develop, as may skin changes such as melanosis, keratoses, and malignancies. Mees lines are white transverse striations of the nails (striate leukonychiae) that appear 3 to 6 weeks after exposure (Fig. 58.1). As a nonspecific manifestation of nail matrix injury, Mees lines can be seen in a number of other conditions including thallium poisoning, chemotherapy, and a variety of systemic disorders.

Fig. 58.1 Mees lines in arsenic neuropathy.

The neuropathy involves both large- and small-diameter fibers. Initial symptoms are typically of distal painful dysesthesias and are followed by distal weakness. Proprioceptive loss may be severe, leading to marked ataxia. The severity of weakness depends on the extent of exposure. The respiratory muscles are sometimes affected, and the disorder may simulate Guillain-Barré syndrome both clinically and electrophysiologically. Electrodiagnostic studies may initially suggest a demyelinating polyradiculoneuropathy, but the changes of an axonal neuropathy subsequently develop. Arsenic levels in hair, nail clippings, or urine may be increased, especially in cases of chronic exposure.

Detection of arsenic in urine is diagnostically useful within 6 weeks of a single large-dose exposure or during ongoing low-level exposure. Total inorganic arsenic urinary excretion should be measured over 24 hours. Methods are available in reference laboratories to distinguish between inorganic (toxic) and organic (seafood-derived) arsenic compounds. Arsenic bound to keratin can be detected in hair or nails months to years after exposure. Pubic hair is preferable to scalp hair for examination because it is less liable to environmental contamination. Levels exceeding 10 µg/g of tissue are abnormal. Other abnormal laboratory features include aplastic anemia with pancytopenia and moderate CSF protein elevation. Nerve conduction studies in chronic arsenic neuropathy reflect the changes of distal axonopathy with low-amplitude or unelicitable sensory and motor evoked responses and preserved conduction velocities. EMG typically shows denervation in distal extremity muscles. In the subacute stages, however, some electrophysiological features such as partial motor conduction block, absent F responses, and slowing of motor conduction velocities are suggestive of demyelinating polyradiculoneuropathy. Progressive slowing of motor conduction velocities sufficient to invoke consideration of segmental demyelination has been reported in the first 3 months after massive exposure. Biopsies of peripheral nerves show axonal degeneration in chronic cases. Arsenite compounds react with protein sulfhydryl groups, interfere with formation of coenzyme A and several steps in glycolysis, and are potent uncouplers of oxidative phosphorylation. These biochemical reactions are responsible for the impaired neuronal energy metabolism, which in turn results in distal axonal degeneration.

Chelation therapy with either water-soluble derivatives of dimercaprol (DMSA or DMPS) or penicillamine is effective in controlling the systemic effects of acute arsenic poisoning and may prevent the development of neuropathy if it is started within hours of ingestion. There is little evidence that chelation in the later stages of arsenic neuropathy promotes clinical recovery. The neuropathy itself often improves gradually over the course of many months, but depending on the severity of the deficit when exposure is discontinued, a substantial residual neurological deficit is common.

Lead

Occupational exposure to lead occurs in workers in smelting factories and metal foundries and those involved in demolition, ship breaking, manufacturing of batteries or paint pigments, and construction or repair of storage tanks. Occupational exposure also occurs in the manufacture of ammunition, bearings, pipes, solder, and cables. Nonindustrial sources of lead poisoning are home-distilled whiskey, Asian folk remedies, earthenware pottery, indoor firing ranges, and retained bullets. Lead has been used to artificially increase the weight of illicit marijuana and has then been inhaled with it (Busse et al., 2008). Artifical turf may also pose an exposure threat to unhealthy levels of lead: the lead is released in dust that may be ingested or inhaled, but whether in sufficient amount to cause neurotoxicity is unclear. Lead neuropathy reached epidemic proportions at the end of the 19th century because of uncontrolled occupational exposure but now is rare because of strict industrial regulations. Exposure also may result from ingestion of old lead-containing paint in children with pica and consumption of illicit spirits by adults. Absorption is commonly by ingestion or inhalation but occasionally occurs through the skin.

The toxic effects of inorganic lead salts on the nervous system commonly differ with age, producing acute encephalopathy in children and polyneuropathy in adults. Children typically develop an acute gastrointestinal illness followed by behavioral changes, confusion, drowsiness, reduced alertness, focal or generalized seizures, and (in severe cases) coma with intracranial hypertension. At autopsy, the brain is swollen, with vascular congestion, perivascular exudates, edema of the white matter, and scattered areas of neuronal loss and gliosis. In adults, an encephalopathy is less common, but behavioral and cognitive changes are sometimes noted. In adults, lead produces a predominantly motor neuropathy, sometimes accompanied by gastrointestinal disturbances and a microcytic, hypochromic anemia. The neuropathy is manifest primarily by a bilateral wrist drop sometimes accompanied by bilateral footdrop or by more generalized weakness that may be associated with distal atrophy and fasciculations. Sensory complaints are usually minor and overshadowed by the motor deficit when the neuropathy develops subacutely following relatively brief exposure to high lead concentrations, but they are more conspicuous when the neuropathy develops after many years of exposure (Thomson and Parry, 2006). The tendon reflexes may be diminished or absent. Older reports describe a painless motor neuropathy with few or no sensory abnormalities and distinct patterns of weakness affecting wrist extensors, finger extensors, and intrinsic hand muscles. Preserved reflexes, fasciculations, and profound muscle atrophy may simulate amyotrophic lateral sclerosis. A rare sign of lead exposure is a blue line at the gingival margin in patients with poor oral hygiene. Hypochromic microcytic anemia with basophilic stippling of the red cells, hyperuricemia, and azotemia should stimulate a search for lead exposure. Prognosis for recovery from the neuropathy is good when the neuropathy is predominantly motor and evolves subacutely, but it is less favorable when the neuropathy is motor-sensory in type and more chronic in nature (Thomson and Parry, 2006).

Lead intoxication is confirmed by elevated blood and urine lead levels. Blood levels exceeding 70 µg/100 mL are considered harmful, but even levels greater than 40 µg/100 mL have been correlated with minor nerve conduction abnormalities. Subjects should be removed from further occupational exposure if a single blood lead concentration exceeds 30 µg/100 mL or if two successive blood lead concentrations measured over a 4-week interval equal or exceed 20 µg/100 mL (Kosnett et al., 2007). Lead inhibits erythrocyte δ-aminolevulinic acid dehydratase and other enzymatic steps in the biosynthetic pathway of porphyrins. Consequently, increased red cell protoporphyrin levels emerge together with increased urinary excretion of δ-aminolevulinic acid and coproporphyrin. Excess body lead burden, confirming past exposure, can be documented by increased urinary lead excretion after a provocative chelation challenge with calcium ethylenediaminetetraacetic acid. Only a few electrophysiological studies have been reported in patients with overt lead neuropathy. These investigations indicate a distal axonopathy affecting both motor and sensory fibers. These observations corroborate changes of axonal degeneration seen in human nerve biopsies. Contrary to the findings in humans, lead produces segmental demyelination in animals. Lead is known to cause early mitochondrial changes in cell culture systems, but the biochemical mechanisms leading to neurotoxicity remain unknown.

Lead encephalopathy is managed supportively, but corticosteroids are given to treat cerebral edema. Chelating agents (dimercaprol or 2,3-dimercaptopropane sulfonate) are also prescribed for patients with symptoms of lead toxicity (Kosnett et al., 2007). No specific treatment exists for lead neuropathy other than prevention of further exposure to lead. Chelation therapy does not hasten recovery.