Acrylamide

Acrylamide polymers are used as flocculators and are constituents of certain adhesives and products such as cardboard or molded parts. They also are used as grouting agents for mines and tunnels, a solution of the monomer being pumped into the ground where polymerization is allowed to occur. The monomer is neurotoxic, and exposure may occur during its manufacture or in the polymerization process. Most cases of acrylamide toxicity occur by inhalation or cutaneous absorption. Acrylamide can be formed by cooking various carbohydrate-rich foods at high temperatures, but consumption is unlikely to be sufficient for neurotoxicity. The acrylamide is distributed widely throughout the body and is excreted primarily through the kidneys. The mechanism responsible for its neurotoxicity is unknown. Studies in animals have shown early abnormalities in axonal transport, which may account for the histopathological changes discussed here.

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.

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.

Manganese

Manganese miners may develop neurotoxicity following inhalation for prolonged periods (months or years) of dust containing manganese. Headache, behavioral changes, and cognitive disturbances (“manganese madness”) are followed by the development of motor symptoms such as dystonia, parkinsonism, retropulsion, and a characteristic gait called cock-walk manifested by walking on the toes with elbows flexed and the spine erect. There is usually no tremor, and the motor deficits rarely improve with l-dopa therapy. MRI may show changes in the globus pallidus, and this may be helpful in distinguishing manganese-induced parkinsonism from classic Parkinson disease (PD). Manganese intoxication has been reported in miners, smelters, welders, and workers involved in the manufacture of dry batteries, after chronic accidental ingestion of potassium permanganate, and from incorrect concentration of manganese in parenteral nutrition. Welders with PD were found to have their onset of PD an average of 17 years earlier than a control population of PD patients, suggesting that welding, possibly by causing manganese toxicity, is a risk factor for PD (Racette et al., 2001). However, a recent nationwide record linkage study from Sweden did not support a relationship between welding and PD or any other movement disorder (Fored et al., 2006). The controversy regarding the relationship between welding and PD has been reviewed by Jankovic (2005). In addition to welding and manganese mining, manganese toxicity may occur with chronic liver disease and long-term parenteral nutrition. Manganese intoxication may be associated with abnormal MRI (abnormal signal hyperintensity in the globus pallidus and substantia nigra on T1-weighted images). In contrast to PD, fluorodopa positron emission tomography (PET) studies are usually normal in patients with manganese-induced parkinsonism, and raclopride (D2 receptor) binding is only slightly reduced in the caudate and normal in the putamen. Neuronal loss occurs in the globus pallidus and substantia nigra pars reticularis, as well as in the subthalamic nucleus and striatum. There is little response to l-dopa of the extrapyramidal syndrome, which may progress over several years. Myoclonic jerking may occur, sometimes without extrapyramidal accompaniments (Ono et al., 2002).

Chelation therapy is of uncertain benefit in patients with manganese toxicity, although claims of improvement in parkinsonism among small series of manganese-exposed subjects have been made (Herrero Hernandez et al., 2006).

Mercury

The toxic effects of elemental mercury (mercury vapor), inorganic salts, and short-chain alkyl-mercury compounds predominantly involve the central nervous system (CNS) and dorsal root ganglion sensory neurons. Inorganic mercury toxicity may result from inhalation during industrial exposure, as in thermometer and battery factories, mercury processing plants, and electronic applications factories. In the past, exposure occurred particularly in the hat-making industry. No evidence exists that the mercury contained in dental amalgam imposes any significant health hazard. Differences in health and cognitive function between dentists and control subjects cannot be attributed directly to mercury (Ritchie et al., 2002). Clinical consequences of exposure include cutaneous erythema, hyperhidrosis, anemia, proteinuria, glycosuria, personality changes, intention tremor (“hatter’s shakes”), and muscle weakness. The personality changes (“mad as a hatter”) consist of irritability, euphoria, anxiety, emotional lability, insomnia, and disturbances of attention with drowsiness, confusion, and ultimately stupor. A variety of other central neurological deficits may occur but are more conspicuous in patients with organic mercury poisoning.

The effects of methyl mercury (organic mercury) poisoning have come to be widely recognized since the outbreak that occurred in Minamata Bay (Japan) in the 1950s when industrial waste discharged into the bay led to contamination of fish that were then consumed by humans. Outbreaks have also occurred following the use of methyl mercury as a fungicide, because intoxication occurs if treated seed intended for planting is eaten instead. Methyl and ethyl mercury compounds have been used as fungicides in agriculture and in the paper industry. Methyl mercury and elemental mercury are potent neurotoxins that cause neuronal degeneration in the cerebellar granular layer, calcarine cortex, and dorsal root ganglion neurons. The primary molecular target of methyl mercury is probably sulfhydryl ligands in enzyme complexes or critical membrane sites.

The characteristic features of chronic methyl mercury poisoning are sensory disturbances, constriction of visual fields, progressive ataxia, tremor, and cognitive impairment. Electrophysiological studies have shown that these symptoms relate to central dysfunction. Sensory disturbances result from dysfunction of sensory cortex or dorsal root ganglia rather than peripheral nerves, and the visual complaints also relate to cortical involvement. Pathological studies reveal neuronal loss in the cerebral cortex, including the parietal and occipital regions, as well as in the cerebellum. A few cases presenting with peripheral neuropathy or a predominantly motor neuronopathy resembling amyotrophic lateral sclerosis have been described in association with intense exposure to elemental mercury vapors.

The diagnosis of elemental or inorganic mercury intoxication usually can be confirmed by assaying mercury in urine. Monitoring blood levels is recommended for suspected organic mercury poisoning.

Chelating agents increase urinary excretion of mercury, but insufficient evidence exists to substantiate the claim that chelation increases the rate or extent of recovery.

Tellurium

Tellurium is used in the manufacture of various alloys, the production of rubber, the manufacture of thermoelectric devices, and the coloring of glass, ceramics, and metalware. Inhalation of volatile tellurium compounds may lead to headache, drowsiness, a metallic taste, hypohidrosis, rashes and skin discoloration, and a curious odor resembling garlic on the breath. Recovery generally occurs spontaneously.

Thallium

Thallium salts cause severe neuropathy and CNS degeneration that has led to their discontinued use as rodenticides and depilatories. Most intoxications result from accidental ingestion, attempted suicide, or homicide. After consumption of massive doses, vomiting, diarrhea, or both occur within hours. Neuropathic symptoms, heralded by limb pain and severe distal paresthesia, are followed by progressive limb weakness within 7 days. Cranial nerves, including optic nerves, may be involved. Ptosis is common. In severe cases, ataxia, chorea, confusion, and coma as well as ventilatory and cardiac failure may ensue. Alopecia, which appears 2 to 4 weeks after exposure, provides only retrospective evidence of acute intoxication. A chronic progressive, mainly sensory neuropathy develops in patients with chronic low-level exposure. In this form, hair loss is a helpful clue.

Electrocardiographic findings of sinus tachycardia, U waves, and T-wave changes of the type seen in potassium depletion are related to the interaction of thallium and potassium ions. Electrophysiological findings are characteristic of distal axonal degeneration. Autopsy study results confirm a distal axonopathy of peripheral and cranial nerves. Studies in animals show accumulation of swollen mitochondria in distal axons before wallerian degeneration of nerve fibers. The diagnosis is confirmed by the demonstration of thallium in urine or bodily tissues. High levels are found in CNS gray matter and myocardium. The toxic effects of thallium may be related to binding of sulfhydryl groups or displacement of potassium ions from biological membrane systems.

With acute ingestion, gastric lavage and cathartics are given to remove unabsorbed thallium from the gastrointestinal tract. Oral potassium ferric ferrocyanide (Prussian blue), which blocks intestinal absorption, together with IV potassium chloride, forced diuresis, and hemodialysis have been used successfully in acute thallium intoxication.

Tin

Although ingested inorganic tin usually produces little or no systemic or neurological complications, organic tin compounds used in various industrial processes have definite neurotoxicity. Intoxication with trimethyl tin leads to multifocal central dysfunction with conspicuous behavioral disturbances, emotional lability, confusion, disorientation, cognitive disturbances, sleep dysfunction, headaches, and visual disturbances. Triethyl tin may lead to severe cerebral edema with headache, papilledema, and behavioral abnormalities that generally resolve some weeks after discontinuation of exposure.

Encephalopathy

Radiation encephalopathy is best considered according to its time of onset after exposure (Grimm and DeAngelis, 2008).

Acute radiation encephalopathy occurs within a few days of exposure and is characterized by headache, nausea, and a change in mental status. It may be related to increased intracranial pressure from breakdown of the blood-brain barrier due to the immediate effects of the energy dispersal in the nervous tissue. It typically occurs after exposure of a large brain volume to more than 3 Gy. Treatment with high-dose corticosteroids usually provides relief.

Early delayed radiation encephalopathy is probably caused by demyelination and occurs between 2 weeks and 4 months after irradiation. Headache and drowsiness are features, as is an enhancement of previous focal neurological deficits. Symptoms resolve after several weeks without specific treatment. A brainstem encephalopathy that manifests as ataxia, nystagmus, diplopia, and dysarthria also may develop if the brainstem was included in the irradiated field. Spontaneous recovery over a few weeks is usual, but the disorder sometimes progresses to obtundation, coma, or death.

Delayed radiation encephalopathy occurs several months or longer after cranial irradiation, particularly when doses exceed 35 Gy. It may be characterized by diffuse cerebral injury (atrophy) or focal neurological deficits. Slowness of executive function may occur, and there may be marked alterations of frontal functions such as in attention, judgment, and insight (Moretti et al., 2005). The disorder may result from focal cerebral necrosis caused by direct radiation damage or vascular changes. Immunological mechanisms also may be involved. Occasionally patients develop a progressive disabling disorder with cognitive and affective disturbances and a disorder of gait approximately 6 to 18 months after whole-brain irradiation. Such a disturbance may occur more commonly in elderly patients after irradiation. Pathological examination in some instances has shown demyelinating lesions.

Myelopathy

A myelopathy may result from irradiation involving the spinal cord. Transient radiation myelopathy usually occurs within the first year or so after incidental spinal cord irradiation in patients treated for lymphoma and neck and thoracic neoplasms. Paresthesias and the Lhermitte phenomenon characterize the syndrome, which is self-limiting and probably relates to demyelination of the posterior columns. A delayed severe radiation myelopathy may occur 1 or more years after completion of radiotherapy, especially with doses exceeding 60 Gy to the spinal cord. Patients present with a focal spinal cord deficit that progresses over weeks or months to paraplegia or quadriplegia. This may simulate a compressive myelopathy or paraneoplastic subacute necrotizing myelopathy, but the changes on MRI are usually those of a focal increased T2-weighted myelomalacia with cord atrophy in the originally irradiated field. The CSF is usually normal, although the protein concentration is sometimes elevated. Corticosteroids may lead to temporary improvement, but no specific treatment exists. The disorder is caused by necrosis and atrophy of the cord, with an associated vasculopathy (Okada and Okeda, 2001). Occasional patients develop sudden back pain and leg weakness several years after irradiation, with MRI revealing hematomyelia; symptoms usually improve with time.

In some instances, inadvertent spinal cord involvement, usually by irradiation directed at the paraaortic nodes in cases of seminoma, leads to a focal lower-limb lower motor neuron syndrome (see Chapter 74). The neurological deficit may progress over several months or years but eventually stabilizes, leaving a flaccid asymmetrical paraparesis. Recovery does not occur.

Plexopathy

A radiation-induced plexopathy may rarely occur soon after radiation treatment for neoplasms, particularly of the breast and pelvis, and must be distinguished from direct neoplastic involvement of the plexus (Dropcho, 2010). Paresthesias, weakness, and atrophy typify the disorder, which tends to plateau after progressing for several months. The plexopathy may develop 1 to 3 years or longer after irradiation that involves the brachial or lumbosacral plexus. In this regard, doses of radiation exceeding 60Gy, use of large daily fractions, involvement of the upper part of the brachial plexus, lymphedema, induration of the supraclavicular fossa, and the presence of myokymic discharges on EMG all favor a radiation-induced plexopathy. Although radiation plexopathy is often painless, a point favoring this diagnosis rather than direct infiltration by neoplasm, pain is conspicuous in some patients. Symptoms progress at a variable rate. The plexopathy is associated with small-vessel damage (endarteritis obliterans) and fibrosis around the nerve trunks.

Pharmacological Effects of Drug Abuse

Indirect Complications of Drug Abuse

Snakes

Over 5 million snakebites occur worldwide per year, with half of them venomous, resulting in about 400,000 amputations and up to 125,000 deaths. Only about 6800 cases with fewer than 10 deaths are reported in the United States each year (Langley, 2008). In contrast, cases are commonly encountered in Africa, Asia, and Latin America. Mortality and morbidity are particularly associated with impoverished rural communities (Williams et al., 2010).

The majority of venomous snakebites are inflicted by the pit vipers (subfamily Crotalidae), a group that includes rattlesnakes (genera Crotalus and Sistrurus), fer-de-lances (genus Bothrops), and the bushmaster (Lachesis muta). Moccasins (genus Agkistrodon), including cottonmouths and copperheads, account for up to half of pit viper envenomations in the United States. Pit vipers are so named because of an identifiable heat-sensing foramen, or “pit,” between each eye and nostril; they have a triangular head with elliptical pupils and retractable canalized fangs (Gold et al., 2002). Important venomous snakes in other parts of the world include Elapidae such as cobras, mambas, kraits, coral snakes (Maticora species), and most Australian venomous snakes. Viperidae (true vipers) include the puff adder (Bitis arietans), Gaboon viper (Bitis gabonica), rhinoceros-horned viper (Bitis nasicornis, and Russell’s viper (Daboia russelii). Hydrophiidae (pelagic sea snakes) have highly neurotoxic venom but rarely bite humans.

Low-molecular-weight polypeptides in snake venoms have neurological activities on both pre- and postsynaptic elements of the neuromuscular junction. Some toxins may be directly myotoxic, resulting in rhabdomyolysis and compartment syndromes. Just as important are the diverse systemic effects that affect platelets, endothelial cells, the coagulation cascade, and other organs. As many as 25% to 50% of venomous snakebites are “dry” and do not result in envenomation. When envenomation occurs, signs and symptoms vary and depend on the venom composition of the local snakes. Bites by the same species may cause primarily neuromuscular paralysis in one region and coagulopathy and hemorrhage in another area.

Patients typically present with local pain, swelling, and erythema after a snake bite. Early indications of envenomation include tender regional lymph nodes, nausea, and a metallic, rubbery, or minty taste in the mouth. Systemic symptoms appear over the ensuing 12 to 24 hours and consist of a variable combination of perioral or limb paresthesias, muscle fasciculations, weakness, hypotension, and shock. Cranial nerve palsies, dysphagia, diffuse weakness, areflexia, and respiratory suppression may develop, usually after a delay of about 24 hours. When weakness is present, the pattern generally resembles myasthenia gravis, with predilection for the neck flexors, ocular, bulbar, and proximal limb and respiratory muscles. Clinical outcome principally depends on the availability and sophistication of emergency medical care.

Initial laboratory evaluation should include complete blood cell and platelet counts, coagulation panel, fibrinogen, fibrin split products, serum chemistries, creatine kinase, and urinalysis. In patients with weakness, nerve conduction studies with repetitive stimulation may reveal a pattern of either pre- or postsynaptic blockade. The observed changes consist of reduced amplitude of compound muscle action potentials, decremental response to low-frequency repetitive stimulation, and postexercise and posttetanic facilitation. Treatment includes calming and supportive measures. Even in the absence of life-threatening symptoms, a patient should be monitored for at least 6 hours if bitten by a pit viper and 12 hours if bitten by a coral snake. Appropriate immunoglobulin antivenom may be administered as soon as it is certain that significant envenomation has occurred (Warrell, 2010). In survivors of snake bites, the main source of disability is local tissue necrosis that may lead to disfigurement or limb amputation.

Spiders

Of the commonly encountered spiders, few produce significant symptoms in humans. The female widow spider (Latrodectus sp.) is the most important to the neurologist. Of the approximately 2600 widow bites reported annually in the United States, 13 had major health consequences, and no fatality occurred (Langley, 2008). Black widow spider (Latrodectus mactans mactans) venom contains α-latrotoxin, a potent neurotoxin capable of inducing release and blocking reuptake of neurotransmitter at presynaptic cholinergic, noradrenergic, and aminergic nerve endings. Venom of Phoneutria banana spiders from South America and Atrax funnel web spiders from Australia also cause neurotoxicity. Another clinically important spider, the brown recluse spider (Loxosceles reclusa), is responsible for local tissue damage and systemic symptoms that rarely may include disseminated intravascular coagulation, hemolysis, shock, and multisystem failure.

Although latrotoxin found in widow spider venom is more potent than the neurotoxins found in snake venom, most spider bites cause only a small volume of envenomation. Sometimes a characteristic erythematous ring surrounding a paler center (“target” or “halo” lesion) develops around the site of the spider bite. In the rare instances with neurological complications, pain and involuntary muscle spasms appear in abdominal muscles followed by spread to the limb musculature (so-called lactrodectism). Symptoms may appear as early as 30 to 60 minutes and may last up to 6 to 12 hours after envenomation. Respiratory failure can result from diaphragmatic muscle involvement. Dysautonomia, piloerection, and sweating may be present. Other associated symptoms include priapism, salivation, sweating, bronchospasm, and bronchorrhea. Hypertension is common in affected individuals. Serum creatine kinase may be elevated. Treatment begins with careful monitoring of respiration and vital signs and intensive care support if necessary. Benzodiazepines and opioids are used to control spasmodic effects and pain. Muscle spasms may also be treated with slow infusion of calcium gluconate or methocarbamol. Antivenom may be beneficial if administered early, but there is no vigorous clinical trial data.

Scorpions

Although only a few of the approximately 1400 scorpion species are of neurological importance, bites by poisonous scorpions are generally more dangerous than spider bites. Scorpion envenomation is second only to snake bites as a public health problem in the tropics and North Africa. In Mexico alone, 100,000 to 200,000 scorpion bites occur annually, resulting in 400 to 1000 fatalities. In the United States on average, approximately 14,700 scorpion bites with no fatalities are reported annually (Langley, 2008). Small children in particular are prone to developing neurological effects, and as many as 80% of bites are symptomatic. The venoms of the poisonous scorpions contain a wide range of polypeptides that have a net excitatory effect on the nervous system.

Presenting symptoms are highly variable, from local pain (which may be secondary to serotonin found in scorpion stings) to a general state of intoxication. Paresthesias are common and usually experienced around the site of the bite but also may be felt diffusely. Autonomic symptoms of sympathetic excess (tachycardia, hypertension, and hyperthermia) are often present, but parasympathetic symptoms including the SLUD syndrome (salivation, lacrimation, urination, and defecation) may be present as well. Muscle fasciculations, spasms, limb flailing, dysconjugate roving or rotary ocular movements, dysphagia, and other cranial nerve signs are sometimes seen. With severe envenomation, encephalopathy may result from direct CNS toxicity or secondary to uncontrolled hypertension. Symptom control, cardiovascular and respiratory support, and antivenom administration are the mainstays of treatment. Scorpion antivenom appeared to be effective in a small randomized control trial in children with neurotoxicity (Boyer et al., 2009). Generalization of this result is uncertain owing to geographical differences in the venom and in the quality and safety of the antivenom.

Tick Paralysis

Tick paralysis is caused by tick bites, most notably by Dermacentor and Ixodes species. The majority of cases are reported in Australia and North America. Most cases in North America appear in the Pacific Northwest, Rocky Mountains, and southeastern United States. Paralysis is due to inoculation of a toxin in the saliva of the tick. Continuing attachment of the tick for 1 or more days is necessary before the appearance of clinical symptoms. In most cases, the tick is eventually found in the scalp and neck area. Other areas where a tick may go undetected for days are the ear and nose canals and the genital areas. Children are the most likely victims. Girls outnumber boys, presumably because a tick is harder to find in longer hair.

The clinical presentation of tick paralysis mimics Guillain-Barré syndrome. Weakness typically starts in the legs and spreads to the arms and eventually to the bulbar and respiratory muscles. Instability of gait or limb incoordination may be the first sign in young children. Examination shows limb weakness (most prominent in the legs), hypoactive or unobtainable stretch reflexes, and normal or mildly impaired sensation. Respiratory muscle weakness, if present, manifests as rapid shallow breathing and diminished forced vital capacity. There are reports of atypical presentations such as cranial neuropathy, encephalopathy, autonomic dysfunction, and brachial plexopathy.

Electrodiagnostic findings are likely to be nonspecific during the acute phase of the disease, although only limited data are available. One study reported low-amplitude compound muscle action potentials with normal conduction velocities and sensory nerve conduction studies (Vedanarayanan et al., 2002). There is a case report of unilateral conduction block at the lower trunk of the brachial plexus from a tick bite in the ipsilateral axilla (Krishnan et al., 2009). Repetitive nerve stimulation studies are usually normal. The key to diagnosis is to find the culpable tick by careful inspection of the patient’s skin. The tick can then be removed, leading to rapid and dramatic clinical improvement usually over just a few hours.

Jimson Weed

Jimson weed (Datura stramonium), first grown by early settlers in Jamestown from seeds brought from England, was initially used to treat asthma. It is now found throughout the United States. Intoxication is not uncommon, with the majority occurring among young people who intentionally ingest the plant for its psychic effects (Forrester, 2006). The chief active ingredient is the alkaloid, hyoscyamine, with lesser amounts of atropine and scopolamine. Symptoms of anticholinergic toxicity appear within 30 to 60 minutes after ingestion and often continue for 24 to 48 hours because of delayed gastric motility. The clinical picture can include hyperthermia, delirium, hallucinations, seizures, and coma. Autonomic disturbances such as mydriasis, cycloplegia, tachycardia, dry mouth, and urinary retention are often present. Treatment includes gastrointestinal decontamination with or without the induction of emesis. Supportive measures and symptom relief should be provided, but physostigmine should be reserved for severe or life-threatening intoxications.

Poison Hemlock

The dangers of ingesting poison hemlock (Conium maculata) have been known since ancient times. This was reportedly the method used to execute Socrates. The Old Testament describes rhabdomyolysis in Israelites who ate quail fed on hemlock (coturnism). The highest concentration of toxin is in the root of this plant that may be mistaken for wild carrots. Alkaloid toxins structurally similar to nicotine initially cause CNS activation and general autonomic stimulation. In severe cases, a depressant phase may then ensue, presumably secondary to acetylcholine receptor depolarization blockade. Death is usually secondary to respiratory paralysis.

Water Hemlock

Water hemlock (Cicuta maculata) is a highly toxic plant found primarily in wet, swampy areas and is sometimes mistakenly ingested as wild parsnips or artichokes. Although related to poison hemlock, its clinical toxidrome is quite different. The principle toxin, the long-chain aliphatic alcohol, cicutoxin, is a highly potent noncompetitive GABA receptor antagonist (Uwai et al., 2000). Symptoms consist of initial gastrointestinal effects (abdominal pain, salivation, and diarrhea) followed by generalized convulsions, obtundation, and coma. Mortality is secondary to refractory status epilepticus; seizures are treated with standard protocols.

Peyote

Peyote (Lophophora williamsii) is a small cactus native to the southwestern United States and Mexico, but it can be cultivated anywhere. The principal agent is mescaline, which has actions similar to those of the hallucinogenic indoles. A peyote button, the top portion of the cactus, contains about 45 mg of mescaline; approximately six to nine buttons are sufficient to be hallucinogenic. Dizziness, drowsiness, ataxia, paresthesias, sympathomimetic symptoms, nausea, and vomiting are frequent accompanying clinical features. Ingestions are rarely life threatening.

Morning Glory

The active agents in morning glory (Ipomoea tricolor) seeds are various amides of lysergic acid. The seeds are consumed for purposes of drug abuse. The neuropsychological effects are similar to those of LSD and consist of hallucinations, anxiety, mood changes, depersonalization, and drowsiness. Acute clinical effects may also include mydriasis, nausea, vomiting, and diarrhea.

Medicinal Herbs

Treatment of illness with herbal remedies, either purchased over the counter at health food stores or procured from practitioners of traditional medicine, may lead to undesired toxicity. The labels, if present, may not fully represent the myriad of compounds contained within. Potentially harmful ingredients may be included as contaminants or intentionally added to increase a desired effect. Contamination of products with Atropa belladonna (deadly nightshade), Datura spp., and Mandragora officinarum (mandrake) have been reported. Common herbal preparations such as kava-kava (Piper methysticum) and St. John’s wort (Hypericum perforatum) have neurotoxic potential, particularly if combined with other herbal or standard pharmaceuticals. Podophyllum peltatum (mayapple), widely used in Chinese herbal medicine, is potentially neurotoxic.

Excitatory Amino Acids

Various Lathyrus species, including Lathyrus sativus (chickling pea), Lathrus clymenum (Spanish vetch), and Lathrus cicera (flat-podded pea), are responsible for lathyrism. These hardy plants are an important part of the diet of people in the Indian subcontinent, Africa, China, and some parts of Europe. Epidemics of lathyrism often coincide with periods of famine or war, probably a result of excessive dietary dependency on these legumes. The putative toxin is β-N-oxalylamino-l-alanine (l-BOAA), an amino acid with potent agonist activity at the (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subclass of glutamate receptors. l-BOAA is capable of inducing lathyrism in several animal models. Clinically affected patients present with subacute or insidious onset of upper motor neuron signs and gait instability. Muscle aching and paresthesias may be present, but the sensory examination is largely normal. Cognition and cerebellar functions are spared. Partial recovery after discontinuation of Lathyrus intake is possible, but interestingly, there are reports of deterioration without further exposure many years later.

Another excitatory amino acid, β-methylamino-l-alanine (BMAA), is found in cycad seeds, a dietary staple of the Chamorro people of Guam. When given in sufficient quantity, BMAA can induce neurotoxicity in primates. An unusually high incidence of amyotrophic lateral sclerosis, parkinsonism, and dementia was observed in the Chamorros around the second World War, and it has been postulated that BMAA may play an etiological role (Bradley and Mash, 2009). A causal relationship in humans, however, is difficult to prove.

Mushroom Poisoning

Of the more than 5000 varieties of mushrooms, approximately 100 are known to be toxic to humans. Accidental poisoning is common because poisonous mushrooms often closely resemble edible varieties. Aside from accidental ingestion, mushrooms such as Psilocybe spp., Panaeolus, Amanita muscaria, and Amanita pantherina are popular among drug users for their psychoactive effects. Many are used in tribal ceremonies as an intoxicant. Full description of the poisonous mushrooms is beyond the scope of this chapter. The common mushrooms associated with neurological morbidity are listed in Table 58.3.

Supportive care and decontamination are the mainstays of treatment. This can be further supplemented by specific treatments such as infusion of pyridoxine (gyromitrin poisoning), atropine (muscarine poisoning), or physostigmine (ibotenic acid and muscimol poisoning) as needed.

Ciguatera Fish Poisoning

The ciguatera toxins are produced by algae that thrive in the tropical or subtropical coral reef ecosystem, mainly in the Indo-Pacific and the Caribbean waters between latitudes 35° north and 35° south. The algae are consumed by small herbivorous fish that in turn are eaten by carnivorous ones. As a result, larger and older fish such as barracuda, eel, sea bass, grouper, red snapper, and amberjack are likely to be more toxic, although practically any reef fish eaten in significant quantity can cause ciguatera. Outbreaks can also occur in residents of temperate areas after a return from travel or from consumption of imported fish. The prevalence of ciguatera ranges from 0.1% in residents of large continents to 50% or more in those living in South Pacific and Caribbean islands (Dickey and Plakas, 2010).

A number of toxins are responsible for ciguatera, including ciguatoxins and maitotoxin. Ciguatoxins are a group of lipid-soluble molecules that act on tetrodotoxin-sensitive voltage-gated Na⁺ channels in nerve and muscle, leading to increased Na⁺ permeability at rest and membrane depolarization. Maitotoxin is the most potent nonproteinaceous toxin known. It is a water-soluble compound that increases Ca²⁺ influx through voltage-independent Na⁺ channels. Gambierol and palytoxin have also been implicated in ciguatera poisoning.

Symptoms are typically dose dependent, with more severe poisonings occurring after consumption of the toxin-rich head, liver, and viscera of contaminated fish. Abdominal pain, nausea, vomiting, and diarrhea first appear within hours of ingestion. Bradycardia and hypotension may accompany the initial acute symptoms. Neurological symptoms then follow (Lewis, 2006). Patients develop centrifugal spread of paresthesias, involving the oral cavity, pharynx, limbs, trunk, and most disagreeably, the genitalia and perineum. Particularly characteristic is a paradoxical temperature reversal. Cold is perceived as burning, tingling, or unbearably hot. Less frequently, warm is perceived as cold. Headache, weakness, fatigue, arthralgia, myalgia, metallic taste, and pruritus are common. Symptoms may be worsened by alcohol consumption, exercise, sexual intercourse, or diets. Some patients are referred to psychiatrists by clinicians unfamiliar with the disease.

Cold allodynia in the distal limbs is a common finding on neurological examination (Schnorf et al., 2002). Some patients have findings of a mild sensory neuropathy. Weakness is generally not present, though rare cases of polymyositis have been reported. A case of transient brain MRI abnormality has been reported (Liang et al., 2009). Most neurological symptoms remit in approximately 1 week, although some degree of paresthesias, asthenia, weakness, and headache may persist for months to years. Lipid storage and slow release of toxin may underlie the prolonged nature of some symptoms.

Diagnosis is based on history of ingestion and the characteristic gastrointestinal, cardiovascular, and neurological disturbances. Clustering of cases in people who consumed the same fish helps with the diagnosis, though there is variation in individual susceptibility. An assay for ciguatoxins in fish is commercially available. Nerve conduction studies may show slowing of both sensory and motor conduction velocities, with prolongation of the absolute refractory, relative refractory, and supernormal periods. These findings are consistent with prolonged opening of Na⁺ channels in the axonal cell membranes.

Gastric lavage may be beneficial if the patient presents soon after ingestion. Intravenous mannitol (20%; 1 g/kg at 500 mL/h) has been used for treatment of acute ciguatera poisoning. The mechanism of action is postulated to be reduction of edema in Schwann cells. The efficacy of mannitol is supported only by uncontrolled case series that report dramatic neurological improvement, especially if mannitol is given soon after symptom onset. One small controlled trial in 50 patients found no difference in outcome between mannitol and saline placebo (Schnorf et al., 2002), although many of the patients were treated over 24 hours after symptom onset. Supportive care during acute disease may include fluid replacement, control of bradycardia, and symptomatic treatment of anxiety, headache, and pain. Calcium gluconate, anticonvulsants, and corticosteroids have been tried with varying results. The chronic symptoms of ciguatera poisoning are difficult to treat. Gabapentin, pregabalin, amitriptyline, or other tricyclic antidepressants may provide partial relief of neuropathic pain.

Puffer Fish Poisoning

Tetrodotoxin (TTX) is the causative agent in puffer fish poisoning. Puffer fish (family Tetraodontidae) have a worldwide distribution in both fresh and salt waters but are most commonly found in Japan and China. More than 100 species are identified, known variously as puffer fish, tambores, porcupine fish, jugfish, and blowfish, among other names. Other sources of TTX include the ocean sunfish, toadfish, parrotfish, Australian blue-ringed octopus, gastropod mollusk, horseshoe crab (eggs), atelopid frogs (skin), newts (genus Taricha), and some salamanders. The source of puffer fish TTX is thought to be marine bacteria, possibly Vibrio, that colonize the fish and allow for TTX to be sequestered. Concentrations are especially high in the skin, liver, roe, and gonads and relatively low in the muscles. Fugu refers to a preparation of puffer fish in Japan that is considered a delicacy. Specially trained and certified fugu chefs fillet the fish in such a way to avoid contamination by the deadly viscera. Toxicity is seasonal, and puffer fish is served only from October to March. Despite these precautions, fugu poisoning accounts for approximately half of the fatal food poisonings in Japan, with up to 50 deaths each year.

Tetrodotoxin is a heat-stable, water-soluble small molecule that selectively blocks voltage-gated Na⁺ channels in excitable membranes. It interferes with the inward (excitatory) flow of Na⁺ current that occurs during an action potential, blocks impulse conduction in somatic and autonomic nerve fibers, reduces the excitability of skeletal and cardiac muscles, and has profound effects on vasomotor tone and central mechanisms involved in respiration. A dose of 1 to 2 mg of purified TTX can be lethal. Toxicity has been documented with the consumption of as little as 1.4 ounces of fugu.

Lip, tongue, and distal limb paresthesias appear within minutes to about 2 hours of ingestion. Nausea, vomiting, diarrhea, and abdominal pain are common. Perioral paresthesias and progressive ascending weakness are apparent in moderately severe cases. Dysphonia, dysphagia, hypoventilation, bradycardia, and hypotension develop in severe intoxications. Coma and seizures may be seen. Fatality rates are high in severely affected individuals and due to respiratory insufficiency, cardiac dysfunction, and hypotension (Chowdhury et al., 2007). Treatment is supportive. Gastric lavage and charcoal are indicated if presentation is early. Neostigmine has been used with anecdotal success. Patients who survive the acute period of intoxication (approximately the first 24 hours) often recover without neurological sequelae.

Liquid chromatography also can detect TTX in serum or urine. Electrophysiological studies may test nerve excitability and show characteristic elevation in threshold and slow conduction in TTX poisoning (Kiernan et al., 2005).

Shellfish Poisoning

Three neurological syndromes result from consumption of shellfish contaminated by toxins: paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), and amnestic shellfish poisoning (ASP) (James et al., 2010). All of them are primarily associated with ingestion of bivalve mollusks (clams, mussels, scallops, oysters), filter feeders that can accumulate toxic microalgae. Rarely, poisoning is seen after consumption of other seafood such as predator crabs that may have eaten contaminated shellfish. Outbreaks are more frequent during the summer months, especially during periods of red tides, but they may occur in any month and in the absence of red tides. Shellfish may remain toxic for several weeks after the bloom subsides.