Effects of Toxins and Physical Agents on the Nervous System

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, but it has been related to an inhibitory effect on presynaptic function ( ), by damage to the nerve terminal involving membrane fusion mechanisms and tubulovesicular alterations ( ), and to abnormalities of kinesin-based fast axonal transport. Axonal swellings due to accumulations of neurofilaments relate to impaired retrograde axonal transport.

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. 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 but recovery may occur if further exposure is prevented. 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 ( ).

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 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. Intra-axonal accumulation of neurofilaments occurs multifocally before axonal degeneration in animals exposed to this compound. Similar changes may also occur 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 300–400 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 ( ). Neuroimaging may reveal cortical—especially frontal—atrophy, as well as lesions in the globus pallidus and putamen. Computed tomography (CT) angiography and perfusion studies have revealed decreased cerebral blood flow in total brain parenchyma and basal ganglia, decreased cerebral blood volume in the basal ganglia, and a prolonged mean transit time in the total brain parenchyma and the territories of the internal carotid artery, basal ganglia, and occipital lobe. Such findings have been held to support the presence of a microangiopathy ( ).

A clinical or subclinical polyneuropathy develops after exposure to levels of 100–150 ppm for several months or to lesser levels for longer periods and is characterized histologically by axonal loss, focal axonal swellings, and neurofilamentary accumulations. Clinically there is stocking-glove impairment of all sensory modalities together with distal weakness and absent ankle reflexes. The concurrence of neuropathy and parkinsonism should suggest the possibility of carbon disulfide intoxication.

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, 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. New therapies aimed at the inflammatory effects and oxidative stress induced by carbon monoxide poisoning or helping remove carbon monoxide from the body, as with porphyrin complexes or modified globin proteins, are under study ( ).

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 periventricular white matter, globus pallidus, and elsewhere. There may be diffuse brain atrophy.

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 by-product, 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, with seizures and disturbances of consciousness. Respiration may be impaired. Treatment is supportive. 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 the 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 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. 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. Clinical and electrophysiological recovery of the peripheral neuropathy may take several years and may not be complete when involvement is severe ( ). As the polyneuropathy resolves, 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, but its use has been banned in many countries because of its ozone-depleting properties. 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. The electroencephalogram (EEG) may show frontally predominant slow waves or polyspike-wave complexes, while magnetic resonance imaging (MRI) reveals involvement of the dentate nucleus, brainstem, and splenium of the corpus callosum ( ).

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.

The basis of the neurotoxicity is uncertain but methyl phosphates formed in cells may contribute to its neuron-specific toxicity via cholinesterase inhibition ( ). Treatment is symptomatic and supportive. Hemodialysis may help in removing bromide from the blood. Chelating agents are of uncertain utility.

Organochlorine Pesticides

The organochlorine pesticides include aldrin, dieldrin, and lindane, as well as the once-popular insecticide dichlorodiphenyl-trichloroethane, 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, slurred speech, and opsoclonus. Minor cognitive changes, memory loss, and benign intracranial hypertension may occur. The signs may reverse over months or longer. The pathophysiology of the disorder has not been established.

The risk of developing Parkinson disease (PD) is reportedly increased by exposure to organochlorine insecticides but the involved mechanisms are unclear ( ).

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. Cardiac and respiratory function must be supported and seizures controlled pharmacologically. 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 ( ).

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 2–3 weeks after acute exposure even in the absence of cholinergic toxicity. In the past, contamination of illicit alcohol with tri-ortho cresyl phosphate (“Jake”) led to large numbers of such cases. There is no evidence that peripheral nerve dysfunction follows prolonged low-level exposure to organophosphates ( ). 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 tri-ortho cresyl 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 ( ). 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, as is the role of NTE in axonal degeneration. No specific treatment exists to prevent the occurrence of neuropathy following exposure, but the 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 2–3 weeks ( ). 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 ( ). Whether these complaints relate to mild organophosphate toxicity is uncertain. Similarly uncertain is whether chronic effects (persisting behavioral and neurological dysfunction) may occur in the absence of acute toxicity or follow acute exposure to organophosphates as a result of the respiratory and cardiac complications that sometimes occur ( ). A meta-analysis of well-designed studies, however, did find an association between low-level exposure and impaired neurobehavioral function ( ). 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. Their neurotoxicity in mammals may also relate to their effect on sodium channels but voltage-gated calcium and chloride channels have been implicated as alternative or secondary sites of action for certain pyrethroids ( ). 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. Local application of a cool cloth or of a cream containing vitamin E may help relieve the sensory complaints. Treatment is otherwise purely supportive. Coma and convulsions may result if substantial amounts of pyrethroids are ingested, however, necessitating urgent hospitalization.

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 an irreversible disturbance of cognitive function that related to long-term exposure to mixtures of organic solvents. Many studies of exposed workers since then have documented the occurrence of cognitive symptoms (impaired memory, difficulty in concentration, poor attention span), affective complaints, and changes in personality, with impaired motivation and ease of fatigue. The symptoms are generally nonspecific in nature. The neurological examination is typically normal or reveals minor nonspecific abnormalities, as do neuroimaging and electrophysiological tests. However, other 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, and solvent mixtures vary in different occupational settings, complicating the interpretation of published studies. Because of these factors and the nonspecific character of symptoms, the existence of so-called painter’s (or chronic solvent) encephalopathy in those exposed to low levels of organic solvents for a prolonged period has been questioned. Nevertheless, the World Health Organization has published diagnostic criteria for this syndrome, later refined by a commission of the European Union and by others ( ), and it is accepted as an occupational disease by the International Labour Organization.

Certain neurodegenerative diseases, including Parkinson and Alzheimer diseases, have been related to occupational exposure to organic solvents in some but not other studies. Difficulties in interpreting individual studies relate to methodological factors such as the manner in which exposure is estimated, varying diagnostic criteria, and the presence of confounding risk factors. Certain neurodegenerative disorders are not homogeneous but consist of a heterogeneous group of conditions with a similar clinical phenotype, complicating still further the interpretation of different epidemiological studies concerning their possible association with solvent exposure.

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 . 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 in glue-sniffers and 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 ( ). 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. The cerebellar dysfunction, which may be permanent, may lead to dysarthria, action tremor, gait ataxia, and occasionally downbeat nystagmus ( ). 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 ( ) or an encephalopathy, but the 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. Upon discontinuation of exposure, the clinical deficit generally resolves, sometimes over 1–2 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 depression and 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. A role for aluminum in the pathogenesis of Alzheimer disease is disputed ( ).