ENVIRONMENTAL TOXINS AND DISORDERS OF THE NERVOUS SYSTEM

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CHAPTER 111 ENVIRONMENTAL TOXINS AND DISORDERS OF THE NERVOUS SYSTEM

Jean Lud Cadet, Karen I. Bolla

Individual cases of lead poisoning were reported as early as 200 B.C. Nevertheless, the need for the evaluation and treatment of the medical effects caused by exposure to chemicals was not recognized until the 20th century. Many of the offending chemicals affect both the central nervous system (CNS) and peripheral nervous system (PNS), and high-level exposure often results in delirium, seizures, or coma.1–4 Although residual effects can include mood and cognitive disorders, they are often not attributed to exposure to these chemicals.

Because the diagnosis of toxin-mediated neurological deficits is one of exclusion, it is important to substantiate a history of significant exposure. Neurological examination and neuroimaging techniques are not very helpful in making a specific diagnosis of toxic encephalopathy but might rule out other causes for the patient’s clinical presentation.5,6 Neuropsychological assessment is essential in the evaluation of these patients. However, decrements in performance on these tests may be erroneously interpreted by clinicians who are not versed in neurobehavioral toxicology. In addition, evaluation of toxic effects on the brain must be considered in the context of each patient’s personality because psychiatric changes can be primary or secondary to chemical exposure.

The clinical manifestations that result from exposure to distinct classes of agents (e.g., metals, organic solvents) are described in this chapter. However, a patient exposed to a certain chemical might not necessarily suffer from all of the symptoms associated with that substance. As with any diagnostic process, the differential diagnosis of neurotoxic exposure, neurological disorders, psychiatric diathesis, or malingering is based on the combined evidence derived from occupational and medical histories; from neurological, psychiatric, and neuropsychological examination findings; and from results of appropriate ancillary studies.

METAL INTOXICATION

Arsenic

Cause and Pathogenesis

The National Institute for Occupational Safety and Health estimates that about 900,000 workers have potential daily exposure to arsenic. Arsenic poisoning occurs mainly via the oral route. The metal is stored in the liver, kidneys, intestines, spleen, lymph nodes, and bones. After a few days, arsenic is also deposited in hair, where it can stay for many years. Arsenic is excreted slowly in the urine and in the feces, and it takes as long as 2 weeks for a single large dose of the toxin to be excreted. Arsenic affects oxidative metabolism and prevents the transformation of thiamine into acetyl–coenzyme A, rendering patients thiamine deficient. Organic arsenicals release the poison slowly and are therefore less likely to produce acute symptoms than is the elemental metal. Brains of patients who die of arsenic encephalopathy exhibit congestion, hemorrhagic lesions throughout the white matter, and areas of necrosis. Peripheral nerves exhibit decreased numbers of myelinated fibers and degenerative changes, including swelling, granularity, and a reduction in the number of axons.

Clinical Features and Diagnosis

Acute toxicity is characterized by fever, headaches, anxiety, and vertigo. Seizures are common. Neurological examination reveals nystagmus, increased tendon reflexes, neck stiffness, and sometimes paralysis.7 Mees’ lines (white lines in the nails) usually appear 2 to 3 weeks after acute exposure to arsenic. Encephalopathy with marked excitement followed by lethargy and signs of acute peripheral neuropathy can develop within a few hours. In patients with fatal acute poisoning, coma and death ensue within a few days. Patients with subacute or chronic arsenic encephalitis can suffer from relentless headaches, physical and mental fatigue, vertigo, restlessness, and focal pareses. Spinal cord involvement is associated with weakness, sphincter disturbances, and motor and sensory impairments. Optic neuritis, manifested by cloudy vision and visual field defects, can also occur subacutely or be delayed for years. In general, a mixed sensory and motor neuropathy develops within 7 to 10 days after ingestion of toxic amounts of arsenic, and patients often complain of severe burning sensation in the soles of the feet. Long-standing cognitive changes have been reported.

Arsenic intoxication should be considered in a patient with severe abdominal pain, dermatitis, painful peripheral neuropathy, and seizures. A history of arsenic exposure and toxic arsenic levels in hair, urine, or nails confirm the diagnosis. Arsenic is poorly tolerated in the presence of alcohol. Therefore, patients with alcohol-related disease have a greater risk of developing arsenic neuropathy. Although hair and nail samples may be useful, measurement of urinary arsenic levels is the test of choice. A level of arsenic in urine (24-hour measurement) greater than 50 μg/g creatinine is considered elevated. Because urinary level may be high after ingestion of seafood, a dietary history should be obtained. More reliable values can be obtained by measuring urinary inorganic arsenic metabolites: monomethylarsonic acid and dimethylarsinic acid.

Management

In patients with acute oral ingestion of arsenic, gastric lavage with electrolyte replacement is recommended. Excretion of absorbed arsenic can be enhanced by chelation with dimercaprol (British antilewisite), D-penicillamine, or dimercaptosuccinic acid. Chelating agents can reverse or prevent the attachment of heavy metals to various essential body chemicals (Table 111-1). Although chelating agents may alleviate the acute symptoms, they might not improve chronic symptoms such as peripheral neuropathy or encephalopathy. Dimercaprol treatment is not considered effective after the appearance of neuropathy. Intravenous fluids for dehydration and morphine for abdominal pain are also recommended. Prognosis with severe arsenic poisoning is poor, with a mortality rate of 50% to 75%, usually within the first 48 hours.

TABLE 111-1 Overview of Central and Peripheral Complications of Heavy Metal Exposure

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Lead

Inorganic Lead

Cause and Pathogenesis

Lead poisoning has a very long history. Although it was identified as early as 200 B.C., it remains a common occurrence even today. More than 1 million workers in more than 100 occupations are exposed to lead. In lead-related industries, workers not only inhale lead dust and lead fumes but may eat, drink, and smoke in or near contaminated areas, increasing the probability of lead ingestion. Family members can also be exposed to lead dust by workers who do not wash thoroughly before returning to their homes. Other sources of lead exposure include surface dust and oils. The de-leading of gasoline has significantly decreased that source of lead exposure. The current major sources of lead in the environment are lead paint in homes built before 1950 and lead used in plumbing, which was restricted in 1986. In 1991, median blood levels of lead in adults in the United States were estimated at 6 μg/dL.8

Children 5 years old or younger are especially vulnerable to the toxic effects of lead. Elevated lead levels in children are caused by pica (compulsive eating of nonfood items) or by the mouthing of items contaminated with lead from paint dust. Children also absorb and retain more lead than do adults. For example, approximately 10% of ingested lead is absorbed by adults whereas 40% to 50% of ingested lead is absorbed by children. Young children with iron deficiency have increased lead absorption. The risk of in utero exposure is high because lead readily crosses the placenta.9

After inorganic lead is absorbed, it binds to erythrocytes and is excreted unchanged in humans. The rate of absorption depends on age and nutritional status. For example, iron and calcium deficiencies cause significant increases in lead absorption. Once absorbed, lead is also distributed to soft tissues (kidney, bone marrow, liver, and brain) and mineralized tissues (bones and teeth); 95% of the total body burden of lead is found in teeth and bones. Pregnancy, menopause, and chronic diseases are associated with mobilization of lead from bones and increased levels in blood. The turnover rate of lead in cortical and trabecular bone is slow, its half-life ranging from years to decades. Lead excretion is through the kidneys or the biliary system into the gastrointestinal tract. Although a person’s blood levels may begin to return to normal after a single exposure, the total body burden of lead may still be elevated. For lead poisoning to occur, significant acute exposures are not necessary because the body accumulates lead over time and releases it slowly.

Lead encephalopathy has been associated with softening and flattening of convolutions in the brain. On occasion, there are punctate hemorrhages, dilation of the vessels, and dilation of the ventricular system, especially in the frontal lobes. Histologically, extensive involvement of the ganglion cells is evident. The developing brain appears to be vulnerable to levels of lead that were once thought to cause no harmful effects.

Clinical Features and Diagnosis

In children, exposure to toxic doses of lead can cause listlessness, drowsiness with clumsiness, and ataxia. Very high levels can cause convulsions, respiratory arrest, and coma. A diagnosis of lead toxicity should be considered in a child who shows changes in mental status, gait disorder, or seizures. Chronic low-level exposure in children can result in attention and learning disabilities or in cognitive decline. Children chronically exposed to lead have been reported to show a drop in mean verbal IQ score of 4.5 points. Primary school children with high lead levels in teeth, but without a history of lead exposure, had larger deficits in speech and language processing, psychometric intelligence scores, and classroom performance than did children with lower levels of lead. Children with high lead levels in their teeth are sevenfold more likely not to graduate from high school. They have a greater prevalence of poor eye-hand coordination, reading disabilities, poor fine motor skills, and poor reaction time.9–11

At present, acute lead encephalopathy resulting from industrial exposure is not common. Signs and symptoms generally include delirium, combative irrational behavior, sleep disturbances, decreased libido, increased distractibility, increased irritability, and mental status changes marked by psychomotor slowing, memory dysfunction, and seizures.12

Involvement of both sensory and motor peripheral nerves can be seen in adults with chronic lead intoxication. Sensory complaints include paresthesias and pain. Motor signs include fasciculations, atrophy, and weakness. Severe cases can manifest with wristdrop and footdrop. Extensive bilateral neuropathy involving the fingers, the hands, and the biceps, triceps, and deltoid muscles has also been reported. In individuals with predominantly motor findings, nerve conduction velocity may not be altered even after significant occupational exposure, but mild slowing in nerve conduction velocity has been reported. Anemia, abnormal kidney function, hypertension, and gout can also occur. Miscarriage and stillbirths are common among women who work with lead. Men may suffer from reduced sperm motility and/or counts.

Patients with lead intoxication show increased levels of whole blood lead, free erythrocyte protoporphyrins (FEP), and urinary coproporphyrins. Blood lead levels reflect recent exposure to lead, whereas free erythrocyte protoporphyrin levels reflect chronic exposure. Free erythrocyte protoporphyrin levels begin to rise in adults once blood lead levels reach 30 to 40 μg/dL. These levels may remain elevated for several months even after exposure has ceased. The body burden of lead is measured through diagnostic chelation. Urinary lead excretion is measured after infusion of 1 g of calcium ethylenediamine tetra-acetic acid (EDTA). More than 600 g of lead excreted in the urine over a period of 72 hours is considered an elevated level. A noninvasive method of measuring body lead burden in bone is x-ray fluorescence. Computed tomography and magnetic resonance imaging are not useful in making a diagnosis of lead exposure. In some studies, neuropsychological evaluation of workers with lead blood levels below 30 μg/dL has revealed decrements in visuomotor integration, psychomotor speed, short-term visual and verbal memory, and problem-solving skills.

Management

Immediate removal from the sources of exposure and administration of chelating agents are the main lines of defense against lead intoxication. Intravenous infusion of calcium disodium–EDTA, oral administration of succimer (dimercaptosuccinic acid), and chelation with oral D-penicillamine can be used (up to 2 g/day). Multiple chelation cycles might be necessary, and 24 hours of rest between cycles is recommended. Adequate hydration should be maintained because chelating agents can cause renal toxicity and because they can increase circulating levels of lead as a result of their ability to unbind lead from bones. Dimercaptosuccinic acid is reportedly safer than EDTA and D-penicillamine. Common side effects include hypertension and renal problems. Chelation therapy is recommended for children with blood lead levels above 45 μg/dL. Although chelation therapy may reduce symptoms of acute lead poisoning, it might not affect neurological and renal sequelae of acute or chronic lead intoxication. Prevention of lead toxicity in children includes removal of young children from contaminated environments such as houses with peeling paint. Individuals who are occupationally exposed to lead should use mandatory personal protective equipment. Complete recovery of higher cognitive functions may not occur in children with early childhood exposure to lead.

Organic Lead

Organic lead (tetraethyl lead) is used as an antiknock agent in gasoline and jet fuels. Tetraethyl lead is absorbed rapidly by the skin, the lungs, and the gastrointestinal tract. It is converted to triethyl lead, which might be responsible for its toxicity. Because of its highly lipophilic nature, tetraethyl lead passes the blood-brain barrier readily and accumulates in the limbic forebrain, frontal cortex, and hippocampus. Symptoms of acute high-level exposure include delirium, nightmares, irritability, and hallucinations. Chronic effects of tetraethyl lead include poor neurobehavioral scores in tests of manual dexterity, executive ability, and verbal memory. Treatment is mainly supportive.

Manganese

Cause and Pathogenesis

Manganese is found in mining dusts and as an antiknock additive in gasoline.

Hospitalized patients receiving total parenteral nutrition therapy that includes manganese can develop distinctive T1-weighted hyperintense signals in the region of the globus pallidus on magnetic resonance images. Although these changes tend to disappear after cessation of total parenteral nutrition, their presence is correlated with high blood manganese levels and with clinical signs of parkinsonism.

Inhalation is the primary source of manganese exposure. Neuropathologically, affected cells, including neurons in the pallidus, show histopathological changes. Neuronal death has been reported in the substantia nigra, the frontal and parietal cortices, cerebellum, and the hypothalamus.

Clinical Features and Diagnosis

The onset of manganese toxicity depends on the intensity of exposure and on individual susceptibility. Symptoms may appear as soon as 1 or 2 months or as late as 20 years after exposure. The earliest symptoms of manganism include anorexia, apathy, hypersomnolence, and headaches. Neurobehavioral changes include irritability, emotional lability, and, after continued exposure, psychosis and speech abnormalities that sometimes lead to mutism. Other signs and symptoms include masklike facies, bradykinesia, micrographia, retropulsion and propulsion, fine or coarse tremor of the hands, and gross rhythmical movements of the trunk and head.13

A diagnosis of manganism requires a history of exposure to the toxin. Forty three percent of manganese body burden is in the bone. Excretion is biphasic, and consists of a rapid phase with a half-life of 4 days and a slower phase with a half-life of about a month. Individual manganese levels in blood and urine might not necessarily be correlated with the degree of current or past exposure.

Management and Prognosis

The patient must be removed from the source of exposure. Manganese-induced movement disorders may or may not respond to levodopa. Patients may respond to levodopa doses of more than 3 g/day, with the best effects on rigidity. Chelation therapy may be useful. The neurological syndrome is usually progressive. In the very early stages, signs and symptoms may improve over a period of months after removal of the patient from the source of exposure, but the improvement is not necessarily correlated with a reduction in manganese concentration.

Mercury

Inorganic Mercury

Cause and Pathogenesis

Inorganic mercury compounds have been used as antiseptics, disinfectants, and purgatives. Mercury was also used formerly in the form of cinnabar, a red pigment used for painting and coloring. Metallic mercury becomes volatile at room temperature and enters the body via inhalation. Mercury is a pollutant in air and water. Between 1953 and 1956, an epidemic of methyl mercury poisoning occurred in Japan when a large number of villagers developed chronic mercurialism (Minamata disease) from ingesting fish contaminated with methyl mercury from industrial waste. Individual susceptibility to the toxic effects of mercury varies, depending on the form of mercury involved, hygiene, diet (including vitamin deficiency), and intrinsic differences in mercury metabolism.

Elemental mercury in the plasma is bound to hemoglobin and proteins and is taken up into the brain. Mercury has been detected in the urine as long as 6 years after initial exposure. Although the kidneys are the organs most affected by mercury, the effect on the CNS is substantial, and the highest concentrations are in the brainstem, cerebellum, cerebral cortex, and the hippocampus. Inorganic mercury alters cell membranes, but postmortem studies have revealed no or only slight neuronal damage in the presence of intracellular mercury.

Clinical Features and Diagnosis

Acute mercury poisoning can be caused by accidental ingestion of an antiseptic found in a medicine cabinet. Affected patients suffer from irritable, hyperactive, psychotic behaviors. Patients might develop acute weakness in the lower extremities. Chronic mercury toxicity is also associated with progressive personality changes, together with tremor and weakness of the limbs. Mercury-induced tremors, also known as “hatter’s shakes” or “Danbury shakes,” consist of fine tremors that occur at rest and are interrupted by myoclonic jerks. Patients might also develop gait and balance difficulties. Parkinsonism, dyskinetic movements, and seizures have been reported. Mercury poisoning may also be accompanied by peripheral polyneuropathy (sensorimotor axonopathy) that affects mainly the lower extremities. These are characterized by painful paresthesias and muscle atrophy. Blurred vision, narrowing of the visual fields, optic neuritis, optic atrophy, nystagmus, vertigo, and sensory ataxia have also been observed. Personality and cognitive changes might become manifest before the appearance of other neurological signs. “Mercurial neurasthenia,” which consists of extreme fatigue, hyperirritability, insomnia, pathological shyness, and depression, may develop weeks or months before the patient seeks treatment. In addition, violence and homicidal behaviors have been reported.

Acrodynia, as chronic mercury toxicity in children used to be called, is a syndrome characterized by painful neuropathy and autonomic changes. This syndrome includes redness and coldness of hands and feet, painful limbs, profuse sweating of the trunk, severe constipation, and weakness. Affected children may also suffer from personality and cognitive changes and from tremors similar to those found in adults.

Serum concentrations of mercury are not reliable indicators of inorganic or organic mercury toxicity because blood levels vary greatly between individuals. The threshold biological exposure indexes are 15 μg/L for blood and 35 μg/g of creatine for urine. Urinary excretion is not a good measure of toxicity because there is no correlation between symptoms and amount of mercury excreted in the urine. Because the signs of mercury intoxication mimic those of common neurological syndromes such as parkinsonism, the correct diagnosis depends on occupational history and documentation of mercury in the patient’s blood, urine, or hair.

Management and Prognosis

Removal of the patient from the sources of exposure and chelation with N-acetyl-D-penicillamine are recommended. Long-term computed tomographic follow-up of survivors of Minamata disease revealed decreased bilateral attenuation in the visual cortex and diffuse atrophy of the cerebellum, especially the vermis.13a

Organic Mercury

Cause and Pathogenesis

Intoxications can be caused by ingestion of fish containing methyl mercury, homemade bread prepared from seed treated with methyl mercury–containing fungicide, or meat from livestock fed grain treated with mercury-containing fungicides. Organic mercury is absorbed via the gastrointestinal tract and is slowly excreted through the kidneys; the half-life ranges from 40 to 105 days. Mercury readily crosses the placenta, and the blood concentrations in the fetus are equal to or greater than those in the maternal blood. Fetal methyl mercury poisoning can occur in asymptomatic mothers. Because methyl mercury can also be secreted in breast milk, mercury poisoning can also occur in breastfed children.

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