Yuen T. So, MD, PhD
Diseases of the nervous system are known for their diverse clinical manifestations. When the central nervous system is affected, symptoms may include headache, cognitive and psychiatric disturbances, visual changes, seizures, ataxia, tremors, rigidity, weakness, and sensory loss. In peripheral nervous system diseases, pain, weakness, paresthesias, and numbness are common, and in some instances, there may be additional autonomic disturbances.
The pattern of neurologic symptoms depends on the nature of the insult. For instance, excessive exposure to many industrial or environmental chemicals causes a generalized disorder of peripheral nerves, that is, peripheral neuropathy. This presents usually as a diffuse and symmetric clinical syndrome. In contrast, some occupations may predispose workers to physical injuries to peripheral nerves. Common examples are carpal tunnel syndrome from median nerve entrapment and lumbar radiculopathy from compression of the spinal roots. Single nerves or spinal roots are affected in these instances, leading to a localized pattern of neurologic symptoms and signs. Focal nerve injuries are discussed in Chapters 9 and 10 and are not further covered in this chapter.
GENERAL PRINCIPLES
Neurologic evaluation of patients largely depends on bedside history and physical examination, supplemented by traditional diagnostic tests such as computed tomography (CT) and magnetic resonance imaging (MRI) of the brain or spine, electroencephalography (EEG), nerve conduction study, electromyography (EMG), lumbar puncture, and neuropsychological testing.
With few exceptions, the pathophysiology of most neurotoxic injuries is not well understood. Animal models of toxin exposure provide at best a rough guide to human disease. Moreover, it is nearly impossible to study the effects of toxins under controlled conditions in humans. Much of our current knowledge is gained from clinical observations of intense exposures during accidents or chronic heavy occupational exposures. Extrapolation of these classic observations to other situations is problematic. For instance, for many compounds, there is considerable uncertainty concerning the exposure level and duration necessary to cause neurologic injury. It has been especially difficult to ascertain the sequelae of chronic low-level exposure, a situation particularly likely to be encountered by today’s physicians.
Despite our incomplete understanding in many of these diseases, several generalizations have been useful in the clinical approach to these disorders.
1. A dose-toxicity relationship exists in the majority of neurotoxic exposures. In general, neurologic symptoms appear only after a cumulative exposure reaches a threshold level. Individual susceptibility varies over a limited range, but idiosyncratic reactions seldom occur.
2. Exposure to toxins typically leads to a nonfocal or symmetric neurologic syndrome. Significant asymmetry such as weakness or sensory loss of one limb or one side of the body with complete sparing of the contralateral side should suggest an alternate cause.
3. There is usually a strong temporal relationship between exposure and the onset of symptoms. Immediate symptoms after acute exposure are often a consequence of the physiologic effects of the chemical (eg, the cholinergic effects of organophosphates). These symptoms subside quickly with elimination of the chemical from the body. Delayed or persistent neurologic deficits that occur after toxic exposures (eg, delayed neuropathy after organophosphate poisoning) generally are a result of pathologic changes in the nervous system. Recovery is still possible, but it tends to be slow and incomplete.
4. The nervous system has a limited capability to regenerate, but some recovery is possible after removal of the insulting agent. By contrast, worsening neurologic deficits more than a few months after cessation of exposure to a toxin generally argues against a direct causative role of the toxin.
5. Multiple neurologic syndromes are possible from a single toxin. Different neuron populations and different areas of the nervous system react differently to the neurotoxin. The intensity and duration of exposure, as well as physiologic variables such as the subject’s age and genetic susceptibility, influence the clinical manifestations. A well-known example is lead toxicity, which may lead to an acute confusional state, chronic mental slowing, or a peripheral neuropathy.
6. Few toxins present with a pathognomonic neurologic syndrome. Symptoms and signs may be mimicked by many psychiatric, metabolic, inflammatory, neoplastic, and degenerative diseases of the nervous system. It is therefore important to exclude other neurologic diseases with appropriate clinical examination and laboratory investigations.
A noteworthy caveat is the phenomenon of coasting—the continuing deterioration sometimes seen for up to a few weeks after discontinuation of toxic exposure. Coasting has been well documented in toxic neuropathies caused by pyridoxine (vitamin B6) abuse, n-hexane toxicity, and vincristine chemotherapy. The delay reflects the time necessary for the pathophysiologic steps to evolve to neuronal injury and death.
Another qualification is illustrated by a hypothesis used to explain the pathogenesis of chronic degenerative diseases such as Parkinson disease, amyotrophic lateral sclerosis, and Alzheimer dementia. It has been postulated that an environmental or toxic exposure may reduce the functional reserve of the brain. The patient, however, remains asymptomatic until aging or other biologic events further deplete the neuronal pool over many more years. Symptoms appear only when neuronal attrition reaches a threshold level. The hypothesis predicts a long latent period between toxic exposure and symptom manifestation. Although present evidence does not totally support an environmental cause, age-related neuronal attrition is an important concept in our understanding of neurodegenerative diseases. The prevalence and severity of these disorders increase with age. Attrition may explain the occasional observation of continuing deterioration for many years after cessation of a toxic exposure (eg, extrapyramidal dysfunction after manganese poisoning and worsening many years after mercury poisoning in the Minamata Bay epidemic).
APPROACH TO PATIENTS
A confident diagnosis of a neurotoxic disorder can be made only after the documentation of all the following: (1) a sufficiently intense or prolonged exposure to the toxin, (2) an appropriate neurologic syndrome based on knowledge about the putative toxin, (3) evolution of symptoms and signs over a compatible temporal course, and (4) exclusion of other neurologic disorders that may account for a similar syndrome.
A detailed history of the nature, duration, and intensity of the exposure is essential in every evaluation. What are the potential toxins? What is the mode of exposure? How long and how intense are the exposures? Are there other confounding factors such as alcoholism, psychosocial issues, and possibility of secondary gains? Chronic exposures are especially difficult to assess. Not only is it essential to assess the average intensity and total duration of exposure, but intermittent peak exposures also are important to quantify.
The toxicology history should be followed by a detailed characterization of the neurologic complaints. Patients frequently use descriptors such as weakness, dizziness, forgetfulness, pain, and numbness to refer to vastly different personal experience. Dizziness may mean vertigo from vestibular dysfunction, gait imbalance from sensory loss, or simply a nonspecific sense of ill feeling. Fatigue or asthenia may be referred to as weakness. Fatigue implies reduced endurance or a disinclination for physical activity rather than true weakness. Fatigue may be seen in association with depression, various systemic illnesses, and a wide range of neurologic diseases. Only weakness specifically implies motor system dysfunction. Each patient’s complaints therefore should not be accepted at face value. It is especially useful to inquire about the functional consequences of the neurologic deficits. Questioning about activities of daily living is particularly useful both to better understand the nature of the complaints and to provide a reasonably objective measure of severity.
Documentation of the temporal course of the disease is very important. Symptoms may appear acutely (minutes or days), subacutely (weeks or months), or chronically (years). Fluctuating symptoms may suggest recurrent exposures or unrelated superimposed factors. Recovery after discontinuation of exposure helps to implicate the exposure. By contrast, a continuing progression of deficits beyond the “coasting” period argues against an etiologic role of the exposure.
Central Nervous System
Symptoms and deficits depend on which groups of brain or spinal cord neurons are affected primarily (Table 27–1). A common syndrome is an encephalopathy from diffuse dysfunction of cortical or subcortical structures. Acutely, the encephalopathy may be associated with alteration in the level of consciousness. Chronically, the primary symptoms may be cognitive and psychiatric. Some toxins cause relatively selective injury to the vestibular system or the cerebellum, resulting in dysequilibrium, vertigo, and gait or limb ataxia. Basal ganglia involvement may lead to an extrapyramidal syndrome of bradykinesia, tremors, and rigidity. This may resemble idiopathic Parkinson disease for all practical purposes.
Table 27–1. Neurologic symptoms and signs.
Evaluation of cognitive complaints should include at least a mini–mental state examination. Referral to neuro-psychological testing may be needed in patients with prominent cognitive complaints to better understand the pattern and severity of the deficits. Good patient cooperation and an experienced interpreter are necessary for meaningful neuropsychological testing. Patients with gait unsteadiness, dizziness, or vertigo should be examined for cranial nerve or cerebellar deficits. The evaluation should include testing of gait, tandem walk, and Romberg sign. The examiner also should note extraocular movements and the presence or absence of nystagmus, hearing deficits, limb ataxia, and sensory deficits. Tremors, if present, should be characterized with the outstretched hands, with the hands at rest, and with the hands performing pointing maneuvers (eg, the finger-to-nose test). Muscle tone should be tested for rigidity. Rapid tapping of the fingers, hands, or feet is a useful test of the motor system. Along with formal strength testing, they should be part of the routine neurologic examination.
Laboratory tests, such as brain or spine imaging studies (eg, MRI or CT), lumbar puncture, electroencephalogram (EEG), and evoked potentials, are often needed to evaluate the anatomic integrity and physiology function of the central nervous system and to exclude neurologic diseases that may mimic a neurotoxic disorder. In some instances of neurotoxicity, various patterns of MRI signal abnormalities may be seen in the brain, although the appearance is not pathognomonic (see specific toxins below). However, in many clinical settings and especially in the mildly affected patients, these studies may not show any abnormality.
Peripheral Nervous System
Peripheral nervous system disorders lead to sensory disturbances and weakness, often accompanied by impairment of the deep tendon reflexes on physical examination (see Table 27–1). Of the various components of the peripheral nervous system, the peripheral nerve is by far the most vulnerable to exogenous toxins. Because toxins reach the nerves systemically and affect all nerves simultaneously, the resulting syndrome is typically a symmetric peripheral neuropathy. This is also called a polyneuropathy, in contrast to the mononeuropathy that is more frequently the result of local mechanical injury. With few exceptions such as the myopathy caused by alcoholism and medical use of the statins (eg, hydroxymethyl glutaryl coenzyme A reductase inhibitors), toxic myopathy is uncommon.
The hallmark of most polyneuropathies is the distal distribution of the clinical symptoms and signs. The most common syndrome is subacute onset of tingling or numbness experienced in a symmetric stocking-and-glove distribution. Neuropathic pain is sometimes present and is described variously as burning, deep aching, or lancinating. Pain may be evoked by normally innocuous stimuli such as touching or stroking of the skin, a phenomenon known as hyperpathia or allodynia. Involvement of the motor nerve fibers manifests as muscle atrophy and weakness. These deficits may appear first in the distal-most muscles (ie, the intrinsic foot and hand muscles). More severe cases may involve muscles of the lower legs and forearms, leading to bilateral foot drop or wrist drop.
Physical examination of patients with peripheral nervous system disorders should include testing of muscle strength, sensation, and tendon reflexes of all four extremities. Are the sensory and motor deficits relatively symmetric? Are the feet more affected than the hands? Because the longest axons are the most vulnerable, neurologic deficits frequently are more severe in the feet than in the hands. Most polyneuropathies are accompanied by diminished or absent stretch reflexes of the Achilles tendons and demonstrable sensory impairment in the toes. Testing of these functions therefore should be included in any screening examination of the peripheral nervous system.
The clinical pattern of sensory and motor nerve involvement is useful in the differential diagnosis of peripheral neuropathy (Table 27–2). The most nonspecific syndrome is a distal symmetric sensorimotor polyneuropathy. This is indistinguishable from the neuropathies caused by common systemic diseases such as alcoholism, uremia, diabetes mellitus, and vitamin B12 deficiency. Some toxins, such as lead, cause a neuropathy with prominent weakness. The differential diagnosis of such a neuropathy is relatively narrow and encompasses a few hereditary and immunologic neuropathies.
Table 27–2. Toxic polyneuropathies.
Mostly sensory or sensorimotor polyneuropathy (little or no weakness)
Acrylamide
Carbon disulfide
Ethylene oxide
Metals: arsenic, lead, mercury, thallium
Methyl bromide
Polychlorinated biphenyls (PCBs)
Thallium
Predominantly motor polyneuropathy or sensorimotor polyneuropathy with significant weakness
Hexacarbons: n-hexane, methyl n-butyl ketone
Metals: lead, arsenic, mercury
Organophosphates
“Purely” sensory neuropathy (disabling sensory loss with no weakness)
cis-Platinum
Pyridoxine abuse
Cranial neuropathy
Thallium
Trichloroethylene (trigeminal neuropathy)
Prominent autonomic dysfunction
Acrylamide
n-Hexane (glue-sniffer)
Thallium
Vacor (PNU)
Possible association with neuropathies (mostly anecdotal)
Benzene
Carbon monoxide
Dioxin
Methyl methacrylate
Pyrethrins
There are literally hundreds of causes of peripheral neuropathies. Nontoxic causes of neuropathy, such as those caused by systemic diseases, should be investigated and excluded. Approximately one-half of all polyneuropathies remain undiagnosed despite thorough investigation. Thus the absence of an alternate etiology does not necessarily implicate a toxin. Aside from the presence of sufficient exposure and a compatible syndrome, the diagnosis depends on the documentation of progressive sensory or motor deficits during exposure and recovery of function months or years after cessation of exposure.
Nerve conduction studies and EMG are the primary tools in the laboratory evaluation of neuromuscular disorders. These two tests are often performed together, and the term EMG is often used loosely to refer to both tests. Nerve conduction and EMG studies, occasionally supplemented by nerve biopsy, are important in the pathophysiologic characterization of peripheral neuropathies. A fundamental categorization subdivides neuropathies into those with primary degeneration of nerve axons (axonal neuropathy) and those with significant myelin breakdown (demyelinative neuropathy). Diagnostic management of polyneuropathies is best left to experienced specialists.
There are several drawbacks to nerve conduction and EMG studies. These tests are at times painful and uncomfortable at best, with occasional patients tolerating them poorly. Another drawback is the need to use specialized and expensive equipment. Although simplified electronic devices have been advocated, especially in the setting of occupational health screening (eg, screening for carpal tunnel syndrome), there is an unavoidable compromise in accuracy. Furthermore, proper interpretation and performance of these tests require specialized training, and the expertise of providers may vary. Misleading conclusions from improper performance and interpretation are not uncommon.
Ultrasonography is gaining acceptance in the imaging of peripheral nerves, especially for visualization of the nerve at sites of entrapment, such as the carpal tunnel and the ulnar groove. Ultrasonography typically reveals enlargement and change in the echogenicity of compressed nerve. Resolution of these abnormalities may follow successful decompression, providing a way to follow patients in the course of treatment.
Magnetic resonance imaging (MRI) and computed tomography (CT) are important adjunctive tools to evaluate neuropathies. They are employed most frequently to assess cervical and lumbar radiculopathies, conditions that mimic neuropathy. The main limitation is their relative lack of specificity in diagnosing symptomatic disease. Asymptomatic but radiologically significant spondylitic disease is seen frequently in the normal population. Varying degree of MRI or CT abnormalities are encountered in more than 50% of asymptomatic subjects older than 50 years of age and in approximately 20% of those younger than 50 years of age. Thus imaging studies should never replace a careful clinical evaluation.
NEUROLOGIC DISORDERS CAUSED BY SPECIFIC TOXINS
The reader is referred to the corresponding chapters on specific toxins for more detailed discussion on general toxicology and health effects. The discussions below are restricted to neurologic complications.
Acrylamide
The population most at risk of developing neurologic toxicity consists of workers who handle monomeric acrylamide in the production of polyacrylamides and those exposed to monomeric acrylamide used in grouting. Intoxication occurs by inhalation or skin absorption. Features of poisoning include local skin irritation, weight loss, lassitude, and neurologic symptoms of central and peripheral nervous system involvement.
Acute exposure typically causes a confusional state, manifesting as disorientation, memory loss, and gait ataxia. These symptoms are largely reversible, although irreversible dysfunction does occur after very intense exposure. Chronic lower-dose exposure sometimes leads to dizziness, increased irritability, emotional changes, and sleep disturbances. The primary site of action of acrylamide, however, is the peripheral nerve. A neuropathy may develop as a delayed manifestation a few weeks after acute exposure or insidiously after chronic exposure. Both sensory and motor nerves are affected, leading to sensory loss, weakness, ataxia, and loss of tendon reflexes. The loss of reflexes especially may be generalized, unlike other toxic neuropathies, in which only distal reflexes are lost. Autonomic involvement, such as hyperhidrosis and urinary retention, is common.
Acrylamide causes abnormal accumulation of neurofilaments in axons. In this respect, its action is similar to that of organic solvents, notably the hexacarbons. Unlike hexacarbons, secondary demyelination does not occur. Nerve-conduction studies typically show a neuropathy accompanied by little or no slowing of nerve-conduction velocities, that is, a neuropathy predominantly with features of axonal degeneration.
Arsenic
Arsenic compounds are used as wood preservatives, as gallium arsenide in the semiconductor industry, and as defoliant and desiccant in agriculture. Contamination of well water may result from leaching of arsenic by-products in smelting or heavy agricultural use of arsenicals. Acute intoxication by arsenical compounds leads to nausea, vomiting, abdominal pain, and diarrhea. Dermatologic lesions, such as hyperkeratosis, skin pigmentation, skin exfoliation, and Mees lines, occur in many patients 1–6 weeks after onset of disease.
Peripheral neuropathy is the most common neurologic manifestation of toxicity and may occur after either acute or chronic exposure. After a single massive dose, an acute polyneuropathy develops within 1–3 weeks. This neuropathy mimics Guillain-Barré syndrome in many ways, and respiratory failure may occur rarely. Symmetric paresthesias and pain may occur in isolation or may be accompanied by distal weakness. With progression of neuropathy, sensory and motor deficits spread proximally. Shoulder and pelvic girdle weakness, as well as gait ataxia, are common in severe cases. Chronic exposure leads to a more insidious sensorimotor polyneuropathy, although there is no agreement for a threshold limit.
Intense exposure to arsenic may lead to mental confusion, psychosis, anxiety, seizure, or coma. Chronic low-level exposure to arsenic, often from environmental or occupational sources, has been associated with more subtle impairment of memory and concentration. In exposed children, there are also reports of lower verbal performance and hearing impairment.
EMG and nerve-conduction studies provide evidence of a nonspecific axonal neuropathy. Arsenic is detectable in blood and urine during ongoing exposure, and may persist in urine for several weeks after a single massive exposure. With a low-level exposure, blood arsenic level returns to normal in about 12 hours, and urine arsenic clears within 48–72 hours after exposure. Arsenic remains detectable in hair and nails for months after exposure. Thus hair or nail analysis can be useful. However, external arsenic contamination may give false-positive results. Pubic hair is preferable to scalp hair for its lesser susceptibility to contamination.
Carbon Disulfide
Carbon disulfide is employed as a solvent in perfume production and varnishes, in soil fumigants and insecticides, and in industrial manufacturing. Relatively brief inhalation exposure to a toxic level (≥300 ppm) of carbon disulfide causes dizziness and headache, followed by delirium, mania, or mental dulling. Concentrations above 400 ppm have a narcotizing effect and may lead to convulsion, coma, and respiratory failure.
Chronic exposure has been associated with both central nervous system abnormalities and peripheral neuropathy. The peripheral neuropathy presents with paresthesias and pain in the distal legs, loss of Achilles reflexes, and evidence of involvement of sensory and motor axons on nerve-conduction study. A nonspecific syndrome of fatigue, headache, and sleep disturbances is attributable to chronic low-level exposure to carbon disulfide. On MRI of the brain, some exposed patients have scattered abnormal foci in the subcortical white matter. The radiologic picture resembles that seen in patients with small-vessel disease and multiple subcortical strokes, although pathologic confirmation is not available.
Carbon Monoxide
Carbon monoxide binds to hemoglobin to form carboxy-hemoglobin and causes neuronal hypoxia. Inhaling low concentrations (0.01–0.02%) of carbon monoxide causes headache and mild confusion. A higher concentration of 0.1–0.2% may result in somnolence or stupor, and inhalation of 1% for more than 30 minutes can be fatal. Early on, symptoms include headache, dizziness, and disorientation. More prolonged or severe hypoxia is accompanied by a varying combination of tremor, chorea, spasticity, dystonia, rigidity, and bradykinesia. Recovery from the hypoxia may be incomplete. Residual dementia, spasticity, cortical blindness, and parkinsonian features are relatively common.
Occasional patients recover completely after acute exposure only to worsen again 1–6 weeks later with acute disorientation, apathy, or psychosis. Neurologic examination often reveals an encephalopathy with prominent signs of frontal lobe and extrapyramidal dysfunction. Physical findings include bradykinesia, retropulsion, frontal release signs, spasticity, and limb rigidity. Risk factors for developing this delayed encephalopathy are a significant period of unconsciousness and an advanced age. CT or MRI most commonly shows abnormalities in bilateral subcortical white matter. Some patients also have involvement of the basal ganglia, especially the globus pallidus and the thalamus. Rarely, hemorrhagic infarction of the white matter or basal ganglia may be seen. Partial recovery is possible but may take one or more years. Some residual memory deficits and parkinsonism are common.
The effect of long-term exposure to low levels of carbon monoxide is unclear. A number of nonspecific symptoms—anorexia, headache, personality changes, and memory disturbances—are attributed to carbon monoxide, but a causal relationship has not been proven.
Hexacarbons (n-Hexane & Methyl n-Butyl Ketone)
n-Hexane and methyl n-butyl ketone represent a group of widely used volatile organic compounds employed in homes and industries as solvents and adhesives. Human disease is a result of a toxic intermediary metabolite g-diketone 2,5-hexanedione. Toxic exposure results from inhalation, especially in poorly ventilated spaces, or excessive skin contact. Another solvent used in paints and adhesives, methyl ethyl ketone, may potentiate the neurotoxicity.
Like other organic solvents, the hexacarbons can induce an acute encephalopathy characterized by euphoria, hallucination, and confusion. The acute euphoric effect of hexacarbons leads to their abuse as a recreational drug. The most well-known syndrome is a distal symmetric sensorimotor polyneuropathy, the so-called glue-sniffer’s neuropathy. Early symptoms are paresthesias and sensory loss. Weakness follows and involves distal muscles initially. Proximal musculatures are affected in more severe cases. Patients complain of easy tripping because of ankle weakness. Optic neuropathy and facial numbness may be present. Autonomic symptoms are uncommon and are present only in very severe cases. Nonspecific central nervous system (CNS) symptoms, such as insomnia and irritability, may be present. On examination, sensory loss and weakness are readily demonstrable. Achilles stretch reflexes are lost early in the disease. Recovery begins after a few months of abstinence and may be incomplete. In some instances, spasticity and hyperreflexia appear paradoxically during the recovery stage. In these cases, there is probably degeneration of central axons, and the CNS signs are masked initially by the severe neuropathy.
A less dramatic polyneuropathy was recognized in the 1960s in workers in the shoe and adhesive industries, well before the recognition of glue-sniffer’s neuropathy. The exposure to n-hexane was less intense and more chronic than that of glue sniffers. The clinical features are essentially similar, although the syndrome evolves more slowly and results in less severe deficits.
n-Hexane neuropathy has a distinctive neuropathology. Multiple foci of neurofilament accumulations form inside the nerve axons. Demyelination is common, but it is probably secondary to the axonal pathology. Because of this demyelination, nerve-conduction studies show slowing of motor nerve-conduction velocities. Cerebrospinal fluid (CSF) protein content is typically normal, in contrast to most other demyelinating neuropathies, which are associated with elevated CSF protein.
Lead
Lead is present in paint, batteries, pipes, solder, ammunition, and cables. Nonindustrial sources include pottery, bullet fragments, and traditional folk remedies. Acute high-level exposure typically comes from accidental ingestion, inhalation, or industrial exposure. It results in a syndrome of abdominal colic and intermittent vomiting, accompanied by neurologic symptoms such as headache, tremor, apathy, and lethargy. Massive intoxication can lead to convulsions, cerebral edema, stupor, or coma and eventually to transtentorial herniation. Lead encephalopathy typically appears in adults at blood levels of 50–70 μg/dL or higher. Children are more vulnerable than adults probably because of the immaturity of the blood-brain barrier. Behavioral disturbances and neuropsychological impairment may be present at blood levels as low as 10 μg/dL, although the exact threshold is debatable. Chronic low-level exposure to lead is responsible for impaired intellectual development in children. Studies link chronic exposure to decreased global IQ, as well as a wide range of behavioral disturbances, such as poor self-confidence, impulsive behavior, and shortened attention span.
Emerging data suggest that adults with past industrial exposure may have a faster rate of cognitive decline than that expected from normal aging. These subjects typically have normal blood lead levels but elevated lead levels in bone, as measured by x-ray fluorescence. The lead storage in bone potentially can be mobilized throughout life, particularly with bony fractures. It remains to be seen whether the accelerated decline in cognition is a result of continuing exposure to lead or from accelerated aging or attrition of neuronal reserves.
Peripheral neuropathy is a well-recognized complication of chronic lead poisoning in adults. Asymptomatic nerve-conduction-study abnormalities are detectable at lead levels greater than 40 μg/dL. The best-known clinical syndrome is a predominantly motor neuropathy with little, if any, sensory symptoms. The classic description emphasizes bilateral wrist drop and foot drop. Toxicity also may manifest as a generalized proximal and distal weakness and loss of the tendon reflexes. Some patients have preserved reflexes, and their syndrome thus mimics a motor neuron disease such as amyotrophic lateral sclerosis (Lou Gehrig disease). In addition to the classic syndrome of motor neuropathy, some patients may present with distal limb paresthesias and no weakness. This is especially likely in patients with long-term low-level lead exposure.
In patients with acute lead-induced encephalopathy, brain CT or MRI may show focal areas of edema, most commonly in bilateral thalami and basal ganglia. Imaging studies, and sometimes autopsy, may detect intracranial calcification in patients with chronic lead toxicity. The radiologic findings are not specific to lead, and the differential diagnosis may include other causes of calcification, inflammation, and demyelination.
Manganese
Manganese is used widely in the manufacture of steel, alloys, and welding. Manganese is also found in alkaline batteries and various fungicides. Poisoning occurs most commonly in the mining, smelting, milling, and battery-manufacturing industries, although there are occasional reports of environmental contamination. Of recent interest is the potential risk of organic manganese in the form of methylcyclopentadienyl manganese tricarbonyl (MMT), an additive used in gasoline.
The classic syndrome of manganese poisoning, or manganism, is the appearance of an extrapyramidal disorder that resembles idiopathic Parkinson disease. Tremor, rigidity, masked facies, and bradykinesias develop slowly. Dystonia, an uncommon finding in idiopathic Parkinson disease, has been reported in some patients. Compared with idiopathic Parkinson disease, the extrapyramidal symptoms of manganism are less responsive to dopaminergic therapy. Also, neurologic deficits often continue to progress for many years after cessation of exposure.
Manganese preferentially accumulates in the globus pallidus and selectively damages neurons in globus pallidus and the striatum. On brain MRI, manganese accumulation can be visualized as increased signal on T1-weighted images in the globus pallidus, a distinctive finding not seen in Parkinson disease and other forms of parkinsonism. A variable syndrome of parkinsonism, cognitive impairment, and gait ataxia has been seen in patients with chronic liver failure. These patients also may have an abnormal T1 signal in the globus pallidus and a mildly elevated blood manganese level. The liver is responsible for clearance of dietary manganese. It is likely that the neurologic abnormalities of these patients are also due to manganese toxicity.
Mercury
Mercury poisoning results from exposure to methyl mercury or other alkyl-mercury compounds, elemental mercury (mercury vapor), and inorganic mercuric salts. Mercury is used in batteries, fungicides, electronics, and other industries. Mercury in sludges and waterways is methylated by microbes into methyl mercury that is readily absorbed by humans. Several large endemics resulted from methyl mercury contamination in Minamata Bay (Japan) in the 1950s and 1960s, in Iraq in the 1970s, and in the Amazon River basin in the 1990s. Exposure occurred primarily through ingestion of contaminated fish. There is uncertainty concerning the neurologic effect of low-level mercury exposures such as that from dental amalgam and dietary fish consumption. Overall, there is no definitive evidence to associate low-level exposure with significant neurologic disease.
Like many other toxins, mercury poisoning causes a diffuse encephalopathy. In its early stage, the encephalopathy is characterized by euphoria, irritability, anxiety, and emotional lability. More severe exposure leads to confusion and an altered level of consciousness. Patients may develop tremor and cerebellar ataxia. Hearing loss, visual field constriction, hyperreflexia, and Babinski sign may be present. All the preceding symptoms may be encountered in intoxication from organic mercury, metallic mercury, mercury vapor, or inorganic salts. Organic mercury poisoning typically presents with prominent CNS disturbances, with little or no peripheral nervous system involvement. Neuropathy is associated primarily with inorganic mercury. A subacute predominantly motor neuropathy has been reported after metallic mercury or mercury vapor exposure. If acute, the syndrome resembles Guillain-Barré syndrome, whereas a more subacute syndrome may mimic amyotrophic lateral sclerosis. Nerve-conduction study and nerve biopsy suggest a primary axonal loss.
Methanol
The neurotoxicity of methanol is caused largely by formaldehyde and formate, the end products of alcohol dehydrogenase and aldehyde dehydrogenase. Most cases result from accidental ingestion or occupational exposure. Neurologic symptoms usually appear after a latent period of 12–24 hours after intoxication. Patients suffer from headache, nausea, vomiting, and abdominal pain. Tachypnea, if present, indicates significant metabolic acidosis. Visual symptoms appear early and range from blurring to complete blindness. These are accompanied by an encephalopathy, from mild disorientation to convulsion, stupor, or coma. In severely affected individuals, bilateral upper motor neuron signs such as hyperreflexia, weakness, and Babinski sign are present. Brain CT or MRI may reveal infarction or hemorrhage localized in bilateral putamina, often accompanied by similar involvement of subcortical white matter.
Treatment of acute poisoning depends on control of the metabolic acidosis with sodium bicarbonate, competitive inhibition of the conversion of methanol to formaldehyde (by administration of fomepizole or ethanol), and swift removal of methanol by gastric lavage or hemodialysis.
The neurologic effect of chronic low-level methanol is less clear. There are case reports of parkinsonism developing after exposure, although a causal relationship has not been confirmed.
Methyl Bromide and Methyl Iodide
Organic bromides are thought to be more toxic than inorganic ones. They are used in greenhouses and fields for control of nematodes, fungi, and weeds. Methyl bromide (MeBr) has been associated with acute central nervous system toxicity and with longer exposures peripheral neuropathy along with cerebellar, pyramidal tract and neuropsychiatric dysfunction. Methyl iodide (MeI) has been used in various pharmaceutical and pesticide synthesis processes. MeI is known to be a narcotic, and case reports have mentioned parkinsonism, cerebellar, and latent neuropsychological sequella similar to MeBr.
Nitrous Oxide
Excessive exposure to nitrous oxide, usually in the setting of substance abuse, causes a myeloneuropathy indistinguishable from vitamin B12 (cobalamin) deficiency. Patients present with paresthesias in the hands and feet. Gait ataxia, sensory loss, Romberg sign, and leg weakness may be present. Tendon reflexes may be diminished or lost (peripheral neuropathy) or may be pathologically brisk (spinal cord involvement; ie, myelopathy). Nitrous oxide inactivates vitamin B12 and interferes with B12-dependent conversion of homocysteine to methionine. Serum vitamin B12 and the Schilling test often are normal, whereas the serum homocysteine level may be elevated. Repeated exposures are necessary to cause symptoms in normal individuals. Of interest is the observation that a brief exposure to nitrous oxide, for example during anesthesia, is sufficient to precipitate symptoms in patients with asymptomatic B12 deficiency.
Organophosphates
Organophosphates (OPs) are used commonly as pesticides and herbicides and, to a lesser extent, as petroleum additives, antioxidants, and flame retardants. They are highly lipid soluble and are absorbed through skin contact or through mucous membranes via inhalation and ingestion. All the OPs share a common property of inhibiting the enzyme acetylcholinesterase.
The acute neurologic effects of OPs are those of muscarinic and nicotinic overactivity. Symptoms usually are apparent within hours of exposure. These include abdominal cramps, diarrhea, increased salivation, sweating, miosis, blurred vision, and muscle fasciculations. Convulsions, coma, muscle paralysis, and respiratory arrest occur with severe intoxication. Unless there are complications from secondary anoxia or other insults to the brain, these symptoms improve either with atropine treatment or metabolism and excretion of the OP. Recovery usually is complete within 1 week, even though the acetylcholinesterase activity level may be restored only partially.
In some patients, an intermediate syndrome may occur within 12–96 hours of exposure. This is a result of excessive cholinergic stimulation of nicotinic receptors in skeletal muscles. This leads to blockade of neuromuscular junction transmission. Weakness of proximal muscles, neck flexors, cranial muscles, and even respiratory muscles may be evident. Sensory function is spared. Electrodiagnostic testing is useful in diagnosis, with the most characteristic finding being the presence of repetitive muscle action potentials after a single electrical stimulus applied to motor nerves. Another finding is a decremental motor response to repetitive nerve stimulation.
In some other patients, a delayed syndrome of peripheral neuropathy occurs 1–4 weeks after acute exposure. There is little or no correlation between its onset and the severity of acute or intermediate symptoms. Paresthesias and cramping pain in the legs are often the first symptoms. Weakness begins distally and progresses to involve proximal muscles. Weakness dominates the clinical picture and at times may be very severe. Spasticity and other upper motor neuron signs suggesting concomitant spinal cord involvement are present in some patients. Recovery is slow and incomplete and depends on the degree of motor axons loss.
OPs inhibit another enzyme, neuropathy target esterase (NTE), forming an OP-NTE complex. This inhibition becomes irreversible when the OP-NTE complex undergoes a second step known as aging (loss of an R group from the OP molecule). Compounds that lead to aging are neurotoxic, resulting in the delayed neuropathy. All the neurotoxic compounds are phosphates, phosphoramidites, or phosphonates. Important examples are tricresyl phosphates (eg, triorthocresyl phosphate), mipafox, leptophos, trichlorphon, trichlornate, dichlorovos, and methamidophos. Of these, triorthocresyl phosphate probably has caused the largest number of neuropathies. The so-called jake paralysis was a result of drinking extracts of contaminated Jamaica ginger during the prohibition era. Other well-known outbreaks include contamination of cooking oil in Morocco and gingili oil in Sri Lanka.
By the time neuropathy appears, nerve-conduction studies show an axonal polyneuropathy affecting motor greater than sensory axons. These findings are not pathognomonic for OPs but are useful to distinguish this neuropathy from other causes of acute weakness such as Guillain-Barré syndrome and neuromuscular junction disorders.
Persistent subtle neuropsychological impairment after an episode of acute poisoning may be more prevalent than previously thought. Also, chronic low-level exposure to OPs is linked to an encephalopathy with forgetfulness and other cognitive dysfunctions as chief complaints, although the clinical significance or severity of this effect is being debated. Some epidemiologic studies have suggested a link between organophosphate and subsequent development of amyotrophic lateral sclerosis (ALS), though more data are needed.
Organic Solvents
Clinically important exposure to organic solvents occurs primarily as a result of industrial contact or volitional abuse. Most organic solvents possess acute narcotizing properties. Brief exposure at high concentrations causes a reversible encephalopathy. Coma, respiratory depression, and death occur after extremely high exposures. Chronic exposure to moderate or high levels of solvent can cause a dementing syndrome, with personality changes, memory disturbances, and other nonspecific neuropsychiatric symptoms. A sensorimotor polyneuropathy also may be present either as the only manifestation or in combination with CNS dysfunction. The better known syndromes are either discussed under specific headings or are tabulated in Table 27–3.
Table 27–3. Neurologic manifestations of toxins not discussed in text.
Despite general agreement on the effects of moderate to high doses of organic solvents, the effect of chronic low-level exposure is less certain. The sequelae of this low-level exposure have been variously termed painters’ syndrome, chronic solvent encephalopathy, and psycho-organic solvent syndrome. The neurologic symptoms are diverse and nonspecific and include headache, dizziness, asthenia, mood and personality changes, inattentiveness, forgetfulness, and depression. Many studies reported a higher-than-expected incidence of cognitive and psychiatric impairment, electrophysio-logic abnormalities, and cerebral atrophy in chronically exposed subjects. Other studies have not identified significant differences between exposed subjects and controls.
Hexacarbons (n-Hexane and Methyl n-Butyl Ketone)
Like other organic solvents, the hexacarbons can induce an acute encephalopathy characterized by euphoria, hallucination, and confusion. The acute euphoric effect of hexacarbons leads to their abuse as a recreational drug. Occasionally, MRI may reveal abnormalities in the brain. However, the best recognized neurologic syndrome is that of the peripheral nervous system, a distal symmetric sensorimotor polyneuropathy. Early symptoms are paresthesias and sensory loss. Weakness follows and involves distal muscles initially. Proximal musculatures are affected in more severe cases. Patients complain of easy tripping because of ankle weakness. Optic neuropathy and facial numbness may be present. Autonomic symptoms are uncommon and are present only in very severe cases. Nonspecific central nervous system (CNS) symptoms, such as insomnia and irritability, may be present. On examination, sensory loss and weakness are readily demonstrable. Achilles stretch reflexes are lost early in the disease. Recovery begins after a few months of abstinence and may be incomplete. In some instances, spasticity and hyperreflexia appear paradoxically during the recovery stage. In these cases, there is probably degeneration of central axons, and the CNS signs are masked initially by the severe neuropathy. n-Hexane neuropathy has a distinctive neuropathology. Multiple foci of neurofilament accumulations form inside the nerve axons. This is accompanied by secondary demyelination. Because of this demyelination, nerve-conduction studies show slowing of motor nerve-conduction velocities. Cerebrospinal fluid (CSF) protein content is typically normal, in contrast to most other demyelinating neuropathies, which are associated with elevated CSF protein. A recent case report of a patient in Japan who sniffed solvent containing 62% n-hexane revealed abnormal MRI with hyperintensity near the lateral ventricle. The patient was also assessed by magnetic resonance spectroscopy (MRS) and when exposure ceased with admission, her condition improved and her MRS lactate levels normalized.
Zinc
Zinc myeloneuropathy may present similarly to a nitrous oxide myelopathy. Zinc is present in various common foods and in some denture creams. Zinc may also be inhaled as an occupational hazard in welding, construction, or the automotive industry. Excessive zinc ingestion antagonizes copper absorption, leading to hypocupremia, a condition associated with myelopathy and neuropathy. The diagnosis is made by the presence of elevated zinc and depressed copper levels in the serum.
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SELF-ASSESSMENT QUESTIONS
Select the one correct answer to each question.
Question 1: Encephalopathy
a. raises the level of consciousness
b. symptoms may be cognitive but not psychiatric
c. may be the result of toxins
d. is never confused with parkinsonism
Question 2: Cognitive complaints
a. should include at least a mini–mental state examination
b. require referral to neuropsychological testing
c. mask the pattern and severity of the cognitive deficits
d. are reliable symptoms of lead poisoning
Question 3: Peripheral nervous system disorders
a. lead to sensory disturbances but no weakness
b. are often accompanied by impairment of the deep tendon reflexes
c. demonstrate heightened CNS vulnerability to toxins
d. occur because toxins directly affect single nerves
Question 4: Polyneuropathy
a. is a syndrome with asymmetric peripheral neuropathy
b. frequently results from local mechanical injury
c. is typically characterized by the distal distribution of the symptoms and signs
d. has no neuropathic pain
Question 5: Peripheral neuropathy
a. has only a few known causes
b. is seldom caused by systemic diseases
c. often does not have an identified cause despite extensive testing
d. is almost always painful
Question 6: A focal neuropathy
a. produces localized motor and sensory disturbances
b. leads to generalized weakness
c. causes symmetrical atrophy of limb muscles
d. is usually caused by systemic exposures to toxins
Question 7: Acrylamide
a. exposure typically leads to irreversible dysfunction
b. acts primarily on the central nervous system
c. may produce a delayed neuropathy
d. rarely causes an autonomic involvement
Question 8: Arsenic
a. leads to peripheral neuropathy at only high-dose exposure
b. may produce an acute polyneuropathy within 1–3 hours
c. neuropathy precedes Guillain-Barré syndrome
d. chronic exposure leads to a more insidious sensorimotor polyneuropathy
Question 9: Mercury
a. poisoning causes a diffuse encephalopathy
b. exposure may present with euphoria, irritability, anxiety, and emotional lability
c. exposure may cause tremor but not cerebellar ataxia
d. causes Guillain-Barré syndrome
Question 10: Organophosphates
a. diminish muscarinic and nicotinic activity
b. with severe intoxication cause convulsions, coma, muscle paralysis, and respiratory arrest
c. intoxication typically lasts less than 12 hours
d. acetylcholinesterase activity must be restored before recovery occurs