Neurotoxins 

Updated: Aug 18, 2013
  • Author: Abir L Mukherjee, MD; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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Definition

Neurotoxins are substances that damage, destroy, or impair the functioning of neural tissue. Without a well-developed blood-brain barrier, the immature brain is particularly vulnerable to neurotoxins. Even in adults, some regions of the nervous system (eg, choroid plexus, neurohypophysis, area postrema, pineal gland, circumventricular organs) lack a fully developed blood-brain barrier.

Neurotoxins may affect neurons, axons, or glial cells. They may cause metabolic imbalance that can secondarily affect the central nervous system (CNS). Some neurotoxins like manganese and MPTP have typical regional predilections. The following is a concise review of selected commonly encountered neurotoxins.

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Epidemiology

Carbon monoxide

Carbon monoxide poisoning can be accidental or suicidal. Mortality due to carbon monoxide poisoning has declined in the last two decades, but the incidence rate remains unchanged (40,000-50,000 emergency department visits annually). [1]

Common scenarios include grilling, cooking indoors, and working in mines and foundries. Suicide attempts using automobile exhaust fumes are also common. The incidence of carbon monoxide poisoning spikes during evacuations from natural disaster situations owing to improper use of portable electrical power generators. [2]

Sulfide, cyanide, and azide

Hydrogen sulfide is formed in sewers and can be an occupational hazard in the oil and gas industry. Cyanide exposure can occur industrially, as well as during suicidal/homicidal attempts. Azide is used in rocket fuels and as a herbicide/insecticide.

Ethanol

In the United States, 7% of adults and 19% of adolescents have problems related to alcohol consumption, including addiction, physical dependence, and problem drinking. [3]

Methanol

Methanol toxicity is uncommon and usually results from consumption of adulterated alcohol. Methanol is also used to manufacture formaldehyde and some antifreeze solutions.

Solvents

It is now well recognized that many solvents can cause peripheral neuropathy, as well as acute reversible encephalopathy. The exposure to solvents can be industrial or recreational.

Pharmaceutical agents

Pharmaceutical neurotoxicity is very common and may be iatrogenic or self-initiated. A few typical examples are discussed below; a detailed discussion is beyond the scope of this article.

Metals

Metals have been known to be neurotoxic for centuries.

Contamination of groundwater with arsenic has been associated with epidemics of arsenic poisoning in some parts of south Asia. [4]

Increased awareness of lead toxicity over the past decades and regulations regarding the use of lead-based paints has decreased the incidence of lead toxicity.

Manganism was described as recently as 1989 in Taiwan.

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Etiology

Carbon monoxide

Carbon monoxide is a colorless odorless gas produced by incomplete combustion of materials containing carbon.

The etiology of carbon monoxide neurotoxicity is multifactorial and complex. Hemoglobin has a 250-fold greater affinity for carbon monoxide than oxygen. Carbon monoxide also increases the oxygen-binding affinity of hemoglobin. These factors result in tissue hypoxia. Furthermore, carbon monoxide binds to other iron-containing proteins such as myoglobin, cytochrome p450, catalase, peroxidase, and cytochrome oxidase. Lastly, carbon monoxide is a vasodilatory second messenger, analogous to nitric oxide. [5] Cardiac failure and hypotension can complicate carbon monoxide poisoning and contribute to carbon monoxide encephalopathy.

Sulfide, cyanide, and azide

These agents cause histotoxic hypoxia owing to inhibition of cytochrome oxidase in the mitochondria. They also cause profound cardiac hypotension. However, prior to these effects, they hyperpolarize respiratory neurons in the medulla, thereby causing apnea and instantaneous death. [6, 7]

Ethanol

Alcohol has neuroprotective effect in mild to moderate quantities. However, in higher quantities, alcohol is neurotoxic, possibly owing to up-regulation of glutamate receptors. Alcohol inhibits excitatory glutamate receptors, with receptor up-regulation during abstinence resulting in withdrawal syndrome. [8]

Persons with alcoholism may have coexistent nutritional deficiency, cerebral trauma, and hepatic failure. The combination of ethanol-induced glutamate receptor up-regulation and thiamine-induced glutamate release results in excitotoxicity as seen in Wernicke-Korsakoff syndrome. Alcohol is also teratogenic and may be complicated by fetal alcohol syndrome spectrum disorder. Central pontine myelinosis and Marchiafava-Bignami disease probably result from osmotic demyelination.

Methanol

Methanol is metabolized in the body to formic acid or formate salts, which inhibit cytochrome oxidase, thus impairing energy metabolism. [9]

Solvents

Examples of neurotoxic solvents include carbon disulfide (CS2), n-hexane, and toluene. Carbon disulfide is used as a solvent for various fats, oils, waxes, and resins. It causes cross-linking of axonal proteins such as neurofilament. N-hexane is used as a solvent in quick-drying rubber cements and glues, inks, varnishes, and seed oil extractions. Toluene is used in the manufacture of chemicals and in paints and coatings as a solvent. N-hexane and toluene are also abused by inhalation (glue sniffing).

Pharmaceutical agents

Chloroquine is a 4-aminoquinoline derivative used in antimalarial therapy and in higher doses as an anti-inflammatory agent.

Cisplatin is a chemotherapeutic agent used to treat various neoplasms and is a first-line drug in the treatment of testicular cancer.

Tacrolimus is a potent immunosuppressant used to prevent rejection following solid organ transplantation.

Metals

Most reports of acute and chronic arsenic toxicity result from arsenic trioxide. In the United States, the drinking water standard for arsenic is 100 ppb.

Lead exists in 3 forms: metallic, inorganic, and organic. Lead is absorbed through the gastrointestinal tract or lungs. Approximately 99% of lead is in erythrocytes, and 1% is in plasma and serum. Lipid-rich tissue of the CNS is particularly sensitive to the organic form of lead. Lead’s ability to interfere with regulatory effects of calcium in cell systems may lead to its effect on voltage-gated channels and synaptic transmission.

Manganese is an essential trace element widely distributed in the environment. Most cases of manganese toxicity result from chronic inhalation of manganese dioxide.

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Location

Carbon monoxide

Bilateral necrosis of globus pallidus is typically observed in delayed death (>6 days following exposure) of carbon monoxide intoxication. Pars reticulata of substantia nigra is also affected. Both these areas of brain are rich in iron. Hemorrhagic and necrotic lesions can also be observed in the cerebral cortex, hippocampi, and cerebral white matter.

Sulfide, cyanide, and azide

Areas of the brain traditionally vulnerable to hypoxia include the hippocampi, cerebellar Purkinje cells, and cortical watershed areas.

Ethanol

Alcohol causes cortical atrophy predominantly in the frontal lobe (superior frontal gyrus) with reduction in white matter. [10] Neuronal loss is also seen in the supraoptic and paraventricular nuclei of hypothalamus, anterior and dorsomedial nuclei of thalamus, dorsal raphe nucleus, superior portion of vermis, and adjacent cerebellar cortex. Marchiafava-Bignami syndrome affects the corpus callosum. Alcohol-associated thiamine deficiency affects the hypothalamus, periaqueductal gray matter, and floor of fourth ventricle. Central pontine myelinosis affects the basis pontis.

Methanol

Ocular toxicity is common in methanol poisoning, affecting the retina and optic nerve. Bilateral necrosis of lateral portion of putamen and adjacent claustrum is typical of methanol poisoning.

Solvents

Carbon disulfide affects distal sensory and motor nerves, as well as the CNS. N-hexane acts on distal sensory nerves. Toluene has a predilection for affecting cerebral and cerebellar white matter.

Pharmaceutical agents

The most serious effect of chloroquine is dose-related retinopathy by damage to the retinal pigmented epithelium. Ototoxicity and peripheral neuropathy is also common. Peripheral sensory nerve damage is the most serious effect of cisplatin toxicity. Tacrolimus damages the cerebral white matter.

Metals

Arsenic affects both motor and sensory peripheral nerves. Lead affects the motor nerves of upper and lower extremity. Acute lead poisoning can affect the CNS. Manganese can accumulate in globus pallidus and cause toxicity.

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Clinical Features and Imaging

Carbon monoxide

Clinical manifestations depend on the concentration of carboxyhemoglobin in the blood, which in turn depends on the duration of exposure and concentration of carbon monoxide in the ambient environment. Nonsmokers have less than 0.5% saturation of carbon monoxide; it can be up to 6%-7% in smokers. Headache and dizziness starts at 20%-30% saturation. Impaired vision, hearing, and mentation occur at 40%-50%, coma and convulsions at 50%-60%, and death above 70% saturation. The classic cherry red color of skin, blood, and viscera is more often observed as a postmortem phenomenon.

A subset of patients with carbon monoxide exposure develop chronic neurologic sequel. In some cases, with incomplete necrosis of globus pallidus, develop a syndrome termed psychic akinesia, which is marked by inactivity, lethargy, and an amotivational state. [11] A delayed postanoxic encephalopathy may be seen in 3% of patients with acute carbon monoxide–induced coma 4 days to 4 weeks following the exposure. [12]

CT scan and MRI demonstrates bilateral complete/partial necrosis of globus pallidus. [13]

Sulfide, cyanide, and azide

Immediate death following exposure is the typical scenario.

Ethanol

Acute intoxication progresses through euphoria and disinhibition to stupor and respiratory depression. The clinical effects of chronic alcoholism are a consequence of anatomic regions of the brain affected by alcohol. Frontal lobe functions such as planning ability, self-control, and goal-setting are affected.

Cerebellar atrophy results in cerebellar ataxia. Wernicke encephalopathy is characterized by the triad of occulomotor abnormality, cerebellar dysfunction, and altered mental status. A subset of patients with Wernicke encephalopathy develop profound anterograde amnesia called Korsakoff psychosis.

Marchiafava-Bignami disease is a rare condition characterized by altered consciousness and seizures in the acute phase and progressive dementia in the chronic phase. Central pontine myelinosis is characterized by quadriparesis, dysarthria, and dysphagia following rapid correction of hyponatremia.

Fetal alcohol syndrome is characterized by intrauterine growth retardation, dysmorphic facial features, and low IQ.

Methanol

Methanol initially produces an acute intoxication like ethanol but is followed by nausea, vomiting, headache, loss of vision, and extrapyramidal signs.

Solvents

Acute exposure to carbon disulfide causes confusion, hallucinations, memory impairment, and emotional lability. Chronic exposure causes a combination of a progressive sensorimotor distal asymmetric polyneuropathy and CNS abnormalities. [14]

N-hexane causes a distal symmetric peripheral neuropathy. A universal feature of n-hexane neurotoxicity is continuous progression of disability (coasting) after removal of exposure. [15] Coasting usually lasts for 1-4 month.

Toluene intoxication causes cognitive impairment, cerebellar ataxia, deafness, visual impairment, and abnormal ocular movements. MRI studies show cortical cerebral atrophy and increased periventricular signal intensity on T2-weighted images. [16]

Pharmaceutical agents

CNS toxicity of chloroquine may include encephalopathy, psychosis, and an acute extrapyramidal syndrome with torticollis and dystonia in children. Peripheral nervous system toxicity includes myopathy, polyneuropathy, and visual disturbance. [17] Peripheral neuropathy is correlated with the cumulative dose of cisplatin, generally appearing after receiving 400-500 mg/m2 of cisplatin.

Symptoms begin with acral numbness and paresthesias commencing during therapy. [18] Central neurotoxic effects of tacrolimus are common, including encephalopathy, seizures, akinetic mutism, tremor, and headaches. Tacrolimus is associated with reversible posterior encephalopathy syndrome (PRES), [19] with encephalopathy, headache, seizures, and visual disturbances including cortical blindness. MRI T2 and FLAIR sequences show reversible diffuse white matter hyperintensity with a parietooccipital predilection. [19]

Metals

Arsenic causes a gastrointestinal disease characterized by vomiting and diarrhea, which may be followed by an encephalopathy with confusion, seizure, and coma. Chronic arsenic toxicity is a multisystem disease, characterized by sensorimotor polyneuropathy, skin changes, and alopecia.

The major target of lead toxicity is the peripheral nervous system in adults and CNS in children. [20] Intense toxicity may lead to an acute illness characterized by encephalopathy or an acute abdomen. Chronic lead exposure leads to predominantly motor neuropathy, affecting the upper extremity more than the lower. The minimum blood concentration needed is 10 µg/dL in children and 40 µg/dL in adults.

Initial signs and symptoms of manganese toxicity are nonspecific: headache, asthenia, somnolence, anorexia, and/or loss of sexual drive. Manganese causes an extrapyramidal syndrome characterized by progressive parkinsonism, dystonia, and neuropsychiatric symptoms (Manganese madness). [21] MRI shows a hyperintense T1 signal in the pallidum.

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Gross Findings

Carbon monoxide

Acutely, the brain may appear pink and edematous with scattered petechial hemorrhage. Pallidal lesions are centered in the inner segment of globus pallidus but may extend into the outer segment or internal capsule. Cortical and hippocampal atrophy may be seen in longstanding cases. The chronic white matter lesions have a granular appearance.

Sulfide, cyanide, and azide

Gross findings are identical to acute hypoxic ischemic injury due to other causes.

Ethanol

The neuronal and white matter loss caused by chronic alcohol abuse is best demonstrated by morphometric methods. Atrophy of the anterior-superior vermis may be evident grossly. Wernicke-Korsakoff syndrome is marked by hemorrhagic lesions in mamillary body, periventricular areas, periaqueductal, floor of fourth ventricle, and thalamus. Chronic cases show atrophy and brownish discoloration of the mamillary bodies with dilatation of the third ventricles.

Marchiafava-Bignami disease is marked by thinning, discoloration, and cavitation of the corpus callosum. Central pontine myelinosis is characterized by symmetrical, triangular, or butterfly-shaped lesions in the basis pontis.

Neuropathologic changes in fetal alcohol syndrome are varied and nonspecific, including microcephaly, hydrocephalus, leptomeningeal and periventricular neuroglial heterotopia, agenesis of corpus callosum, and cerebellar vermis.

Methanol

Acute intoxication results in cerebral edema. Delayed death results in bilateral hemorrhagic necrosis in the lateral portion of putamen and adjacent claustrum. Extensive necrosis of cerebral and cerebellar white matter is seen following severe methanol intoxication.

Solvents

Gross changes are nonspecific, affecting both the CNS and peripheral nervous system.

Pharmaceutical agents

Gross changes are nonspecific, affecting both the CNS and peripheral nervous system.

Metals

Acute lead poisoning can lead to an acute hemorrhagic encephalopathy with severe edema associated with lead concentrations over 90 µg/dL.

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Microscopic Findings

Carbon monoxide

The histopathological changes are identical to those of other hypoxic-ischemic insults. White matter disease is characterized by demyelination with a variable degree of axonal loss (Grinker myelinopathy).

Sulfide, cyanide, and azide

Microscopic findings are identical to those of acute hypoxic ischemic injury due to other causes and develop if the patient survives long enough.

Ethanol

Cerebellar atrophy is due mainly to loss of Purkinje and granular cells, with thinning of the molecular layer. Wernicke-Korsakoff syndrome, in its acute phase, is characterized by edema, hypertrophy of endothelial cells, and extravasations of erythrocytes. The chronic phase is marked by gliosis and hemosiderin-laden macrophages.

Both central pontine myelinolysis and Marchiafava-Bignami disease are characterized by foci of demyelination. Initially, there is loss of myelin with relative preservation of axons. Longstanding lesions show axonal degeneration and contain foamy macrophages.

Methanol

The histopathological changes are identical to those of other hypoxic-ischemic insults.

Solvents

Peripheral nerves in carbon disulfide poisoning show segmental demyelination and axonal degeneration. N-hexane causes axonal neuropathy and paranodal demyelination. Toluene causes widespread demyelination of cerebral and cerebellar white matter with perivascular collection of macrophages.

Pharmaceutical agents

Sural nerve biopsy in chloroquine toxicity shows mild to severe loss of myelinated fibers, as well as segmental demyelination and remyelination. Laminated myeloid inclusions are found in Schwann cells. Muscle biopsy usually shows a vacuolar myopathy with intracellular myeloid or curvilinear bodies. Sural nerve biopsy in cisplatin toxicity shows prominent loss of myelinated fibers. Some studies have provided neuropathological correlates of tacrolimus toxicity, with evidence of endothelial damage and vasogenic edema. [22]

Metals

Sural nerve biopsy in patients with arsenic poisoning shows axonal degeneration involving myelinated axons of all sizes with relative sparing of unmyelinated axons. Nerve biopsy in lead poisoning shows both axonal degeneration and segmental demyelination with prominent endoneural edema. Manganese encephalopathy is characterized by selective neuronal loss and gliosis in globus pallidus with relative sparing of the substantia nigra. There is also some involvement of the subthalamic nucleus and mamillary bodies. [23]

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Differential Diagnosis

Carbon monoxide

Global ischemia and cyanide poisoning may mimic some of the features of carbon monoxide poisoning.

Cyanides

Global ischemia and carbon monoxide poisoning may mimic cyanide poisoning.

Solvents

Peripheral neuropathy from other causes is a differential diagnosis.

Pharmaceutical agents

Pharmaceutical agents are associated with a wide array of neurologic conditions, including acute and chronic encephalopathy, posterior reversible encephalopathy syndrome, seizures, extrapyramidal syndromes, optic neuropathy, ototoxicity, myelopathy, myopathy, and peripheral neuropathy.

Metals

Other disorders associated with T1 pallidal hyperintensity include hyperglycemia, Wilson disease, abnormal calcium metabolism, neurofibromatosis, hypoxia, and sequelae of cerebral hemorrhage.

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