Neurotoxins 

Updated: Jul 31, 2018
  • Author: Ashley Holloman, MD; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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Definition

Neurotoxins are synthetic or naturally occurring substances that damage, destroy, or impair the functioning of the central and/or peripheral nervous system. Neurotoxins may damage neurons, axons, and/or glia resulting in loss of specific nuclei and/or axonal tracts or demyelination. They may also cause metabolic imbalances that can secondarily affect the central nervous system (CNS). The following is a concise review of selected commonly encountered neurotoxins.

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Epidemiology

Carbon monoxide

Carbon monoxide poisoning is responsible for approximately 50,000 visits to the emergency department annually and results in about 1,200 deaths per year in the United States. [1]

Sulfide, cyanide, and azide

In 2016, the Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS) reported 670 cases of hydrogen sulfide exposure and 198 cases of cyanide exposure. [2] There were no data reported for exposure to azides.

Ethanol

In the National Epidemiologic Survey on Alcohol and Related Conditions III, the 12-month and lifetime prevalence of alcohol use disorder based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5) definition among adults in the United States were 13.9% and 29.1%, respectively. [3] According to the Centers for Disease Control and Prevention (CDC), excessive alcohol consumption contributed to over 87,000 adult deaths in the United States from 2006 to 2010, with 44% due to chronic conditions and 56% due to acute conditions. [4]

Methanol

Methanol toxicity is uncommon and usually results from consumption of adulterated alcoholic beverages. In one study, exposure to methanol alone (excluding methanol mixtures in automotive and cleaning products) was reported in 526 cases. [2]

Solvents

Many industrial and recreational solvents can cause neurotoxicity. Carbon disulfide, N-hexane, and toluene are some of the more common industrial solvents. In 2016, 464 cases of toluene diisocyanate exposure were reported by the NPDS. [2] No data were reported for carbon disulfide and N-hexane exposures.

Pharmaceutical agents

Pharmaceutical neurotoxicity is very common and may be iatrogenic or self-initiated. A few typical examples are discussed in the following sections; 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. [5] In 2016, the NPDS identified 769 exposures of arsenic poisoning in the United States. [2]

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. However, lead toxicity still occurs. In 2016, the NPDS reported cases of 43 lead exposures. [2] In more recent years, contamination of drinking water in Flint, Michigan, resulted in increased lead exposure among adult and pediatric residents ("Flint water crisis").

Manganese toxicity/manganism is rare but accounted for 128 exposures in the United States in 2016. [2]

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Etiology

Carbon monoxide

Carbon monoxide is a colorless and odorless gas resulting from the incomplete combustion of carbon materials. Exposure to carbon monoxide commonly occurs through inadequate ventilation of heating sources, including house/building fires, grilling indoors, motor vehicle exhausts, as well as through occupational hazards, including mining. The incidence of carbon monoxide poisoning may increase during natural disasters owing to the improper use of portable electrical power generators. [6]

Carbon monoxide binds to hemoglobin, which has a 210-fold greater affinity for carbon monoxide than for oxygen. [7] This binding results in a left-shift of the oxygen-hemoglobin dissociation curve, leading to tissue hypoxia. Furthermore, carbon monoxide binds to other iron-containing proteins such as myoglobin, cytochrome p450, catalase, peroxidase, and cytochrome oxidase. In addition, carbon monoxide is a vasodilatory second messenger, analogous to nitric oxide. [7]

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 (electroplating, mining, jewelry manufacturing), as well as during suicidal/homicidal attempts. Azide is used in rocket fuels and as an herbicide/insecticide. [8]

These agents cause toxicity by inhibiting cytochrome oxidase in mitochondria, which prevents cells from using oxygen, ultimately leading to hypoxia and lactic acidosis as well as profound hypotension. In the central nervous system (CNS), they hyperpolarize respiratory neurons in the medulla, thereby causing apnea and, potentially, instantaneous death. [9, 10]

Ethanol

Ethanol enhances the effects of gamma-aminobutyric acid (GABA), which has inhibitory effects in the CNS. It also inhibits excitatory glutamate receptors, mainly N-methyl-D-aspartate (NMDA) receptors, which participate in cognitive function and are upregulated during alcohol abstinence, resulting in withdrawal syndrome. [11]

Persons with alcoholism may have coexistent nutritional deficiencies, cerebral trauma, and/or hepatic failure. Thiamine (vitamin B1) deficiency may cause Wernicke-Korsakoff syndrome. Central pontine myelinosis (osmotic demyelination syndrome) occurs following rapid correction of electrolyte imbalances, classically hyponatremia. Marchiafava-Bignami disease is a very rare disease that causes demyelination of the corpus callosum; although its exact etiology is unknown, vitamin deficiencies have been implicated. [12] Alcohol is also teratogenic and may result in fetal alcohol spectrum disorder, including fetal alcohol syndrome.

Methanol

Methanol (methyl alcohol, wood alcohol) is a common solvent found in household cleaners, perfumes, antifreeze solutions, and windshield wiper fluid. It is metabolized into formaldehyde and then into formic acid or formate salts, which inhibit cytochrome oxidase, thus impairing energy metabolism. [13]

Solvents

Carbon disulfide is used as a solvent for various fats, oils, waxes, perfumes, varnishes, and resins, as well as in the manufacturing of rayon and cellophane. Toxicity occurs following inhalation, ingestion, or skin contact. N-hexane is used as a solvent in quick-drying rubber cements and glues, inks, varnishes, and seed oil extractions. Both carbon disulfide and n-hexane are thought to cause toxicity by crosslinking proteins, including neurofilaments. [14]

Toluene is a widely used solvent found in gasoline, acrylic paints, varnishes, lacquers, paint thinners, adhesives, glues, rubber cement, airplane glue, inks, and shoe polish. [15] N-hexane and toluene are also abused by inhalation (glue sniffing, huffing).

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. Arsenic is thought to cause toxicity by binding to sulfhydryl groups on enzymes, rendering them inactive as well as causing oxidative stress and interfering with metabolism.

Lead exists in three forms: metallic, inorganic, and organic. Lead is absorbed through the gastrointestinal tract or lungs. Approximately 99% of lead is found in erythrocytes and 1% is found in plasma and serum. Lipid-rich tissues of the CNS are particularly sensitive to the organic form of lead owing to its ability to interfere with the regulatory effects of calcium in cell systems, which 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 while mining, welding, and smelting. Manganese toxicity is also associated with methcathinone (ephedrine) abuse.

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Clinical Features and Imaging

Carbon monoxide

Clinical manifestations of carbon monoxide toxicity 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. Signs/symptoms include headache, dizziness, irritability, confusion, disorientation, nausea and vomiting, breathing difficulties, impaired coordination, seizures, coma, and death. [7] A delayed neuropsychiatric syndrome in survivors may occur days (as early as 3 days) to months (up to 240 days) after exposure. [7, 16]

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) demonstrate bilateral, partial, or complete necrosis of the globus pallidus. Early changes in the globus pallidus and substantia nigra may be visualized on diffusion-weighted MRI. Restricted diffusion may also be seen in the white matter following acute intoxication. [7, 17]

Sulfide, cyanide, and azide

Following exposure to sulfide, cyanide, or azide, immediate death due to heart failure is the typical scenario. Associated brain damage is thought to be secondary to hypotension. [8]

On MRI, acute cyanide toxicity can be associated with hemorrhagic necrosis of the basal ganglia and pseudolaminar cortical necrosis. [18]

Ethanol

Acute ethanol intoxication progresses through euphoria and disinhibition to stupor and respiratory depression. The clinical effects of chronic alcoholism are a consequence of the anatomic regions of the brain affected by alcohol. Frontal lobe functions such as planning ability, self-control, and goal-setting are affected. Alcoholic cerebellar degeneration results in cerebellar ataxia. Wernicke encephalopathy is characterized by the clinical triad of oculomotor abnormality, cerebellar dysfunction, and altered mental status. A subset of patients with Wernicke encephalopathy develops profound anterograde amnesia called Korsakoff psychosis. MRI reveals symmetrical areas of hyperintensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in the mammillary bodies, medial thalami, periaqueductal gray matter, and superior and inferior colliculi. [19]

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 intelligence quotient (IQ).

Methanol

Methanol initially produces an acute ethanol-like intoxication that is followed by nausea, abdominal pain, vomiting, headache, loss of vision, and extrapyramidal signs. Ocular toxicity is common in methanol poisoning, affecting the retina and optic nerve. Neuroimaging shows bilateral increased T2-weighted signal in the putamina that is consistent with putaminal necrosis.

Solvents

Acute exposure to carbon disulfide causes confusion, hallucinations, memory impairment, and emotional lability. Chronic exposure results in a combination of a progressive sensorimotor distal asymmetric polyneuropathy and CNS abnormalities. [20]

N-hexane exposure leads to a distal symmetric peripheral neuropathy. A universal feature of n-hexane neurotoxicity is continuous progression after removal of the exposure ("coasting"), which can last from 2 to 4 months. [21]

Toluene inhibits NMDA glutamate receptors [15] ; toluene intoxication causes cognitive impairment, cerebellar ataxia, deafness, visual impairment, and abnormal ocular movements. MRI studies show T2-weighted hyperintensity in the periventricular white matter, T2-weighted hypointensity in the basal ganglia and thalamus, and cerebral cortical atrophy. [22, 23]

Pharmaceutical agents

Chloroquine is a neuromyotoxin that can affect the peripheral nerves, skeletal muscle, and cardiac muscle. [24] CNS toxicity may include encephalopathy, psychosis, and an acute extrapyramidal syndrome with torticollis and dystonia in children. The most serious toxic effect of chloroquine is a dose-related retinopathy caused by damage to the retinal pigmented epithelium.

Cisplatin toxicity causes a distal sensory neuropathy and ototoxicity. Peripheral neuropathy is correlated with the cumulative dose of cisplatin, generally appearing after receiving 400-500 mg/m2 of cisplatin. [25]

Tacrolimus is associated with posterior reversible encephalopathy syndrome (PRES)/tacrolimus leukoencephalopathy which is clinically characterized by a constellation of signs/symptoms including headache, seizures, visual disturbances, altered mental status, and focal neurologic deficits. [26] CT scanning and MRI reveal bilateral and symmetric white matter edema in the parieto-occipital region. [27]   

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, featuring sensorimotor polyneuropathy, skin changes, and alopecia. Its major mechanism of toxicity is thought to be disruption of pyruvate decarboxylation. [14]

The major target of lead toxicity is the peripheral nervous system in adults and the CNS in children. In adults, chronic lead exposure leads to a predominantly motor neuropathy that affects the upper extremities more frequently than the lower. In children, high doses of lead toxicity can result in acute hemorrhagic encephalopathy; lower levels of lead exposure may result in a dose-related decline in IQ. [28]

Manganese disrupts mitochondria, interfering with energy generation. [14] Initial signs/symptoms of manganese toxicity are nonspecific and include headache, weakness, somnolence, anorexia, and/or loss of sexual drive. Manganese toxicity can cause a progressive levo-dopa–resistant parkinsonism characterized by extrapyramidal symptoms, dystonia, "cock walk" gait, and neuropsychiatric symptoms ("manganese madness"). [29] MRI demonstrates bilateral T1-weighted hyperintensity in the globus pallidus with a normal T2-weighted signal.

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Gross Findings

Carbon monoxide

In acute carbon monoxide toxicity, the gross brain may appear pink to cherry-red and edematous with scattered petechial hemorrhages. If survival is longer than 48 hours, bilateral necrosis of the globus pallidus occurs. [7]  Pallidal necrosis is typically centered in the inner segment of the globus pallidus, but it may extend into the outer segment or even the internal capsule. Necrosis in the substantia nigra, hippocampus, or cerebral cortex may also be seen. Foci of demyelination and/or necrosis may be present in the white matter (ie, Grinker myelinopathy).

Gross appearance of carbon monoxide poisoning with Gross appearance of carbon monoxide poisoning with bilateral necrosis of the globus pallidus. Courtesy of Peter Cummings, MD.

Sulfide, cyanide, and azide

Gross cerebral findings of sulfide, cyanide, or azide toxicity are identical to those of acute hypoxic-ischemic injury due to other causes.

Ethanol

In alcoholic cerebellar degeneration, the cerebellum shows atrophy in the anterior-superior portion of the cerebellar vermis, particularly lobules I-IV.

Gross appearance of the cerebellar vermis in alcoh Gross appearance of the cerebellar vermis in alcoholic cerebellar degeneration. The cerebellum shows anterior superior vermian atrophy (arrow). Courtesy of M Beatriz S Lopes, MD, PhD.

Wernicke encephalopathy is marked by hemorrhagic lesions in the mammillary bodies, periventricular areas, periaqueductal region, floor of fourth ventricle, and thalamus. Chronic Wernicke-Korsakoff syndrome shows atrophy and brownish discoloration of the mammillary bodies with dilatation of the third ventricles.

Central pontine myelinosis is characterized by granular, soft, gray discoloration in the midline of the basis pontis. Marchiafava-Bignami disease is marked by thinning, discoloration, and cavitation of the corpus callosum.

Central pontine myelinolysis with gray discolorati Central pontine myelinolysis with gray discoloration in the midline basis pontis (arrow).

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

Methanol

Acute methanol intoxication results in cerebral edema. If there is a period of survival, bilateral and symmetric hemorrhagic necrosis of the putamen develops. Hemorrhagic leukoencephalopathy may also occur.

Solvents

Gross changes from solvent toxicity are nonspecific, affecting both the CNS and peripheral nervous system (PNS).

Pharmaceutical agents

Gross changes are nonspecific, affecting both the CNS and PNS.

Metals

Acute lead poisoning can lead to an acute hemorrhagic encephalopathy with severe cerebral edema.

Gross cerebral findings crom arsenic and manganese toxicity are nonspecific.

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Microscopic Findings

Carbon monoxide

In patients with carbon monoxide intoxicitaiton, pallidal necrosis is associated with an infiltration of macrophages with variable amounts of hemorrhage. Long-standing pallidal lesions may be cystic and gliotic. Foci of demyelination in the white matter typically show relative preservation of axons and sparing of arcuate U-fibers.

Sulfide, cyanide, and azide

Microscopic findings of sulfide, cyanide, or azide toxicity are identical to those of acute hypoxic-ischemic injury due to other causes. Areas of the brain traditionally vulnerable to hypoxic-ischemic injury include the cerebral cortex, hippocampi, and the cerebellum (Purkinje cells). However, if the patient dies soon after exposure, the brain may appear histologically normal.

Ethanol

Chronic ethanol use causes neuronal loss within the superior frontal gyrus and in the supraoptic and paraventricular nuclei of the hypothalamus. [30] The neuronal loss is best demonstrated by morphometric methods.

Acute Wernicke encephalopathy is characterized by edema and hypertrophy of endothelial cells in the mammillary bodies, hypothalamus, periaqueductal gray matter, and floor of fourth ventricle, as well as extravasation of erythrocytes. Chronic Wernicke-Korsakoff syndrome is marked by gliosis and hemosiderin-laden macrophages.

Alcoholic cerebellar degeneration is occurs mainly due to loss of Purkinje cells and internal granule cells, with thinning of the molecular layer.

Alcoholic cerebellar degeneration histology. A. Lo Alcoholic cerebellar degeneration histology. A. Low power magnification of the cerebellar vermis shows atrophy of the folia within the superior vermis (black arrow). The inferior vermis (blue arrow) shows normal folia. B. The inferior vermis shows normal neuronal density. C. The superior vermis shows loss of Purkinje and internal granule cells, thinning of the molecular layer, and Bergmann gliosis.

Both central pontine myelinolysis and Marchiafava-Bignami disease are characterized by foci of demyelination associated with lipid-laden macrophages. Classically, central pontine myelinolysis affects the central midline portion of the basis pontis. Marchiafava-Bignami disease affects the corpus callosum. Initially, there is loss of myelin with relative preservation of axons. Longstanding lesions may show axonal degeneration.

Central pontine myelinolysis. Luxol fast blue (LFB Central pontine myelinolysis. Luxol fast blue (LFB) stain highlights loss of myelin in the midline region of basis pontis in central pontine myelinolysis.

Methanol

Methanol poisoning causes bilateral hemorrhagic necrosis of the putamen, which may extend into the adjacent claustrum. Long-standing lesions may show cavitation. Ocular toxicity results in loss of retinal ganglion cells with optic nerve atrophy and gliosis.

Solvents

Carbon disulfide poisoning causes a peripheral nerve axonopathy with axonal swellings, with accumulation of neurofilaments and axonal degeneration. [14]

N-hexane causes axonal neuropathy with axonal swellings in the proximal paranodal region that contains aggregates of neurofilaments, as well as distal degeneration in the long ascending and descending tracts. [14]

Toluene causes widespread demyelination of the white matter tracts, particularly in the periventricular regions, with gliosis and microglial activation.

Pharmaceutical agents

Sural nerve biopsy in patients with chloroquine toxicity reveals mild to severe loss of myelinated fibers, as well as segmental demyelination and remyelination. Lamellar and crystalline inclusions are found in axons and Schwann cells. [31] Muscle biopsy usually reveals a vacuolar myopathy with intracellular myeloid or curvilinear bodies on electron microscopy.

Sural nerve biopsy in those with cisplatin toxicity shows prominent loss of myelinated fibers.

Tacrolimus leukoencephalopathy demonstrates evidence of vascular endothelial damage and vasogenic edema. [32]

Metals

Sural nerve biopsy in patients with arsenic poisoning shows axonal degeneration involving large and small myelinated axons with sparing of unmyelinated axons. [31]  Chromatolysis and loss of anterior horn cells may also be present. [14]  Arsenic poisoning may demonstrate an acute hemorrhagic leukoencephalopathy, with fibrinoid necrosis of intraparenchymal blood vessels and surrounding hemorrhage. [14]

Acute lead encephalopathy causes edema, swelling of the capillary endothelial cells, petechial hemorrhages, and neuronal necrosis with gliosis, most prominently in the cerebral cortex and cerebellum. [33] The motor neuropathy associated with lead poisoning involves segmental demyelination and axonal degeneration.

Manganese encephalopathy is characterized by selective neuronal loss, demyelination, and gliosis within the globus pallidus and substantia nigra zona reticulata, with sparing of the zona compacta. [33] Some involvement of the subthalamic nucleus and mamillary bodies may be present. [34]

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Differential Diagnosis

Carbon monoxide

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

Cyanide

Global ischemia and carbon monoxide poisoning may mimic cyanide poisoning.

Solvents

Peripheral neuropathy from other causes should be considered in the differential diagnosis of solvent intoxication.

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

The differential diagnosis of manganese toxicity includes other diseases with pallidal lesions such as hyperglycemia, Wilson disease, neurofibromatosis, and sequelae of cerebral hemorrhage. However, in contrast to manganese toxicity, which shows T1-weighted hyperintensity in the globus pallidus, these other disorders show both T1- and T2-weighted hyperintensities. [35]

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