Toxic

Michael R. Dobbs, M.D.1,2

ABSTRACT

Neurotoxic exposures are common. Although there are myriad substances that can cause encephalopathy, this review focuses on common environmental neurotoxins, such as select heavy metals, organic industrial toxins, and pesticides. The central is susceptible to toxic injury, and many environmental neurotoxins are capable of causing encephalopathy. When a patient presents with toxic encephalopathy, the differential diagnosis is initially broad. The clinical presentation after exposure to a toxin varies in severity among patients. Arriving at the correct diagnosis is often a diagnostic challenge. The importance of taking a good history and performing a comprehensive examination cannot be overemphasized. Neuroimaging and neurophysiologic testing typically play ancillary roles. Confirmatory laboratory testing is available for some toxins. Treatment of most toxic is not supported by clinical trials; additional research is needed in the field.

KEYWORDS: Toxic encephalopathy, neurotoxin, neurotoxicology, encephalopathy

BACKGROUND fusion, attention deficits, , and coma. CNS Neurotoxins have been known to cause disease since capillary damage, hypoxia, and antiquity.1 In modern times, we estimate that millions of play major roles.7 Depending on the toxin, the dose, people around the world work with neurotoxic substan- and the individual, neurologic symptoms may resolve ces.2 Many others are exposed at home or through other with removal from exposure. However, a single ex- inadvertent mechanisms. There are hundreds of sub- posure to some toxins can result in permanent deficits 3–5

stances known to be neurotoxic. There are probably or death. Downloaded by: Emory University. Copyrighted material. many unrecognized neurotoxins in our environments as The chronic toxic encephalopathy may exhibit well.6 insidious symptoms and signs that go unrecognized as The central nervous system (CNS) is to some being due to a toxic exposure. Sometimes, clinical extent protected from toxic exposure by the blood–brain symptoms may not manifest until years after exposure barrier, but remains vulnerable to many toxins nonethe- begins.8 Mood disturbances, , and cognitive dys- less. Nonpolar, lipid-soluble substances gain the easiest function may be seen. Significant recovery may take access to the CNS. Once a toxin gains access to the months or years after removal of the toxin. Sometimes CNS, neurons are easy targets due to their high lipid recovery may never occur. content and high metabolism. White matter can also be Most classes of neurotoxins have encephalopathic easily damaged by lipophilic toxins. effects. Some classic examples include neuromanganism Acute toxic encephalopathies exhibit symptoms and lead encephalopathy from the metals, encephalop- and signs along a spectrum that includes mild con- athy in carbon monoxide (CO) survivors, mixed solvent

Departments of 1Neurology and 2Preventive Medicine, University of Samuels, M.D. Kentucky, College of Medicine, College of Public Health, Lexington, Semin Neurol 2011;31:184–193. Copyright # 2011 by Thieme Kentucky. Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, Address for correspondence and reprint requests: Michael R. USA. Tel: +1(212) 584-4662. Dobbs, M.D., 740 South Limestone Street, Wing D Kentucky Clinic DOI: http://dx.doi.org/10.1055/s-0031-1277989. L-412, Lexington, KY 40536 (e-mail: [email protected]). ISSN 0271-8235. Acute and Subacute Encephalopathies; Guest Editor, Martin A. 184 TOXIC ENCEPHALOPATHY/DOBBS 185 encephalopathy, Korsakoff’s alcoholic encephalopathy, With toxic leukoencephalopathy, the clinical pre- acute ethylene glycol poisoning, and the encephalopathy sentation will usually parallel the degree of white matter of chemotherapy. damage. The clinical severity may therefore range from This review will focus on important and common mild confusion to coma. Neurobehavioral function may environmental causes of toxic encephalopathy. Iatro- be the sphere most often affected in toxic leukoence- genic (pharmaceutic) causes of encephalopathy, though phalopathy.17 very important, will not be addressed in detail. Nor will the neurologic complications of ethanol be reviewed. Illicit recreational drugs will be briefly discussed as they Mixed Toxic Encephalopathy pertain to important agents that cross over into the The symptoms that follow toxic cerebral injury gener- industrial arena. For additional information on the ally reflect damage to both gray and white matter neurotoxic effects of pharmaceuticals, ethanol, and illicit processes. Common complaints include memory dis- drugs, there are several excellent chapters and reviews turbance, impaired cognition, mood disturbance, fa- available.9–12 tigue, and . It is rare to see prominent gray matter signs such as aphasia, apraxia, or agnosia on examination of patients with pure toxic encephalop- RECOGNIZING TOXIC ENCEPHALOPATHY athy. might be an exception, although cortical blindness due to neurotoxicity is Toxic Cortical Encephalopathy controversial. A pure cortical encephalopathy results from toxic dam- Posterior reversible encephalopathy syndrome age to neurons. The cerebral and cerebellar cortices, as (PRES) may be the etiology in some cases of toxic well as deep gray matter nuclei, may be involved in the cortical blindness, and PRES has been reported with process. Cortical encephalopathy may result from expo- toxic exposures.18 In a study of 120 patients diagnosed sure to CO, carbon disulfide, hydrogen sulfide, ethanol, with PRES, 47 patients (42%) were being treated with organophosphates, lead, manganese, aluminum, and immunosuppressive agents. The authors concluded others. However, a pure cortical encephalopathy is that PRES is common in patients with autoimmune probably rare. Most toxins that cause cortical damage conditions, which were present in 51 (45%) of the also cause injury to white matter tracts. This includes patients, and did not correlate PRES with toxic effects CO.13 of medication.19 Aradiologystudyof30patients Injury to the may produce parkin- with PRES that included 24 hypertensive patients, sonism. Cerebellar injury causes typical cerebellar signs, and 6 patients without hypertension in whom PRES such as ataxia and poor balance. Focal cerebral cortical was associated with neurotoxic exposures, found no signs of prominence such as aphasia, apraxia, and agnosia difference in magnetic resonance imaging (MRI) find- are rare in toxic encephalopathy, but may be seen on ings between the hypertensive and toxic groups.20 careful examination. Frontal release signs are possible. PRES may sometimes be due to toxic mechanisms of The syndrome of cortical blindness can result from multiple cancer chemotherapeutic agents, especially exposure to many substances, including organic mercury, in children with hematopoietic disorders.21–24 Cyclo- Downloaded by: Emory University. Copyrighted material. vincristine,14 interferon,15 and other cancer chemother- sporine administration is frequently associated with apeutic agents.16 PRES.25–27 Whether PRES can be a consequence of primary neurotoxicity will remain a point of debate for now. Toxic Leukoencephalopathy White matter lesions, like gray matter lesions, can present with distinct clinical pictures depending on the Complex Toxic Encephalopathy location of the lesion. White matter tends to be more One might define complex encephalopathy as an ence- resistant to ischemia and hypoxia than gray matter, phalopathy in which there is an underlying brain lesion although many areas of white matter lack collateral that contributes to the clinical encephalopathic picture. blood flow. Perhaps the most common complex encephalopathy Because so many disease categories can preferen- (nontoxic) would be the condition of re-exacer- tially affect white matter, the differential diagnosis of a bation with mild infection. leukoencephalopathy is extensive, of which neurotoxicity Little has been specifically written about the is but one facet. However, in the patient with diffuse patient with complex toxic encephalopathy. However, white matter lesions and encephalopathy, who has it stands to reason that in those patients with toxic known or suspected exposure to potentially neurotoxic encephalopathy and underlying brain lesions that the agents, toxic leukoencephalopathy should be investi- degree of encephalopathy might be intensified, or at least gated. be mixed with focal findings. 186 SEMINARS IN /VOLUME 31, NUMBER 2 2011

CONFIRMING TOXIC ENCEPHALOPATHY PRES, one expects to see focal and symmetrical paren- A good first step in confirming toxic encephalopathy is chymal edema. The parietal and occipital lobes are most narrowing down the list of differential diagnoses. This often affected, but also sometimes the frontal lobes, the may prove challenging because most of the disorders in temporooccipital junction, and the cerebellum.33,34 the differential diagnosis are not toxic.

Neurophysiologic Testing The Clinical Examination Electroencephalography (EEG) may provide useful The examination may contain several clues pointing nonspecific information in cases of suspected toxic en- toward a toxic cause of encephalopathy. Many signs cephalopathy. EEG can be used to objectively quantify are general rather than neurologic, and so one cannot the degree of encephalopathy present and perhaps mon- afford to rush through the general physical exam. Exam- itor response to therapy. Abnormalities on EEG are ples of systemic clues to toxic exposure include blue gums typically diffuse and symmetric (generalized slowing), in lead intoxication, Mees lines (white transverse mark- but paroxysmal discharges may occasionally occur. Quite ings on the fingernails) with arsenic, alopecia with a few toxins can cause seizures, and EEG monitoring of thallium, and acrodynia with mercury poisoning. Ab- patients with known seizurogenic toxin exposure is dominal colic is a sign of arsenic and lead toxicity. important. Arsenic gastrointestinal symptoms resemble cholera Electromyography (EMG) does not have a role in clinically; hence arsenic’s historical value as a poison.28 confirming toxic encephalopathy. However, because so In the absence of a known exposure, there are few many CNS toxins also cause neuropathy, EMG and specific neurologic signs to suggest toxic etiologies. nerve conduction studies can sometimes play an impor- Notable neurologic clues may emerge in some toxic tant ancillary role in substantiating a neurotoxic expo- encephalopathies, however. For example, one sometimes sure. Similarly, evoked potential testing, in addition to will see bilateral trigeminal (and occasionally other encephalopathy, may be useful in cases where auditory or cranial nerve) palsies in cases of trichloroethylene ence- visual deficits are seen or suspected as an ancillary test to phalopathy.29,30 With lead encephalopathy, there may confirm involvement of specific areas of the CNS. concomitantly be a classic radial or peroneal nerve palsy. In arsenic, there may be coexisting encephalopathy and peripheral polyneuropathy. The neuropathy of arsenic Laboratory Testing exposure may mimic Guillain-Barre´’s syndrome.31,32 Blood and urine assays are routinely available for quan- tification of several toxins—especially metals. However, assays are not available for many other toxic substances, Neuroimaging such as most organic industrial toxins. Neuroimaging studies are neither sensitive nor specific A common urine drug screen may be limited to a for toxic causes of encephalopathy. However, in some few pharmaceutic agents and street drugs. Prior to cases neuroimaging may help to rule in or rule out a toxic ordering such a screen, it is advantageous to know

cause. Encephalopathy with brain edema in the absence what to expect from the results, including an under- Downloaded by: Emory University. Copyrighted material. of an underlying lesion can be seen in a variety of standing of their limits. For example, a ‘‘positive’’ am- neurotoxic exposures. This should prompt an emergent phetamine screen is probably an immunoassay that workup for an etiology of the edema, to include appro- detects the broad class of amphetamines. Further iden- priate toxic testing. Many neurotoxins deposit in or tification and quantification of the agent in question damage the basal ganglia, and so the presence of bilateral requires specific testing, such as gas or liquid chroma- basal ganglia lesions raises concern for a toxic etiology. tography. Most neurotoxic agents will not be detected on Heavy metals, particularly manganese, may deposit in routine urine drug screens. relatively hyperemic areas of brain, such as the basal Because many substances are diurnal in urinary ganglia. Diffuse, nonenhancing, small white matter excretion patterns, in general, a 24-hour urine collection lesions similar in radiographic appearance to those seen is more reliable than a random sample when quantifying in small vessel ischemia are sometimes seen in neurotoxic toxic exposure. Nevertheless, a high random urine level exposures. may indicate an elevated body exposure.35 Contrast or gadolinium-enhancing brain lesions Hair and nail testing, though perhaps glamorized are not typically seen in neurotoxic exposures. Meningeal by the media and popular culture crime television shows, enhancement also is not a typical finding of toxic actually has a narrow role in the analysis of the patient encephalopathy. with possible toxic encephalopathy. Hair and nail testing Posterior reversible encephalopathy syndrome, if can be useful for determining timing of exposure. Ele- sometimes neurotoxic, is not known to show neuro- ments that bind to sulfhydryl groups in keratin, such as imaging findings that point to a toxic cause. With some toxins, can be examined to indicate when the TOXIC ENCEPHALOPATHY/DOBBS 187 exposure occurred. Toxins that can be analyzed in this Nevertheless, I take extra precaution when using ‘‘flake manner, include lead, arsenic, and mercury. white.’’ Lead may also be found in dangerous, encephal- Proper collection and processing of hair and nails opathy-causing levels in Ayurvedic and Middle Eastern are vital. The correct hair sample for analysis would be traditional medicines and others.41 washed, close to the skin, scalp or pubic hair, and undyed Children may be especially susceptible to effects (some coloring agents may contain lead or other metals). of lead, and blood lead levels of 5–10 mg/dL have been If nail analysis is to be performed, nails should be washed associated with intellectual impairment.42 The current and a clipping taken from all nails. Do not apply maximum allowed value for child blood lead level is 10 adhesive when submitting hair or nails to the laboratory. mg/dL according to the U.S. Centers for Disease Con- Hair and nail analysis is not generally a good screening trol. The blood lead level is the initial screening test of test for neurotoxic exposures. choice in suspected lead intoxication. Twenty-four-hour urine is useful as a reflection of mobilized lead, and may vary with diet and renal function. Therefore, 24-hour REPRESENTATIVE AGENTS CAUSING urine lead testing should be referenced to renal function. TOXIC ENCEPHALOPATHY In lead encephalopathy, nonspecific findings may In considering substances that produce encephalopathic be seen with computed tomography (CT) and MRI. syndromes, the number is legion. Therefore, we shall Edema of the brain, calcifications, and scattered non- limit our review to those substances commonly causing enhancing signal intensities have been reported.43–45 encephalopathy, those for which there are defined symp- Such findings alone, however, are probably not very tom complexes, and that exhibit clinical pearls useful in helpful in confirming a diagnosis of lead encephalopathy. diagnosis. For additional information, the reader is The first rule of lead poisoning is to remove the referred to chapters in textbooks of clinical neurotox- source of exposure, and chelation may be helpful or life- icology.4,5 saving in specific cases of lead poisoning. It is, however, vital to clear the gut of lead as well. Effective chelating agents for lead, include calcium disodium ethylenedia- Metals minetetraacetic acid (EDTA), dimercaprol (British anti- Lewisite) and dimercaptosuccinic acid (DMSA or Suc- LEAD cimer). DMSA is a safe, effective oral agent with defined Lead is well known to cause encephalopathy in children, protocols. Calcium-EDTA and dimercaprol are more and radial nerve palsy in adults. Classic, but nonspecific, risky and have potential serious adverse effects, such as associated features include bluish gums, abdominal colic, cardiac arrhythmia and renal tubular necrosis. and basophilic stippling of red blood cells. For children, the American Academy of Pedia- Although classically focal neuropathies are seen, trics recommends chelation with DMSA at a blood lead lead poisoning can also manifest as encephalopathy in level of 45 mg/dL. If higher than 70 mg/dL, hospital- adults. A study of several hundred Korean workers with ization with EDTA chelation is recommended.46 The moderately elevated blood lead levels found subclinical latest protocols should be reviewed prior to beginning neurocognitive deficits.36 Another study in workers with chelation therapy. Downloaded by: Emory University. Copyrighted material. blood lead levels of 45–60 mg/dL reported poor per- Often essential in the treatment of lead poisoning formance in psychomotor/perceptual tasks and verbal is rehabilitation of the location where exposure occurred. ability compared with workers with lower blood levels Otherwise, intoxication can happen again. and unexposed workers.37 In the ‘‘Bunker Hill Experi- ence’’ epidemiologic study, the lead-exposed young adult ARSENIC group performed relatively poorly on tests of hand–eye Arsenic exposure can cause encephalopathy. The symp- coordination, reaction time, and simple digit, serial digit, toms may include impaired concentration and memory, learning wave, and progressive matrices in vocabulary along with psychosis.47,48 Frequently seen along with tests.38 encephalopathy is peripheral polyneuropathy, that in its With severe lead encephalopathy, brain edema most severe form can mimic Guillain-Barre´’s syndrome, may develop. Clinical presentation may show vomiting, and sometimes severe cardiomyopathy. apathy, stupor, and coma. Such a patient is at high risk of Twenty-four-hour urine levels greater than 50– early mortality.39,40 100 mg, or urine spot levels greater than 35–50 mg are Lead is found in a myriad of places, including consistent with toxic exposure to arsenic.49–51 Blood house paint prior to 1978, pipes, painted toys, as con- levels can be tested, but are probably not as reliable as stituent material in toys, car batteries, and lead shot for a 24-hour urine sample. If high arsenic levels are found guns. In my hobby of painting, lead carbonate is used as a on initial laboratory testing, this should be followed by pigment in ‘‘flake white’’ oil paint; no other white pig- arsenic speciation to determine whether the arsenic is ment quite gives the same effect in artistry as ‘‘flake.’’ organic or inorganic. Typically, organic arsenic does not 188 SEMINARS IN NEUROLOGY/VOLUME 31, NUMBER 2 2011

cause toxicity and may be elevated transiently after Manganese levels can be measured in blood and a seafood meal. Inorganic arsenic is highly toxic to urine. However, acceptable (normal) levels vary among humans, especially the trivalent state.49 laboratories. Serum levels are lower than blood because Exposure to inorganic arsenic can occur through most manganese is bound to hemoglobin. Laboratory a variety of sources. This includes intentional exposure testing is of limited value in neuromanganism, but a very (poisoning by self or others), inhalation of arsine gas high level should raise alarm. It has been suggested that a through burning of treated lumber, and workplace 24-hour urine excretion greater than 50 mg should be exposure with poor industrial hygiene. Arsenic is considered highly dangerous.35 used in a variety of industrial applications. Contami- There are scarce data on chelation for manganese. nation of groundwater is also a frequent source, which Customarily, calcium-EDTA is used, albeit with mixed can occur naturally and through industrial or agricul- results.62,63 tural pollution.52,53 One should ask the exposed patient if they drink untreated water, such as from a MERCURY well or spring. Mercury is a classic metallic cause of encephalopathy, Chelation is effective in treating arsenic poison- written about in stories with characters such as the Mad ing. Options include DMSA, penicillamine, and dimer- Hatter in Lewis Carroll’s Alice’s Adventures in Wonder- caprol. land. Indeed the phrase ‘‘mad as a hatter’’ probably relates to chronic mercury encephalopathy occurring in THALLIUM makers of felt hats in prior eras, who made use of Thallium may cause a severe encephalopathy, but it is mercuric salts. Chronic mercuric salt exposure tends to most notorious for causing cranial/peripheral neuropa- cause , cognitive decline, emotional lability, and thies and alopecia. It is rapidly absorbed throughout the social withdrawal. body after ingestion, but not usually in high concen- Mercury occurs in several forms (elemental, in- trations in the CNS.54 Thus, encephalopathy is typically organic salts, and organic) all of which can be toxic in only seen in high-dose thallium intoxication. sufficient doses. Methylmercury can occur in ecosys- Diagnosis can be difficult. Alopecia, the most tems when mercury that is introduced into water recognizable sign of thallium poisoning, may not be becomes methylated by microorganisms and ingested seen until 2 weeks after poisoning.55 However, a pulled by other organisms in the food chain. It becomes more hair may show darkening of the hair root under light concentrated at each step in the food chain. This microscopy as early as 4 days after exposure.56 Urine ‘‘bioamplified’’ mercury can be ingested by humans levels with a 24-hour urine study above 20 mg/specimen who eat fish or other seafood from the contaminated are considered elevated. Hair levels, though not consid- environment. Industrial dumping of methylmercury ered as reliable as urine, are considered elevated when itself may also occur, such as in Minimata Bay, Japan greater than 15 ng per gram of hair.57 in the 1950s. Although not supported by randomized clinical Methylmercury is rapidly absorbed in the gastro- trials, Prussian blue is considered the mainstay of treat- intestinal tract. Methylmercury is slowly metabolized in

ment to remove thallium from the body. Prussian blue the body and then actively transported across the blood– Downloaded by: Emory University. Copyrighted material. has been shown to decrease the CNS concentration of brain barrier where gray matter is primarily affected. thallium in animals.58 There may be a latent period of several weeks. The cerebellum, visual cortex, and insula are especially af- MANGANESE fected. Signs of methylmercury toxicity include pares- Neuromanganism is a classic and well-known conse- thesias, incoordination, hearing loss, encephalopathy, quence of manganese exposure in miners and smelters of and constriction of the visual fields progressing to blind- manganese ore. Far more controversial is whether weld- ness. Coma and death may occur. ers who work with manganese rods can develop neuro- Dimethylmercury is astonishingly toxic. It has toxic sequelae. little practical use, but may be used as a reference toxin The classic clinical picture of neuromanganism is in nuclear magnetic resonance spectroscopy. Fatal ex- severe unresponsive to levodopa therapy. posure occurs even with small amounts, and it is rapidly Encephalopathy is often part of the picture, and may be absorbed across the skin. It passes through latex and severe. MRI can show manganese deposition in the basal most other laboratory gloves. If exposed across the skin, ganglia, although not always.59,60 one should undergo immediate skin decontamination. Manganese is excreted through the biliary system. Even a few drops may prove deadly. A latent period of People with biliary disease are more prone to manganese several months after exposure may occur, after which toxicity, especially from parenteral nutrition. Cases of time it is too late to treat.64 Early chelation may help can be complicated by manga- and expert consultation should occur immediately after nese deposition in the basal ganglia.60,61 exposure. TOXIC ENCEPHALOPATHY/DOBBS 189

Mercury chelation may be accomplished with brief exposure generally has a good prognosis for com- DMSA and dimercaprol. As with all chelation therapy, plete recovery over hours to days. Prolonged exposures check protocols and monitor the patient closely. may lead to long-term injury, with cranial nerve palsies and chronic encephalopathy. Short-term memory and attention deficits, impaired visuospatial skills, depres- Organic Industrial Toxins sion, and apathy are other commonly persisting symp- There are significant challenges in diagnosing a neuro- toms. Slow improvement of most features can occur over toxic organic industrial exposure. Particularly limiting several months.69–72 In chronic low-level exposure, be- are that there are few biomarkers to confirm and havioral and mood changes are often the first signs. quantify exposure, and such exposures are rarely ‘‘clean’’ Fatigue, dizziness, and headache follow.68,73 or limited to a single toxin. Confirmation of exposure In a case series of 30 individuals with chronic may relate to determining the degree of likelihood that TCE exposure at work for 8–33 years, chronic TCE findings could be caused by chemicals encountered in exposure was found to be a risk factor for the develop- the workplace. A dose may therefore be impossible to ment of parkinsonism. This clinical study was coupled calculate. with validation of an animal model for TCE-induced Common organic solvents/industrial agents may parkinsonism via damage to mitochondrial complex I.74 be classified by chemical structure as aliphatic, aromatic, halogenated, or cyclic hydrocarbons, ketones, amines, ETHYLENE GLYCOL alcohols, aldehydes, and ethers. They are typically found Ethylene glycol is found in automotive antifreeze and in in compounds, such as degreasing agents and cleaning de-icing compounds. It has a pleasant taste and therefore solutions, paints, inks, lacquers, varnishes, and adhesives. can be mistaken for a beverage. There are many cases of There may be two or more neurotoxic solvent molecules intentional poisoning. Ethylene glycol’s metabolites are in a given compound. Frequently encountered toxic highly toxic to the CNS and kidneys. Ethylene glycol organic industrial agents, include toluene, trichloroethy- can be detected with blood testing, although it is not lene, carbon disulfide, perchlorethylene, benzene, xylene, customarily part of a routine alcohol screen. Antidotes and styrene. include ethanol and 4-fomepizole, and if administered quickly, can be lifesaving. TOLUENE Toluene, which is found in glues, gasoline, and some CARBON DISULFIDE paints, is highly toxic to the brain, although the precise Carbon disulfide is used in the manufacture of various mechanism of toxicity is debatable. It is both a recrea- polymers, including rayon and cellophane. Acute severe tional drug and an industrial toxin. Clinically there is intoxication may result in agitated delirium with perma- initial euphoria and lightheadedness. This is followed by nent sequelae. Chronic exposure may lead to progressive confusion and cognitive deficits, poor coordination, and cognitive impairment with co-existing cranial and pe- disequilibrium. Bizarre behaviors and nystagmus may ripheral neuropathies. There may also be parkinsonism. also be seen. Although a rapid recovery to mild-moder- Treatment is removal from the source of exposure, ate acute exposure is typical, repeated exposures (inten- followed by monitoring over time for improvement. Downloaded by: Emory University. Copyrighted material. tional or not) can result in permanent encephalopathy over time.65,66 MRI in the toluene exposed patients tends to show damage to white matter (relative to gray Mixed Solvent Encephalopathy matter) structures and periventricular/subcortical more Many organic industrial exposures fall in the category of so than cortical regions. This apparently lipid-dependent mixed solvent encephalopathy. Workers in industrial distribution of toluene appears to correlate with the settings typically encounter many chemicals at the work- common symptoms and signs of toluene encephalop- place, including products that are prepared as mixtures. athy.67 Common mixed products include mineral turpentine, dry-cleaning safety solvent, mineral spirit, and naphtha TRICHLOROETHYLENE safety solvent. Such solvent mixtures are made from Trichloroethylene (TCE), used commercially as a de- refined petroleum, contain a variety of potentially neuro- greasing agent, is an unsaturated chlorinated hydro- toxic organic solvents, and are used as cleaning agents or carbon. It is also present in some insecticides and thinners. The first steps in such cases are to remove the cleaning solutions. It is sometimes used as a vehicle for patient from the exposure source, determine what neuro- paints, solvents, and glues. The dose–response for TCE toxic chemicals are at the site, and decide what the neurotoxicity is unclear. Trigeminal neuropathy, with or patient may reasonably have been exposed to in toxic without other cranial nerve dysfunction, is a classic sign amounts. Following good industrial hygiene and occu- of TCE poisoning and raises the index of suspicion for pational medicine principles are sometimes the only exposure. Peripheral neuropathy may also be seen.68 A treatments possible. 190 SEMINARS IN NEUROLOGY/VOLUME 31, NUMBER 2 2011

Carbon Monoxide The organophosphate insecticides are acetylcho- Carbon monoxide (CO) is a colorless, odorless, tasteless linesterase inhibitors similar in clinical effects to mili- gas, which is highly neurotoxic to humans and animals in tary-grade nerve agent chemical weapons. Acute sufficient concentrations. Carbon monoxide combines intoxication manifests as confusion, delirium, loss of with hemoglobin to form carboxyhemoglobin, which is consciousness, seizures, and death. There may also be not effective for oxygen delivery to tissues, such as the nausea/vomiting, diarrhea, rhinorrhea, bronchial con- brain. The acute CNS effects of CO poisoning may be striction, and increased bronchial fluids. Levels of poi- entirely related to hypoxemia. Carboxyhemoglobin can soning with organophosphates may be indirectly be measured, and a carboxyhemoglobin level of 50% or monitored by measuring the concentration of cholines- greater will result in coma, seizures, and death. The terase in blood. Atropine acts to block acetylcholine at Occupational Safety and Health Administration the receptor, mitigating effects of acetylcholinesterase (OSHA) limits workplace background CO to 50 ppm inhibition. Specific antidotes are pralidoxime (approved averaged over 8 hours.75 by the U.S. Food & Drug Administration) and obidox- Initial signs of CO poisoning are nonspecific. ime, which remove the organophosphate compound Headache, dizziness, fatigue, nausea, vomiting, and from acetylcholinesterase. Benzodiazepine drugs, such confusion are the initial symptoms followed by loss of as diazepam, effectively treat seizures associated with consciousness, seizures, and death. Treatment includes organophosphates, and are administered in severely in- immediate removal from the source to fresh air, resusci- toxicated, unconscious patients whether convulsing or tation, and hyperbaric oxygen therapy. not. It appears that some surviving victims of organo- Chronic low-level exposure to CO (50 ppm or phosphate exposure have chronic cognitive deficits. less) may result in and mild encephalopathy. The carbamate insecticides also inhibit acetylcho- It is unclear whether chronic low-level exposure can linesterase. However, they tend to be less toxic that the result in permanent neurologic injury. organophosphates. Nonetheless, high-dose exposures of People who survive exposure to toxic amounts carbamate insecticides can be fatal. of carbon monoxide are at risk of development of delayed neurologic sequelae. Delayed neurologic sequelae typically begin between 5 and 30 days post- CONCLUSIONS exposure, and may include depression, suicidal thoughts, Toxic encephalopathy is difficult to diagnose, and often mood swings, cognitive problems, poor balance, challenging to treat. Confirmatory tests are lacking for and inattention. There may also be superimposed many neurotoxins. Definitive therapies are either non- parkinsonism with CO-induced injury to the basal existent or (in most cases) not supported by strong ganglia.76–78 scientific evidence. Furthermore, therapies such as che- The putative mechanism for delayed effects is lation for heavy metals can be very risky. We need more lipid peroxidation. Carbon monoxide exposure results research funding allocated to the field. in release of nitric oxide from endothelial cells and Novel neurotoxic agents, or old agents in fresh platelets. Formation of oxygen free radicals ensues.79 forms, are seemingly constantly emerging. As of this

The end result is apoptosis and lipid peroxidation with writing, there are emerging illicit drugs similar in class to Downloaded by: Emory University. Copyrighted material. demyelination of white matter.80,81 methamphetamines that are legally marketed abroad as MRI of the brain in delayed neurologic sequelae niche-product bath salts. These agents may be purchased from CO may show bilateral T2 white matter hyper- over the Internet and are typically snorted, smoked, or intensities with or without basal ganglia lesions.78,82 injected. The active agents in the ‘‘bath salts’’ are meph- There is no definitive treatment for delayed neurologic edrone and methylenedioxypyrovalerone, or MDPV. sequelae from CO. It is reasonable to treat symptomati- Frank psychosis and self-mutilation have been reported cally with antidepressants, stimulants, and cognitive from ingesting these substances. Laws regulating or rehabilitation as individually indicated. prohibiting their sale are being considered. The practi- tioner needs to keep up with the daily news and always stay alert for novel exposures. Pesticides The United States National Academy of Sciences Most pesticides can cause encephalopathy in sufficient has called for development of original in vitro toxicity doses. This includes the organochlorines (DDT and assays based on toxicity pathways. Toxicity pathways are similar substances) and pyrethroids. However, the con- cellular-response networks, that when overtaxed, result centration that is likely to be required to cause acute in toxic injury.83 If such assays are refined for reliable use encephalopathy is very high. The organophosphate in humans, the diagnosis of neurotoxic syndromes may insecticides, however, are rather toxic to humans, and become much easier. encephalopathy is an important part of the clinical In the meantime, and indeed after better testing picture of exposure. becomes available, practitioners who might see patients TOXIC ENCEPHALOPATHY/DOBBS 191 with toxic encephalopathy will have to keep a high index 18. Moawad FJ, Hartzell JD, Biega TJ, Lettieri CJ. Transient of suspicion. We need to maintain familiarity with blindness due to posterior reversible encephalopathy syndrome classes of toxins, representative symptoms, and know following ephedra overdose. South Med J 2006;99(5):511–514 how and where people may be exposed. The toxins seen 19. Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA. Posterior reversible encephalopathy syndrome: in clinical practices may vary from location to location. It associated clinical and radiologic findings. 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