Other Ancillary Testing

Ancillary testing is directed by specific clinical findings. Electroencephalography (EEG) is important to exclude subtle or subclinical seizures in intoxicated patients who display altered mental status. Neuroimaging studies have at least three roles. First, in the acutely intoxicated child or teenager, a cranial computed tomography (CT) scan may be required if there is suspicion of concomitant trauma or hemorrhage. Second, brain MRI findings may explain a patient’s neurologic findings when clinical history and other laboratory studies do not. As neuroimaging of an increasing number of poisoned children and adults has occurred, a couple of recurring MRI patterns have become evident. Agents that cause hypoxic injury, including cellular respiratory poisons, may result in an MRI picture of bilateral symmetric cortical and subcortical gray-matter injury, although white-matter changes occur as well [Halavaara et al., 2002; Kim et al., 2003; Rachinger et al., 2002]. This includes methanol poisoning [Karayel et al., 2010]. Medications used for immunosuppression and those that cause hypertension or changes in blood–brain barrier permeability may contribute to a characteristic neuroradiographic pattern of bilateral posterior reversible leukoencephalopathy (so-called posterior reversible leukoencephalopathy syndrome) [Renard et al., 2004]. Third, the increasing use of diffusion-weighted MRI sequences and apparent diffusion coefficient calculations (apparent diffusion coefficient mapping) often provides a method to delineate early cerebral injury.

Biologic Toxins

Biologic toxins include snake, tick, insect, and fish toxins, botanical toxins, and bacterial toxins (e.g., diphtheria, tetanus, botulism) [Piradov et al., 1991; Stommel, 2008]. Botanical poisonings are especially common among children; whereas most are mild and result from ingestion of easily accessible houseplants, other botanical poisonings may have more serious consequences (see Table 100-1, Box 100-2, and Boxes 100-4 to 100-9) [Krenzelok et al., 1996]. Current parental concern over possible but unproven vaccination side effects may result in a resurgence of previously controlled neurotoxic pathogens. See also reviews by Hardin and Arena [1974], Kunkel [1983], Langford and Boor [1996], and Stommel [2008].

Snake venoms, which, in the United States, are primarily from rattlesnakes and copperheads, are strong neurotoxins. In addition to the local effects of envenomation, there are systemic symptoms of fever, nausea, vomiting, diarrhea, and tachycardia, as well as altered blood coagulation. Neurotoxins affect the neuromuscular junction, causing paralysis of the diaphragm and the intercostal and limb muscles and, more rarely, altered states of consciousness and convulsions. There is controversy concerning the use of local incisions, fasciotomy, application of ice packs, and steroids. Exercise hastens absorption of venom. Intravenous administration of specific antivenoms is recommended [Grant et al., 1997; Hawgood and Sir Joseph Fayrer, 1996; Podgorny, 1983]. The occurrence of the various envenomations depends partially on regional fauna. In New South Wales, Australia, the percentage of poisoning from envenomation ranges from 3.1 percent (females aged 15–19 years) to 84.1 percent (males aged 5–9 years) [Lam, 2003]. In the United States, young males comprise the largest risk group due to accidental or intentional exposure to potentially poisonous snakes [Stommel, 2008].

Under-appreciated in the USA, but a significant concern in Mexico and Central America, is scorpion envenomation [Stommel, 2008; Cheng et al., 2007]. Deaths from scorpion stings far exceed those from snake bites in these areas. Scorpion toxins have complex actions, but their neurotoxicity is due to massive excitation of both the parasympathetic and sympathetic nervous systems.

Tick paralysis is an infrequent but treatable cause of acute paralysis or ataxia caused by neurotoxins from Dermacentor andersoni (wood tick), Dermacentor variabilis (dog tick), Amblyomma americanum (Lone Star tick), Amblyomma maculatum, Ixodes scapularis (black-legged tick), and Ixodes pacificus (western black-legged tick) [Centers for Disease Control and Prevention, 1996a]. Although most prevalent in states west of the Rocky Mountains, tick paralysis also occurs in the southeastern and northeastern United States [Schaumburg and Albers, 2008]. Small children are most likely to be paralyzed. The scalp and neck at the hairline are the most common sites for attachment of the gravid tick, which produces a neurotoxin that prevents liberation of acetylcholine at the neuromuscular junction [Swift and Ignacio, 1975]. Within 5–6 days after tick attachment, the child develops restlessness and irritability, followed, within 24 hours, by progressive ataxia and difficulty walking, or by symmetric ascending flaccid paralysis with loss of deep tendon reflexes. Removal of the tick in the early stage of the disease leads to reversal of the clinical manifestations within 24 hours, whereas failure to remove the tick may result in progressive bulbar paralysis and death. Insect repellents, especially permethrin-containing products applied to children’s clothing, may be used as a preventive measure.

Botulinum toxin blocks presynaptic release of acetylcholine and causes neuromuscular junction blockade. Infection with Clostridium botulinum spores results primarily in three different clinical syndromes: childhood or adult food-borne, infantile, and wound botulism. Inhalation botulism has been reported. Food-borne botulism occurs after ingestion of food, which is frequently home-cooked and canned, that is contaminated with C. botulinum. Nonacidic canned vegetable products and soups are implicated frequently, and recent reports also implicate dairy products as a source of botulism poisoning [Aureli et al., 1996; Townes et al., 1996]. There are prominent gastrointestinal symptoms of diarrhea and vomiting, followed by rapidly developing progressive paralytic disease associated with visual blurring and diplopia, dysphagia, dysarthria, and subsequent weakness of extremities and intercostal muscles. Generally, onset is within 2 days; a prolonged incubation period may correlate with milder disease [Stommel, 2008]. Antitoxin is effective only if given early, and practical concerns regarding availabilty and administration preclude its use in most cases [Cherington, 1974; Newmark, 2008)]. Treatment otherwise is supportive and neuromuscular effects may linger, even after recovery.

Infantile botulism, which occurs almost exclusively in the first months of life, can be a severe paralytic disease affecting the limbs, trunk, bulbar musculature, and cranial nerves. It is preceded almost universally by a history of severe constipation without other gastrointestinal symptoms. This illness has been reported in clusters in both California and Pennsylvania, but it also has been observed in isolated instances throughout the United States and, in some instances, has been related to the ingestion of honey-containing botulinum spores [Glatman-Freedman, 1996; Johnson et al., 1979; Midura, 1996].

Wound botulism, the rarest form of botulism, is both a local infection of contaminated wounds and a systemic intoxication. Incubation period is longer than in the food-borne type. It can produce a paralytic illness that may be indistinguishable clinically from the disorder produced by food-borne botulism. The most common cause of wound botulism in the United States is secondary to intravenous drug abuse [Centers for Disease Control and Prevention, 1996b]. Rarely, wound botulism may result from small intranasal or septal abscesses in nasal cocaine abusers. Botulism mimicking Guillain-Barré syndrome has been reported [Griffin et al., 1997].

Mortality for wound botulism is approximately 15 percent. Food borne botulism carries a 5 percent mortality [Stommel, 2008].

Pediatric tetanus is extremely rare in the vaccination era. Neonatal tetanus is reported, resulting from infection of the umbilical stump. Some forms of culturally specific perinatal manipulation of the umbilical cord may increase this risk. Presentation is generalized rigidity and mortality is high, especially in neonates less than 10 days of age [Bennett et al., 1999].

Insecticides

Organophosphate and carbamate insecticides account for most childhood insecticide exposures. Fortunately, most childhood exposures do not result in poisoning. Fewer than 10 percent of the 8500 insecticide exposures reported to 16 regional poison control centers in 1983 were symptomatic or associated with more than minor symptoms [Veltri and Litovitz, 1984]. A later nine-state study from 1999 to 2002 confirmed that, even with active community spraying programs, symptomatic exposure was rare. In that study, 133 cases were reported among a population of 118 million people. Of these cases, 29 resulted from a single incident in which a mosquito-control truck inadvertently sprayed a malathion-containing product during a softball game. Only one person, who survived, had severe toxicity [Patel et al., 2003]. However, these agents are acetylcholinesterase inhibitors, which may result in serious cholinergic signs. Deaths have been reported in other series [Levy-Khademi et al., 2007]. Toxins can be absorbed through the skin and gastrointestinal tract, but most childhood poisonings are the result of ingestion. Signs of acute intoxication occur usually within 12–24 hours, but can develop in minutes after an acute exposure, indicating severe intoxication and a medical emergency. Salivation, lacrimation, bronchoconstriction, wheezing, and increased pulmonary secretions are all muscarinic manifestations. Peripheral nicotinic signs include muscle weakness, decreased respiratory effort, and muscle fasciculations. CNS signs are anxiety, restlessness, confusion, headache, slurred speech, ataxia, and generalized seizures. Opsoclonus has been reported with diazinon poisoning in an adult [Liang et al., 2003]. With low-dose organophosphate exposure, muscarinic signs predominate, but in more severe acute intoxication, the nicotinic and CNS signs appear. In the series of Levy-Khademi et al., 71 percent of poisoned childen presented with encephalopathy and/or convulsions [Levy-Khademi et al., 2007]. Nicotinic effects appear to mediate delayed peripheral toxicity. With longer-acting agents, such as chlorpyrifos (Dursban), recovery is protracted and possibly incomplete [Sherman, 1995]. Rarely, a myopathy may complicate the picture [Marrs, 1993; Rusyniak and Nanagas, 2004].

A scoring system called Acute Physiology and Chronic Health Evaluation II (APACHE II) has been applied to adults with organophosphate poisoning and has indicated high predictive value for intensive care unit admission and subsequent mortality [Lee and Tai, 2001]. Cholinesterase levels may be used to predict subsequent weaning off mechanical ventilation in surviving patients.

Treatment includes decontamination, general supportive therapy, and administration of specific antidote, including atropine and pralidoxime or obidoxime, the oximes being cholinesterase reactivators [Mortensen, 1986]. Prompt decontamination protects both the patient and attendant health-care workers [Stacey et al., 2004]. The dose of atropine for children younger than 12 years is 0.02–0.05 mg/kg, followed by maintenance doses of 0.02–0.05 mg/kg repeated every 10–30 minutes (maximum dose, 1–2 mg), until cholinergic signs are reversed. For children older than 12 years, the adult dose of atropine (1–2 mg) may be used. As pralidoxime does not cross the blood–brain barrier, atropine must be continued in addition to pralidoxime to reverse central and muscarinic receptor overstimulation. The response to antidote virtually confirms the diagnosis suggested by the history of exposure and the characteristic acute cholinergic symptoms, although intermediate (1–4 days after exposure) and delayed effects are not influenced by atropine or oxime therapy [Marrs, 1993]. These delayed effects are not seen generally in insecticides available in the United States and Europe, and it is thought that the delayed central effects are mediated, not by cholinergic mechanisms, but rather by direct phosphorylation of neuronal structures [Marrs, 1993]. A newer therapeutic agent, liposome encapsulating organophosphorus hydrolase, has demonstrated promise in the laboratory, raising the median lethal dose of paraoxon beyond that provided by pralidoxime and atropine combined [Petrikovics et al., 2004].

Endosulfan, a chlorinated hydrocarbon, may pose a chronic and endemic threat to children with repeated exposure. Acute intoxication causes respiratory distress, gagging, vomiting, diarrhea, agitation, convulsions, ataxia, and coma in severe cases. Mild cases may present with only anxiety and gastrointestinal symptoms [Durukan et al., 2009]. Fatal status epilepticus occurs, and endosulfan-related fatalities occurred in Sri Lanka in 1998 before the agent was banned that year [Roberts et al., 2003]. Dewan and associates reported recurrent convulsions and several deaths in a rural area of India due to wheat flour being stored in containers previously used for endosulfan storage [Dewan et al., 2004]. Amitraz, a formamidine pesticide, has side effects similar to clonidine overdose (CNS depression, miosis, bradycardia, hypotension, emesis, and hyperglycemia). With adequate support, death is rare [Aydin et al., 2002].

Nerve Agents

Nerve agents are related chemically to organophosphate insecticides but are far more potent [Newmark, 2008]. A single drop of VX on the skin may kill a person. Childhood exposure would likely be a result of deliberate attack with nerve agents. They are divided into two classes: G agents and V agents. Tabun (GA), Sarin (GB), and Soman (GD) are clear, tasteless, colorless, and mostly odorless. Tabun and Soman may have a slightly fruity odor, but this property is not clinically useful. VX is amber and oily, but also odorless and tasteless. All may exert their effects within seconds to minutes, depending on route of exposure. Onset after cutaneous exposure may be delayed up to a day. Presenting symptoms may depend on type of exposure. Vapor exposure may present with miosis and concomitant blurring and dimming of vision, followed by salivation. Transdermal exposure first causes local sweating and fasciculations, followed by systemic compromise. Pupillary changes may occur later in the course. Management, as with insecticide poisoning, rests on decontamination; airway, breathing, and cardiovascular stabilization; and specific antidotes, as described previously [Rotenberg and Newmark, 2003; Smythies and Golomb, 2004; Newmark, 2008]. Field treatment requires aggressive treatment with monitoring of respiratory status, rather than attention to peripheral signs and symptoms of cholinergic toxicity. Benzodiazepines are the drugs of choice to treat nerve agent-induced status epilepticus.

Metals

Solvents

Isopropyl alcohol poisoning most commonly results from the ingestion of common household “rubbing alcohol.” Isopropyl alcohol vaporizes readily and is rapidly absorbed through the lungs. Alcohol sponging for fever reduction, especially in a poorly ventilated room, can result in intoxication and coma. Ingestion of as little as 20 mL can produce symptoms [McFadden and Haddow, 1969]. Peak serum levels are reached in about 1 hour, with adverse initial symptoms, primarily gastrointestinal complaints, occurring within 30 minutes after ingestion. CNS effects include headache, confusion, dizziness, ataxia, stupor, and deep coma, which may be caused partially by the formation of acetone during metabolism [Mydler et al., 1993]. Hypotension and hypothermia may occur. The diagnosis is suggested by history, characteristic odor on the patient’s breath, and the presence of large amounts of ketones in the urine without significant metabolic acidosis. Urine toxicology may be revealing [Mydler et al., 1993]. Treatment is primarily supportive. Intermittent or continuous gastric lavage has been suggested, but use of syrup of ipecac is contraindicated; charcoal may be beneficial [Leikin and Paloucek, 1995].

Intoxication has also been reported with benzyl alcohol, which was used as an antibacterial agent and a preservative in saline solution. This form of intoxication, called the gasping syndrome, was reported after the administration of saline solutions as intravenous flushes in small, preterm infants [American Academy of Pediatrics Committee on Drugs, 1997; Gershanik et al., 1982]. The infusion of small amounts of flush solutions containing 0.9 percent benzyl alcohol may cause severe metabolic acidosis, encephalopathy, respiratory depression with gasping, and death. Intoxication from other sources of benzyl alcohol (i.e., as a preservative in medications other than saline) is unlikely.

Children may suffer from clinically significant environmental exposure to solvents. This exposure may occur especially in areas with little child labor protection, resulting in occupational exposure [Saddik et al., 2003].

Other Nonpharmacologic Compounds

A patient presented in coma, after ingesting matchstick heads, of which potassium chlorate is the major component; his MRI indicated bilateral symmetric deep gray-matter and temporal lobe hyperintensity on T2-weighted images. He recovered after hyperbaric oxygen therapy and supportive care [Mutlu et al., 2003].

Cocaine

Cocaine abuse has reached epidemic proportions, especially among young adults. Lifetime incidence of cocaine use is 15 percent among high school seniors and more than 20 percent among college students. There is a suggestion of a decrease in cocaine use, although the same may not be true of crack cocaine. Almost 1 in 20 high-school seniors have tried crack cocaine [O’Malley et al., 1991].

Cocaine, a stimulant alkaloid, is derived from the leaves of the shrub Erythroxylum cocoa. Cocaine inhibits reuptake of norepinephrine, dopamine, and serotonin. Acute toxicity, manifested by tremors, diaphoresis, tachycardia, cardiac dysrhythmias, vasoconstriction, and hypertension, is probably the result of cocaine’s effect on norepinephrine reuptake. Behavioral effects are most likely caused by its actions on the dopaminergic system. Cocaine use results in an enhanced sense of well-being, increased alertness and excitement, and apparent enhancement of the reward response. These effects are followed by anxiety, depression, exhaustion, and sometimes paranoid psychosis. Addiction follows continued use. Stroke, intracranial hemorrhage, and seizures have been reported [Levine et al., 1990; Sloan et al., 1991; Walsh and Garg, 1997; Saleh et al., 2010]. Infants and children passively exposed to cocaine may have similar complications; however, some have disputed these effects [Wurtzel et al., 1988]. Increased cerebral blood flow velocity has been found in infants exposed to cocaine [Van de Bor et al., 1990].

Narcotics

Data regarding numbers of established narcotic users in childhood are scanty; a great percentage of narcotic users never come to the attention of poison control centers. High-school students are among the population at risk, as are children younger than 5 years of age who reside with adults who are narcotic abusers. Narcotics such as morphine, heroin, hydromorphone (Dilaudid), levorphanol (Dromoran), meperidine (Demerol), and methadone share the toxic properties of the opiate group, but the onset and duration of toxic signs vary after ingestion. Methodone intoxication, both accidental and intentional, has been described even in infants [Glatstein et al., 2009]. Opiate users may also be exposed simultaneously to multiple other toxic agents, which are either adulterants of the opiates or are taken concurrently. The signs and symptoms of acute opiate poisoning most commonly follow rapid intravenous administration, and include apnea, circulatory collapse, convulsions, and cardiopulmonary arrest. The less severely poisoned patient experiences varying degrees of CNS depression, ranging from drowsiness to profound coma, miotic pupils, and respiratory depression.

Narcotic poisoning in younger children more commonly results from ingestion of various analgesics, such as meperidine, codeine, oxycodone (Percodan), and pentazocine (Talwin). Ingestion of a large dose, whether accidental or iatrogenic, of the antidiarrheal medication diphenoxylate (Lomotil), which also contains atropine, may result in signs of opiate toxicity with CNS and respiratory depression, as well as signs of atropine overdose, such as facial flushing, tachycardia, dry mouth, hyperpyrexia, and agitation [Brunton, 1996; POISINDEX, 2010].

Treatment of opiate intoxication includes administration of naloxone, a specific and highly effective opiate antagonist, and maintenance of respiration and circulation. The initial dose of naloxone is 0.01 mg/kg; if there is no response, the dose can be increased up to 10-fold, to 0.1 mg/kg. Naloxone can be given intravenously, intramuscularly, or even through an endotracheal tube, with effects lasting 30–45 minutes. Constant monitoring of the patient is required, with repeated doses of naloxone administered as needed in addition to supportive care.

Nanan and associates reported the case of a 14-year-old female with intentional morphine sulfate overdose and leukoencephalopathy involving the corpus callosum, centrum semiovale, and cerebellar white matter [Nanan et al., 2000]. The MRI findings were not explained adequately by hypoxic-ischemic injury, and a drug-induced neurotoxicity was suggested. Other cases of severe neurotoxicity resulting from polypharmacy are reported [Nebelsieck, 2004]. Injected heroin also has been reported to produce a spongiform leukoencephalopathy [Robertson et al., 2001].

Cannabis

Cannabis usually is taken recreationally by inhalation (smoking marijuana cigarettes) or ingestion. The active compound is tetrahydrocannabinol. Tetrahydrocannabinol intoxication produces psychomotor slowing acutely, short-term memory loss, analgesia, and appetite stimulation. Coma has been reported in children ingesting cannabis-laced cookies. Cannabis ingestion should be considered in cases of coma, especially when associated with conjunctival hyperemia, pupillary dilatation, and tachycardia, and when there is no other obvious cause [Boros et al., 1996].

Tetrahydrocannabinol acts through the CB1 receptor (cannabinoid receptor type 1) [Iverson, 2003]. Interestingly, anandamide, an endogenous ligand for the CB1 receptor, has been implicated in the “runner’s high” [Sparling et al., 2003]. Long-term biologic sequelae of cannabis use are ill defined. Dependency may occur, as may apparently reversible mild cognitive impairment. Psychosocial consequences may be more severe.

Gamma-Hydroxybutyrate

Gamma-hydroxybutyrate is a schedule I sedative-hypnotic drug. Although it is used volitionally as a recreational drug, its most infamous use is when it is given surreptitiously as a “date-rape” drug. There is a suggestion in the literature that its sedative effects may be reversed by physostigmine, but no conclusive data exist [Caldicott and Kuhn, 2001; Traub et al., 2002]. As discussed previously, it may be found in addition to other agents in screens of people suspected of substance abuse.

Volatile Solvents and Propellants

Hydrocarbon-based solvents frequently are used by adolescents for their euphoria-producing effects. The compounds commonly in use include various glues, rubber and model airplane cements, typewriter correction fluids, gasoline, lighter fluids, and aerosols [Doring et al., 2002]. Neurologic effects develop within minutes and last several hours, with an initial excitatory stage of euphoria, mental confusion, ataxia, and dysarthria, followed by lethargy, sleep, and coma. Cerebellar dysfunction and sensorimotor neuropathy from chronic gasoline sniffing have been reported [Prockop, 1979; Prockop et al., 1974; Young et al., 1977]. Permanent cognitive impairment and CT evidence of diffuse atrophy of the cerebral hemispheres, cerebellum, and brainstem have also been documented [Hormes et al., 1986]. More sequelae occur with abuse of leaded gasoline [Cairney et al., 2004]. One MRI series demonstrated cerebral atrophy, white-matter hyperintensity on T2-weighted images, and hypointensity involving the basal ganglia and thalami on T2-weighted images, as well as focal enhancement. Although a correlation was found between the degree of neurologic impairment and extent of white-matter disease, no correlation was seen between radiographic evidence of damage to subcortical gray structures and clinical findings [Caldemeyer et al., 1996]. Late sequelae of recreational hydrocarbon inhalation may also include peripheral neuropathy [Kumar, 2008].

Nitrous Oxide

Nitrous oxide abuse is governed by access and therefore is rare in children, although it has been reported in college students [Kumar, 2008]. Neurotoxicity is related to nitrous oxide’s ability to interfere with the cobalamin co-factor of methionine synthetase. Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B₁₂. Children with 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme mutations may be at increased risk of nitrous oxide toxicity. Neurologic deterioration leading to death in a child following two exposures to nitrous oxide anesthesia has been reported [Selzer et al., 2003]. Neurologic toxicity, which occurs after months of daily use, presents as subacute combined degeneration of the spinal cord [Seppelt, 1995].

Hallucinogens

Phencyclidine, also known as angel dust or PCP, is a readily available drug of abuse that is commonly inhaled or ingested. The clinical syndrome of phencyclidine palmitate toxicity includes euphoria and a “high” appearance, at times with violent behavior associated with extreme muscular rigidity and Herculean displays of muscle strength. Vertical and horizontal nystagmus is common, along with marked pupillary dilatation. Instead of excitation, the intoxicated patient may manifest a syndrome of catatonic rigidity, opisthotonus, dystonic posturing, stupor or profound fluctuations in the level of consciousness, seizures, and myoclonus. Extreme elevations of blood pressure are common. Intracranial hemorrhage has been reported [Bessen, 1982; Boyko et al., 1987]. The phencyclidine palmitate-intoxicated patient should be sedated, especially if agitated or seizing, cooled for extreme degrees of hyperthermia, and treated for systolic hypertension with hydralazine or diazoxide [Kulberg, 1986]. Gastric lavage is helpful in removing ingested but unabsorbed drug. Urinary acidification promotes drug excretion.

LSD remains a potent and frequently abused hallucinogen. LSD intoxication results in acute personality changes, hallucinations, and feelings of depersonalization. Acute panic reactions, or “bad trips,” may occur with neurologic signs of excitation, including ataxia, tremors, diaphoresis, convulsions, and, with severe toxicity, coma and respiratory arrest. Most of the milder cases resolve spontaneously; there is no specific antidote or treatment for LSD poisoning, other than general support and sedation.

Finally, new synthetic and naturally occuring hallucinogens continue to emerge. Bromo-dragonfly, or BDF (5-HT_2A agonist and α₁-agonist), K2/spice (cannabinoid receptor agonist), and salvia (kappa opioid receptor agonist) are but three of a myriad of newer agents. BDF and others have life-threatening and fatal side effects, including peripheral and visceral vasoconstriction and sympathetic toxidromic symptoms [Gussow, 2010]. Spice and salvia remain legal in many states. Recreational drug culture websites may be useful tools to help identify potential hallucinogens in the emergency department and clinic settings.

Amphetamines

Amphetamines, such as dextroamphetamine, benzedrine, and methamphetamine, cause clinically similar effects, including a sense of well-being and decreased fatigue. With increasing doses, acute paranoid psychosis may develop, with mania, hyperactivity, and severe sympathomimetic effects, including mydriasis, flushing, diaphoresis, and tachycardia. Convulsions are rare. Cerebral vasculitis, cerebral infarction, and intracranial hemorrhage have been reported with amphetamine use [Delaney and Estes, 1980; Matick et al., 1983; Rothrock et al., 1988]. Gastric lavage is useful in elimination of the toxin. Severe agitation or seizures may be treated with intravenous benzodiazepines; hallucinations may also be treated with haloperidol. Hyperthermia should be treated aggressively; diazoxide or nitroprusside may be indicated for severe hypertension. Adverse effects of medicinal amphetamine use are discussed later in this chapter.

“Ecstasy”

3,4-Methylenedioxymethamphetamine (commonly known as ecstasy) continues to be a popular drug of abuse. Its primary mode of action is to both stimulate and block reuptake of serotonin (5-HT) [Parrott, 2002]. It also has a lesser effect on other monoaminergic neurotransmitters. Taken at dance parties called raves, it promotes a feeling of closeness and heightens sensory experience. It also causes euphoria. Acutely, it commonly causes serotonergic symptoms of confusion, hyperkinesis, and increased body temperature. These symptoms may be exacerbated by conditions that may prevail at raves: overcrowding, high ambient temperature, and coincident use of other stimulants. Rarely, these symptoms can develop into a full-blown serotonergic syndrome and a medical emergency. Once the acute effects wear off, depressive symptoms resulting from monoaminergic depletion occur. There are both laboratory animal and human data suggesting subsequent serotonergic axonal damage [Parrott, 2002].

Ethanol

Ethanol is abused increasingly often by children; acute alcohol intoxication and even chronic alcoholism have become serious problems in children as young as 10 years of age. The signs of acute alcohol intoxication are familiar, but a pediatrician confronted with a child who exhibits incoordination, ataxia, wide mood swings, impaired awareness, and gastrointestinal distress may not consider the diagnosis. Profound CNS depression follows ingestion of large amounts of alcohol. Alcohol withdrawal syndromes are rare in children. Alcohol intoxication may occur in mixed substance abuse. Accidental alcohol intoxication also has been reported in young children drinking attractively packaged and flavored mouthwashes. These mouthwashes have a significant ethanol content (14.2–26.9 percent) [Selbst et al., 1985], as do a variety of medicinal preparations, including cough medicines, decongestants, and teething preparations [Pruitt, 1984]. Chronic ethanol exposure in pregnant women causes fetal alcohol syndrome, as well as lesser fetal alcohol effects (see later discussion); some studies have suggested radiographically demonstrable brain injury in infants born to pregnant women consuming large amounts of alcohol [Holzman et al., 1995; Mattson et al., 1994]. Alcohol abuse may have a relationship to teenage suicide [Esposito-Smythers and Spirito, 2004]. Alcohol intoxication may increase the risk for suicidal attempts acutely. Its long-term disruptive influence on the young person’s life also may lead to further depressive symptoms and subsequent suicidal behavior.

Barbiturates

Barbiturate poisoning in small children is usually the result of accidental ingestion, whereas barbiturate poisoning in teenagers is seen often in suicide attempts. Barbiturate intoxication produces confusion and varying degrees of sedation and coma; lesser amounts may result in ataxia. Respiratory depression, flaccid areflexia, miotic pupils, and absent brainstem reflexes occur with more severe poisoning. Although barbiturates are absorbed rapidly, gastric lavage should be considered within 1 hour of ingestion. Activated charcoal also is indicated in the management of barbiturate poisoning; the half-life of longer-acting barbiturates is shortened by repeated doses of activated charcoal administered over 3–4 days. Urine alkalinization and forced diuresis enhance the clearance of barbiturates. As there are no antidotes to barbiturates and the use of stimulant drugs is contraindicated, the prime consideration in the treatment of the child with barbiturate intoxication is respiratory and circulatory support. Renal function monitoring is necessary because renal failure may be a consequence of hypotension and shock. Hemodialysis is of unproved value but may benefit severely intoxicated patients.

Barbiturates are an uncommon cause of reflex sympathetic dystrophy [Falasca et al., 1994; Botella et al., 1996].

Benzodiazepines

Intoxication with benzodiazepines is common because of their ready availability. These compounds produce depression and sedation at low doses, and confusion, somnolence, and coma at higher doses. Respiratory depression and hypotension may occur. The combination of benzodiazepines and other CNS depressants is potentially fatal. Treatment consists of supportive care and administration of flumazenil, a specific benzodiazepine antagonist. An optimal dose is not defined, but an initial dose of 0.01–0.02 mg/kg (maximum dose, 0.125 mg) is suggested; repeated doses or continuous infusion may be necessary. Flumazenil-induced convulsions may occur in individuals with chronic benzodiazepine use [Leikin and Paloucek, 1995; Perry and Shannon, 1996].

Other Sedatives

Chloral hydrate, ethchlorvynol (Placidyl), methaqualone, and glutethimide (Doriden) are sedatives that can cause severe intoxication with CNS depression. With mild intoxication, the child may be lethargic, confused, and ataxic; with severe intoxication, profound hypotonia, coma, and ophthalmoplegia may occur. Glutethimide, in particular, is associated with prolonged periods of unconsciousness. Careful attention must be given to respiratory support, which may be prolonged, and premature weaning must be avoided [Nicholson, 1983]. Glutethimide and its metabolites persist in the blood because they recirculate from fat stores and undergo enterohepatic circulation, resulting in reabsorption from the gastrointestinal tract; however, there is a poor correlation between plasma levels of glutethimide and clinical effects. Activated charcoal and resin hemoperfusion have been used in patients who have not responded to standard supportive measures. There are no specific antidotes for these sedative agents, although methylene blue is used to treat glutethimide-induced methemoglobinemia.

Despite its notoriety as a teratogen, the hypnotic agent thalidomide has been used in many infectious and inflammatory conditions, including human immunodeficiency virus (HIV)-related complications, leprosy, graft-versus-host disease, and lupus erythematosus. Although it typically causes limb and craniofacial birth defects, fetal thalidomide exposure also can cause congenital cranial neuropathies. Its effects suggest a toxic neural cristopathy. Postnatally, thalidomide acts as a potent neurotoxin, causing a potentially severe and often prolonged, if not permanent, sensory neuropathy [Alexander and Wilcox, 1997; Forsyth et al., 1996; Haslett et al., 1997; LeQuesne, 1993; Rodier et al., 1997].

Antipsychotic Agents (Neuroleptics)

Major tranquilizers include phenothiazines and related compounds, as well as butyrophenones, which are associated with a variety of serious neurologic complications, including sedation, acute dystonic reactions, akathisia, pseudoparkinsonism, withdrawal, emergent dyskinesia, tardive dyskinesia, and neuroleptic malignant syndrome. Newer antipsychotic agents include clozapine, sertindole, olanzapine, and risperidone, and reportedly have fewer neurologic side effects [Caroff et al., 2002]. Acute intoxication in a young child usually results in a confusional state or depressed level of consciousness. Acute dystonic reactions, often observed in children after a single dose of phenothiazine or haloperidol, may manifest as an oculogyric crisis or sudden dystonic posturing of the head and neck, including opisthotonus, retrocollis, torticollis, facial grimacing, and tongue thrusting. These acute reactions are not necessarily dose-related, and are usually readily reversed with the intravenous administration of 25–50 mg of diphenhydramine. Miosis, coma, hypothermia or hyperthermia, and hypotension may occur after ingestion of a large dose of either phenothiazines or butyrophenones. Respiratory depression suggests the ingestion of additional agents, such as narcotics [Knight and Roberts, 1986].

Akathisia, an internal feeling of restlessness, is a dose-related neurologic complication of neuroleptic treatment and is thought to be rare in children [Sachdev, 1995]. It is one of the most distressing adverse effects of neuroleptic use but usually responds to treatment with anticholinergic drugs or blockers.

Neuroleptic malignant syndrome is a rare complication of neuroleptic drug therapy and is characterized by fever, muscular rigidity, autonomic dysfunction, and altered sensorium, with waxing and waning of consciousness. The patient may be in a catatonic-like stupor and may be mute. In children, neuroleptic malignant syndrome occurs during therapy with neuroleptics, as well as after accidental phenothiazine ingestion [Klein et al., 1985b]. Myoglobinuria and acute renal failure may supervene. Treatment consists of intensive supportive care, with monitoring of vital signs, aggressive fluid management, and, in selected cases, dantrolene administration [Caroff and Mann, 1993; Tueth, 1994]. Although reported more often in association with older antipsychotic medications, neuroleptic malignant syndrome also occurs with newer agents such as clozapine, albeit possibly with less dramatic clinical and laboratory findings [Sachdev et al., 1995]. A clinical presentation of confusion, myoclonus, hyperreflexia, diaphoresis, and diarrhea, progressing to fever, coma, and rigidity that improved over 10 days with bromocriptine and aggressive intensive care unit support, was seen in a young woman taking risperidone and fluvoxamine [Reeves et al., 2002]. It was thought that this may not have been neuroleptic malignant syndrome but rather serotonin syndrome. Aripiprazole has been reported to cause neuroleptic malignant syndrome as well, although the one pediatric report to date leaves open a broader differential diagnosis [Palakurthi et al., 2007].

Tardive dyskinesia after chronic phenothiazine or haloperidol use is extremely rare in children [Singer, 1986]. The propensity to develop tardive dyskinesia may be related to the patient’s underlying neural substrate, as found in a recent study. Juckel and colleagues [1995], using auditory event-related potentials, demonstrated an association between a small P300 evoked potential and subsequent tardive dyskinesia.

The newer “novel” antipsychotics, such as clozapine, risperidone, olanzapine, and sertindole, have clinically significant pharmacologic activity at multiple receptors, and fewer typical antidopaminergic side effects such as acute parkinsonism, akathisia, and tardive movement disorders [Baldessarini, 1996; Casey, 1996a; Krebs, 1995; Lindstrom et al., 1995; Schooler, 1996]. Clozapine, in particular, appears to be associated with less bradykinesia and akathisia than haloperidol, although not necessarily less tremor [Kurz et al., 1995]. Acute extrapyramidal effects have been seen in children after an overdose of 100 mg of clozapine [Goetz et al., 1993; POISINDEX, 2010]. Confusion, lethargy, and ataxia also have been reported in children. Although clozapine-associated seizures have been reported at doses of 250 mg/day, the prevalence of seizures is higher (5 percent) in adults taking 600–900 mg/day [Haller and Binder, 1990; Tueth, 1994]. Myoclonus also has been reported at higher doses [Bak et al., 1995]. Extrapyramidal side effects (acutely, dystonia) and tardive dyskinesia are reported infrequently with risperidone [Buzan, 1996; Daniel et al., 1996; Faulk et al., 1996]. Olanzapine appears to have an extrapyramidal side-effect profile intermediate between that of the older antipsychotics and its newer cousins [Casey, 1996b].

Antidepressants

Tricyclic antidepressants, such as amitriptyline, imipramine, and desipramine, have been associated with acute toxicity and significant morbidity and mortality. Acute encephalopathy occurs within 4 hours of ingestion and includes ataxia, hallucinations, and nystagmus. Somnolence occurs subsequently, and tremor or myoclonus may occur. Cardiac conduction abnormalities, including tachycardia, heart block, atrial fibrillation, and ventricular flutter, are the most common and serious non-neurologic results of tricyclic intoxication [Pimentel and Trommer, 1994]. Dry mouth, palpitations, and tachycardia occur as typical anticholinergic effects. Death may occur as a result of progressive coma, seizures, and cardiac conduction defects. In acute poisoning, activated charcoal with a cathartic may be helpful; lavage may be attempted if fewer than 6 hours have passed since ingestion. Up to 2 mg of physostigmine administered intravenously may awaken a comatose patient but should be avoided in patients with bradycardia. Keeping the blood pH slightly alkaline (e.g., 7.5) helps in the treatment of tachyarrhythmias. A prolonged QRS interval is a good predictor of seizures and cardiac dysrhythmias in acute intoxication with tricyclics, but serious CNS depression may occur with relatively normal QRS intervals [Boehnert and Lovejoy, 1985]. Amoxapine, a newer tricyclic antidepressant, also frequently induces seizures when taken in toxic amounts, but unlike the other drugs of this class, it does not seriously alter the electrocardiogram [Rogol et al., 1984].

SSRIs are some of the most frequently used medications in the United States at the present time. Such popularity stems from their broad range of efficacy and relatively favorable side-effect profile. Although cases of SSRI toxicity have increased as a result of this wide availability, serious neurotoxicity is limited generally to accidental ingestions or intentional overdoses, especially in combination with other medications or drugs of abuse [Klein-Schwartz and Anderson, 1996; Lavin et al., 1993; Bronstein et al., 2007]. Paradoxic behavioral reactions and SSRI-induced hyperkinetic movement disorders are perhaps the most likely adverse neurologic effects. In a review of 469 SSRI intoxication cases in adults, a more severe serotonergic syndrome, with coma or convulsions, occurred in 2.4 and 1.9 percent, respectively [Isbister et al., 2004]. Of note, of the five different SSRIs involved, citalopram had relative QTc prolongation, although its clinical significance was unclear. In a study of isolated accidental fluoxetine ingestion of 20 mg or more in 120 children younger than 6 years, 96 percent were asymptomatic. Sedation and vomiting were the only side effects reported in symptomatic children [Baker and Morgan, 2004]. A recent report of 26 cases of citalopram intoxication revealed generally mild cardiac toxicity (albeit with one death by cardiac arrest), but more severe encephalopathy and seizures [Jimmink et al., 2008]. Intensive care admission is recommended for all cases of citalopram intoxication. A neonatal withdrawal syndrome, including neonatal convulsions, has been described in newborns whose mothers were taking SSRIs during the pregnancy [Sanz et al, 2005].

Lithium

Lithium carbonate, used for the treatment of bipolar depression in adults, is effective in the treatment of certain behavioral and affective disorders in children [Goetting, 1985]. Most cases of lithium intoxication occur during the course of prolonged therapy. The typical patient has apathy, drowsiness, nystagmus, tinnitus, dysarthria, ataxia, coarse muscle tremors, vomiting, and diarrhea. Choreiform movements, dystonic posturing, and cogwheel rigidity may occur. Severity of symptoms correlates well with the serum lithium concentration. Seizures and coma indicate severe toxicity (i.e., serum lithium level >3.0 mmol/L). Treatment of acute poisoning (<30 minutes) should include induction of emesis or gastric lavage. However, because of the slow excretion of lithium, symptoms may progress, despite cessation of the medication. There is no specific treatment, other than attention to fluid balance and support. Sodium chloride administration enhances urinary excretion, particularly if the patient is hyponatremic. Peritoneal dialysis or hemodialysis is used in cases of clinically severe intoxication with serum lithium levels greater than 3 mmol/L [Tueth, 1994]. Prolonged hemodialysis may be necessary to prevent a rebound in serum lithium concentration [Sansone and Ziegler, 1985].

Salicylates and Acetaminophen

Salicylates are present in a myriad of medicinal preparations, ranging from aspirin tablets to oil of wintergreen and long-used Chinese medicinal oils [Chan et al., 1995]. Poisoning has been reported with all forms through both oral and topical routes [Abdel-Magid and el-Awad Ahmed, 1994]. Absorption rate depends on the preparation. Acute aspirin dosages of >200 mg/kg are toxic; doses of 500 mg/kg may be lethal [Cataletto, 2010]. Neurologic, hepatic, and pulmonary toxicity occurs in concert with other metabolic derangements [Bari, 1995]. Symptom onset in acute intoxications is within a few hours. Salicylates directly affect the CNS and cause central hyperventilation with respiratory alkalosis. Poisoning of the Krebs cycle and increased skeletal muscle metabolism result in increased oxygen consumption, increased carbon dioxide production, and metabolic acidosis. Salicylates also contribute directly to this acidosis. Mortality is related to brain salicylate concentration; respiratory decompensation and subsequent worsening acidosis facilitate salicylic acid passage into the CNS [Yip et al., 1994]. Severe intoxication is more likely in children younger than 4 years.

Chronic toxicity occurs after several days of use and sometimes may be more difficult to discern because of symptoms of the patient’s underlying illness. CNS disturbances occur in up to 60 percent of patients and include lethargy, coma, and convulsions; however, the predominant toxicity with chronic salicylism is pulmonary edema [English et al., 1996; Yip et al., 1994].

Poisoning also may result from chronic excessive use of bismuth subsalicylate (Pepto-Bismol). The combination of typical signs of chronic salicylate toxicity and radiopaque bismuth precipitate seen on radiographs of the abdomen suggests the diagnosis [Hearney et al., 1996; Vernace et al., 1994].

Failure to recognize salicylate poisoning and treat it aggressively contributes to morbidity and mortality. As in most intoxications, early recognition optimizes outcome. The classic triad of acute poisoning is hyperventilation, tinnitus, and gastrointestinal irritation. Supportive therapy and aggressive measures to speed elimination of salicylates from the body are the mainstays of treatment. Fluid diuresis, coupled with urinary alkalinization, is used in milder cases; more severe poisonings may require blood alkalinization. This alkalinization and early hemodialysis may be life-saving in severe intoxications [Yip et al., 1994]. Activated charcoal is beneficial, but the advantage of multiple-dose over single-dose regimens is not proved [Cienki et al., 1995]. Hypoglycemia may complicate salicylate poisoning. Intravenous fluids should contain at least 5 percent glucose; 10 percent glucose solutions should be used in young children with documented hypoglycemia or mental status changes. Aspirin tablets may form bezoars within the stomach; these provide a reservoir for prolonged salicylate absorption and may require dilutional catharsis. Gross overuse of bismuth-containing antacids may also cause a bismuth encephalopathy, characterized by delirium, myoclonus, tremor, and ataxia [Kumar, 2008].

Unlike salicylates, acetaminophen (and paracetamol) appears not to have a recognizable primary toxic effect on the brain. CNS effects result from acetaminophen-induced liver failure. Hepatic coma and life-threatening cerebral edema may be present in severe acute overdoses, although peak symptoms may not occur until 1–3 days after ingestion [Leikin and Paloucek, 1995]. Early lack of symptoms does not exclude a potentially fatal ingestion, and need for therapy is directly related to dose and measured acetaminophen blood level. Conservative estimates of the acute pediatric toxic dose are 140–150 mg/kg, but many authors use doses of 200 mg/kg, up to an adult toxic dose of about 7.5 g [Anker and Smilkstein, 1994]. Home ipecac administration for this and other suspected poisonings once was considered standard of care; however, the current American Academy of Pediatrics recommendation is to not have ipecac in the home [American Academy of Pediatrics Committee on Injury, Violence, and Poison Prevention, 2003; Bond, 1995; Shannon, 2003]. Gastric lavage is effective if performed within 1 hour after ingestion. Activated charcoal should be given up to 4 hours after ingestion. If dosage at or above toxic range is suspected, N-acetylcysteine should be started; efficacy of oral versus intravenous therapy is debated. A 4-hour postingestion blood acetaminophen level is compared with a standard nomogram to determine the need to continue N-acetylcysteine therapy [Brandwene et al., 1996]. N-acetylcysteine coupled with a molecular absorbant recirculating system, if started early, may allow hepatic regeneration and obviates the need for liver transplantation [Koivusalo et al., 2003]. After ingestion of extended-release acetaminophen preparations, a second blood acetaminophen level should be obtained 4–6 hours after the first (but at least 8–12 hours after ingestion) [Cetaruk et al., 1997; Leikin and Paloucek, 1995].

Stimulants

Stimulant medications, such as dextroamphetamine, pemoline, and methylphenidate, used for the treatment of attention-deficit hyperactivity disorder, may produce increased activity and varying dyskinesias, including motor tics and chorea [Jimenez-Jimenez et al., 1997; Nakamura et al., 2002; Stork and Cantor, 1997]. Some children receiving methylphenidate may develop Tourette’s syndrome, but a recent study of males with attention-deficit hyperactivity disorder and Tourette’s syndrome demonstrated that tics increased reversibly with stimulant use [Castellanos et al., 1997].

Atomoxetine is a nonstimulant agent approved for the treatment of attention-deficit hyperactivity disorder. Generally, side effects are mild, but limiting tachycardia can occur. Kashani and Ruha reported a single case of atomoxetine overdose (2840 mg with typical dose 1.2–1.8 mg/kg/day) in an adolescent who then presented with a seizure [Kashani and Ruha, 2007].

Theophylline

Theophylline and aminophylline, commonly used for treating apnea of prematurity and asthma, may cause neurologic symptoms as a result of either accidental ingestion or therapeutic error. Although theophylline concentrations higher than 20 mg/L are believed to be toxic, and clinical toxicity with nausea, vomiting, tachycardia, and agitation, followed by seizures, is more common when theophylline levels are greater than 30–40 mg/L, some children suffer lesser side effects with levels above 12–15 mg/L [Barr et al., 1994]. Gastrointestinal symptoms do not necessarily precede the onset of seizures, and seizures may occur with serum theophylline concentrations as low as 25 mg/L, although they are more common when concentrations exceed 50 mg/L [Gal et al., 1980; Jira et al., 1996]. Treatment of theophylline toxicity is supportive. Although activated charcoal absorbs the drug well within the gastrointestinal tract, hemoperfusion is considered the definitive treatment. Peritoneal dialysis has been used successfully in neonates and infants [Colonna et al., 1996; Jira et al., 1996]. Ipecac should be avoided. Seizures may be difficult to control but should be treated initially with benzodiazepines [Leikin and Paloucek, 1995]. Status epilepticus associated with increased theophylline levels carries a risk for increased morbidity over status epilepticus in general [Dunn and Parekh, 1991]. This risk may be secondary to theophylline-induced decreased cerebral blood flow or to increased risk for hypoxia due to underlying pulmonary disease.

Diphenhydramine

The antihistamine diphenhydramine is contained commonly in over-the-counter cold remedies and in topical preparations. Although neurologic side effects usually are mild (sedation or, paradoxically, hyperactivity), more overt symptoms can occur. Hallucinations and seizures have been reported. Rarely, diphenhydramine overdose results in death. Even excessive topical administration may lead to toxic blood levels. Risk factors may include use in a very young child, and anything that increases transdermal absorption, including excoriation due to pruritus and vasodilatation after a warm bath [Turner, 2009].

Atropine and Related Alkaloids

Many drugs with anticholinergic properties, such as atropine, may produce an acute anticholinergic syndrome if taken in excess (see previous toxidrome discussion). Examples of drugs with significant anticholinergic properties include atropine, scopolamine, and local mydriatics, such as cyclopentolate (Cyclogyl) and tropicamide (Mydriacyl); a few antihistaminics, such as diphenhydramine and tripelennamine; gastrointestinal antispasmodics, such as dicyclomine (Bentyl) and propantheline (Pro-Banthine); and older tricyclic antidepressants. The scopolamine-containing transdermal patches used for the prevention of motion sickness are a novel way to administer excessive amounts of scopolamine to children. The transdermal patch was developed primarily for adults and contains 1.5 mg of scopolamine, which can produce toxic psychosis in children and should be used with caution [Klein et al., 1985a; Lewis et al., 1994]. These patches also are used in some developmentally disabled children (e.g., with cerebral palsy) to decrease drooling. Poisoning also may occur after ingestion of plants containing belladonna alkaloids (Atropa belladonna, also known as deadly nightshade). Recreational abuse of such plants (e.g., tea made with Brugmansia [angel’s trumpet] and Datura spp.) in teenagers has been reported, although seizures or fatalities resulting from drinking the prepared tea appear unlikely [Isbister et al., 2003; Patel et al., 2003].

Supportive measures are the mainstay of therapy. Physostigmine may be used but may precipitate cholinergic toxicity, including seizures and bradyarrhythmias, and its use requires availability of adequate supportive therapy for these potential complications [Kulig and Rumack, 1983]. Physostigmine (0.5 mg intravenously) is administered slowly in children; it may be repeated every 10 minutes for a maximum total dose of 2 mg.

Cyclosporine

Cyclosporine, a potent immunosuppressant, is being used increasingly in solid organ transplantation [de Groen et al., 1987; Lee and Vacanti, 1996]. It probably is implicated most in neurologic sequelae of transplantation drugs [Faraci et al., 2002]. Neurotoxicity, nephrotoxicity, and hypertension are complications of cyclosporine therapy. Cyclosporine is lipophilic, a property that allows it relatively easy access to the CNS. The most common side effects of cyclosporine on the nervous system are headache, confusion, and seizures, but cortical blindness, hemiparesis, ataxia, and tremor also are reported [Adams et al., 1987; Boon et al., 1988; Garg et al., 1993; Ghalie et al., 1990; Miller, 1996; Reece, 1991; Soy et al., 1995; Trzepacz et al., 1993]. A syndrome of encephalopathy, seizures, and cerebral white-matter changes also has been described. The white-matter changes are more prominent in the parieto-occipital areas and resemble posterior reversible encephalopathy syndrome [Miller, 1996; Truwit et al., 1991; Nishie et al., 2003]. Marchiori and associates reported a case of cyclosporine-associated posterior reversible encephalopathy syndrome and reversible opsoclonus in a teenager after orthotopic liver transplantation [Marchiori et al., 2004]. These complications seem to be reversible but may require a decrease in the cyclosporine dose. Side effects usually are associated with high levels of cyclosporine. Other factors that exacerbate cyclosporine toxicity include hypertension, fever, hypomagnesemia, hypocholesterolemia, aluminum overload (especially in patients undergoing renal transplantation), and concurrent methylprednisolone treatment [Bhatt et al., 1988; de Groen et al., 1987; Thompson et al., 1984; Trzepacz et al., 1993].

OKT3

OKT3 is a murine monoclonal anti-pan-T-cell antibody of the immunoglobulin G2a isotype. OKT3 has been used extensively as an immunosuppressant agent in acute cellular allograft rejection or graft-versus-host disease [Norman, 1989]. The target of OKT3 is CD3, a 17- to 20-kDa molecule found on mature T cells that is selectively removed during treatment with this monoclonal antibody. OKT3 blocks both the generation and function of cytotoxic T cells. The half-life of injected OKT3 is about 18 hours [Fung, 1991; Norman, 1989]. A picture of aseptic meningitis with fever, photophobia, cephalgia, and cerebrospinal fluid pleocytosis has been described with OKT3 use [Adair et al., 1991; Emmons et al., 1986; Martin et al., 1988]. Other complications have included cerebral edema, seizures, cerebritis, and tremor [Capone and Cohen, 1991; Garg et al., 1993; Thomas et al., 1987; Trzepacz et al., 1993].

Tacrolimus (FK-506)

Tacrolimus, or FK-506, is used primarily to prevent organ rejection in liver transplant recipients [Diasio and LoBuglio, 1996; Lee and Vacanti, 1996]. Like cyclosporine, it inhibits interleukin-2 and is thought to act by inhibiting T-cell activation. Serum levels of tacrolimus are altered significantly by multiple drugs, including cyclosporine, methylprednisolone, metoclopramide, some antiepileptic drugs, and various antifungal agents.

Tacrolimus has clinical toxicity similar to that of cyclosporine. At serum levels greater than 3 ng/mL, delirium has been reported [Trzepacz et al., 1993]. Other neurologic side effects include dysphasia, seizures, and tremor. The dose relationship of these side effects is unclear, although increased toxicity has been noted with concomitant use of agents that increase tacrolimus delivery to the small intestine (e.g., metoclopramide) [Backman et al., 1994; Trzepacz et al., 1993; Prescott et al., 2004]. MRI may indicate white-matter change, but reversibility may be predicted by apparent diffusion coefficient mapping [Shimono et al., 2003; Furukawa et al., 2001].

Chloramphenicol

Chloramphenicol has been associated with the development of a reversible optic neuritis, demonstrable clinically and by visual-evoked potentials, in patients with cystic fibrosis who undergo long-term treatment with chloramphenicol [Leikin and Paloucek, 1995; Leitman et al., 1964; Spaide et al., 1987].

Nitrofurantoin

Polyneuropathy is a known complication in patients treated over prolonged periods with nitrofurantoin, particularly in the presence of impaired renal function. Patients have ascending sensory and motor polyneuropathy associated with increased spinal fluid protein [Spring et al., 2001].

Aminoglycosides

Aminoglycosides are potentially ototoxic. Recent data suggest that susceptibility to aminoglycoside-induced ototoxicity is associated with a mitochondrial mutation (nucleotide 1555) [Usami et al., 1997]. Symptoms may arise not only from oral or parenteral administration of the drugs, but also after wound irrigation. A myasthenic-like syndrome accompanied by generalized muscle weakness, which is partially antagonized by neostigmine, may result from the administration of aminoglycosides such as streptomycin, neomycin, kanamycin, bacitracin, colistin, and gentamicin. This reaction usually occurs in association with the simultaneous administration of a neuromuscular blocking agent (e.g., succinylcholine, d-tubocurarine, decamethonium bromide). This neuromuscular blocking effect is especially pronounced when these antibiotics are placed in the pleural or abdominal cavities, with resultant rapid absorption and high plasma levels. These antibiotics may also cause a transient clinical deterioration in patients with myasthenia gravis [Kaeser, 1984].

Beta-Lactam Antibiotics

The β-lactam antibiotics are a diverse group of medications with potential for myriad systemic and neurologic side effects. Seizures caused by the penicillins, cephalosporins, and carbapenems result from the inhibition of gamma-aminobutyric acid (GABA) receptors [Asensi et al., 1993; Sunagawa and Nouda, 1996]. Movement disorders and change in sensorium also may occur. Effects may be magnified in a child with an altered blood–brain barrier.

Vinca Alkaloids

Vincristine and vinblastine are potent antineoplastic agents with variable degrees of neurotoxicity, some of which is reversible. Impaired nutrition appears to increase susceptibility to vincristine toxicity. Greater neurotoxicity is also related to higher concentrations of drug per dose and increased frequency and duration of therapy. Some degree of symmetric peripheral neuropathy, with areflexia involving early and consistent loss of Achilles tendon reflexes, slapping gait, muscle atrophy, and leg weakness, develops frequently, even with customary doses of vincristine. Numbness and tingling paresthesias in hands and feet are common with preserved cutaneous sensation, although the child may complain of hand clumsiness before the onset of footdrop [Tuxen and Hansen, 1994]. Muscle cramps are also a frequent symptom of vincristine-associated motor neuropathies, occurring in both proximal and distal distributions [Haim et al., 1991]. Cranial nerve palsies also may occur, with involvement of cranial nerves II to VIII and X. The most common ocular findings are variable degrees of ophthalmoparesis and ptosis. Autonomic dysfunction is another aspect of vincristine neurotoxicity, with colicky abdominal pain, paralytic ileus, constipation (in 33–46 percent of patients), and bladder atony [Christensen et al., 1994; Tuxen and Hansen, 1994]. Generalized seizures and inappropriate secretion of antidiuretic hormone are additional but rare complications of vincristine treatment [Sandler et al., 1969; Shurin et al., 1982]. Vincristine’s peripheral neurotoxic effects may be potentiated by itraconazole [Ariffin et al., 2003; Kamaluddiin et al., 2001]. Vinorelbine has the potential to cause similar neurotoxic effects but, possibly because of its greater selectivity for mitotic rather than axonal microtubules, does so less often [Tuxen and Hansen, 1994].

Vincristine also causes a necrotizing myopathy [Le Quintrec and Le Quintrec, 1991]. Especially with concomitant steroid therapy, a combined myoneuropathy picture may develop [Bradley et al., 1970; DeAngelis et al., 1991]. Improvement usually ensues with completion of therapy.

Methotrexate

Myelopathy, headache, vomiting, nuchal rigidity with aseptic meningitis, truncal ataxia, tremor, paraplegia, delirium, and somnolence have been described as complications of both intrathecal and systemic therapy with methotrexate. Meningoencephalopathy can occur as late as several months after completion of methotrexate therapy. Scattered subcortical intracerebral calcifications may result from large cumulative doses of intravenous methotrexate, and concurrent administration of cytosine arabinoside may increase the risk for this complication [McIntosh et al., 1977]. The most devastating effect of methotrexate therapy, originally thought to be related to a combination of a high dose of intrathecal methotrexate and CNS irradiation, is a subacute and usually progressive leukoencephalopathy. A characteristic pattern of decreased density of periventricular white matter is evident on CT or as increased periventricular signal on T2-weighted MRI. Clinical manifestations include mental deterioration with dementia, seizures, and focal neurologic deficits. This complication may occur between 3 and 9 months after high-dose methotrexate therapy. An immediate and fatal necrotizing leukoencephalopathy has been reported in association with an inadvertent, more than 50-fold intrathecal overdose of methotrexate [Ettinger, 1982]. Leukoencephalopathy can occur with intravenous methotrexate therapy plus cranial irradiation without intrathecal administration of the methotrexate [McIntosh et al., 1977; Price and Jamieson, 1975; Weiss et al., 1974; Shuper et al., 2002]. Animal studies suggest that concomitant administration of steroids may play a role in this neurotoxicity [Mullenix et al., 1994]. In addition, underlying disease may potentiate methotrexate toxicity. Miller and Wilkinson describe 79–93 percent reduction in local cerebrospinal fluid clearance of intraventricularly administered methotrexate in three individuals with carcinomatous meningitis [Miller and Wilkinson, 1989]. Improvement also has been described in a single report using a combination of high-dose folinic acid and aminophylline [Jaksic et al., 2004].

l-Asparaginase

l-Asparaginase therapy may produce changes in mentation, somnolence, and EEG slowing [Moure et al., 1970; Tuxen and Hansen, 1994]. Intracranial thrombosis or hemorrhage and peripheral arterial thrombosis with headache, obtundation, hemiparesis, and seizures have also been recognized as complications in 1–2 percent of children receiving l-asparaginase [Priest et al., 1982]. The associated coagulation disorder is thought to be secondary to l-asparaginase-induced decrease in antithrombin III level [Kieslich et al., 2003]. Despite this, it is not yet clear that l-asparaginase-related cerebrovascular thrombosis responds to replacement of factors, or that it is resistant to low-molecular-weight heparin therapy.

Platinum Agents

Ototoxicity is a common complication of cisplatin therapy; peripheral sensory neuropathy may also occur, with dysesthesias and paresthesias, diminished reflexes, decreased vibratory and light touch sensation, and sensory ataxia [Cavaletti et al., 1996; Thompson et al., 1982; Steeghs et al., 2003; Markman, 2003]. Although retinal toxicity is reported in adults, it is rare in children and may be associated with abnormal renal function [Hilliard et al., 1997]. Autonomic neuropathy is rare. Oxaliplatin has similar neurotoxic potential; carboplatin appears somewhat less toxic to the nervous system [Tuxen and Hansen, 1994]. Possible neuroprotectant agents that may minimize this neurotoxicity include calcium channel antagonists, thiol compounds, adrenocorticotropic hormone analogs, and neurotropic factors [Cavaletti et al., 1996].

Cytosine Arabinoside

Cytosine arabinoside has been associated with transient paraplegia after intrathecal administration. In childhood acute myelogenous leukemia, patients given intrathecal and intravenous cytosine arabinoside have exhibited progressive ascending paralytic disease, with onset delayed up to 6 months after treatment, accompanied by spinal cord demyelination [Dunton et al., 1986]. Cytosine arabinoside may also cause cerebellar ataxia, change in sensorium (the latter at high doses), and, rarely, peripheral neuropathy or brachial plexopathy [Tuxen and Hansen, 1994].

Cyclophosphamide and Ifosfamide

Cyclophosphamide and ifosfamide both may cause CNS toxicity (10–30 percent incidence in the case of the latter) [DiMaggio et al., 1994; Tuxen and Hansen, 1994]. This toxicity is manifest as mental status changes, seizures, and ataxia. Cranial neuropathies also are possible. In the case of ifosfamide, toxicity may be evident within 2 hours after infusion is begun, and may continue for 1–3 days after a 5-day course of therapy [Pratt et al., 1989; Nicolao and Giometto, 2003; Rieger et al., 2004]. It is more likely to occur in the face of common concomitants of malignancy, including hepatic or renal dysfunction, hypoalbuminemia, acidosis, or prior CNS abnormality. Improvement has been reported with methylene blue administration [Raj et al., 2004.

Other Agents Used in Cancer Chemotherapy

Fludarabine, cladribine, and pentostatin are newer purine analogs that currently are used more often in adults than in children. They carry potential for fatal neurotoxicity at higher than recommended doses; at the recommended dosage, each carries a 15 percent risk for (usually reversible) neurotoxicity [Cheson et al., 1994].

Finally, as cytokines find increasing roles in cancer chemotherapy, their neurotoxicity is becoming more evident. Evidence is strongest for interferon and interleukin-2. Interferon therapy has been associated with frontal lobe dysfunction (decreased executive functions, transient aphasia), migraine, parkinsonism and akathisia, and peripheral neuropathy. Conversely, interleukin-2 use has been linked to neurobehavioral changes ranging from lethargy to delirium. The mechanism of neurotoxicity is unclear, although it is postulated that they circumvent the blood–brain barrier through a poorly understood mechanism. Quantification of the degree of toxicity awaits prospective studies [Forman, 1994; Margolin, 1994].