E. Lee Murray, MD
CHAPTER CONTENTS
OVERVIEW
Toxin exposure is a common reason for a ED visit, and although most of these are managed by emergency physicians and internists, neurologists are sometimes called on to assist with selected toxin exposures. Prescription medications and household chemicals are common causes of toxic neurologic symptoms, some acute, some insidious. Here, we focus on some of the most important toxic exposures, selected by virtue of frequency or severity.
PRESCRIPTION MEDICATIONS
A list of medications with potential neurologic toxicity is far beyond the scope of this book, but a brief synopsis of some of the most important is discussed. It is sometimes difficult to distinguish between idiosyncratic effect, hypersensitivity, allergy, and dose-dependent toxicity, so some of these are blended in this discussion. The neurologic toxicity of some common medications includes:
◦Exacerbation of seizures: Several, especially carbamazepine.1
◦Hyponatremia: especially carbamazepine and oxcarbazepine.
◦Acute dystonic reaction: Many
◦Tardive dyskinesia: Many, less for atypical neuroleptics
◦Neuroleptic malignant syndrome: Many
◦Parkinsonism: Especially typical neuroleptics
◦Tremor: Most common neurological complication, postural and intention2
◦Parkinsonism: Uncommon3
◦Encephalopathy: Can be profound
Antidepressants are associated with a variety of neurologic complications; however, they are overrepresented even in patients who are not treated.4
ETHANOL AND OTHER ALCOHOLS
Alcohol intoxication is usually presumed to be ethanol, but this term includes others, especially isopropanol, methanol, and ethylene glycol. This section will focus on ethanol with subsequent brief discussions of the other alcohols.
Ethanol
Hospital neurologists see the spectrum of ethanol effects from acute intoxication to chronic neuronal degeneration to neurologic manifestations of liver failure. The list presents some of the important syndromes resulting in neurologic consultation:
•Hepatic failure: Chapter 11
•Wernicke-Korsakoff syndrome: Chapter 29
•Central pontine myelinolysis (CPM): Chapter 13
Ethanol Intoxication
Ethanol intoxication manifests a range of symptoms that depend on individual susceptibilities and metabolism. Levels that are well-tolerated by some may produce severe intoxication in others. Chronic ethanol use can produce neuronal degeneration directly and/or manifest neurologic symptoms through coexistent nutritional deficiency.
PRESENTATION may be excitatory or depressive. Patients may have agitation, excitement, and enhanced loquaciousness. Alternatively, they may be lethargic or somnolent. There may be cognitive dysfunction with disinhibition progressing to confusion, stupor, and even coma. Motor manifestations are most commonly dysarthria and gait ataxia. Rare complications are acute psychosis and “blackouts”—epochs for which the patient is amnestic.
DIAGNOSIS is suspected with the clinical presentation of cognitive and behavioral deficits with ataxia and dysarthria. Clinicians usually notice the typical breath of ethanol intoxication. Confirmation is by documentation of elevated ethanol levels. Note that identification of ethanol intoxication does not rule out coexistent disorder so computed tomography (CT) should be performed if the symptoms are out of proportion to the ethanol level or if there are clinical signs of head injury, mental status changes, focal deficits, or seizures.
MANAGEMENT begins with supportive care for most patients. Hemodialysis is considered for refractory patients and those with extremely high ethanol levels.
Ethanol Withdrawal
Ethanol withdrawal can cause an array of neurologic manifestations. Timing of onset depends on the manifestation. Persistent intake and abrupt withdrawal can begin to produce symptoms within 6 hours, whereas delirium tremens (DTs) has an onset 48–72 hours later.
PRESENTATION begins in about 6 hours with mild tremor, the “morning shakes.” With progressive time and severity, progression through delirium to DTs can occur. Symptoms of ethanol withdrawal are summarized here:
•Mild: Tremulous, sweating, headache, and often GI symptoms
•Moderate: Restlessness, agitation; may be hyper-alert
•Severe: Delirium tremens with confusion, agitation, hallucinations, often with associated fever, tachycardia, and diaphoresis
Seizures are common during the withdrawal period, usually around 12 hours from last intake. They are usually single; repetitive seizures are less likely.
DIAGNOSIS is suspected with the development of agitated delirium especially with seizure in the absence of another obvious cause. Studies include CT brain for structural lesion, electroencephalogram (EEG) for seizure activity, and sometimes lumbar puncture (LP) for infection. Fever and encephalopathy should prompt consideration of LP even if the patient is a known alcoholic since meningitis and encephalitis still would be in the differential diagnosis.
MANAGEMENT begins with supportive care including fluid and electrolyte management. Patients commonly are dehydrated, malnourished, and are predisposed to hyponatremia, hypokalemia, and hypomagnesemia.
•Thiamine supplementation is given if ethanol abuse is suspected, even if the diagnosis is not confirmed.
•Sedation with chlordiazepoxide, diazepam, or lorazepam is often helpful. Phenobarbital is sometimes used for refractory cases.
•Seizure recurrence can be reduced by lorazepam (often 2 mg IV) after the first seizure. Long-term antiepileptic drugs are usually not needed.
Alcoholic Cerebellar Degeneration
Alcoholic cerebellar degeneration is progressive gait ataxia due to neuronal degeneration. Although this is most commonly seen in alcoholics, it is also seen in patients with nutritional deficiency for other reasons.
PRESENTATION is with gait ataxia, consisting of a wide-based stance. Gait often has a shuffling appearance. Ocular findings are uncommon but can include nystagmus and saccadic pursuit. The presentation of unexplained gait ataxia should prompt questioning and investigation of possible ethanol use.
DIAGNOSIS is suspected with progressive gait ataxia without another evident cause. Ethanol toxicity is suspected especially with ocular motor findings. Limb ataxia or dysarthria as part of a cerebellar syndrome suggests other diagnoses.
Brain imaging shows no strokes or other structural lesion, but there is prominent atrophy of the superior cerebellar vermis on sagittal magnetic resonance imaging (MRI); this finding may not be noted by some radiologists—yet another reason for neurologists to view images themselves.
MANAGEMENT is supportive. There is no specific treatment for the ataxia. Cessation of ethanol intake is key. Nutritional supplementation is given, including thiamine as well as other vitamins and nutrients. The ataxia often persists despite abstinence.
Optic Neuropathy with Alcohol Abuse
Optic neuropathy can develop in patients with ethanol abuse. This is likely multifactorial, a direct effect of ethanol plus other agents. Tobacco-alcohol amblyopia is a manifestation of this. Effects may be indirect, including nutritional deficiency, B1 and B12 deficiency, or mediated by accumulation of formic acid with resultant mitochondrial dysfunction.
PRESENTATION is with subacute development of blurred or dim vision. Visual difficulty develops over weeks and is painless. Exam shows centrocecal scotoma. Optic nerves may show pallor, especially on the temporal aspect of the discs.5 Visual loss may progress to blindness.
DIAGNOSIS is suggested by the presentation of bilateral painless visual loss in a patient with a history of significant ethanol use, especially if there is also a smoking history. Coexistent cerebellar ataxia or neuropathy supports the diagnosis. MRI brain and even LP often have to be performed to look for other causes. However, optic neuritis is usually not painless and also can be associated with very different funduscopic findings.
MANAGEMENT begins with cessation of ethanol consumption. Nutritional supplementation is given to ensure adequate protein-calorie intake and specifically sufficient B1 and B12. Improvement in vision is expected with optimal treatment and ethanol abstinence.
Alcoholic Neuropathy
Alcoholic neuropathy is a common complication of chronic ethanol use. It is seldom found in isolation; it usually is seen in combination with other complications of alcoholism.
PRESENTATION is with sensory more than motor symptoms, although both develop. Pain and paresthesias can develop.
DIAGNOSIS is suspected with symptoms and signs of neuropathy and a confirmed or suspected history of ethanol abuse. Nerve conduction studies and electromyogram (NCS/EMG) can confirm the neuropathy. Additional labs for hepatic and other associated abnormalities are helpful.
MANAGEMENT is with cessation of ethanol intake and adequate nutrition. Medications for neuropathic pain may be needed; non-narcotic meds are preferred.
Alcoholic Myopathy
Alcoholic myopathy can be acute or chronic. It can lead to rhabdomyolysis (Chapter 21).
PRESENTATION is with muscle weakness, usually proximal, with pain, and this is usually contemporaneous with an increase in alcohol consumption.
DIAGNOSIS is suspected when a patient presents with rhabdomyolysis (acutely) or weakness with a myopathic character (chronically) and has a known or suspected history of ethanol abuse.
MANAGEMENT is by cessation of ethanol use and adequate nutrition. There are no other specific treatments.
Isopropanol
Isopropanol (isopropyl alcohol) is most commonly encountered as the principal ingredient of some brands of rubbing alcohol. Isopropanol is sometimes consumed by accident or intentionally as an ethanol substitute.6
PRESENTATION can be mild or severe. Mild symptoms include nausea and vomiting. Severe symptoms include CNS and respiratory depression and progressive deterioration. Cardiovascular collapse can develop.
DIAGNOSIS is most likely to be suspected with a history of ingestion. In the absence of this history, it is suspected when the patient is noted to have a breath with a sweet smell and is found to have ketosis without acidosis. Isopropanol levels are elevated.
MANAGEMENT is supportive for most patients. For patients with severe poisoning, hemodialysis should be considered.
Methanol
Methanol is a commonly used solvent and is also found in some home-distilled drinks. Methanol is suspected especially when a patient presents with visual difficulty after an episode of intoxication, but this is unfortunately late in the process. Formic acid is produced in the retina. Exposure may be as an ethanol substitute or in a suicide attempt.
PRESENTATION early is with clinical intoxication similar to that of ethanol. After 1–2 days, visual difficulty may develop with blurring and flashes of light. Subsequently, headache then cognitive changes can develop with confusion, possibly progressing to lethargy and coma.
DIAGNOSIS is considered with unexplained encephalopathy and increased osmolar gap. Amylase is often increased. Hemorrhagic pancreatitis can develop. Methanol level is elevated.
MANAGEMENT is supportive. Fluid and electrolytes and acid–base balance are managed. Ethanol or fomepizole are sometimes used to delay methanol metabolism until otherwise eliminated. Hemodialysis is used for selected patients with severe toxicity, especially with visual deficits, high methanol levels, or high volumes ingested.
Ethylene Glycol
Ethylene glycol is a component mainly of radiator fluids as antifreeze. Because of the sweet taste, animals and humans are susceptible to ingestion.
PRESENTATION is initially with clinical intoxication similar to that of ethanol. Mental status changes predominate. Delayed effects start after about 12 hours with tachycardia, hypertension, tachypnea, acute respiratory distress syndrome (ARDS), and or cardiac arrhythmias.
DIAGNOSIS is usually suspected by either a history of ingestion or an early osmolar gap that develops into a high anion gap metabolic acidosis. Ethylene glycol levels can be measured in some labs. Otherwise, UV light examination of urine may reveal fluorescein fluorescence because this compound is added to radiator fluid to facilitate identification of leaks.
MANAGEMENT begins with supportive care with fluid and electrolyte management. Cardiac and respiratory monitoring and management are required. Antidotes include fomepizole and ethanol, the former preferred. Thiamine and pyridoxine supplementation is occasionally used to enhance metabolism, but this is not routine.
HEAVY METALS
The most important heavy metals producing human toxicity are:
Although there is overlap in presentation and management, they are discussed individually. Suspicion is the key to diagnosis of heavy metal intoxication. Hypochromic microcytic anemia can occur in any of these.
Lead Poisoning
Lead intoxication is most likely to be from occupational exposure, water contamination, or household contamination.
PRESENTATION depends on the acuteness of the exposure:
•Acute high-dose exposure: Encephalopathy, neuropathy, renal failure
•Chronic exposure: Cognitive changes, especially in children; weakness, sleep disturbance
DIAGNOSIS is suspected by hypochromic microcytic anemia, which would suggest lead or other heavy metal toxicity. Blood lead levels can be measured. Free erythrocyte protoporphyrin level is increased with chronic exposure but typically not with acute exposure.
MANAGEMENT begins with cessation of exposure. Chelation is used for patients with high lead levels, especially with organ damage including encephalopathy or renal damage.
Mercury Poisoning
Inorganic mercury is not absorbed through the GI tract but organic mercury, particularly methylmercury, is absorbed well.
PRESENTATION is often with prominent neurologic symptoms with central and peripheral manifestations:
•Neuropathic deficits can include numbness, weakness, dysesthesias.
•Central deficits can include cognitive disturbance visual loss, and hearing loss.
•Inhalation of mercury vapor can acutely cause nausea, vomiting, abdominal pain and cramps, with neurologic manifestations of headache, dizziness, and weakness.
DIAGNOSIS of mercury poisoning is suspected with a history of exposure; without this, diagnosis can be difficult.
•Neuropsychiatric manifestations with renal insufficiency may suggest the diagnosis.
•Mercury can be measured in blood and urine.
•EMG may show neuropathic findings.
MANAGEMENT starts with supportive care and cessation of exposure.
•Gastric lavage can be used for recent organic mercury ingestion. Abdominal x-ray may show mercury still in the stomach.
•Chelation can be helpful for patients with prominent symptoms.
•Hemodialysis is used especially if renal function has deteriorated.
Arsenic Poisoning
Arsenic poisoning can be intentional or from contaminated food or drink or occupational exposure. Presentation can be acute or chronic:
•Acute: Confusion, delirium; possible seizures; tachycardia, hypotension
•Chronic: Neuropathy, dermatitis; Mees lines on the fingernails. Hemolytic anemia can occur.
DIAGNOSIS may be suspected with microcytic hypochromic anemia. Urine assay is generally a 24-hour collection. If arsenic levels are elevated, the lab must differentiate between inorganic and organic arsenic because the inorganic version is responsible for most toxicity.
MANAGEMENT requires careful monitoring, especially if arrhythmia is present. Chelation is used for symptomatic patients.
CHOLINESTERASE INHIBITORS
Cholinesterase inhibitors (ChEI) are sometimes termed acetylcholinesterase (AChE) inhibitors, but we prefer the more generic term since there are other cholinesterases.
ChEIs are used for symptomatic treatment of Alzheimer disease and some neuromuscular transmission disorders, and as insecticides, and they are also part of a class of nerve agents used in chemical warfare. Two prominent classes of cholinesterase inhibitors are organophosphates and carbamates. They produce similar clinical presentations.
Cholinesterase-inhibitor intoxication can begin with exposure to insecticides or from overdose of ChEIs given as medications for medical reasons. A terrorist attack might also use these agents.
PRESENTATION starts with generalized muscular weakness. Fasciculations are common and suggest the diagnosis. Encephalopathy and seizures can occur with acute high-dose exposure. Cardiac arrhythmia may also occur with high-level exposure. Chronic exposure can produce progressive weakness and neuropathy.
DIAGNOSIS may be suspected with a presentation of marked weakness, respiratory difficulty, fasciculations, and miosis. RBC cholinesterase assay helps with diagnosis when available. Atropine can produce marked improvement in symptoms, which is helpful diagnostically as well as therapeutically.
MANAGEMENT is usually with a combination of the following agents:
•Atropine can improve especially the respiratory symptoms.
•Pralidoxime (2-PAM) is used for neurologic symptoms.
•Benzodiazepines (e.g., diazepam/lorazepam) is used for control of seizures.
