History
Symptom history
Carbamazepine toxicity should be considered in the differential diagnosis of patients presenting with ataxia. Query about the following:
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Whether the patient is carbamazepine naive or has been taking carbamazepine on a long-term basis
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Time of ingestion
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Drug formulation (immediate vs extended release)
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Approximate dose ingested
Signs and symptoms of carbamazepine toxicity may include the following:
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Drowsiness
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Slurred speech
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Ataxia
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Hallucinations
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Nausea, vomiting
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Tremors
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Seizures
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Oliguria
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Blurred vision
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Bullous skin lesions
Carbamazepine toxicity should be considered in any child who presents with seizures, apnea, or an unexplained change in mental status, particularly when the child has access to the drug. The serum concentration may not always directly correlate with the clinical picture. The severity of toxicity is assessed on the basis of the clinical status and not the serum carbamazepine concentration.
Symptoms usually appear within 6 hours after ingestion but significant symptoms may be delayed for as long as 24 hours. Case reports indicate the possibility of delayed absorption, which causes levels to peak as late as 72 hours. Overdose of controlled-release formulations of carbamazepine can result in delayed presentations of toxicity; levels may not peak for 96 hours from the time of ingestion. [20]
Mild toxic ingestions cause vomiting, drowsiness, ataxia, slurred speech, nystagmus, dystonic reactions, and hallucinations. Infrequently, hyperglycemia may be present. [21]
Severe intoxications may produce hypotension, respiratory depression, seizures, and coma. Neurologic symptoms are the most common manifestations seen with severe overdoses. For example, a case report describes a 7-year-old boy presenting to the emergency department in a coma after ingesting the equivalent of 100 mg/kg of carbamazepine. [22]
Ingestion history
In children younger than 6 years, ingestions of carbamazepine are commonly unintentional. Suicidal ingestions typically occur in adolescents.
Other causes of carbamazepine poisoning include iatrogenic overdose; dosage errors; and interactions with drugs such as erythromycin, cimetidine, and isoniazid. All these drugs increase the levels of carbamazepine by competitively inhibiting its metabolism.
The medication source is usually the patient or another family member who is taking carbamazepine for seizure control or the treatment of other illness.
An important cause of toxicity in children who are using the suspension is failure to adequately shake the bottle. Because the drug settles to the bottom of the bottle, if the full bottle is not shaken, the patient actually receives a low dose of the drug, which may lead to subtherapeutic levels and seizures. However, if the child is subsequently given doses of the drug from the bottom of the unshaken bottle, toxicity may occur because the active drug has been concentrated there.
Physical Examination
Vital signs
Tachycardia is common with carbamazepine toxicity. Hypothermia may occur after an acute overdose and may last as long as 10 hours.
Neurologic effects
Common neurologic effects include ataxia, slurred speech, nystagmus, dystonia and other extrapyramidal movements, and various degrees of central nervous system depression. A waxing and waning delirium is commonly seen. Seizures are common in children with an underlying epileptic disorder. In severe cases, coma and status epilepticus may occur.
Syndrome of inappropriate antidiuretic hormone secretion has also been reported, though this complication is much more common with long-term use. [23, 24]
Respiratory effects
Respiratory depression or apnea that requires mechanical ventilation may be observed within first 24 hours of the patient's presentation. Pulmonary edema or aspiration pneumonia may occur. Fulminant interstitial pneumonitis may also be noted. [25]
Cardiovascular effects
Cardiovascular effects are rarely observed in children. Hypotension, bradycardia, and conduction disorders may occur in patients with an abnormal myocardium or a preexisting conduction defect. A 2:1 atrioventricular (AV) block due to carbamazepine has been reported, which may occur even at therapeutic serum carbamazepine levels, and can be reversible after discontinuation of carbamazepine therapy. [26]
Gastrointestinal and hepatic effects
Antimuscarinic effects include delayed gastric emptying and decreased intestinal motility.
With acute carbamazepine toxicity, chemical pancreatitis without accompanying pain or abnormalities may be present.
Hepatitis and, rarely, liver failure may occur. This is usually due to an idiosyncratic reaction rather than an overdose. Studies in mice demonstrate that liver injury due to carbamazepine is probably due to metabolic activation of enzymes followed by the stimulation of immune responses. Prostaglandin E administration appeared to ameliorate the liver toxicity caused by carbamazepine in mice. [27]
Hematologic effects
Neutropenia, agranulocytosis, thrombocytopenia, and aplastic anemia may occur with therapeutic doses or chronic intoxication but not after an acute overdose. Carbamazepine in therapeutic doses has also been reported to have induced immunoglobulin deficiency in some cases; [28] however, this has not been reported in acute intoxication.
Thrombocytopenia or aplastic anemia can result in bleeding. However, this effect is rarely seen with acute poisoning.
Dermatologic effects
Dermatologic effects are due to idiosyncratic reactions rather than to an overdose of carbamazepine. Severe cutaneous adverse reactions such as the following may occur:
Patients of Asian descent, especially Han Chinese, are particularly at risk for severe cutaneous adverse reactions. This sensitivity is linked to carriage of the HLA-B*1502 allele. The US Food and Drug Administration has recommended screening for the HLA-B*1502 allele before starting carbamazepine therapy in patients of Asian ancestry. [8] In Europeans, the HLA-A*3101 allele has been associated with carbamazepine-induced hypersensitivity reactions, but this is much less common than that seen in Asians who have the HLA-B*1502 allele. [33]
Endocrine effects
Long-term use of carbamazepine may decrease free T4 levels. Usually the body compensates by increasing thyrotropin levels. Therefore, thyroid function tests should be monitored in patients on carbamazepine, and thyroid hormone supplementation can be given if clinically indicated. [34]
Hyponatremia
Hyponatremia is not usually seen after acute overdoses but is known complication of chronic use. There are several risk factors for hyponatremia associated with carbamazepine use: age greater than 40 years, concomitant use of drugs associated with hyponatremia, menstruation, psychiatric conditions, surgery, (psychogenic) polydipsia, and female gender. Symptoms such as unsteadiness, dizziness, difficulty concentrating, reduced attention span, mild confusion, and lethargy should alert the physician to check the sodium levels. In patients with multiple risk factors, hyponatremia may occur much faster and can even cause life-threatening symptoms. In such cases, preventive fluid restriction can be of great value. [9]
Fatalities
Death may result from any of the following:
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Apnea
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Status epilepticus
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Aspiration pneumonitis
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Severe hepatitis
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Aplastic anemia
