Pediatric Neurology xxx (2015) 1e5
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Bupropion Overdose Presenting as Status Epilepticus in an Infant Marianna S. Rivas-Coppola MD, Amy L. Patterson MD, Robin Morgan MD, James W. Wheless MD * Division of Pediatric Neurology, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital Neuroscience Institute, Memphis Tennessee
abstract BACKGROUND: Bupropion is a monocyclic antidepressant in the aminoketone class, structurally related to amphetamines. The Food and Drug Administration withdrew this product from the market in 1986 after seizures were reported in bulimic patients. It was later reintroduced in 1989 when the incidence of seizures was shown to be dose-related in the immediate release preparation. Massive bupropion ingestion has been associated with status epilepticus and cardiogenic shock in adults. Seizures have been reported in children, but not status epilepticus. This report highlights a patient who presented with status epilepticus and developed cardiopulmonary arrest after bupropion ingestion. False-positive amphetamine diagnosis from urine drug screen on presentation was reported. METHOD: We review the presentation, clinical course, diagnostic studies, and outcome of this patient. We then review the literature regarding bupropion overdose in children. RESULT: Symptoms of bupropion toxicity and risk for seizures are dose-dependent and fatalities have been reported. Our patient developed status epilepticus and cardiopulmonary arrest and then progressed to have a hypoxic ischemic encephalopathy and refractory symptomatic partial seizures. CONCLUSION: Our report highlights the need to keep this medication away from children, preventing accidental overdose. Keywords: status epilepticus, cardiogenic shock, hypotension, bupropion, toxicity, children
Pediatr Neurol 2015; -: 1-5 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Bupropion is an atypical antidepressant that was originally approved by the Food and Drug Administration in the United States in 1985 for treatment of depression in adults but was withdrawn by the Food and Drug Administration in 1986 after an increased incidence of seizures was noted in bulimic patients.1,2 It was reintroduced in 1989 when the incidence of seizures was shown to be dose-related, with an incidence of seizures similar to that of other antidepressants.3 Status epilepticus and cardiogenic shock after massive bupropion ingestion has been reported in adults.4 Seizures Article History: Received March 23, 2015; Accepted in final form May 23, 2015 * Communications should be addressed to: Dr. Wheless; Division of Pediatric Neurology; University of Tennessee Health Science Center; Le Bonheur Children’s Hospital; Neuroscience Institute; 51 N. Dunlap St., Suite 335; Memphis, TN 38105, United States. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.05.018
have been reported after bupropion overdose in an infant and children,5-7 but no cases of status epilepticus have been reported in children. Refractory hypotension and transient cardiac dysfunction in an infant from a massive bupropion overdose have been described.5 Our report illustrates the unique presentation of an infant with status epilepticus and cardiopulmonary arrest after accidental ingestion of bupropion. She initially exhibited a false-positive drug urine screen for amphetamines. A high frequency of false-positive amphetamine screens resulting from bupropion was recently reported.8 We review the clinical presentation, hospital course, and diagnostic studies to educate other health care providers about this entity. Patient Description Our patient is a 15-month-old previously healthy girl who presented with new-onset seizures. The initial seizure was described as an episode of eye rolling with generalized jerking of all four extremities. She was initially evaluated by paramedics and was noted to be experiencing
2
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generalized tonic-clonic seizure activity for which she was transferred to a local emergency room and treated with two doses of intravenous lorazepam with transient cessation of seizure activity. She was lethargic and continued to have intermittent seizures consisting of jerking of the upper and lower extremities over the next few hours. Approximately 78 hours from presentation, she had worsening of the rhythmic jerking and was treated with a third dose of intravenous lorazepam (doses of lorazepam not documented in available records) and a loading dose of fosphenytoin (20 mg/kg). She had no improvement in her mental status over the next several hours. Approximately 16-17 hours after initial presentation, she became apneic with pulseless cardiac arrest. Intubation and cardiopulmonary resuscitation were performed. She received three doses of epinephrine, lactate ringer bolus, and one dose of sodium bicarbonate. After 15-20 minutes, sinus rhythm was restored. She was transferred to the intensive care unit in our tertiary care hospital, where further history was obtained from her mother and grandmother, whose custody she was in at the time of seizure onset. They adamantly denied that the child had access to prescription medications or illicit substances. The review of systems was significant for mild runny nose and cough, but no fever. Her medical history and birth history was unremarkable, including no history of seizures, meningitis, or head trauma. Family history was positive in the maternal uncle and maternal greatgrandfather for seizures. There was no reported family history of psychiatric illnesses. Developmental history including gross motor, fine motor, language, and social skills were appropriated for age. Her initial physical examination on arrival to our facility included a temperature of 34.4 C, blood pressure 74/52 mmHg, and heart rate 104. Dopamine drip and warming measures were started. She was intubated and had no respiratory effort. Neurological examination revealed bilateral dilated, nonreactive pupils, with gaze deviation to the left, no brain stem reflexes, and no withdraw to painful stimuli. The laboratory results from the referring hospital showed evidence of metabolic acidosis before her cardiopulmonary arrest with a pH of 7.21, bicarbonate 19 mmol/dL, and base excess of negative 8.7 on an arterial blood gas. Urine drug screen was positive for amphetamines and was negative for barbiturates, benzodiazepine, cocaine, opiates, and cannabinoids. Blood chemistry and liver enzymes were normal. Complete blood count was remarkable for mild microcytic anemia but no leukocytosis. Computed tomography scan of the head obtained after arrival at the outside facility approximately 1 hour after seizure onset revealed no hemorrhage, edema, mass, or midline shift. Electrocardiogram showed sinus tachycardia that was appreciated on telemetry tracing. She arrived to our facility after the cardiopulmonary arrest and approximately 22 hours from seizure onset; significant laboratory abnormalities included a blood gas revealing mild lactic acidosis (2.75 mmol/L), pH 7.08, bicarbonate 15 mmol/dL, and base excess of negative 11. Liver function tests revealed an elevated aspartate aminotransferase of 1169 unit/L and alanine aminotransferase of 242 unit/L. Urine drug screen was negative. Lumbar puncture was completed on arrival, and she had 2 white blood cells/F, 193 red blood cells/G, glucose 98 mg/dL, and protein 21 mg/dL. A five hour electroencephalograph was obtained, within an hour of arrival, and was abnormal with status epilepticus noted for the first 105 minutes, then for the next 3.25 hours intermittent background suppression, and biposterior epileptiform discharges over the left and right parietal, temporal, and occipital head regions. (No further seizures.) She was treated with two doses of intravenous lorazepam (0.2 mg/kg/ dose), one loading dose of levetiracetam (40 mg/kg), and one dose of intravenous fosphenytoin (20 mg/kg) with no improvement in clinical or electrographic seizure activity. However, after one loading dose of intravenous phenobarbital (20 mg/kg), clinical and electrographic seizure activity stopped. She was treated with supportive care and started on maintenance levetiracetam (40 mg/kg/day given bid), fosphenytoin (8 mg/kg/day), and phenobarbital (5 mg/kg/day) all given intravenously. Over the next 24 hours, spontaneous eye opening, corneal reflex, and gag reflex were appreciated. She also had irregular respiratory effort. She continued to have gaze deviation, no tracking, and minimal movement of all four extremities to noxious stimuli. Echocardiography was performed
22 hours after seizure onset and it revealed normal anatomy, ventricular size, and systolic function. Magnetic resonance imaging of the brain and brain stem performed 48 hours after cardiopulmonary arrest showed findings consistent with severe hypoxic ischemic encephalopathy with areas of restricted diffusion involving bilateral occipital lobes, bilateral superior aspect of the lentiform nuclei, and caudate nucleus. (Figure). Over next few weeks, she showed clinical signs of global hypoxic ischemic encephalopathy, including cortical blindness and spastic quadriparesis. Tracheostomy and gastric tube placement were required. She developed symptomatic, refractory partial epilepsy and is currently taking multiple medications. Although the family adamantly denied that she took any medications, confirmatory laboratory testing of her serum was submitted on arrival to our facility. High-power liquid chromatography detected bupropion.
Discussion
Our patient presented after experiencing multiple seizures followed by cardiopulmonary arrest requiring cardiopulmonary resuscitation. Afterwards she was noted to be in status epilepticus (i.e., electroencephalographic and subtle clinical seizures) that was responsive to phenobarbital treatment. The initial clinical presentation of acute onset seizures in a previously developmentally normal and healthy infant with a positive urine drug screen for amphetamines and a negative computed tomography could be explained by amphetamine ingestion. However, the status epilepticus and cardiopulmonary arrest, followed by significant hypotension, were not as easy to explain, especially given the repeat urine drug screen was negative for amphetamine. Further diagnostic studies including cerebrospinal studies were negative for central nervous system infection. The rest of the laboratory studies showed lactic acidosis, metabolic acidosis, and elevated liver function test, all a consequence of the cardiopulmonary arrest. The etiology of the arrest did not become completely clear until chromatography confirmed bupropion ingestion. Bupropion is an atypical monocyclic antidepressant commonly prescribed in the United States for the treatment of major depressive disorder, seasonal affective disorder, adult attention deficit hyperactivity disorder, and smoking cessation. All forms of bupropion combined totaled 20,745,363 prescriptions in the United States in 2008.9 The amino-ketone structure of bupropion is metabolized in the liver by the cytochrome P450 isoenzyme CYP2B6 to the active metabolites R,R-hydroxybupropion, S,Shydroxybupropion, threohydrobupropion, and erythrohydrobupropion, which are responsible for the pharmacological activity of bupropion.10 Different formulations are available for bupropion including immediate, sustained, and extended-release. It has a plasma half-life of 10 hours, but longer half-lives have been reported for the metabolites.6 Bupropion, erythrohydrobupropion, and threohydrobupropion have chemical structures similar to amphetamine, which may result in cross-reactivity with antibodies used in urine drug screen immunoassays.8-10 Three reports demonstrated false-positive amphetamine urine drug screens associated with bupropion. A recent study evaluating the incidence of false-positive amphetamine screening associated with therapeutic use of bupropion showed that bupropion appeared to be the most frequent cause of false-positive urine drug screens for amphetamines
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3
FIGURE. Magnetic resonance imaging of the brain 48 hours after cardiopulmonary arrest. Diffusion-weighted images (A,B) and apparent diffusion coefficient (C) showing areas of restricted diffusion involving bilateral occipital lobes (arrows), bilateral superior aspect of lentiform nuclei, and caudate nucleus (arrow heads). T2-weighted (D), T2 fluid-attenuated inversion recovery (E), and T1-weighted images showing no brain signal abnormalities or structural brain abnormalities (F). No brainstem abnormalities were noted. (The right side of the brain is on the left side of the photo.)
in their population.8 This can explain the false-positive result obtained on our patient’s initial urine drug screen at the outside hospital. Repeat urine drug screen approximately 22-23 hours from seizure onset was negative. We hypothesized, based on the half-life of 10 hours reported for bupropion, that by the time that the test was performed, the urinary concentration of bupropion and its metabolites were significantly lower (now below the threshold to detect with the urine drug screen), corresponding with our negative result. Clinically significant toxicity after bupropion overdose is primarily neurological and cardiovascular in nature, with the most significant risk being seizures.5 However, most information comes from reports of adults or older adolescents with massive ingestions of bupropion as part of a suicide attempt.2,11,12
A recent report documented a 35-year-old man who presented with cardiogenic shock and status epilepticus after massive bupropion overdose of eighty 150-mg sustained-release tablets (12 g). Quantitative bupropion assays confirmed the massive overdose with serum levels more than 15 times therapeutic levels (0.05-0.1 mg/L). His status epilepticus appeared to be attributable to bupropion. In this particular case, the onset of status epilepticus corresponded to the peak of serum bupropion concentration (3 hours from the ingestion), and the severity of the status epilepticus was probably related to the massive dose ingested and subsequent high cerebral concentrations.4 In published data, cerebrospinal fluid concentrations of bupropion are 10- to 25-fold higher than blood concentration.13,14
4
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Although the mechanism of action of bupropion has not been fully elucidated, the drug and its metabolites have a weak inhibitory effect on the reuptake of norepinephrine and dopamine with no effect on the reuptake of serotonin,15 Bupropion’s sympathomimetic amine structure may also suggest possible stimulation of the hypothalamus to release catecholamines into the central nervous system.6 It is this second mechanism that might be partially responsible for the status epilepticus seen in our patient and the seizures reported in other cases of bupropion overdose. Unintentional ingestion of bupropion in younger children has generally resulted in limited toxicity.7,16 This can be explained by the fact that usual accidental ingestions in children are of low doses of bupropion. In a retrospective study by Spiller et al.,12 reviewing bupropion ingestions in 407 children younger than 6 years, only 18% were symptomatic. Sinus tachycardia was the most common adverse effect (68%), followed by nausea and vomiting (43%), hyperactivity (23%), seizures (4%), and hypertension (2.5%). Dose ingested and patient weights were known for 218 patients in their study, and 88% of those patients ingested less than 20 mg/kg. Multiple seizures after bupropion overdose have been reported in a school-age child.4 Otherwise, status epilepticus in an infant after bupropion overdose has not been reported, especially after cardiopulmonary arrest. Our patient received multiple doses of lorazepam, levetiracetam, and fosphenytoin loads without resolution of her status epilepticus. She responded to a phenobarbital load. The same observation has been reported in two other case reports in which multiple seizures and status epilepticus were successfully treated after a phenobarbital load.4,6 Shenoi reports that benzodiazepines and barbiturates should be preferred in the treatment of drug-induced seizures. Psychotropic drug-induced seizures are typically treated with a benzodiazepine as first-line therapy and phenobarbital as second-line therapy.17 Phenytoin, although considered second-line therapy for most seizures, is not believed to be as effective for drug-induced seizures. Had we known our patient’s status epilepticus was due to bupropion overdose, we would have used phenobarbital earlier. This is important for physicians to keep in mind when treating refractory status epilepticus. At the outside facility, our patient developed persistent sinus tachycardia and her mental status failed to improve despite seizure treatment. Around 16-17 hours from seizure onset, she experienced a cardiac arrest required cardiopulmonary resuscitation for 15-20 minutes, with three doses of epinephrine, a lactated ringer bolus, and one dose of sodium bicarbonate. On arrival to our facility, she was hypothermic and hypotensive, for which epinephrine and dobutamine were administered. In most published examples of bupropion ingestion the dose was much lower and the clinical effects less dramatic; the most common cardiovascular effects were sinus tachycardia, conduction disorders with widening of QRS complex, and prolongation of the QT interval.18-21 Fatalities after massive bupropion ingestion have been documented.22 Massive overdoses are responsible for rapid death from asystolic cardiopulmonary arrest usually from long intervals between the time of ingestion and the time of initial management.
Shenoi et al. recently reported an 11-month-old child with refractory hypotension following a massive bupropion overdose who was successfully treated with extracorporeal membrane oxygenation.5 No abnormalities were seen on this patient’s echocardiogram, suggesting that his refractory hypotension and metabolic acidosis could be related to massive vasodilation. Initial sinus tachycardia was appreciated in our patient with her cardiopulmonary arrest. After cardiac resuscitation, hypotension persisted despite normal cardiac function, requiring pressor support for 48-72 hours. We believe that these cardiovascular findings could be related to the bupropion ingestion. The profound autonomic response in massive overdose in young children is hypothesized to cause depletion of endogenous catecholamine stores and loss of vascular tone and hypotension.5 This child presented with status epilepticus and a falsepositive urine drug screen for amphetamines and experienced persistent sinus tachycardia and a cardiopulmonary arrest secondary to bupropion overdose. She experienced hypoxic ischemic encephalopathy and currently is neurologically devastated and has refractory symptomatic epilepsy. Early recognition and aggressive treatment of patients with this toxic syndrome could significantly improve the outcome and prognosis. The work was done in the Pediatric Neurology Division, The University of Tennessee Health Science Center, and Le Bonheur Children’s Hospital, Neuroscience Institute, Memphis, Tennessee. Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
References 1. Horne RL, Ferguson JM, Pope Jr HG, et al. Treatment of bulimia with bupropion in a multicenter controlled trial. J Clin Pyschiatry. 1988; 18:1-20. 2. Shepherd G, Velez LI, Keyes DC. Intentional bupropion overdose. J Emerg Med. 2004;27:147-151. 3. Davidson J. Seizures and bupropion: a review. J Clin Psychiatry. 1989;50:256-261. 4. Morazin F, Lumbroso A, Harry P, et al. Cardiogenic shock and status epilepticus after massive bupropion overdose. Clin Toxicol. 2007;45: 794-797. 5. Shenoi AN, Gertz SJ, Mikkilineri S, Kalyanaraman M. Refractory hypotension from massive bupropion overdose successfully treated with extracorporeal membrane oxygenation. Pediatr Emerg Care. 2011;27:43-45. 6. Spiller HA, Schaeffer SE. Multiple seizures after bupropion overdose in a small child. Pediatr Emerg Care. 2008;24:474-475. 7. Spiller HA, Bosse GM, Beuhler M, et al. Unintentional ingestion of bupropion in children. J Emerg Med. 2010;38:332-336. 8. Casey ER, Scott MG, Tang S, Mullins ME. Frequency of false positive amphetamine screens due to bupropion using the Syva Emit II Immunoassay. J Med Toxicol. 2011;7:105-108. 9. PDR Network LLC. Red Book: Pharmacy’s fundamental reference, 2009 edition. 113th ed. Montvale: Thompson PDR; 2009. 10. Hesse L, Venkatakrishnan K. CYP2B6 mediates the In Vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos. 2000;28:1176-1183. 11. Balit CR, Lynch CN, Isbister GK. Bupropion poisoning: a case series. Med J Aust. 2003;178:61-63. 12. Spiller HA, Ramoska EA, Krenzelok EP, et al. Bupropion in overdose: a three year multicenter retrospective evaluation. Am J Emerg Med. 1994;12:43-45. 13. Ferris RM, Beaman OJ. Bupropion: A new antidepressant drug, the mechanism of action of which is not associated with down-
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14. 15.
16. 17.
regulation of postsynaptic Beta-adrenergic, serotoninergic (5-HT2), alpha 2- adrenergic, imipramine and dopaminergic receptors in brain. Neuropharmacology. 1983;22:1257-1267. Ferris RM, Cooper BR, Maxwell RA. Studies of bupropion’s mechanism of antidepressant activity. J Clin Psychiatry. 1983;44:74-78. Gobbi G, Slater S, Boucher N, et al. Neurochemical and psychotropic effects of bupropion in healthy male subjects. J Clin Psychopharmacol. 2003;23:233-239. Belson MG, Kelley TR. Bupropion exposures: clinical manifestations and medical outcome. J Emerg Med. 2002;23:223-230. Judge BS, Rentmeester LL. Antidepressant Overdose-induced Seizures. Psychiatr Clin North Am. 2013;36:245-260.
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18. Biswas AK, Zabrocki LA, Mayes KL, Morris-Kukoski CL. Cardiotoxicity associated with intentional ziprasidone and bupropion overdose. J Toxicol Clin Toxicol. 2003;41:101-104. 19. Curry SC, Kashani JS, Lo Vecchio F, Holubeck W. Intraventricular conduction delay after bupropion overdose. J Emerg Med. 2005;29: 299-305. 20. Isbister GK, Balit CR. Bupropion overdose: QTc prolongation and its clinical significance. Ann Pharmacother. 2003;37:999-1002. 21. Dutreika D, Zed PJ. Cardiotoxicity following bupropion overdose. Ann pharmacother. 2002;35:1791-1795. 22. Harris CR, Gualtieri J, Stark G. Fatal Bupropion overdose. J Clin Toxicol. 1997;35:321-324.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Bupropion Overdose Presenting as Status Epilepticus in an Infant Marianna S. Rivas-Coppola MD, Amy L. Patterson MD, Robin Morgan MD, James W. Wheless MD * Division of Pediatric Neurology, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital Neuroscience Institute, Memphis Tennessee
abstract BACKGROUND: Bupropion is a monocyclic antidepressant in the aminoketone class, structurally related to amphetamines. The Food and Drug Administration withdrew this product from the market in 1986 after seizures were reported in bulimic patients. It was later reintroduced in 1989 when the incidence of seizures was shown to be dose-related in the immediate release preparation. Massive bupropion ingestion has been associated with status epilepticus and cardiogenic shock in adults. Seizures have been reported in children, but not status epilepticus. This report highlights a patient who presented with status epilepticus and developed cardiopulmonary arrest after bupropion ingestion. False-positive amphetamine diagnosis from urine drug screen on presentation was reported. METHOD: We review the presentation, clinical course, diagnostic studies, and outcome of this patient. We then review the literature regarding bupropion overdose in children. RESULT: Symptoms of bupropion toxicity and risk for seizures are dose-dependent and fatalities have been reported. Our patient developed status epilepticus and cardiopulmonary arrest and then progressed to have a hypoxic ischemic encephalopathy and refractory symptomatic partial seizures. CONCLUSION: Our report highlights the need to keep this medication away from children, preventing accidental overdose. Keywords: status epilepticus, cardiogenic shock, hypotension, bupropion, toxicity, children
Pediatr Neurol 2015; -: 1-5 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Bupropion is an atypical antidepressant that was originally approved by the Food and Drug Administration in the United States in 1985 for treatment of depression in adults but was withdrawn by the Food and Drug Administration in 1986 after an increased incidence of seizures was noted in bulimic patients.1,2 It was reintroduced in 1989 when the incidence of seizures was shown to be dose-related, with an incidence of seizures similar to that of other antidepressants.3 Status epilepticus and cardiogenic shock after massive bupropion ingestion has been reported in adults.4 Seizures Article History: Received March 23, 2015; Accepted in final form May 23, 2015 * Communications should be addressed to: Dr. Wheless; Division of Pediatric Neurology; University of Tennessee Health Science Center; Le Bonheur Children’s Hospital; Neuroscience Institute; 51 N. Dunlap St., Suite 335; Memphis, TN 38105, United States. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.05.018
have been reported after bupropion overdose in an infant and children,5-7 but no cases of status epilepticus have been reported in children. Refractory hypotension and transient cardiac dysfunction in an infant from a massive bupropion overdose have been described.5 Our report illustrates the unique presentation of an infant with status epilepticus and cardiopulmonary arrest after accidental ingestion of bupropion. She initially exhibited a false-positive drug urine screen for amphetamines. A high frequency of false-positive amphetamine screens resulting from bupropion was recently reported.8 We review the clinical presentation, hospital course, and diagnostic studies to educate other health care providers about this entity. Patient Description Our patient is a 15-month-old previously healthy girl who presented with new-onset seizures. The initial seizure was described as an episode of eye rolling with generalized jerking of all four extremities. She was initially evaluated by paramedics and was noted to be experiencing
2
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generalized tonic-clonic seizure activity for which she was transferred to a local emergency room and treated with two doses of intravenous lorazepam with transient cessation of seizure activity. She was lethargic and continued to have intermittent seizures consisting of jerking of the upper and lower extremities over the next few hours. Approximately 78 hours from presentation, she had worsening of the rhythmic jerking and was treated with a third dose of intravenous lorazepam (doses of lorazepam not documented in available records) and a loading dose of fosphenytoin (20 mg/kg). She had no improvement in her mental status over the next several hours. Approximately 16-17 hours after initial presentation, she became apneic with pulseless cardiac arrest. Intubation and cardiopulmonary resuscitation were performed. She received three doses of epinephrine, lactate ringer bolus, and one dose of sodium bicarbonate. After 15-20 minutes, sinus rhythm was restored. She was transferred to the intensive care unit in our tertiary care hospital, where further history was obtained from her mother and grandmother, whose custody she was in at the time of seizure onset. They adamantly denied that the child had access to prescription medications or illicit substances. The review of systems was significant for mild runny nose and cough, but no fever. Her medical history and birth history was unremarkable, including no history of seizures, meningitis, or head trauma. Family history was positive in the maternal uncle and maternal greatgrandfather for seizures. There was no reported family history of psychiatric illnesses. Developmental history including gross motor, fine motor, language, and social skills were appropriated for age. Her initial physical examination on arrival to our facility included a temperature of 34.4 C, blood pressure 74/52 mmHg, and heart rate 104. Dopamine drip and warming measures were started. She was intubated and had no respiratory effort. Neurological examination revealed bilateral dilated, nonreactive pupils, with gaze deviation to the left, no brain stem reflexes, and no withdraw to painful stimuli. The laboratory results from the referring hospital showed evidence of metabolic acidosis before her cardiopulmonary arrest with a pH of 7.21, bicarbonate 19 mmol/dL, and base excess of negative 8.7 on an arterial blood gas. Urine drug screen was positive for amphetamines and was negative for barbiturates, benzodiazepine, cocaine, opiates, and cannabinoids. Blood chemistry and liver enzymes were normal. Complete blood count was remarkable for mild microcytic anemia but no leukocytosis. Computed tomography scan of the head obtained after arrival at the outside facility approximately 1 hour after seizure onset revealed no hemorrhage, edema, mass, or midline shift. Electrocardiogram showed sinus tachycardia that was appreciated on telemetry tracing. She arrived to our facility after the cardiopulmonary arrest and approximately 22 hours from seizure onset; significant laboratory abnormalities included a blood gas revealing mild lactic acidosis (2.75 mmol/L), pH 7.08, bicarbonate 15 mmol/dL, and base excess of negative 11. Liver function tests revealed an elevated aspartate aminotransferase of 1169 unit/L and alanine aminotransferase of 242 unit/L. Urine drug screen was negative. Lumbar puncture was completed on arrival, and she had 2 white blood cells/F, 193 red blood cells/G, glucose 98 mg/dL, and protein 21 mg/dL. A five hour electroencephalograph was obtained, within an hour of arrival, and was abnormal with status epilepticus noted for the first 105 minutes, then for the next 3.25 hours intermittent background suppression, and biposterior epileptiform discharges over the left and right parietal, temporal, and occipital head regions. (No further seizures.) She was treated with two doses of intravenous lorazepam (0.2 mg/kg/ dose), one loading dose of levetiracetam (40 mg/kg), and one dose of intravenous fosphenytoin (20 mg/kg) with no improvement in clinical or electrographic seizure activity. However, after one loading dose of intravenous phenobarbital (20 mg/kg), clinical and electrographic seizure activity stopped. She was treated with supportive care and started on maintenance levetiracetam (40 mg/kg/day given bid), fosphenytoin (8 mg/kg/day), and phenobarbital (5 mg/kg/day) all given intravenously. Over the next 24 hours, spontaneous eye opening, corneal reflex, and gag reflex were appreciated. She also had irregular respiratory effort. She continued to have gaze deviation, no tracking, and minimal movement of all four extremities to noxious stimuli. Echocardiography was performed
22 hours after seizure onset and it revealed normal anatomy, ventricular size, and systolic function. Magnetic resonance imaging of the brain and brain stem performed 48 hours after cardiopulmonary arrest showed findings consistent with severe hypoxic ischemic encephalopathy with areas of restricted diffusion involving bilateral occipital lobes, bilateral superior aspect of the lentiform nuclei, and caudate nucleus. (Figure). Over next few weeks, she showed clinical signs of global hypoxic ischemic encephalopathy, including cortical blindness and spastic quadriparesis. Tracheostomy and gastric tube placement were required. She developed symptomatic, refractory partial epilepsy and is currently taking multiple medications. Although the family adamantly denied that she took any medications, confirmatory laboratory testing of her serum was submitted on arrival to our facility. High-power liquid chromatography detected bupropion.
Discussion
Our patient presented after experiencing multiple seizures followed by cardiopulmonary arrest requiring cardiopulmonary resuscitation. Afterwards she was noted to be in status epilepticus (i.e., electroencephalographic and subtle clinical seizures) that was responsive to phenobarbital treatment. The initial clinical presentation of acute onset seizures in a previously developmentally normal and healthy infant with a positive urine drug screen for amphetamines and a negative computed tomography could be explained by amphetamine ingestion. However, the status epilepticus and cardiopulmonary arrest, followed by significant hypotension, were not as easy to explain, especially given the repeat urine drug screen was negative for amphetamine. Further diagnostic studies including cerebrospinal studies were negative for central nervous system infection. The rest of the laboratory studies showed lactic acidosis, metabolic acidosis, and elevated liver function test, all a consequence of the cardiopulmonary arrest. The etiology of the arrest did not become completely clear until chromatography confirmed bupropion ingestion. Bupropion is an atypical monocyclic antidepressant commonly prescribed in the United States for the treatment of major depressive disorder, seasonal affective disorder, adult attention deficit hyperactivity disorder, and smoking cessation. All forms of bupropion combined totaled 20,745,363 prescriptions in the United States in 2008.9 The amino-ketone structure of bupropion is metabolized in the liver by the cytochrome P450 isoenzyme CYP2B6 to the active metabolites R,R-hydroxybupropion, S,Shydroxybupropion, threohydrobupropion, and erythrohydrobupropion, which are responsible for the pharmacological activity of bupropion.10 Different formulations are available for bupropion including immediate, sustained, and extended-release. It has a plasma half-life of 10 hours, but longer half-lives have been reported for the metabolites.6 Bupropion, erythrohydrobupropion, and threohydrobupropion have chemical structures similar to amphetamine, which may result in cross-reactivity with antibodies used in urine drug screen immunoassays.8-10 Three reports demonstrated false-positive amphetamine urine drug screens associated with bupropion. A recent study evaluating the incidence of false-positive amphetamine screening associated with therapeutic use of bupropion showed that bupropion appeared to be the most frequent cause of false-positive urine drug screens for amphetamines
M.S. Rivas-Coppola et al. / Pediatric Neurology xxx (2015) 1e5
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FIGURE. Magnetic resonance imaging of the brain 48 hours after cardiopulmonary arrest. Diffusion-weighted images (A,B) and apparent diffusion coefficient (C) showing areas of restricted diffusion involving bilateral occipital lobes (arrows), bilateral superior aspect of lentiform nuclei, and caudate nucleus (arrow heads). T2-weighted (D), T2 fluid-attenuated inversion recovery (E), and T1-weighted images showing no brain signal abnormalities or structural brain abnormalities (F). No brainstem abnormalities were noted. (The right side of the brain is on the left side of the photo.)
in their population.8 This can explain the false-positive result obtained on our patient’s initial urine drug screen at the outside hospital. Repeat urine drug screen approximately 22-23 hours from seizure onset was negative. We hypothesized, based on the half-life of 10 hours reported for bupropion, that by the time that the test was performed, the urinary concentration of bupropion and its metabolites were significantly lower (now below the threshold to detect with the urine drug screen), corresponding with our negative result. Clinically significant toxicity after bupropion overdose is primarily neurological and cardiovascular in nature, with the most significant risk being seizures.5 However, most information comes from reports of adults or older adolescents with massive ingestions of bupropion as part of a suicide attempt.2,11,12
A recent report documented a 35-year-old man who presented with cardiogenic shock and status epilepticus after massive bupropion overdose of eighty 150-mg sustained-release tablets (12 g). Quantitative bupropion assays confirmed the massive overdose with serum levels more than 15 times therapeutic levels (0.05-0.1 mg/L). His status epilepticus appeared to be attributable to bupropion. In this particular case, the onset of status epilepticus corresponded to the peak of serum bupropion concentration (3 hours from the ingestion), and the severity of the status epilepticus was probably related to the massive dose ingested and subsequent high cerebral concentrations.4 In published data, cerebrospinal fluid concentrations of bupropion are 10- to 25-fold higher than blood concentration.13,14
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Although the mechanism of action of bupropion has not been fully elucidated, the drug and its metabolites have a weak inhibitory effect on the reuptake of norepinephrine and dopamine with no effect on the reuptake of serotonin,15 Bupropion’s sympathomimetic amine structure may also suggest possible stimulation of the hypothalamus to release catecholamines into the central nervous system.6 It is this second mechanism that might be partially responsible for the status epilepticus seen in our patient and the seizures reported in other cases of bupropion overdose. Unintentional ingestion of bupropion in younger children has generally resulted in limited toxicity.7,16 This can be explained by the fact that usual accidental ingestions in children are of low doses of bupropion. In a retrospective study by Spiller et al.,12 reviewing bupropion ingestions in 407 children younger than 6 years, only 18% were symptomatic. Sinus tachycardia was the most common adverse effect (68%), followed by nausea and vomiting (43%), hyperactivity (23%), seizures (4%), and hypertension (2.5%). Dose ingested and patient weights were known for 218 patients in their study, and 88% of those patients ingested less than 20 mg/kg. Multiple seizures after bupropion overdose have been reported in a school-age child.4 Otherwise, status epilepticus in an infant after bupropion overdose has not been reported, especially after cardiopulmonary arrest. Our patient received multiple doses of lorazepam, levetiracetam, and fosphenytoin loads without resolution of her status epilepticus. She responded to a phenobarbital load. The same observation has been reported in two other case reports in which multiple seizures and status epilepticus were successfully treated after a phenobarbital load.4,6 Shenoi reports that benzodiazepines and barbiturates should be preferred in the treatment of drug-induced seizures. Psychotropic drug-induced seizures are typically treated with a benzodiazepine as first-line therapy and phenobarbital as second-line therapy.17 Phenytoin, although considered second-line therapy for most seizures, is not believed to be as effective for drug-induced seizures. Had we known our patient’s status epilepticus was due to bupropion overdose, we would have used phenobarbital earlier. This is important for physicians to keep in mind when treating refractory status epilepticus. At the outside facility, our patient developed persistent sinus tachycardia and her mental status failed to improve despite seizure treatment. Around 16-17 hours from seizure onset, she experienced a cardiac arrest required cardiopulmonary resuscitation for 15-20 minutes, with three doses of epinephrine, a lactated ringer bolus, and one dose of sodium bicarbonate. On arrival to our facility, she was hypothermic and hypotensive, for which epinephrine and dobutamine were administered. In most published examples of bupropion ingestion the dose was much lower and the clinical effects less dramatic; the most common cardiovascular effects were sinus tachycardia, conduction disorders with widening of QRS complex, and prolongation of the QT interval.18-21 Fatalities after massive bupropion ingestion have been documented.22 Massive overdoses are responsible for rapid death from asystolic cardiopulmonary arrest usually from long intervals between the time of ingestion and the time of initial management.
Shenoi et al. recently reported an 11-month-old child with refractory hypotension following a massive bupropion overdose who was successfully treated with extracorporeal membrane oxygenation.5 No abnormalities were seen on this patient’s echocardiogram, suggesting that his refractory hypotension and metabolic acidosis could be related to massive vasodilation. Initial sinus tachycardia was appreciated in our patient with her cardiopulmonary arrest. After cardiac resuscitation, hypotension persisted despite normal cardiac function, requiring pressor support for 48-72 hours. We believe that these cardiovascular findings could be related to the bupropion ingestion. The profound autonomic response in massive overdose in young children is hypothesized to cause depletion of endogenous catecholamine stores and loss of vascular tone and hypotension.5 This child presented with status epilepticus and a falsepositive urine drug screen for amphetamines and experienced persistent sinus tachycardia and a cardiopulmonary arrest secondary to bupropion overdose. She experienced hypoxic ischemic encephalopathy and currently is neurologically devastated and has refractory symptomatic epilepsy. Early recognition and aggressive treatment of patients with this toxic syndrome could significantly improve the outcome and prognosis. The work was done in the Pediatric Neurology Division, The University of Tennessee Health Science Center, and Le Bonheur Children’s Hospital, Neuroscience Institute, Memphis, Tennessee. Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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