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Massive lamotrigine poisoning. A case report
Brain & Development xxx (2016) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Massive lamotrigine poisoning. A case report Salvatore Grosso ⇑, Silvia Ferranti, Carla Gaggiano, Elisabetta Grande, Barbara Loi, Rosanna Di Bartolo Clinical Pediatrics, Department of Pediatrics, University of Siena, Italy Received 9 September 2016; received in revised form 29 October 2016; accepted 2 November 2016
Abstract Lamotrigine (LTG) represents the most commonly prescribed of the so-called new generation antiepileptic drugs. We describe a child who was admitted to the emergency room because of generalized tonic–clonic status epilepticus followed by a complex neurological picture with hyperkinesia and acute ataxia as a result of a LTG intoxication. The experience on acute LTG intoxication is very limited in pediatrics. The present case provides information on the clinical picture related to LTG overdose and confirms that drug intoxications should be considered in the differential diagnosis strategy when severe and polymorphic neurological symptoms occur acutely. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Status epilepticus; Hyperkinesias; Acute ataxia; Antiepileptic drugs; Adverse events
1. Introduction
2. Case report
Lamotrigine (LTG) is a relatively new anti-epileptic drug recommended in children as adjunctive treatment and as monotherapy for partial-onset and secondarily generalized tonic–clonic seizures, for Lennox Gastaut syndrome and as add-on therapy for primarily generalized tonic–clonic seizures. Moreover, it has been proposed as a first line therapy in association with Valproic Acid for the treatment of absence seizures [1]. LTG is considered a quite safe drug. Here we report on a child who presented with a complex neurological picture related to a severe acute LTC intoxication.
We describe a 3.2 year-old male with personal history negative for healthy problems. The child was not receiving any therapy. His father was affected by epilepsy and under treatment with LTG and Valproic Acid. One morning parents found the child lying on the floor, unconscious, with generalized tonic–clonic jerks. Diazepam per rectum was administered twice without seizure control. At the admission in emergency room the child still had generalized tonic–clonic seizures. After 25 min, intravenous push of midazolam (0.25 mg/kg) was able to control seizures. Continuous midazolam infusion was then set at 0.15 mg/kg/h. Diagnostic workup, which included arterial blood gases, cell blood count, electrolytes, liver and kidney function, blood glucose, inflammatory markers, and brain MRI, was unrevealing. Electrocardiogram showed sinus tachycardia and right bundle branch block. EEG recording was started
⇑ Corresponding author at: Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Viale M. Bracci, Le Scotte, 53100 Siena, Italy. Fax: +39 0577586143. E-mail address: [email protected] (S. Grosso).
http://dx.doi.org/10.1016/j.braindev.2016.11.003 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Grosso S et al. Massive lamotrigine poisoning. A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j. braindev.2016.11.003
2
S. Grosso et al. / Brain & Development xxx (2016) xxx–xxx
after 300 from the child admission and showed a post-ictal pattern. After two hours, midazolam infusion was reduced to 0.06 mg/kg/h and brief tonic seizures occurred. Infusion was therefore continued at 0.15 mg/kg/h rate with complete seizure control. After 8 h, seizure were still under control and EEG tracing was normal, therefore midazolam was progressively reduced up to 0,03 mg/kg/h. The child become arousable but appeared agitated with restlessness and malaise. At the neurological examination new physical findings started to outline. Dystonic movements at trunk and limbs where present and associated with lateral flexion of the neck with widely opened mouth, tongue protrusion and profuse sweating. Severe oculogyric crisis occurred and characterized by extreme and sustained upward deviation of the eyes followed by eyes converging, and laterally or downward deviation. An evident truncal ataxia was also noticed in sitting position. Moreover the child started to show excessive, insuppressible sensation of thirst and appetite which lasted three days. LTG intoxication was therefore hypothesized. After 10 h of intravenous fluids, serum LTG concentration was found to be 28.4 mg/L (therapeutic range 1.0– 14.0 mg/L). Meanwhile, the father, who had been invited to check for integrity of LTG blister, found one Lamotrigin-200 mg blister with 8 tablets missing in a corner of the bathroom’s floor. Serum dosage of valproic acid was also performed and resulted negative. In the following hours, the child became progressively more interactive with people and environment; movement patterns returned smooth. During the whole hospitalization intravenous fluids were administered while midazolam infusion was progressively tapered until suspension. However, severe ataxia and striking dysmetria still persisted up to seventy-two hours from the admission, when the child showed a normal neurological examination; EKG and EEG were also normal. Hyperphagia was still present when the child was discharged. 3. Discussion LTG is a broad-spectrum anti-epileptic drug (AED) and the most commonly prescribed of the so-called new generation AEDs. A possible downside of this category of medications is the relative lack of information on their safety in pediatric population [2]. LTG is considered a relatively safe medication, with rare central nervous system adverse effects such as anxiety, ataxia, confusion, depression, headache, insomnia, irritability, and concentration problems. The most significant and common adverse events are skin hypersensitivity reactions which may vary in severity from mild morbilliform rash to Stevens–Johnson [1]. Globally, experience on overdoses of LTG is very limited and mainly based on isolated adult case reports in which effects of the medication must be disentangled
from those of other coingestants likely to be present. Serum drug dosage is only performed in a few specialized centers, results are not readily available and their interpretation can be difficult. The patient we describe was admitted to the emergency room because of a generalized tonic–clonic status epilepticus. After negative results of the diagnostic work-up, the child was considered possibly affected by a status epilepticus as the clinical onset of an idiopathic epileptic disorder. The positive family history of epilepsy seemed to corroborate that hypothesis. However, when in the clinical course symptoms appeared to be more complex and variegated, an acute drug intoxication was promptly considered and rapidly confirmed by serum dosage of LTG levels. Various anticonvulsant medications may be paradoxically proconvulsant for epileptic patients whose intake is at toxic levels [3]. In particular, it has been calculated that about 2% of patients under LTG therapy experiences an increase in seizures frequency [1]. The mechanism of that phenomenon is partially unknown. Although seizure aggravation is well recognized in patients with Dravet syndrome receiving LTG, status epilepticus has rarely been described. LTG-related nonconvulsive status epilepticus has been reported in 3 patients with idiopathic generalized epilepsy [4]. Moreover, an adult affected by a localization-related epilepsy developed a tonic–clonic status epilepticus under LTG intoxication [5]. Paradoxical seizure aggravation was mainly reported in patients affected by epilepsy and under polytherapies [6]. Therefore it was difficult to clearly establish a direct relationship between LTG therapy and seizure aggravation. The patient we describe is a healthy child in whom a generalized tonic–clonic status epilepticus was undoubtedly related to acute LTG intoxication. After having controlled status epilepticus, the reduction of midazolam therapy was followed by the occurrence of severe hyperkinetic movements with dystonia, oculogyric crisis, and prolonged ataxia. While most clinicians are aware that antipsychotic agents can cause extrapyramidal side effects, many are not aware that these side effects have been reported with anticonvulsant agents. Dystonia has recently observed in an adult patient under polytherapy which included LTG [7]. Richter et al., found that LTG actually induced dystonia in hamster models [8]. The inhibition of GABA release and the lack of selectivity of glutamate release inhibition were thought to be critically involved in LTG’s prodystonic tendencies [8]. The risk of LTG-related ataxia is 0.85 episodes per 100 children [1]. Oculogyric crisis are rarely observed in pediatric patients under LTG therapy [9]. The mechanisms leading to oculogyric crisis of any cause have been presumed to involve altered dopaminergic tone. Such mechanisms are likely to be operating during LTG toxicity [9]. In all patients with hyperkinetic and ataxic adverse events,
Please cite this article in press as: Grosso S et al. Massive lamotrigine poisoning. A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j. braindev.2016.11.003
S. Grosso et al. / Brain & Development xxx (2016) xxx–xxx
symptoms disappeared by stopping or reducing LTG dose administration. Similarly, no specific treatment was made in our patient, movement disorders and ataxia slowly disappeared within three days. Severe hyperphagia, which lasted several days, was also observed in our patient who become agitated and very aggressive if food was denied. Moderate increased appetite was reported in only 8 patients out of 3317 patient receiving LTG [1]. Pathogenic mechanisms of that adverse event are unknown. We also documented a transient right bundle branch block. LTG impact on heart conduction is uncommon and likely mediated by the LTG voltage-gated Na channel blocking activity on phase 0 of the cellular action potential [10]. When globally considered, EKG changes potentially provoked by LTG are mainly represented by QRS and QTc prolongation, and right bundle branch block. All of them are reversible with drug discontinuation, as in our patient [10]. Although rash is considered to be associated with a rapid titration, peculiarly no skin hypersensitivity reactions were observed in our patient. In conclusions, we report on a healthy child showing an acute generalized tonic–clonic status epilepticus followed by hyperkinetic disorders and prolonged ataxia related to LTG overdose. The present case confirms that drug intoxications should be considered in the differential diagnosis strategy when severe and polymorphic neurological symptoms occur acutely.
3
References [1] Egunsola O, Choonara I, Sammons HM. Safety of lamotrigine in paediatrics: a systematic review. BMJ Open 2015:e007711. [2] Thundiyil JG, Anderson IB, Stewart PJ, Olson KR. Lamotrigineinduced seizures in a child: case report and literature review. Clin Toxicol 2007;45:169–72. [3] Grosso S, Balestri P. Efficacy and tolerability of add-on Lacosamide in children with Lennox-Gastaut syndrome. Acta Neurol Scand 2014;130:e39–40. [4] Trinka E, Dilitz E, Unterberger I, Luef G, Deisenhammer F, Niedermu¨ller U, et al. Non convulsive status epilepticus after replacement of valproate with lamotrigine. J Neurol 2002;249:1417–22. [5] Dinnerstein E, Jobst BC, Williamson PD. Lamotrigine intoxication provoking status epilepticus in an adult with localizationrelated epilepsy. Arch Neurol 2007;64:1344–6. [6] Wade JF, Dang CV, Nelson L, Wasserberger J. Emergent complications of the newer anticonvulsants. J Emerg Med 2010;38:231–7. [7] Marrero-Gonzalez PC, Ruano OL, Catalano G, Catalano MC. Dystonia associated with lamotrigine therapy: a case report and review of the literature. Curr Drug Safety 2014;9:60–2. [8] Richter A, Lo¨schmann PA, Lo¨scher W. The novel antiepileptic drug, lamotrigine, exerts prodystonic effects in a mutant hamster model of generalized dystonia. Eur J Pharmacol 1994;264:345–51. [9] Veerapandiyan A, Gallentine WB, Winchester SA, Baker J, Kansagra SM, Mikati MA. Oculogyric crises secondary to lamotrigine overdosage. Epilepsia 2011;52:4–6. [10] Chavez P, Casso Dominguez A, Herzog E. Evolving electrocardiographic changes in lamotrigine overdose: a case report and literature review. Cardiovasc Toxicol 2015;15:394–8.
Please cite this article in press as: Grosso S et al. Massive lamotrigine poisoning. A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j. braindev.2016.11.003
Case Report
Massive lamotrigine poisoning. A case report Salvatore Grosso ⇑, Silvia Ferranti, Carla Gaggiano, Elisabetta Grande, Barbara Loi, Rosanna Di Bartolo Clinical Pediatrics, Department of Pediatrics, University of Siena, Italy Received 9 September 2016; received in revised form 29 October 2016; accepted 2 November 2016
Abstract Lamotrigine (LTG) represents the most commonly prescribed of the so-called new generation antiepileptic drugs. We describe a child who was admitted to the emergency room because of generalized tonic–clonic status epilepticus followed by a complex neurological picture with hyperkinesia and acute ataxia as a result of a LTG intoxication. The experience on acute LTG intoxication is very limited in pediatrics. The present case provides information on the clinical picture related to LTG overdose and confirms that drug intoxications should be considered in the differential diagnosis strategy when severe and polymorphic neurological symptoms occur acutely. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Status epilepticus; Hyperkinesias; Acute ataxia; Antiepileptic drugs; Adverse events
1. Introduction
2. Case report
Lamotrigine (LTG) is a relatively new anti-epileptic drug recommended in children as adjunctive treatment and as monotherapy for partial-onset and secondarily generalized tonic–clonic seizures, for Lennox Gastaut syndrome and as add-on therapy for primarily generalized tonic–clonic seizures. Moreover, it has been proposed as a first line therapy in association with Valproic Acid for the treatment of absence seizures [1]. LTG is considered a quite safe drug. Here we report on a child who presented with a complex neurological picture related to a severe acute LTC intoxication.
We describe a 3.2 year-old male with personal history negative for healthy problems. The child was not receiving any therapy. His father was affected by epilepsy and under treatment with LTG and Valproic Acid. One morning parents found the child lying on the floor, unconscious, with generalized tonic–clonic jerks. Diazepam per rectum was administered twice without seizure control. At the admission in emergency room the child still had generalized tonic–clonic seizures. After 25 min, intravenous push of midazolam (0.25 mg/kg) was able to control seizures. Continuous midazolam infusion was then set at 0.15 mg/kg/h. Diagnostic workup, which included arterial blood gases, cell blood count, electrolytes, liver and kidney function, blood glucose, inflammatory markers, and brain MRI, was unrevealing. Electrocardiogram showed sinus tachycardia and right bundle branch block. EEG recording was started
⇑ Corresponding author at: Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Viale M. Bracci, Le Scotte, 53100 Siena, Italy. Fax: +39 0577586143. E-mail address: [email protected] (S. Grosso).
http://dx.doi.org/10.1016/j.braindev.2016.11.003 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Grosso S et al. Massive lamotrigine poisoning. A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j. braindev.2016.11.003
2
S. Grosso et al. / Brain & Development xxx (2016) xxx–xxx
after 300 from the child admission and showed a post-ictal pattern. After two hours, midazolam infusion was reduced to 0.06 mg/kg/h and brief tonic seizures occurred. Infusion was therefore continued at 0.15 mg/kg/h rate with complete seizure control. After 8 h, seizure were still under control and EEG tracing was normal, therefore midazolam was progressively reduced up to 0,03 mg/kg/h. The child become arousable but appeared agitated with restlessness and malaise. At the neurological examination new physical findings started to outline. Dystonic movements at trunk and limbs where present and associated with lateral flexion of the neck with widely opened mouth, tongue protrusion and profuse sweating. Severe oculogyric crisis occurred and characterized by extreme and sustained upward deviation of the eyes followed by eyes converging, and laterally or downward deviation. An evident truncal ataxia was also noticed in sitting position. Moreover the child started to show excessive, insuppressible sensation of thirst and appetite which lasted three days. LTG intoxication was therefore hypothesized. After 10 h of intravenous fluids, serum LTG concentration was found to be 28.4 mg/L (therapeutic range 1.0– 14.0 mg/L). Meanwhile, the father, who had been invited to check for integrity of LTG blister, found one Lamotrigin-200 mg blister with 8 tablets missing in a corner of the bathroom’s floor. Serum dosage of valproic acid was also performed and resulted negative. In the following hours, the child became progressively more interactive with people and environment; movement patterns returned smooth. During the whole hospitalization intravenous fluids were administered while midazolam infusion was progressively tapered until suspension. However, severe ataxia and striking dysmetria still persisted up to seventy-two hours from the admission, when the child showed a normal neurological examination; EKG and EEG were also normal. Hyperphagia was still present when the child was discharged. 3. Discussion LTG is a broad-spectrum anti-epileptic drug (AED) and the most commonly prescribed of the so-called new generation AEDs. A possible downside of this category of medications is the relative lack of information on their safety in pediatric population [2]. LTG is considered a relatively safe medication, with rare central nervous system adverse effects such as anxiety, ataxia, confusion, depression, headache, insomnia, irritability, and concentration problems. The most significant and common adverse events are skin hypersensitivity reactions which may vary in severity from mild morbilliform rash to Stevens–Johnson [1]. Globally, experience on overdoses of LTG is very limited and mainly based on isolated adult case reports in which effects of the medication must be disentangled
from those of other coingestants likely to be present. Serum drug dosage is only performed in a few specialized centers, results are not readily available and their interpretation can be difficult. The patient we describe was admitted to the emergency room because of a generalized tonic–clonic status epilepticus. After negative results of the diagnostic work-up, the child was considered possibly affected by a status epilepticus as the clinical onset of an idiopathic epileptic disorder. The positive family history of epilepsy seemed to corroborate that hypothesis. However, when in the clinical course symptoms appeared to be more complex and variegated, an acute drug intoxication was promptly considered and rapidly confirmed by serum dosage of LTG levels. Various anticonvulsant medications may be paradoxically proconvulsant for epileptic patients whose intake is at toxic levels [3]. In particular, it has been calculated that about 2% of patients under LTG therapy experiences an increase in seizures frequency [1]. The mechanism of that phenomenon is partially unknown. Although seizure aggravation is well recognized in patients with Dravet syndrome receiving LTG, status epilepticus has rarely been described. LTG-related nonconvulsive status epilepticus has been reported in 3 patients with idiopathic generalized epilepsy [4]. Moreover, an adult affected by a localization-related epilepsy developed a tonic–clonic status epilepticus under LTG intoxication [5]. Paradoxical seizure aggravation was mainly reported in patients affected by epilepsy and under polytherapies [6]. Therefore it was difficult to clearly establish a direct relationship between LTG therapy and seizure aggravation. The patient we describe is a healthy child in whom a generalized tonic–clonic status epilepticus was undoubtedly related to acute LTG intoxication. After having controlled status epilepticus, the reduction of midazolam therapy was followed by the occurrence of severe hyperkinetic movements with dystonia, oculogyric crisis, and prolonged ataxia. While most clinicians are aware that antipsychotic agents can cause extrapyramidal side effects, many are not aware that these side effects have been reported with anticonvulsant agents. Dystonia has recently observed in an adult patient under polytherapy which included LTG [7]. Richter et al., found that LTG actually induced dystonia in hamster models [8]. The inhibition of GABA release and the lack of selectivity of glutamate release inhibition were thought to be critically involved in LTG’s prodystonic tendencies [8]. The risk of LTG-related ataxia is 0.85 episodes per 100 children [1]. Oculogyric crisis are rarely observed in pediatric patients under LTG therapy [9]. The mechanisms leading to oculogyric crisis of any cause have been presumed to involve altered dopaminergic tone. Such mechanisms are likely to be operating during LTG toxicity [9]. In all patients with hyperkinetic and ataxic adverse events,
Please cite this article in press as: Grosso S et al. Massive lamotrigine poisoning. A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j. braindev.2016.11.003
S. Grosso et al. / Brain & Development xxx (2016) xxx–xxx
symptoms disappeared by stopping or reducing LTG dose administration. Similarly, no specific treatment was made in our patient, movement disorders and ataxia slowly disappeared within three days. Severe hyperphagia, which lasted several days, was also observed in our patient who become agitated and very aggressive if food was denied. Moderate increased appetite was reported in only 8 patients out of 3317 patient receiving LTG [1]. Pathogenic mechanisms of that adverse event are unknown. We also documented a transient right bundle branch block. LTG impact on heart conduction is uncommon and likely mediated by the LTG voltage-gated Na channel blocking activity on phase 0 of the cellular action potential [10]. When globally considered, EKG changes potentially provoked by LTG are mainly represented by QRS and QTc prolongation, and right bundle branch block. All of them are reversible with drug discontinuation, as in our patient [10]. Although rash is considered to be associated with a rapid titration, peculiarly no skin hypersensitivity reactions were observed in our patient. In conclusions, we report on a healthy child showing an acute generalized tonic–clonic status epilepticus followed by hyperkinetic disorders and prolonged ataxia related to LTG overdose. The present case confirms that drug intoxications should be considered in the differential diagnosis strategy when severe and polymorphic neurological symptoms occur acutely.
3
References [1] Egunsola O, Choonara I, Sammons HM. Safety of lamotrigine in paediatrics: a systematic review. BMJ Open 2015:e007711. [2] Thundiyil JG, Anderson IB, Stewart PJ, Olson KR. Lamotrigineinduced seizures in a child: case report and literature review. Clin Toxicol 2007;45:169–72. [3] Grosso S, Balestri P. Efficacy and tolerability of add-on Lacosamide in children with Lennox-Gastaut syndrome. Acta Neurol Scand 2014;130:e39–40. [4] Trinka E, Dilitz E, Unterberger I, Luef G, Deisenhammer F, Niedermu¨ller U, et al. Non convulsive status epilepticus after replacement of valproate with lamotrigine. J Neurol 2002;249:1417–22. [5] Dinnerstein E, Jobst BC, Williamson PD. Lamotrigine intoxication provoking status epilepticus in an adult with localizationrelated epilepsy. Arch Neurol 2007;64:1344–6. [6] Wade JF, Dang CV, Nelson L, Wasserberger J. Emergent complications of the newer anticonvulsants. J Emerg Med 2010;38:231–7. [7] Marrero-Gonzalez PC, Ruano OL, Catalano G, Catalano MC. Dystonia associated with lamotrigine therapy: a case report and review of the literature. Curr Drug Safety 2014;9:60–2. [8] Richter A, Lo¨schmann PA, Lo¨scher W. The novel antiepileptic drug, lamotrigine, exerts prodystonic effects in a mutant hamster model of generalized dystonia. Eur J Pharmacol 1994;264:345–51. [9] Veerapandiyan A, Gallentine WB, Winchester SA, Baker J, Kansagra SM, Mikati MA. Oculogyric crises secondary to lamotrigine overdosage. Epilepsia 2011;52:4–6. [10] Chavez P, Casso Dominguez A, Herzog E. Evolving electrocardiographic changes in lamotrigine overdose: a case report and literature review. Cardiovasc Toxicol 2015;15:394–8.
Please cite this article in press as: Grosso S et al. Massive lamotrigine poisoning. A case report. Brain Dev (2016), http://dx.doi.org/10.1016/j. braindev.2016.11.003