- Email: [email protected]
Late Adverse Effects of the Coadministration of Valproate and Lamotrigine
Pediatric Neurology 47 (2012) 47e50
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Late Adverse Effects of the Coadministration of Valproate and Lamotrigine Sigride Thome-Souza MD, PhD *, Bernardo Moreira MD, Kette D. Valente MD, PhD Laboratory of Clinical Neurophysiology, School of Medicine, University of São Paulo, and Hospital das Clínicas, São Paulo, Brazil
article information
abstract
Article history: Received 18 October 2011 Accepted 30 April 2012
Individuals treated with combined valproate-lamotrigine rarely present late adverse effects (unrelated to introduction and titration). We describe four patients in whom such effects occurred after continuous, long-term use of valproate-lamotrigine (at 9 months to 2 years after final antiepileptic drug adjustment). The patients presented heterogeneous disturbances, including ataxia, vertigo, and headache, and rare movement disorders, such as tics and abnormal eye movements. Although these effects are heterogeneous in their occurrence and timing, they can alert physicians to the possibility of late neurologic disturbances, and must be considered in order to avoid unnecessary ancillary tests. Treatment discontinuation is unnecessary, given that a small decrease in dose led to remission of these adverse effects. Ó 2012 Elsevier Inc. All rights reserved.
Introduction
Lamotrigine is an antiepileptic drug that is well-tolerated by children and adults. It demonstrates broad-spectrum efficacy, either as monotherapy or in combination with other antiepileptic drugs such as valproate [1]. The mechanism of action of lamotrigine involves Naþ channel blocking, and may entail the activation of N-methylD-aspartate receptors. As monotherapy, lamotrigine demonstrates good absorption after oral administration, a direct kinetic relationship between dose and plasma concentrations, approximately 55% protein binding, and an elimination half-life of 25-30 hours [2]. The half-life of lamotrigine is reduced by approximately half when in the presence of drugs inducing uridine diphosphate glucuronosyl-transferase, such as carbamazepine and phenytoin. On the other hand, if lamotrigine is associated with drugs that inhibit uridine diphosphate glucuronosyltransferase, such as valproic acid, a decrease of lamotrigine clearance and an increase in its plasma concentrations occur. Valproic acid can prolong the elimination half-life of lamotrigine to about 60 hours [2].
* Communications should be addressed to: Dr. Thome-Souza; Rua Dr. Ovidio; Pires de Campos 785; São Paulo, São Paulo 05403-010, Brazil. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2012.04.026
Messenheimer et al. [3], in a multicenter, randomized, double-blind, placebo-controlled, crossover study of 98 patients with refractory partial seizures, reported that adverse experiences were generally minor and most frequently related to the central nervous system (e.g., ataxia, dizziness, diplopia, and headache). However, lamotrigine was safe, effective, and well tolerated in patients with medically refractory partial seizures. Pressler et al. [4], in a double-blind, placebo-controlled, crossover study of 61 children with well-controlled or mild epilepsy, reported that lamotrigine exhibited no clinically significant cognitive effects during adjunctive therapy. A therapeutic synergy is evident between valproate and lamotrigine, but with a potentiation of adverse effects. In a review of lamotrigine treatment, La Roche and Helmers [5] demonstrated that among 3501 patients, side effects led to the discontinuation of lamotrigine in 10.2%, most often because of rash. Some authors postulated that the side effects of lamotrigine can be lessened by slower introduction and titration [5,6]. Lamotrigine was reported to cause movement disorders [7-9] that are frequently associated with titration or overdose (Table 1). Although the addition of valproate increases the efficacy of lamotrigine, it also increases the risk for adverse effects [1]. In children and adults, such effects typically occur during the first 4 months of treatment [1,10]. Few studies have investigated the combination of lamotrigine and valproate in terms of late
48
S. Thome-Souza et al. / Pediatric Neurology 47 (2012) 47e50
Table 1. Late side effects in patients with the use of lamotrigine
Reference
Number of Subjects
Design
Timing
Adverse Effects
Mackay et al. [6]
3994
Cohort study
6 months
Case report Case report Case report
4-10 months 5 months 5-12 months
Ataxia, headache, drowsiness, nausea, vomiting, malaise, and lassitude (in 0.1-0.2% of patients) Tic disorder Excessive, involuntary eye blinking Oculogyric crises
Sotero de Menezes et al. [7] Kim et al. [8] Veerapandiyan et al. [9]
5 1 4
adverse effects. Here, we report on four cases of late adverse effects in patients treated with a combination of lamotrigine and valproate (Table 2). Case Reports Patient 1
A 6-year-old girl had experienced a 42-month history of partial symptomatic epilepsy, characterized by partial motor seizures. Electroencephalography indicated epileptiform discharges over the central parietal region. Magnetic resonance imaging revealed right opercular polymicrogyria. The epilepsy had become refractory to treatment, but was brought under control with a combination of lamotrigine (200 mg/day), valproate (90 mg/day), and nitrazepam (10 mg/day) when the patient was 4 years old. Nine months after the final dose adjustment, she presented with sporadic episodes of vomiting (approximately once every 15 days). Infection and other acute causes, such as metabolic imbalance, were excluded. Another electroencephalogram was performed, and remained unaltered. She also presented with tremor and dizziness. One month later, the patient was clinically evaluated and demonstrated opsoclonus, together with ataxia, vomiting, headache, and vertigo. The opsoclonus was characterized by irregular, nonrhythmic, “agitated” oscillations of the eyeballs in both the horizontal and vertical planes. A decrease of 50 mg in the dose of lamotrigine (150 mg/day) for 2 weeks led to the remission of these disturbances, without worsening the seizures. Valproate and nitrazepam were maintained at the same dose. Patient 2
An 18-year-old woman had manifested refractory epilepsy since age 8 months. Subcortical band heterotopia was observed on magnetic resonance imaging. An electroencephalogram indicated multifocal epileptiform discharges and continuous epileptiform discharges over the right occipital region. A combination of lamotrigine (300 mg/day) and valproate (1000 mg/day) had led to partial seizure control, abolishing the
disabling drop attacks. At 15 months after the final dose adjustment, she presented with involuntary head and neck movements (i.e., tics). Ancillary examinations and determinations of serum levels were performed as listed in Table 2. The electroencephalogram did not reveal electrographic seizures. A 25-mg decrease in the dose of lamotrigine (325 mg/day) led to the remission of tics. She subsequently developed excessive upper-limb tremor, which resolved after a reduction of 250 mg in the dose of valproate (750 mg/day). Patient 3
A 15-year-old girl with an 11-year history of symptomatic epilepsy, characterized by band heterotopia, had been referred for evaluation at age 10 years. The epilepsy later became refractory. Her electroencephalogram indicated multifocal epileptiform discharges. At age 11 years, she began to receive a combination of lamotrigine (300 mg/day) and valproate (1.5 mg/day), which led to partial control. Two years after the final dose adjustment, she presented with an acute episode of nystagmus, ataxia, tremor, and vertigo. Her electroencephalogram findings were unchanged, and electrographic seizures were therefore excluded. The results of ancillary examinations and serum levels are presented in Table 2. A slow, 50-mg decrease in the dose of lamotrigine (250 mg/day) led to the remission of this clinical profile, without worsening the seizures. Patient 4
A 14-year-old boy with a 13-year history of refractory myoclonic epilepsy was referred to our facility at age 12 years. His magnetic resonance imaging findings were normal, and an electroencephalogram revealed generalized spike and polyspike and wave discharges, with a slow posterior dominant rhythm. His condition had been partly controlled with a ketogenic diet that had to be discontinued at age 6 years, which led to myoclonic status epilepticus. He was currently receiving valproate and clonazepam. The lamotrigine was introduced slowly. At high doses of lamotrigine and valproate (400 mg/day
Table 2. Clinical characteristics
Variable Age/sex Epileptic syndrome
Patient 1
6 y/F Symptomatic partial epilepsy (polymicrogyria) AEDs VPA/LTG/NZP Adverse effects Opsoclonus, ataxia, vomiting, headache, and vertigo Timing of adverse effects 0.7 y Serum level of lamotrigine 3.0 mg/mL Serum level of valproate 50 mg/mL Ancillary test results Normal Medical reduction 50-mg decrease in dose of LTG
Abbreviations: AEDs ¼ Antiepileptic drugs CZP ¼ Clonazepam LTG ¼ Lamotrigine NZP ¼ Nitrazepam VPA ¼ Valproate y ¼ Years
Patient 2
Patient 3
Patient 4
18 y/F Symptomatic partial epilepsy (band heterotopia) VPA/LTG Tics of the head and neck
15 y/F Symptomatic partial epilepsy (band heterotopia) VPA/LTG Nystagmus, ataxia, tremor, and vertigo
14 y/M Genetic generalized epilepsy (Dravet syndrome) VPA/LTG/CZP Speech and gait disturbances (cerebral signs)
1.2 y 2.5 mg/mL 60 mg/mL Normal 25-mg decrease in dose of LTG
2y 2.8 mg/mL 40 mg/mL Normal 50-mg decrease in dose of LTG
1y 3.2 mg/mL 45 mg/mL Normal 50-mg decrease in dose of LTG
S. Thome-Souza et al. / Pediatric Neurology 47 (2012) 47e50 and 1.5 g/day, respectively), complete remission of the generalized tonic-clonic seizures and partial control of the myoclonic seizures (continued brief events, approximately once a week) were achieved. After 1 year of combined lamotrigine-valproate treatment, he developed slurred speech and gait disturbance, together with ataxia and disabling tremor. His electroencephalogram findings remained unaltered, without electrographic seizures. Ancillary examinations produced normal results, and his serum levels were below therapeutic levels. A 50-mg decrease in the dose of lamotrigine (350 mg/day) led to the remission of these conditions.
Discussion
The four patients presented here manifested refractory epilepsy and shared an uncommon characteristic, i.e., a 9-month to 2-year interval between their final dose adjustment and the onset of adverse effects that remitted with a low dose decrease, without the need for discontinuing treatment. Few studies have reported on side effects after the chronic (6 months) use of lamotrigine. Mackay et al. [6] evaluated the long-term use of lamotrigine, and reported that skin rash and Stevens-Johnson syndrome comprised earlier manifestations, whereas mood disorder, ataxia, visual blurring, and diplopia occurred 6 months after introduction. The adverse effects are relatively late, and are suggestive of acute rather than chronic toxicity. These adverse effects, in fact, responded to dose reductions. Changes in childhood and adult metabolism may cause elevations of the serum levels of antiepileptic drugs, despite a stable dose. An increase in serum levels despite stable dosing is the most likely culprit of adverse effects, and for this reason must always be investigated. In our patients, doses remained stable and within therapeutic range (Table 2). In all cases, ancillary examinations were performed to exclude most relevant systemic factors that could trigger increases in the serum levels of lamotrigine or valproate. Although the exclusion of all systemic factors is not possible, infections such as viral illnesses and metabolic and electrolyte unbalances were investigated. Liver, kidney, and pancreatic dysfunction were also excluded, as were cerebrospinal fluid protein levels because they are related to alterations in serum levels. Electroencephalograms performed during adverse events did not differ from baseline electroencephalograms, allowing us to exclude electrographic seizures. The mechanism related to these signs (acute vs chronic toxicity) cannot be completely elucidated, and both hypotheses will coexist despite all examinations performed. However, our work led to the important finding that a small dose reduction led to the remission of abnormalities. This finding is relevant for clinicians caring for patients with refractory epilepsy, having to deal with efficacy and adverse effects. Three out of four patients demonstrated movement disorders, two with concomitant signs and one as an isolated finding. The mechanisms of movement disorders are highly hypothetical, and antiepileptic drugs have been postulated to affect Naþ channels, acting on dopaminergic metabolism through an inhibition of glutamine. Abnormal eye movements were also hypothesized to be caused by increased epileptiform discharges [11]. Veerapandiyan et al.
49
[9] associated oculogyric crises with other movement disorders, and suggested that altered dopaminergic tone is involved in the mechanism of all oculogyric crises. Of their four patients, three presented with cerebral damage that may have been responsible for the adverse effects. Sotero de Menezes et al. [7] suggested that, in addition to structural or functional brain abnormalities, a genetic predisposition is involved, and that the use of lamotrigine can induce tics by working in synergy with those factors. Our findings contradict the theory of worsening electroencephalographic indicators leading to adverse effects, but most of our patients exhibited relevant structural abnormalities of the central nervous system (with malformations of cortical development in three). Lamotrigine and valproate, sometimes associated with benzodiazepines, provided excellent control of refractory epilepsy in our patients. This association was reported as effective by our group and by others [12,13]. The synergism between these two drugs has been extensively debated. Pharmacokinetic-pharmacodynamic relationships have been demonstrated in adults and children [1,10]. Therefore, rather than discontinuing the drug, we opted to decrease the dose, as previously recommended [7,8]. Physicians who use combinations of lamotrigine and valproate to treat patients with refractory epilepsy should be alert to the potential for late side effects. Studies involving larger numbers of patients treated with this and other combinations involving lamotrigine, as well as longer followup periods, are required to determine whether late effects are less common in patients treated with lamotrigine alone. Late effects unrelated to titration are typically overlooked. The possibility of severe late adverse effects in patients during long-term treatment with combinations of lamotrigine and valproate must be borne in mind, to avoid unnecessary ancillary tests. We have demonstrated that a small decrease in dose can lead to the remission of such effects, without worsening seizures. References [1] Guberman AH, Besag FMC, Brodie MJ, et al. Lamotrigine-associated rash: Risk/benefit considerations in adults and children. Epilepsia 1999;40:985e91. [2] May TW, Bernhard R, Uwe J. Serum concentrations of lamotrigine in epileptic patients: The influence of dose and comedication. Ther Drug Monit 1996;18:523e31. [3] Messenheimer J, Ramsay RE, Willmore LJ, et al. Lamotrigine therapy for partial seizures: A multicenter, placebo-controlled, double-blind, cross-over trial. Epilepsia 1994;35:113e21. [4] Pressler RM, Binnie CD, Coleshill SG, Chorley GA, Robinson RO. Effect of lamotrigine on cognition in children with epilepsy. Neurology 2006;66:1495e9. [5] La Roche SM, Helmers SL. The new antiepileptic drugs: Clinical applications. JAMA 2004;291:615e20. [6] Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD. Safety of long-term lamotrigine in epilepsy. Epilepsia 1997;38:881e6. [7] Sotero de Menezes MA, Rho JM, Murphy P, Cheyette S. Lamotrigine-induced tic disorder: Report of five pediatric cases. Epilepsia 2000;41:862e7. [8] Kim DG, Oh SH, Kim OJ. A case of lamotrigine-induced excessive involuntary eye blinking. J Clin Neurol 2007;3:93e5. [9] Veerapandiyan A, Gallentine WB, Winchester SA, et al. Oculogyric crises secondary to lamotrigine overdosage. Epilepsia 2011; 52:4e6. [10] Thomé-Souza S, Freitas A, Fiore LA, Valente KD. Lamotrigine and valproate: Efficacy of co-administration in a pediatric population. Pediatr Neurol 2003;28:360e4.
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[11] Cocito L, Maffini M, Loeb C. Long-term observations on the clinical use of lamotrigine as add-on drug in patients with epilepsy. Epilepsy Res 1994;19:123e7. [12] Machado VH, Palmini A, Bastos FA, Rotert R. Long-term control of epileptic drop attacks with the combination of valproate,
lamotrigine, and a benzodiazepine: A “proof of concept, ” open label study. Epilepsia 2011;52:1303e10. [13] Thome-Souza S, Valente KD. Valproate and lamotrigine in children and adolescents with drop attacks: Follow-up after the first year [letter]. Epilepsia 2011;52:2139.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Late Adverse Effects of the Coadministration of Valproate and Lamotrigine Sigride Thome-Souza MD, PhD *, Bernardo Moreira MD, Kette D. Valente MD, PhD Laboratory of Clinical Neurophysiology, School of Medicine, University of São Paulo, and Hospital das Clínicas, São Paulo, Brazil
article information
abstract
Article history: Received 18 October 2011 Accepted 30 April 2012
Individuals treated with combined valproate-lamotrigine rarely present late adverse effects (unrelated to introduction and titration). We describe four patients in whom such effects occurred after continuous, long-term use of valproate-lamotrigine (at 9 months to 2 years after final antiepileptic drug adjustment). The patients presented heterogeneous disturbances, including ataxia, vertigo, and headache, and rare movement disorders, such as tics and abnormal eye movements. Although these effects are heterogeneous in their occurrence and timing, they can alert physicians to the possibility of late neurologic disturbances, and must be considered in order to avoid unnecessary ancillary tests. Treatment discontinuation is unnecessary, given that a small decrease in dose led to remission of these adverse effects. Ó 2012 Elsevier Inc. All rights reserved.
Introduction
Lamotrigine is an antiepileptic drug that is well-tolerated by children and adults. It demonstrates broad-spectrum efficacy, either as monotherapy or in combination with other antiepileptic drugs such as valproate [1]. The mechanism of action of lamotrigine involves Naþ channel blocking, and may entail the activation of N-methylD-aspartate receptors. As monotherapy, lamotrigine demonstrates good absorption after oral administration, a direct kinetic relationship between dose and plasma concentrations, approximately 55% protein binding, and an elimination half-life of 25-30 hours [2]. The half-life of lamotrigine is reduced by approximately half when in the presence of drugs inducing uridine diphosphate glucuronosyl-transferase, such as carbamazepine and phenytoin. On the other hand, if lamotrigine is associated with drugs that inhibit uridine diphosphate glucuronosyltransferase, such as valproic acid, a decrease of lamotrigine clearance and an increase in its plasma concentrations occur. Valproic acid can prolong the elimination half-life of lamotrigine to about 60 hours [2].
* Communications should be addressed to: Dr. Thome-Souza; Rua Dr. Ovidio; Pires de Campos 785; São Paulo, São Paulo 05403-010, Brazil. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2012.04.026
Messenheimer et al. [3], in a multicenter, randomized, double-blind, placebo-controlled, crossover study of 98 patients with refractory partial seizures, reported that adverse experiences were generally minor and most frequently related to the central nervous system (e.g., ataxia, dizziness, diplopia, and headache). However, lamotrigine was safe, effective, and well tolerated in patients with medically refractory partial seizures. Pressler et al. [4], in a double-blind, placebo-controlled, crossover study of 61 children with well-controlled or mild epilepsy, reported that lamotrigine exhibited no clinically significant cognitive effects during adjunctive therapy. A therapeutic synergy is evident between valproate and lamotrigine, but with a potentiation of adverse effects. In a review of lamotrigine treatment, La Roche and Helmers [5] demonstrated that among 3501 patients, side effects led to the discontinuation of lamotrigine in 10.2%, most often because of rash. Some authors postulated that the side effects of lamotrigine can be lessened by slower introduction and titration [5,6]. Lamotrigine was reported to cause movement disorders [7-9] that are frequently associated with titration or overdose (Table 1). Although the addition of valproate increases the efficacy of lamotrigine, it also increases the risk for adverse effects [1]. In children and adults, such effects typically occur during the first 4 months of treatment [1,10]. Few studies have investigated the combination of lamotrigine and valproate in terms of late
48
S. Thome-Souza et al. / Pediatric Neurology 47 (2012) 47e50
Table 1. Late side effects in patients with the use of lamotrigine
Reference
Number of Subjects
Design
Timing
Adverse Effects
Mackay et al. [6]
3994
Cohort study
6 months
Case report Case report Case report
4-10 months 5 months 5-12 months
Ataxia, headache, drowsiness, nausea, vomiting, malaise, and lassitude (in 0.1-0.2% of patients) Tic disorder Excessive, involuntary eye blinking Oculogyric crises
Sotero de Menezes et al. [7] Kim et al. [8] Veerapandiyan et al. [9]
5 1 4
adverse effects. Here, we report on four cases of late adverse effects in patients treated with a combination of lamotrigine and valproate (Table 2). Case Reports Patient 1
A 6-year-old girl had experienced a 42-month history of partial symptomatic epilepsy, characterized by partial motor seizures. Electroencephalography indicated epileptiform discharges over the central parietal region. Magnetic resonance imaging revealed right opercular polymicrogyria. The epilepsy had become refractory to treatment, but was brought under control with a combination of lamotrigine (200 mg/day), valproate (90 mg/day), and nitrazepam (10 mg/day) when the patient was 4 years old. Nine months after the final dose adjustment, she presented with sporadic episodes of vomiting (approximately once every 15 days). Infection and other acute causes, such as metabolic imbalance, were excluded. Another electroencephalogram was performed, and remained unaltered. She also presented with tremor and dizziness. One month later, the patient was clinically evaluated and demonstrated opsoclonus, together with ataxia, vomiting, headache, and vertigo. The opsoclonus was characterized by irregular, nonrhythmic, “agitated” oscillations of the eyeballs in both the horizontal and vertical planes. A decrease of 50 mg in the dose of lamotrigine (150 mg/day) for 2 weeks led to the remission of these disturbances, without worsening the seizures. Valproate and nitrazepam were maintained at the same dose. Patient 2
An 18-year-old woman had manifested refractory epilepsy since age 8 months. Subcortical band heterotopia was observed on magnetic resonance imaging. An electroencephalogram indicated multifocal epileptiform discharges and continuous epileptiform discharges over the right occipital region. A combination of lamotrigine (300 mg/day) and valproate (1000 mg/day) had led to partial seizure control, abolishing the
disabling drop attacks. At 15 months after the final dose adjustment, she presented with involuntary head and neck movements (i.e., tics). Ancillary examinations and determinations of serum levels were performed as listed in Table 2. The electroencephalogram did not reveal electrographic seizures. A 25-mg decrease in the dose of lamotrigine (325 mg/day) led to the remission of tics. She subsequently developed excessive upper-limb tremor, which resolved after a reduction of 250 mg in the dose of valproate (750 mg/day). Patient 3
A 15-year-old girl with an 11-year history of symptomatic epilepsy, characterized by band heterotopia, had been referred for evaluation at age 10 years. The epilepsy later became refractory. Her electroencephalogram indicated multifocal epileptiform discharges. At age 11 years, she began to receive a combination of lamotrigine (300 mg/day) and valproate (1.5 mg/day), which led to partial control. Two years after the final dose adjustment, she presented with an acute episode of nystagmus, ataxia, tremor, and vertigo. Her electroencephalogram findings were unchanged, and electrographic seizures were therefore excluded. The results of ancillary examinations and serum levels are presented in Table 2. A slow, 50-mg decrease in the dose of lamotrigine (250 mg/day) led to the remission of this clinical profile, without worsening the seizures. Patient 4
A 14-year-old boy with a 13-year history of refractory myoclonic epilepsy was referred to our facility at age 12 years. His magnetic resonance imaging findings were normal, and an electroencephalogram revealed generalized spike and polyspike and wave discharges, with a slow posterior dominant rhythm. His condition had been partly controlled with a ketogenic diet that had to be discontinued at age 6 years, which led to myoclonic status epilepticus. He was currently receiving valproate and clonazepam. The lamotrigine was introduced slowly. At high doses of lamotrigine and valproate (400 mg/day
Table 2. Clinical characteristics
Variable Age/sex Epileptic syndrome
Patient 1
6 y/F Symptomatic partial epilepsy (polymicrogyria) AEDs VPA/LTG/NZP Adverse effects Opsoclonus, ataxia, vomiting, headache, and vertigo Timing of adverse effects 0.7 y Serum level of lamotrigine 3.0 mg/mL Serum level of valproate 50 mg/mL Ancillary test results Normal Medical reduction 50-mg decrease in dose of LTG
Abbreviations: AEDs ¼ Antiepileptic drugs CZP ¼ Clonazepam LTG ¼ Lamotrigine NZP ¼ Nitrazepam VPA ¼ Valproate y ¼ Years
Patient 2
Patient 3
Patient 4
18 y/F Symptomatic partial epilepsy (band heterotopia) VPA/LTG Tics of the head and neck
15 y/F Symptomatic partial epilepsy (band heterotopia) VPA/LTG Nystagmus, ataxia, tremor, and vertigo
14 y/M Genetic generalized epilepsy (Dravet syndrome) VPA/LTG/CZP Speech and gait disturbances (cerebral signs)
1.2 y 2.5 mg/mL 60 mg/mL Normal 25-mg decrease in dose of LTG
2y 2.8 mg/mL 40 mg/mL Normal 50-mg decrease in dose of LTG
1y 3.2 mg/mL 45 mg/mL Normal 50-mg decrease in dose of LTG
S. Thome-Souza et al. / Pediatric Neurology 47 (2012) 47e50 and 1.5 g/day, respectively), complete remission of the generalized tonic-clonic seizures and partial control of the myoclonic seizures (continued brief events, approximately once a week) were achieved. After 1 year of combined lamotrigine-valproate treatment, he developed slurred speech and gait disturbance, together with ataxia and disabling tremor. His electroencephalogram findings remained unaltered, without electrographic seizures. Ancillary examinations produced normal results, and his serum levels were below therapeutic levels. A 50-mg decrease in the dose of lamotrigine (350 mg/day) led to the remission of these conditions.
Discussion
The four patients presented here manifested refractory epilepsy and shared an uncommon characteristic, i.e., a 9-month to 2-year interval between their final dose adjustment and the onset of adverse effects that remitted with a low dose decrease, without the need for discontinuing treatment. Few studies have reported on side effects after the chronic (6 months) use of lamotrigine. Mackay et al. [6] evaluated the long-term use of lamotrigine, and reported that skin rash and Stevens-Johnson syndrome comprised earlier manifestations, whereas mood disorder, ataxia, visual blurring, and diplopia occurred 6 months after introduction. The adverse effects are relatively late, and are suggestive of acute rather than chronic toxicity. These adverse effects, in fact, responded to dose reductions. Changes in childhood and adult metabolism may cause elevations of the serum levels of antiepileptic drugs, despite a stable dose. An increase in serum levels despite stable dosing is the most likely culprit of adverse effects, and for this reason must always be investigated. In our patients, doses remained stable and within therapeutic range (Table 2). In all cases, ancillary examinations were performed to exclude most relevant systemic factors that could trigger increases in the serum levels of lamotrigine or valproate. Although the exclusion of all systemic factors is not possible, infections such as viral illnesses and metabolic and electrolyte unbalances were investigated. Liver, kidney, and pancreatic dysfunction were also excluded, as were cerebrospinal fluid protein levels because they are related to alterations in serum levels. Electroencephalograms performed during adverse events did not differ from baseline electroencephalograms, allowing us to exclude electrographic seizures. The mechanism related to these signs (acute vs chronic toxicity) cannot be completely elucidated, and both hypotheses will coexist despite all examinations performed. However, our work led to the important finding that a small dose reduction led to the remission of abnormalities. This finding is relevant for clinicians caring for patients with refractory epilepsy, having to deal with efficacy and adverse effects. Three out of four patients demonstrated movement disorders, two with concomitant signs and one as an isolated finding. The mechanisms of movement disorders are highly hypothetical, and antiepileptic drugs have been postulated to affect Naþ channels, acting on dopaminergic metabolism through an inhibition of glutamine. Abnormal eye movements were also hypothesized to be caused by increased epileptiform discharges [11]. Veerapandiyan et al.
49
[9] associated oculogyric crises with other movement disorders, and suggested that altered dopaminergic tone is involved in the mechanism of all oculogyric crises. Of their four patients, three presented with cerebral damage that may have been responsible for the adverse effects. Sotero de Menezes et al. [7] suggested that, in addition to structural or functional brain abnormalities, a genetic predisposition is involved, and that the use of lamotrigine can induce tics by working in synergy with those factors. Our findings contradict the theory of worsening electroencephalographic indicators leading to adverse effects, but most of our patients exhibited relevant structural abnormalities of the central nervous system (with malformations of cortical development in three). Lamotrigine and valproate, sometimes associated with benzodiazepines, provided excellent control of refractory epilepsy in our patients. This association was reported as effective by our group and by others [12,13]. The synergism between these two drugs has been extensively debated. Pharmacokinetic-pharmacodynamic relationships have been demonstrated in adults and children [1,10]. Therefore, rather than discontinuing the drug, we opted to decrease the dose, as previously recommended [7,8]. Physicians who use combinations of lamotrigine and valproate to treat patients with refractory epilepsy should be alert to the potential for late side effects. Studies involving larger numbers of patients treated with this and other combinations involving lamotrigine, as well as longer followup periods, are required to determine whether late effects are less common in patients treated with lamotrigine alone. Late effects unrelated to titration are typically overlooked. The possibility of severe late adverse effects in patients during long-term treatment with combinations of lamotrigine and valproate must be borne in mind, to avoid unnecessary ancillary tests. We have demonstrated that a small decrease in dose can lead to the remission of such effects, without worsening seizures. References [1] Guberman AH, Besag FMC, Brodie MJ, et al. Lamotrigine-associated rash: Risk/benefit considerations in adults and children. Epilepsia 1999;40:985e91. [2] May TW, Bernhard R, Uwe J. Serum concentrations of lamotrigine in epileptic patients: The influence of dose and comedication. Ther Drug Monit 1996;18:523e31. [3] Messenheimer J, Ramsay RE, Willmore LJ, et al. Lamotrigine therapy for partial seizures: A multicenter, placebo-controlled, double-blind, cross-over trial. Epilepsia 1994;35:113e21. [4] Pressler RM, Binnie CD, Coleshill SG, Chorley GA, Robinson RO. Effect of lamotrigine on cognition in children with epilepsy. Neurology 2006;66:1495e9. [5] La Roche SM, Helmers SL. The new antiepileptic drugs: Clinical applications. JAMA 2004;291:615e20. [6] Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD. Safety of long-term lamotrigine in epilepsy. Epilepsia 1997;38:881e6. [7] Sotero de Menezes MA, Rho JM, Murphy P, Cheyette S. Lamotrigine-induced tic disorder: Report of five pediatric cases. Epilepsia 2000;41:862e7. [8] Kim DG, Oh SH, Kim OJ. A case of lamotrigine-induced excessive involuntary eye blinking. J Clin Neurol 2007;3:93e5. [9] Veerapandiyan A, Gallentine WB, Winchester SA, et al. Oculogyric crises secondary to lamotrigine overdosage. Epilepsia 2011; 52:4e6. [10] Thomé-Souza S, Freitas A, Fiore LA, Valente KD. Lamotrigine and valproate: Efficacy of co-administration in a pediatric population. Pediatr Neurol 2003;28:360e4.
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