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Lamotrigine Adjunctive Therapy in Children with Refractory Epilepsy: A Medical Center Study SHYI -JOU CHEN1, KAI-PING CHANG2, TAI-TONG WONG3, SHANG-YEONG KWAN4, MU-LING HSU5, CHIH-CHIEN WANG1
The aim of this study was to investigate the effects of adjunctive lamotrigine (LTG) in refractory epilepsy in Taiwan, especially including patients who had undergone ineffective epileptic surgeries. Totally, 27 recruited children and adolescents with refractory epilepsy were treated with LTG addon therapy, but 23 were enrolled statistically during 2 years period trial. Ten of the 23 patients (43.5%), including 5 undergoing epileptic surgeries, before had a >50% reduction in seizure frequency. Surprisingly, LTG was found to have excellent response in six patients with LennoxGastaut Syndrome (LGS), 5 of whom had received anterior 2/3 callosotomy prior to the trial. Nonseizure related positive effects were presented in 3 patients, including greater alertness and attentiveness in 2 patients and improvement in mood in one patient. This open trial found that LTG was an effective add-on anti-epileptic drug (AED) in Taiwanese children and adolescents with refractory epilepsy and in cases with LGS even after ineffective callosotomy. (Acta Paediatr Tw 2006; 47:123-6) Key words: Lamotrigine, refractory epilepsy, Lennox-Gastaut syndrome, callosotomy INTRODUCTION Lamotrigine (LTG), a novel antiepilpetic drug (AED), 1-3 has been established as effective for many refractory generalized and partial seizures, as well as epileptic syndromes, both in adults and in children.4-10 However, clinical data on Asian children and adolescents were limited. We studied the effectiveness of LTG as adjunctive treatment in 27 Taiwanese children and adolescents with refractory epilepsy, including 7 who had received epileptic surgery before enrollment. The effects on seizure control, adverse effects, and non-seizure positive results were primarily assessed. Seizure responses were also evaluated for different seizure types, age at the onset of seizures and presence or absence of brain structure lesions. The adverse effects of presence or absence of co-administration of valproic acid (VPA) were also investigated.
SUBJECTS AND METHODS
Initially, 27 children and adolescents (15 males, 12 females) with refractory epilepsy, aged 2 years to 21 years (mean ± SD: 9y9m ± 5y4m) were enrolled in this study. All data were retrospectively collected from the medical records of patients treated in the Department of Pediatrics and the Epileptic Clinic of the Neurology Department of the Taipei Veterans General Hospital. Epilepsy was symptomatic in 15 of 27 patients, and 6 of them had documentation of etiologies. Three had central nervous system (CNS) infections (1 Group B streptococcus meningitis, 1 Herpes Simplex Virus encephalitis, and 1 Epstein-Barr virus encephalitis), one had porencephaly, one had hypoxic-ischemic encephalopathy, and one had head injury. The remaining 12 patients had cryptogenic epilepsy. In addition, all except 6 had other neuro-handicaps. Mental deficit was present in 20 children. Moreover, cerebral palsy had been diagnosed in 7 patients, attention deficit disorder in 3, autism in 2, central hypotonia in 1, speech problem in 1, and hemiparesis in 1.
Department of Pediatrics, Tri-Service General Hospital1, Taipei, Medical Sciences, National Defense Medical Center, Taipei; Department of Pediatrics2, Neurosurgery 3 and Neurology4, Veterans General Hospital-Taipei; Department of Pediatrics, Hualien Armed Forces General Hospital5, Taiwan. Received: September 9, 2005. Revised: June 5, 2006. Accepted: July 10, 2006. Address reprint requests to: Dr. Shyi-Jou CHEN, Department of Pediatrics, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Road, Nei-Hu 114, Taipei, Taiwan. TEL : 886-2-8792-7025 FAX : 886-2-8792-7293 E-mail:
[email protected]
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All patients had been refractory to treatment with at least 2 or more anti-epileptic drugs (AEDs), with each patient having more than 3 fits per month in the preceding 3 months before enrollment.11,12 The median age at the onset of epilepsy was 2 years and 3 months (range: 3m to 9y4m) and ten had seizure onset before the age of 1 year. The median duration of epilepsy at entry was 7 years and 6 months (range: 1y4m to 18y6m). All patients had received either computed tomography (CT) or magnetic resonance imaging (MRI) of the brain before enrollment in the study. Laboratory results were all within normal limits, including complete blood count and liver and renal function profiles. EEG and concomitant serum levels of AEDs were also evaluated regularly. Patients were evaluated regularly every 2 weeks for at least 6 months at the Epileptic Clinic of the Pediatrics Department of the Veterans General Hospital in Taipei. Evaluation of efficacy was based on monthly seizure frequency as recorded daily by the patient’s parents or guardians, as well as the occurrence of any side effects or non-epileptic effects. An additional consent was required for enrollment in the study protocol. Response to the medication was defined as a seizure frequency decrease of more than 50% while “no response” was defined as a seizure frequency decrease of less than 50% or worsened seizure frequency. 12 Patients were considered “seizure-free” if all seizure types had stopped for at least 6 months. Patients were excluded from the statistical analysis if LTG was withdrawn within 3 months after initiation due to side effects, failure to comply with the therapy regimen, or if they lacked detailed seizure attack records. Otherwise, non-seizure efficacy with regard to mental status, behavior, attention, communication and alertness were demonstrated based on medical records. Symptomatic epilepsy was defined as epilepsy with structural brain lesions revealed by abnormal CT and/or MRI. LTG was added to the patient’s preexisting AED regimen, starting with a daily dose of 0.2 mg/kg in patients receiving VPA and 1 mg/kg in patients not receiving VPA, then gradually increased to a maximum of 5 mg/kg in VPA and 10 mg/kg in patients not receiving VPA. A divided daily dosage regimen was prescribed to all patients.
RESULTS Clinical characteristics The types of seizures were defined according to the International Classification of Epileptic Seizures.13 An epileptic syndrome had been diagnosed in 16 children, including infantile spasms in 2, Lennox-Gastaut syndrome
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(LGS) in 8, cryptogenic partial epilepsy in 1, and symptomatic partial epilepsy in 5. There were two or more different types of seizures in 19 children and only one seizure type occurred in 8. The median seizure frequency was 79 fits per month (range: 5-338 fits/month) and the mean frequency was 23 fits/month. Epileptic surgery had been performed previously in 7 patients (anterior 2/3 callostomy for LGS in 6, and temporal lobectomy for mesial temporal sclerosis in 1). All of these patients were included and met the criteria for participation in the LTG add-on trial at least 1 year after surgical intervention. There were a total of eight different AEDs that were being used concomitantly by various patients at the time of LTG add-on therapy in this study (median: 1.7 AEDs/patient, range 1-3 types of AEDs) (Table 1). Adjunctive LTG treatment was continued throughout the study period in a total of 23 patients, including 12 in the generalized epilepsy group and 11 in the partial epilepsy group. LTG treatment was withdrawn in 4 patients within 3 months (adverse effects in 3 patients and an incomplete diary for 1 patient). During the study, the 23 subjects who completed the protocol were treated with LTG for a median of 11.2 months (range 6-24 months). Effectiveness by seizure type Effective response to therapy, defined as a decrease in total seizure frequency by 50% or more compared with baseline levels, was achieved in 10 of the 23 assessable patients, including one who became totally seizure-free. The remaining 13 patients had no seizure effects. There was no statistically significant difference in VPA serum level in patients with LTG add-on therapy and those without. The average of number of seizure types was 1.7 types per case, in terms of that a total count of seizure types was 39 in 23 patients (8 with only one seizure type, 14
Table 1. Concomitant AEDs Used in Patients with Epilepsy Receiving Adjunctive LTG Therapy Used AEDs
No. of patients
Valproate Clobazam Clonazepam Phenobarbital Phenytoin Carbamazepine Acetazolamide Primidone
16 9 5 1 5 6 1 1
Average of No. of AEDs per patient
1.7
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with two, and the remainder with three), and these were analyzed as dichotomous variables for their relationship to the effectiveness of therapy. The responses to adjunctive LTG therapy by seizure type are summarized in Table 2. By classification of seizure types, partial seizure group responded to LTG add-on therapy better than generalized seizure group in this study. Moreover, we observed that patients with atypical absence and GTCS had relatively higher positive seizure response than those with myoclonic and atonic epilepsy. In addition, nine assessable children with age at onset of seizures of less than 1 year showed a tendency of poor seizure control compared to those with age at onset more than 1 year. Unexpectedly, a significantly increased frequency of favorable response was found in patients with symptomatic epilepsy compared to those with cryptogenic epilepsy. Infantile spasm failed to respond to LTG therapy in two patients. Seizure reduction effects of add-on LTG in surgically treated LGS Initially, there were eight patients with LGS (6 had previously undergone anterior 2/3 callostomy) recruited for the trial, but 2 were excluded due to adverse effects. The remaining 6 with LGS (5 had received surgical intervention prior to the trial) were statistically assessed. The seizure reduction in the 6 patients with LGS was 41. 7%, and notable was the 50% seizure reduction in the 5 patients who had undergone previous anterior 2/3 callostomy (Table 3). Non-seizure benefit Significant non-seizure-related positive effects were revealed in 3 patients after adjuvant LTG therapy, with Table 2. Response to Adjunctive LTG Therapy by Seizure Types in the 23 Enrolled Subjects Seizure type
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Percentage (no. of patients) with >50% reduction in seizure frequency
Generalized tonic-clonic Atypical absence Tonic Myoclonic Atonic Average
66.7% 57.1% 33.3% 14.3% 0% 37.5%
(2/3) (4/7) (2/6) (1/7) (0/1) (9/24)
Simple partial Complex partial Partial, secondarily generalized Average
100% 37.5% 60% 53.3%
(2/2) (3/8) (3/5) (8/15)
Total average
43.6% (17/39)
Table 3. Efficacy of LTG in 5 LGS Patients Who Had Undergone Previous Epileptic Surgery Seizure type
Percentage (no. of patients) with >50% seizure reduction
Atypical absence Generalized tonic-clonic Tonic Myoclonic Atonic Total average
66.7% 50% 50% 33.3%
(2/3) (1/2) (1/2) (1/3)
50% (5/10)
2 of them having greater alertness and attentiveness while one experienced an improvement in mood. One patient with IS had ameliorated quality of life, with more alertness and attentiveness. The remaining two patients had both undergone epileptic surgery previously. One who had undergone anterior 2/3 callostomy had both seizure and non-seizure benefits, with better mood after add-on LTG. The other patient, who had undergone temporal lobectomy without seizure effect, continued to receive LTG for non-seizure benefits of more alertness and attentiveness. Adverse effects Adverse effects of LTG therapy occurred in 7 patients (4 with VPA; 3 without VPA). Three patients were withdrawn due to adverse side effects (one with skin rash, one with skin petechiae, and one with intolerance of increased body weight gain). Skin lesions in two patients (both concomitantly treated with VPA) were the leading cause of discontinuing LTG therapy. Other adverse effects recorded include the following: sleepiness (3 patients), ataxia (3 patients), poor appetite (1 patient), blurred vision (1 patient), and constipation (1 patient). No significant difference in the incidence of adverse effects between patients receiving VPA (25%) and patients not receiving VPA (27.2%) was found. VPA serum level in patients treated concomitantly with VPA was not significantly different before and after LTG add-on therapy.
DISCUSSION Although the effectiveness of LTG has been documented2-4 previously, the limited studies in the pediatric age group5-9 are still far less reported in Asians. In contrast to previous results,5-7 partial epilepsy showed better response to LTG add-on therapy than generalized epilepsy did in this study, which may be attributed to the characteristics of enrolled cases. Furthermore, in the generalized epilepsy group, patients with GTCS and
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atypical absence epilepsy had improved seizure responses. But patients with myoclonic and atonic epilepsy had a poor response, as in previous studies.7,10,14 The enrolled cases with intractable epilepsies were mostly referred for the evaluation of pre-epileptic surgery, leading to the limitations of the study including the numbers of enrolled patients. Therefore, more cases need to be enrolled to draw a definitely final conclusion in the future. Many patients who are resistant to AEDs underwent epileptic surgery after detailed assessment, but not all respond well to the intervention.15 Interestingly, our LGS group patients who had undergone callosotomy had rather good response to add-on LTG therapy in terms of seizure reductions and non-seizure effects. To our knowledge, this is the first report of the efficacy of adjunctive LTG therapy in children from Asia with LGS who have undergone surgical intervention. Children who suffer from intractable seizures usually also have mental or behavioral handicaps, and LTG add-on therapy may provide considerable positive psychiatric effects.6-9 Two of our patients received add-on LTG therapy continually due to satisfactory non-seizure benefits even though there was no effective treatment with LTG. Previous surveys demonstrated a high risk of skin lesions associated with the combination of VPA and LTG usage, particularly in children. 16,17 The tendency to develop skin lesions when add-on therapy was concomitant with VPA was also revealed from our results, which were obtained even under meticulous control of the titration of LTG. These findings suggest that although LTG can be a useful adjunctive to VPA and/ or non-VPA AEDs with a tolerable incidence of adverse effects, the concomitant use of LTG with VPA should be assessed cautiously for its potential risk of skin lesions (e. g. rash or petechiae). Recently, two extended studies reported the efficacy of LTG as monotherapy in long-term treatment in pediatric patients with epilepsy,18 and sustained beneficial effects of add-on LTG in children with intractable epilepsy.19 Our study had a relatively small number of enrolled patients, and therefore, advanced studies should be undertaken, including more recruited cases, long-term follow-up and prospective evaluations of the effect of LTG in pediatric patients with epilepsy in Taiwan. Nevertheless, we postulate that LTG is effective in patients with LGS, even for those who have undergone relatively ineffective corpus callostomy, and in patients with symptomatic refractory epilepsy. Accordingly, LTG is a considerable add-on AED in cases of intractable epilepsy in Asian children. ACKNOWLEDGEMENT: We thank GSK Taiwan Branch for supplying English revision. This work was supported in part by a grant (TSGH-C94-92) from TriService General Hospital, Taipei.
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