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Chin Med J (Taipei) 1997;59:303-7.
Department of Neurology, The Neurological Institute, Veterans General Hospital-Taipei; and National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C.
Background. Lamotrigine (LTG), one of the newly developed antiepileptic drugs, is efficacious in treating both partial and generalized seizure disorders including Lennox-Gastaut syndrome. Its effect as an add-on therapy was evaluated in 41 adult Chinese patients with refractory epilepsy. Five of the patients were Lennox-Gastaut syndrome and 36 patients had partial epilepsy.
Methods. We started LTG at 25mg or 50mg per day, respectively, depending on whether the patients were simultaneously taking valproate (VPA) or not. Then, LTG was increased in steps to maximal dosage (200mg or 400mg per day) within seven weeks and maintained for three months while pre-existing antiepileptic drugs remained unchanged. The efficacy of LTG therapy was assessed by the reduction in the overall seizure frequency. Hematological and biochemical parameters were checked before and after the trial in all patients.
Results. In all, 38 patients completed the trial. Twenty-two patients (57.9%) had >= 50% reduction in seizure frequency, including four patients with Lennox-Gastaut syndrome and 18 patients with partial seizures. Among the patients with partial epilepsy, there was no significant difference in the efficacy of LTG whether the seizures were of temporal or extra-temporal origin (p =0. 577). In addition, the efficacy was not determined by the concomitant use of VPA (p =0.189). Thirteen patients (31.7%) complained of adverse experiences, usually mild and dose-dependent. LTG had to be discontinued in only two patients (4.9%) due to severe side effects. The change in blood cell counts and biochemistry profiles was not significant in any of the patients.
Conclusions. We conclude that LTG is an efficacious and safe antiepileptic drug for add-on therapy in adult patients with refractory epilepsy.
[Chin Med J (Taipei) 1997;59:303-7.]
Keywords: lamotrigine, Lennox-Gastaut syndrome, partial seizure, refractory epilepsy
Received: November 11, 1996.
Accepted: January 10, 1997.
Address reprint requests to: Ming-Shung Su, M.D., Department of Neurology, The Neurological Institute, Veterans General Hospital-Taipei, 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan 112, R.O.C.
Lamotrigine (LTG), 3,5-diamino-6-(2,3- dichlorophenyl)-as-triazine, is a newly developed anti-epileptic drug (AED) derived from pyrimethamine, and is an important antimalarial with antifolate and potent anticonvulsant activity [1,2]. Chemically different from commonly available AEDs, LTG most probably exerts its antiepileptic activity by blocking the release of excitatory neurotransmitters, principally glutamate and aspartate, in the central nervous system (CNS) [3]. It will not induce hepatic metabolic enzymes that affect other drugs including AEDs. However, the elimination half-life may be doubled if used concomitantly with valproate (VPA) [4].
Clinical trials have shown LTG to be efficacious in treating both partial seizure and generalized seizure disorders including Lennox-Gastaut syndrome in add-on treatment [5-10]. In addition, LTG monotherapy is comparable with carbamazepine (CBZ) in efficacy in patients with untreated epilepsy [11]. The present study was undertaken to determine the efficacy of LTG as add-on therapy in adult Chinese patients with refractory epilepsy.
This study enrolled epileptic patients who had attended the Adult Epilepsy Clinic at Veterans General Hospital-Taipei for a minimum of six months, including those precluded from surgical treatment by presurgical evaluation and those who had underwent anterior temporal lobectomy. Their seizures had been present for at least two years and were refractory to standard AED treatment (more than two major attacks per month). Diagnosis was supported in all cases by scalp electroencephalogram (EEG) recordings with nasopharyngeal electrodes and computed tomography/magnetic resonance imaging of the head. Seizure patterns and frequency were obtained from a diary issued by Taiwan Epilepsy Society, and recorded by the patients or the caregivers. None ofthe patients had any severe systemic, psychiatric or progressive neurological condition. Patients with intracranial tumors and female patients who were pregnant or breast feeding were not included in this assessment. All patients gave informed consent.
LTG was started at a dose of 25mg or 50mg per day orally, depending on whether patients were taking VPA, and then increased at weekly intervals to a maximum within seven weeks. If adverse experiences occurred, LTG was returned to the previous dosage for one week before attempting a further increase. The maximal dosage of LTG was 200mg per day administered in two divided doses for patients receiving VPA, and 400mg per day for patients who did not receive VPA. The maximum dosage was maintained for 3 months while other pre-existing AEDs remained unchanged. LTG administration was discontinued if intolerable side effects occurred. After the trial, LTG levels were tapered gradually if there was no significant response. Patients may also select to continue LTG treatment.
Patients were assessed along with the diary at each study visit biweekly or monthly. Seizures were classified according to the International Classification of Epilepsies and Epileptic Syndromes [12]. However, we evaluated only the most complicated seizures in this study; i.e. complex partial seizures with or without secondary generalization in the partial epilepsy group, complex partial seizures and generalized seizures including atonic attacks in patients with Lennox-Gastaut syndrome. Aura or simple partial seizures were not included.
The efficacy of LTG therapy was assessed by the reduction in the overall seizure frequency, expressed in percentage form by the following equation:
(A-B) / A x 100%
A represents the total number of seizures in the baseline period (three months before LTG therapy), and B is the total number of seizures during the three-month LTG trial.
We arbitrarily divided the clinical responses into the following categories: >=50% seizure reduction, 25-50% reduction, change within 25% of the baseline, worsening of seizures and withdrawal.
Hematologic and biochemical parameters including glucose, cholesterol, triglyceride, uric acid, liver function tests (alanine aminotransferase/aspartate aminotrans-ferase), renal function tests (blood urea nitrogen/creatinine) were checked during the baseline period and after the trial in all patients
There were 17 men and 24 women. All were Chinese aged 16 to 46 (mean 29.7 years). Thirty-six patients had partial epilepsy; 28 were of temporal origin and eight were extra-temporal origin (four frontal, four centro-parietal). Five patients fulfilled the diagnostic criteria of Lennox-Gastaut syndrome. In pre-existing AEDs, three patients were taking one, 20 were taking two, and 18 were taking three or more AEDs when entering the trial. The most frequently prescribed AEDs in our patients were CBZ in 36 patients, VPA in 21 patients and phenytoin (PHT) in nine patients.
Among the 38 patients who completed the study, 22 (57.9%) had >= 50% reduction in seizure frequency (Table 1). Six patients showed 25-50% seizure reduction, and 10 patients experienced a within 25% change in seizure frequency. No patients had a deterioration in seizures. LTG therapy was discontinued in two patients due to intolerable side effects and in one patient for not having laboratory follow-up.
Regarding to seizure patterns, four patients (80%) with Lennox-Gastaut syndrome had >= 50% reduction in seizure frequency. In the group with partial epilepsy, 18 patients (54.6%) had >= 50% seizure reduction. There was, however, no significant difference in the efficacy of LTG (>= 50% seizure reduction) in controlling seizures of temporal lobe (55.6%) or extra-temporal lobe origin (50%) (p=0.577, Fisher's exact test).
Regarding to the use of VPA, 13 out of 19 (68.4%) patients taking VPA had >= 50% seizure reduction while nine from 19 (47.4%) patients not taking VPA showed a similar response. However, the concomitant use of VPA seemed not to affect the efficacy of LTG treatment for refractory epilepsies (p=0.189, chi-square test).
Adverse experiences were reported in 13 patients (31.7%). Two patients developed allergic prurigo or skin rashes. CNS-related symptoms occurred in 11 patients including drowsiness in four, diplopia in three, dizziness in two and nausea/vomiting in two patients. These side effects were mild and disappeared with a decrease in the dose of LTG. In two patients (4.9%), however, LTG administration had to be discontinued because of intolerable nausea/vomiting and drowsiness.
Hematological results showed no patients to develop new anemia or megaloblastic change in the follow-up survey. Before entering the trials, five female patients were with either anemic or leukopenic pictures. However, no further decrease in cell counts was noted in any of these patients after LTG add-on therapy. The serum biochemistry surveys including liver function tests and renal function tests showed no significant changes compared with their baseline levels. Nevertheless, changes in gamma-glutamyltranspeptidase (GGT) levels were interesting. Eighteen patients were found to have elevated GGT levels before the trial; 15 were taking CBZ, 11 with VPA, five with PHT. In the follow-up survey, GGT levels remained elevated in 16 patients, and returned to normal in two patients. No patients had their GGT levels changing from normal to abnormal afta LTG add-on therapy.
In our study, 18 patients (54.6%) with partial seizures had >= 50% reduction in seizure frequency. This response is quite promising compared with the results of eight randomized double-blind placebo-controlled crossover trials in which a mean of 22% patients, ranging from 7-67%, with refractory partial epilepsy showed more than 50% seizure reduction after LTG add-on treatment [7]. Although definite conclusions on efficacy cannot be made for the open label uncontrolled design, the reduction in seizure frequency is almost certainly attributable to the effects of LTG since pre-existing AEDs were not changed. This study showed no better efficacy of LTG therapy for patients with partial epilepsy of temporal origin than for those of extra-temporal origin. In addition, the efficacy of LTG is not related to concomitant use of VPA although it does usually delay the elimination of LTG.
Lennox-Gastaut syndrome is an early onset of epileptogenic encephalopathy with characteristic slow spike-and-wave complexes in EEG and varied form of generalized or partial seizures [8,12]. Seizures in this syndrome are, in general, refractory to commonly available AEDs. Nevertheless, preliminary results from a total of 45 patients treated with LTG have showed one-third of patients to be seizure-free and one-half patients to have an over 50% reduction in seizures during a two-year follow-up period [8,13,14]. In our patients who had seizures since childhood and appeared mentally retarded, four out of five had >= 50% reduction in seizure frequency, with two being almost seizure-free for up to one year after LTG add-on.
LTG therapy had a satisfactory safety profile. Near one-third of patients (31.7%) experienced mild and reversible allergic skin lesions or CNS-related adverse effects, but these necessitated discontinuation of LTG therapy in only two patients (4.9%). This was in agreement with pooled open and double-blind studies that the side effects of LTG are rarely severe enough to require hospitalization or discontinuation [15,16]. According to Smith et al. [17], LTG improves quality of life by reducing both seizure frequency and severity, with subsequent improvement in psychological parameters. This result partly reflected the fact that the majority of our patients would like to continue LTG treatment at the end of the trial period even when they did not have a significant seizure reduction.
Clinical trials including this series showed no complication of anemia or megaloblastic change in patients treated with LTG, a well known weak antifolate [2,15]. In addition, liver function tests, renal function tests and other biochemistry surveys were without significant change in all patients. LTG did not influence the level of GGT, a nonspecific enzyme found throughout the hepatobiliary system. Elevation of GGT in our patients was attributable to ongoing therapy of other AEDs which induced production of microsomal enzymes.
We conclude that LTG as add-on therapy has a promising antiepileptic effect with mild side effects in patients with refractory partial epilepsy and Lennox-Gastaut syndrome. LTG seems to be a good choice for refractory epileptic patients including those who are not suitable for surgical treatment. In addition, LTG should be tried on all patients with poorly controlled epilepsy before the term "medical intractability" is applied.
The authors would like to thank GlaxoWellcome Taiwan Limited for the supply of lamotrigine, and Dr. Wen-Yung Sheng for assistance of statistical analysis.
Copyright: 1997, Chinese Medical Association (Taipei)