Lamotrigine in typical absence epilepsy

Brain & Development 21 (1999) 303±306

Original article

Lamotrigine in typical absence epilepsy Sabrina Buoni, Salvatore Grosso, Alberto Fois* Institute of Clinical Pediatrics, University of Siena, Siena, Italy Received 12 February 1998; received in revised form 22 January 1999; accepted 15 February 1999

Abstract Lamotrigine (LTG) is an anti-epileptic drug effective in partial seizures and generalized epilepsy. There is growing evidence of the usefulness of LTG in childhood (CAE) or juvenile (JAE) absences resistant to previous treatment. In this study all patients were identi®ed using strict diagnostic criteria and subdivided into two groups. (1) Eight patients affected by absence seizures resistant to valproic acid or ethosuximide, received LTG as an-add-on therapy, (2) seven patients affected by typical absence seizures not previously treated, received LTG monotherapy after the diagnosis. In the patients with resistant absence seizures, a full control of seizures was obtained. In ®ve of them, after a mean period of 12.5 months, the previous anti-epileptic drugs were withdrawn leaving the patients on LTG monotherapy. In one patient, absences relapsed and valproic acid was therefore added again to LTG to regain control of the seizures. In six of the seven patients on LTG monotherapy after the diagnosis, a full control of seizures was obtained. In the seventh patient the drug was stopped due to a skin rash. In conclusion LTG appears to be effective in resistant absence seizures in combination with valproic acid. Moreover, our preliminary data suggest that lamotrigine might be used as monotherapy in typical absence seizures. The advantages and disadvantages of LTG monotherapy in this type of epilepsy are discussed. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Lamotrigine; Absence epilepsy; Anti-epileptic drugs

1. Introduction Lamotrigine (LTG) is a novel anti-epileptic drug (AED) chemically unrelated to any existing class of anticonvulsant agents. The mechanism of action of LTG appears to be mediated through the voltage sensitive sodium channels and the subsequent stabilization of neuronal membrane with inhibition of release of the excitatory amino acids such as glutamate [1±4]. The ef®cacy of lamotrigine in the treatment of refractory partial seizures has been well established in several crossover studies [5±11]. A role for LTG in generalized epilepsies [12,13] as well as in absence seizures resistant to previous treatment [14±17] has also been suggested. In order to draw a conclusion about the ef®cacy of lamotrigine in typical absence seizures, it is important that the patients who took part in the study are diagnosed according to accurate criteria. In fact, typical absence seizures can be confused with several clinical syndromes if strict criteria for the diagnosis are not applied. A `pure' syndromic subform, with characteristics similar to those in our patients, has been recently described [18]. * Corresponding author. Institute of Clinical Pediatrics, University of Siena, Via Bracci, Le Scotte, 53100 Siena, Italy. Tel.: 1 39-577-586547; fax: 1 39-577-586-143.

Since reports about the role of LTG in typical absence seizures are scarce, we consider it useful to supplement this information and to discuss our experience. 2. Patients and methods 2.1. Patients The criteria necessary for patients entering the study group were based on the 1989 ILAE proposal for revised classi®cation of epilepsies and epileptic syndromes, as revised by Loiseau [19] and Wolf [20] and listed in Table 1. We considered two groups of subjects: (a) patients affected by resistant absence seizures; (b) patients who received LTG as monotherapy after the diagnosis was formulated. Clonazepam (CNZ) and phenobarbital (PB) had been prescribed in other institutions in four patients with resistant typical absence seizures. Patients were considered to be `resistant' when seizures did not respond to valproic acid (VPA) and etosuximide (ESM), used either in monotherapy or in combination at maximum tolerated dosage. LTG was introduced as an add-on to the previous drug

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Table 1 Criteria of the 1989 ILAE proposal for revised classi®cation of epilepsies and epileptic syndromes, as reviewed by Loiseau [19] and Wolf [20] a 1

A form of epilepsy with an onset before puberty (childhood AE), or before the age of 17 (juvenile AE) Occurring in previously mentally and neurologically normal children AS as the initial type of seizures Very frequent AS of any kind, except myoclonic absences AS associated in the EEG with bilateral, symmetric, and synchronous discharge of regular 3 per second spike and wave complexes on a normal background activity. Less regular spike-wave activity is possible, when compatible with a diagnosis of typical absences

2 3 4 5

a

AE, absence epilepsy; AS, absence seizures.

regimen in the patients with resistant absence seizures, and prescribed as a ®rst drug in the other group. Informed consent was obtained from the hospital ethic committee and from the patients' parents before administering the drug. In all patients routine scalp EEG was recorded from silver-disk electrodes placed according to the international 10-20 system with monopolar technique and ear lobe reference. EEGs were obtained during wakefulness, spontaneous sleep hyperventilation and photic stimulation, with a recording time of at least 1 h. Video EEGs were performed when considered useful in classifying the type of seizures. Patients were selected among subjects referred to our institute for a comprehensive evaluation of different types of seizures from 1992 to 1997. Family and personal history were obtained, and neurological examination was performed on all patients by the authors. Patients with resistant typical absence seizures were evaluated prospectively. The number of absences/day was estimated utilizing a diary for a period of 3 months before starting treatment with LTG. In patients who were not previously on medication estimation of the absences/day was made on the basis of the parents' report. It was not possible to estimate the number of seizures any other way since this type of epilepsy does not require hospitalization. A full control was obtained when no additional absences were reported in the patient's diary, the EEG during awake and sleep was normal and absences were not provoked by the examiner during 3 min of hyperventilation. The starting dosage of LTG was 0.2 mg/kg per day in patients already on VPA, and 0.5 mg/kg per day in patients with LTG monotherapy after the diagnosis. If a therapeutic result was not obtained with a lower dose, LTG was gradually increased in a 6-week period to a maximum dose of 5 mg/kg per day in the group with resistant typical absence seizures, up to 10 mg/kg per day in patients with typical absence seizures. The reason for the two different dosages depends on the fact that when LTG was ®rst made available to us in 1992 it was considered safe not to exceed the dose of 5 mg/kg per day in patients taking valproate and to limit the

dose to 10 mg/kg per day in patients on LTG monotherapy. During treatment clinical and EEG evaluations were performed twice a month over a period of 3 months, thereafter once every 3 months. Complete peripheral blood counts, urinalysis, blood creatinine, alanine and aspartate aminotransferase determinations were also assayed in those occasions. The presence of adverse effects was obtained from the parents at each control. Fifteen patients with typical absence seizures entered the study. A group of eight, four boys and four girls, classi®ed as having resistant typical absences, were receiving VPA at a median dosage of 38.5 mg/kg per day (SD ^ 4:75), with a median plasma level of 115 mg/ml (SD ^ 14:3) (normal range 40±100), when LTG was added on therapy. In three of them the therapy was associated with ESM. A group of seven patients, two boys and ®ve girls, was treated with LTG monotherapy after the diagnosis of typical absence seizures was formulated. In all patients the age at the onset of epilepsy ranged from 3 years 3 months to 13 years (mean 7.2 years ^ 3:5 SD). The time interval from the onset of absences and the beginning of LTG treatment varied from 1.6 years to 2.8 years (mean 2:2 ^ 0:5 SD). In patients on LTG monotherapy after the diagnosis, the average time interval from the onset of epilepsy to the beginning of the drug treatment was 2 months. Median duration of follow-up was 3.1 years ^ 0:5 SD (range 2 years 4 months±4 years and 4 months) in patients with resistant typical absence seizures, and 1.8 years ^ 0:5 SD (range 5 months±2 years) in the other group.

3. Results After an average period of 19 days from the addition of LTG to the previous therapy, clinical manifestations disappeared completely in all patients affected by resistant typical absence seizures. In patients on LTG monotherapy after the diagnosis, the absences disappeared after an average period of 40 days. Seizure control was obtained when LTG reached a median dosage of 2.9 mg/kg (SD ^ 1:3) in patients with resistant typical absence seizures, and 6.9 mg/kg (SD ^ 3:3) in the other group. In one patient on LTG monotherapy after the diagnosis, the drug was administered at the dose of 1.6 mg/kg per day. After 8 days absences disappeared, but 1 week later a skin rash was noted on the hands, face and trunk. LTG administration was stopped and the rash persisted for 6 days before fading away. The patient was given VPA and a complete control of seizures was obtained. In ®ve patients with resistant typical absence seizures, after a median period of 12.5 months (range 5±33 months), VPA was slowly withdrawn and LTG therapy continued. In one of these patients absences relapsed after 1 month. VPA was therefore added again to LTG and full clinical control

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Table 2 Patients with resistant typical absence seizures and Valproic acid/Lamotrigine therapy Patients

Age at diagnosis

Previous therapy

Control of seizures (days)

EEG normalization (months)

LTG dosage (mg/kg)

CY DVN GE RC PD LG CD FC

4 years 3 years 3 months 7 years 9 months 12 years 5 years 6 years 6 years 6 months 13 years

PB, DPA VPA, ETS VPA, CNZ VPA VPA VPA, PB VPA VPA, PB, ETS

10 37 21 31 43 2 5 2

4 7 2.5 1 3 1 2 3.5

2 3.3 3.5 0.7 3 2 4 5

was once again observed. In the other three patients of this group, VPA and LTG are still being administered (Table 2). 3.1. EEG ®ndings Typical EEG abnormalities of epilepsy with absences were present in all patients when LTG was administered. In all patients with resistant typical absence seizures, EEG normalization was observed after a median period of 3 months of LTG/VPA therapy. In three of the ®ve patients remaining on LTG monotherapy, the EEG is still normal. In one, minimal diffuse spike and waves reappeared after a median period of 15 days since VPA was stopped. In another patient EEG abnormalities and absence seizures appeared. VPA was therefore added again, and EEG normalization as well as clinical control of seizures was registered. In patients on LTG monotherapy after the diagnosis, the EEG became normal in ®ve after a median period of 2 months (SD ^ 0:8). Minimal diffuse spike and wave activity is still present in the other one (Table 3). 4. Discussion There is growing evidence of the usefulness of LTG in primary generalized epilepsy. Steward et al. [13] and Timmings et al. [16] ®rst reported positive effects of LTG in these types of seizures. Schlumberger et al. also noted a positive effect of LTG in seven out of nine patients. In the other two patients seizures were not controlled [21]. Strumia et al. reported a full

suppression of absences in three patients with `pure' absence seizures and in two patients with absences associated with GTCS. Another patient with photosensitive absences did not respond [17]. Ferrie et al. analyzed retrospectively their patients with idiopathic generalized epilepsy and refractory absences. Fifteen patients treated with LTG were identi®ed. Nine patients (64%) had a total cessation of absences. The authors concluded that a lowdose of LTG added to VPA was effective in typical absence seizures, and suggested a therapeutic interaction of the two drugs [14]. Buchanan also reported that four out of six patients with resistant absences became seizure-free with LTG treatment [15]. Our preliminary results con®rm that LTG associated with VPA is a useful AED for refractory AS. This combination may `switch off' the mechanisms generating absences [14]. However, our data suggests that LTG monotherapy may be effective in keeping the mechanisms, generating typical absences `switched-off'. This hypothesis is supported by our observation that four patients with typical absence seizures were fully controlled by administering LTG monotherapy after the formulation of diagnosis. In addition, recent experimental data con®rm the anti-absence effect of LTG monotherapy in the lethargic (lh/ lh) mouse animal model for absence seizures [22]. In other studies [14,15] involving patients affected by resistant absences, LTG was not uniformly effective, our results may differ from previous studies because we were selective in choosing patients affected only with typical absence seizures. It must also be considered that the median age of our patients was lower than that of patients in other

Table 3 Patients with Lamotrigine monotherapy from the diagnosis Patients

Age at diagnosis

Control of seizures (days)

EEG normalization (months)

Lamotrigine dosage (mg/kg)

VS ME CA CE BM a GG RL

5 years 4 years 10 months 5 years 3 months 5 years 4 months 4 years 5 months 5 years 1 month 4 years 10 months

60 10 50 60 8 20 70

3 1 ± 2.5

8 2.7 10 8 1.6 8 10

a

Therapy was stopped after 15 days of treatment.

2 3

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series. It is possible that age in¯uences LTG effectiveness. Further investigations on this aspect are necessary. Our data suggest that seizure control can be obtained earlier in patients in whom LTG is added to VPA, in comparison to the group of patients on LTG monotherapy from the beginning. This impression is supported by statistical analysis (Student's t-test; P ˆ 0:005). However, the number of our cases is small, and further investigation is also necessary to verify this possibility. Whether LTG therapy can substitute VPA or ESM as a ®rst line drug in absence seizures is debatable. VPA is effective in childhood and juvenile absences. Patients can respond rapidly and the EEG can also become normal in a short period of time [23]. However, severe adverse effects on the liver and the hematopoietic system, particularly in very young children, have been observed. Periodic controls of ammonia, platelets and transaminases serum levels are necessary in order to reduce the occurrence of these side effects [24]. In addition marked weight increase is rather frequent [24]. LTG is more expensive and therapeutic results may take longer. Recently, severe reactions such as toxic epidermal necrolysis and the Steven-Johnson syndrome have also been reported. A skin rash is observed in 3±10 % of patients treated with LTG, even if all cases can not be attributed to LTG. Patients treated with LTG and VPA in combination seem to be at an increased risk of developing severe skin reactions. The incidence of skin rash appears to increase with the magnitude of the initial dose and the subsequent rate of dosage escalation [25,26]. In conclusion LTG in children appears to be a very interesting drug and its ef®cacy must be weighed against its side effects. Its use should be restricted, for the moment, to experienced neuropediatricians in particular when treating absence seizures. It seems quite important that in order to reach accurate results LTG, VPA and ESM should be compared in prospective studies in order to understand if LTG should be considered a ®rst line drug in typical absence seizures. Our preliminary results suggest that this is a reasonable possibility. References [1] Leach MJ, Marden CM, Miller AA. Pharmacological studies on Lamotrigine, a novel potential antiepileptic drug II. Neurochemical studies on the mechanism of action. Epilepsia 1986;27:490±497. [2] Fitton A, Goa KI. Lamotrigine: an update of its pharmacology and therapeutic use in epilepsy. Drugs 1995;50:691±713. [3] Miller AA, Wheatley P, Sawyer DA, Baxter MG, Roth B. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug I. Anticonvulsant pro®le in mice and rats. Epilepsia 1986;27:483±489. [4] Porter RJ. Mechanism of action of new antiepileptic drugs. Epilepsia 1989;30(Suppl. 1):S29±S34.

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