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Epileptic Disorders

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Treatment in typical and atypical rolandic epilepsy Volume 2, supplément 4, Supplément 1, Décembre 2000

Treatment of BECTS

Because of the good prognosis, of BECTS and its infrequent partial and nocturnal seizures, it is reasonable to withhold antiepileptic drug (AED) therapy, if the child and the family can accept this approach. This is true particularly in the case of nocturnal seizures, however about 45% of patients will experience seizures when awake [1]. In a long term follow-up, Ambrosetto et al. [2] could not find any difference between treated and not-treated patients regarding the mean number of seizures, the mean duration of active epilepsy, age at last seizure, the frequency of recurrence of seizures or the global outcome.

Antiepileptic drugs (AED)

Monotherapy is recommended unanimously. CBZ is used most often [1, 3-6]. However, some authors [3, 7-11] reported worsening of clinical signs and EEG features up to the precipitation of CSWS by CBZ. Despite the cosmetic problems, haematological side effects, hepatotoxicity or sedative effects, DPH [12], VPA [4, 13] and PHB were seen as first line drugs in BECTS by various authors, who reported that BECTS is easy to control in most cases.

Doose et al. [14] first suggested low dose sulthiame (STM) treatment (3-5-8 mg/kg/day) in BECTS, and reported seizure control in up to 85% of patients. Gross Selbeck published similar results [15] and had the impression of a better control of seizures in typical and atypical rolandic epilepsy by STM as compared to CBZ.

STM is a sulphonamide derivative and its best documented biological effect is a central inhibition of the activity of CNS-expressed carbonic anhydrase [16]. Furthermore, STM inhibits the degradation of phenytoin leading to increased DPH plasma levels [17, 18]. As this mechanism was assumed to be the main reason for its efficacy [15] STM was almost abandoned from the mid-70s. Side effects then reported were due to the very high doses used in the 60s and 70s. However, STM is a very safe drug without any known serious adverse effects on internal organs such as bone marrow, liver, kidneys or pancreas [19] and so far no single case of death has been attributed to STM intake. The main side effect is a mild hyperventilation, which in most cases disappears after reduction of daily STM intake. This hyperventilation is not accompanied by disturbances of bicarbonate, base excess or pH in the blood. Psychotic like reactions reported quite often in the old literature are seen only very seldom nowadays with low doses [20].

In the last two years, the first controlled trials in children with BECTS were reported. Bourgeois et al. [21] published a double-blind, randomised and placebo-controlled multicentre study on the efficacy of gabapentine monotherapy (GBP) (30 mg/kg/day) in children with BECTS. Kaplan-Meier survival plots for treatment failure event (TFE) showed that time to TFE was significantly longer for GBP-treated patients than for those receiving placebo, while at 36 weeks 57% of GBP-treated patients and 44% of placebo-treated patients completed the study without TFE.

Our group recently completed a randomised, double blind, placebo-controlled multicentre study on STM in BECTS [19]. Prepubertal children aged 3 to 10 years (n = 66), suffering from BECTS were assigned to a 6 month treatment either with STM (5 mg/kg/day) (n = 31) or placebo (n = 35). The main terminal event was defined as the first seizure after the end of a seven day run-in phase after the start of medication. Twenty four out of 31 STM-treated patients (80.6%) as against only 10 out of 35 placebo-treated patients (28.6%) completed the trial without a terminal event (p < 0.0001).

Compared to our STM trial, the epilepsy-defined TFE in the GBP study was more permissive: any secondary generalised seizure, any status epilepticus and any third partial seizure versus any seizure in the STM trial. When applying the TFE definition of the GBP trial to our study, one TFE would have occurred in the STM group and 16 in the placebo group (97% versus 54%).

In agreement with these data it should be pointed out that in countries having access to STM - mainly Israel and Germany - pediatric epileptologists are greatly in favour of STM although low dose CBZ is also very effective, has not serious side effects in most cases, and worsening of clinical signs and/or EEG discharge up to CSWS is very uncommon.

Duration of treatment

In most textbooks, a period of (1-) 2-3 years of complete seizure control is recommended before tapering off medication. Because rolandic epilepsy can relapse up to puberty, Loiseau [4] suggests to prolong the treatment up to the age of 14-16 years ("at least in psychologically fragile patients"), while Lüders et al. [5] stated that treatment "should continue until 15 years, independent of age of seizure onset... modified by normalisation of EEG". However, in practice, most pediatric epileptologists will do a trial of reduction of AED after a seizure free period of 2-3 years.

Treatment of atypical rolandic epilepsies - CSWS, Landau-Kleffner (LKS) and Pseudo Lennox syndrome

Unfortunately, the statement by Landau, though referring only to children with LKS [22], is true for the whole group, that there is "no convincing evidence that... any pharmaceutical agent contributes surely to clinical improvement". In atypical rolandic epilepsies one has to differentiate between the treatment for seizures, for EEG features (CSWS) or for other clinical symptoms especially language dysfunction.

It is generally accepted that seizures should be treated according to their type although in many cases they are not the main clinical problem. Because secondary bilateral synchrony may interfere with cognitive processes leading to neuropsychological deterioration all AED available are used to avoid this progression. However, no controlled studies have been done, although thoroughly defined protocols are followed in some institutions [11, 23].

Regarding EEG features and clinical signs, treatment with DPH, PHB, VPA or ESM in most cases is without a definite effect. Again, most often CBZ is used at the beginning of the process, in most cases without success, while others will not use CBZ at all, for fear of aggravation, especially of EEG features [3, 11, 15].

Benzodiazepine

Boel and Casaer [24] reported that lorazepam improved the situation in one child with CSWS, while Yasuhara et al. [25] in his 5 CSWS cases found clonazepam in combination with VPA and/or ESM effective. Marescaux et al. [11] in 3/3 children with LKS treated with clobazam (in combination with other AED) reported an improvement. However, this effect was lost after 3-8 weeks.

Sulthiame

In 5 of his 8 cases with "Pseudo-Lennox" syndrome, Groß Selbeck [15] achieved seizure control with STM. In 5 patients with LKS, the EEG was normalised in two and markedly improved in a further two using STM +/- clonazepam [15].The authors reported that in all cases the improvement of the EEG features was accompanied by an improvement in language and overall intellectual function.

Steroids

Steroids are most often claimed to ameliorate seizure frequency and to improve EEG features or clinical signs. Marescaux et al. [11] proposed repetitive courses of high dose i.v. steroids (12 mg/kg/day) at 2-4 weeks intervals, given over periods of several months. They found this therapy quite effective and claimed that it is important to give steroids early in the course of the disease and initially at high doses. Lerman et al. [26] supported this statement of early treatment steroids at high doses and reported good effects in 4 cases of LKS treated with 80 units ACTH, 60 mg/day prednisone, and 4 mg/day of dexamethasone. Guerreiro et al. [27] described a marked improvement in 2 out of 5 and some effect in a further child with LKS, while the last 2 patients remained unchanged. Roulet-Perez and Deonna [23] recommended prednisone in combination with ESM, which was of help in 3 out of 4 CSWS patients, while they had the feeling that a further patient deteriorated whilst on prednisone.

Immunglobulin

Two papers report the benefit of high-dose i.v. IgG. Fayad et al. [28] pointed to the heterogeneity of LKS and that in the literature, different inflammatory and autoimmune diseases are reported to cause LKS. The assumed pathogenesis lead to the rationale of i.v. IgG. One child who had not responded to a variety of AED, including 2 mg/kg/day prednisolone, was treated with 3 cycles of 400 mg/kg/day i.v. IgG on 5 consecutive days. The authors reported a marked improvement in language performance. Lagae et al. [29] saw a good response on two occasions with 2 mg/kg/day prednisone, in a boy, who demonstrated LKS three times in a week and who was diagnosed immediately. The third relapse was treated by 400 mg/kg/day i.v. IgG on 3 consecutive days with a comparatively good effect.

New AED

No systematic data are available.

Subpial transection

Surgical treatment must be considered in pharmacoresistant LKS. F. Morrell has made the main contribution in this field. In a thorough review [30] they stressed the point that it is of great importance to differentiate between "true" LKS and LKS-like syndromes mostly belonging to the group of CSWS patients. Main inclusion criteria for the group of "true"-LKS have been an acute onset of aphasia (stuttering) and auditory agnosia in an otherwise normal child, a failure to show any signs of improvement of linguistic functions for 2 years, a severe, clearly epileptiform EEG abnormality characterised by bilateral spike wave discharge and electrophysiological evidence of a unilateral origin of the bilateral discharge. Fourteen children met these criteria and underwent subpial transection. In nine of them, the EEG returned to normal, in six the speech normalised, in a further five speech improved while three remained unchanged. The authors recommend a strict differentiation of LKS from other epileptic syndromes with CSWS to achieve good results by epilepsy surgery. However, it should be mentioned that a number of children with LKS or CSWS have been known, who have not undergone surgery, and, even after years of epileptic discharge, have improved spontaneously.