Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases.

OBJECTIVE: Encephalopathy with continuous spike-wave during sleep (CSWS) is a particularly difficult-to-treat childhood epileptic syndrome. This study sought to present the EEG improvement and clinical efficacy of topiramate (TPM), a broad spectrum antiepileptic drug (AED), in a series of 21 children with CSWS encephalopathy. METHODS: We retrospectively reviewed the EEG results and clinical data of children with CSWS followed-up in our institution and treated with TPM. Sleep EEGs were performed 0-3 months prior to TPM introduction and then at 3 and 12 months. The exclusion criteria were (1) introduction of another AED and (2) withdrawal of a potentially aggravating AED during the first 3 months of treatment. In addition to spike index (SI), the severity of EEG abnormalities was rated using an original scale that also considered the spatial extent of interictal epileptiform discharges. RESULTS: 21 patients were included (18 males, 4-14y, three symptomatic cases). At 3 months, sleep EEG was improved in 14 and normalized in four (TPM doses: 2-5.5 mg/kg/day). Among these 18 patients, 16 manifested cognitive or behavioural improvement. In a subgroup of seven patients with frequent seizures, five became seizure-free and one had over 75% decrease in seizure frequency. At the one-year follow-up, 20 children were still on TPM and 10 exhibited persistent EEG improvement without any other AED being introduced, most of them with clinical benefits. CONCLUSION: TPM can decrease EEG abnormalities in epileptic encephalopathy with CSWS, achieving clinical improvement in the majority of patients. However, relapse may occur in the long-term in nearly half of cases. Otherwise, TPM has proven particularly useful in reducing seizure frequency in refractory cases.

Epileptic syndromes: differential treatment in infants, children, and adolescents.

This paper proposes therapeutic guidelines for the management of some epileptic syndromes in infants, children, and adolescents, based on available medical literature and clinical practice in the French Community of Belgium. The guidelines address both epileptic encephalopathies (West syndrome, Lennox-Gastaut syndrome, and Dravet syndrome) and idiopathic epilepsies (typical absence seizures, epilepsy with centro-temporal spikes and juvenile myoclonic epilepsy).

Guidelines for the management of epilepsy in the elderly.

Seizures starting in patients over 60 years old are frequent. Diagnosis is sometimes difficult and frequently under- or overrated. Cerebrovascular disorders are the main cause of a first seizure. Because of more frequent comorbidities, physiologic changes, and a higher sensitivity to drugs, treatment has some specificity in elderly people. The aim of this paper is to present the result of a consensus meeting held in October 2004 by a Belgian French-speaking group of epileptologists and to propose guidelines for the management and the treatment of epilepsy in elderly people.

Clinical and EEG findings in six patients with altered mental status receiving tiagabine therapy.

Tiagabine (TGB), a novel GABA reuptake inhibitor antiepileptic drug, has been reported to induce nonconvulsive status epilepticus (NCSE) in patients with generalized or partial onset seizures. We describe six patients with refractory partial epilepsy treated with add-on TGB. They developed acute intermittent or progressive chronic confusion associated with diffuse slowing of the electroencephalogram (EEG), shortly after an increase in dose of TGB. This remitted in each situation after reduction of the daily dose. The possibility of nonconvulsive status epilepticus or toxic encephalopathy is discussed.

Acute sodium depletion modifies septo-preoptic neuron sensitivities to neurohormones.

Sodium (Na+) depletion induces sodium appetite to replenish Na+ loss. It appears to be a consequence of enhanced levels of aldosterone (Aldo) and angiotensin II (AII) in the plasma as well as in the brain. Mineralocorticoid pretreatment modifies the sensitivity of septo-preoptic neurons to locally applied AII and Aldo. Therefore, we investigated septo-preoptic neuronal sensitivities to AII and Aldo, as well as to the specific AII type-1 receptor (AT-1) non-peptide antagonist losartan (Los) and to the specific AII type-2 receptor (AT-2) non-peptide antagonist PD123319 after one Na+ depletion without repletion. We found that one Na+ depletion induced increases in the proportion of neurons inhibited by iontophoretic application of AII (20.5% vs. 7.8%, p=0.004) whereas, the proportion of neurons excited by Aldo was increased, (23.7% vs. 5%, p=0.001). Moreover, the proportion of neurons changing sensitivity to AII after one application of Aldo was increased in the furosemide group (44.2% vs. 20.4%, p=0.0123). The proportion of neurons inhibited by application of losartan was enhanced, (26.4% vs. 9.3%, p=0.03). No significant changes were found in response to PD123319 by itself. Moreover, there were more neurons which co-localized responses to both Los and PD123319 in the furosemide group than in the control group (29.7% vs. 8.6%, p=0.027). It is known that multidepletions induce an increased need-free sodium appetite and our present findings could well form part of the neuronal basis of this behavior.

Blockade of central angiotensin II type 1 and type 2 receptors suppresses adrenalectomy-induced NaCl intake in rats.

Removal of the adrenal glands, the main site for the synthesis of aldosterone, produces an intake of sodium that is essential for survival. Using central blockade of angiotensin II (Ang II) receptors with SarIle Ang II, previous studies have shown that this intake depends on the stimulation of the brain angiotensin system. In the present study, using intracerebroventricular injection of specific antagonists of Ang II type 1 (AT1) or type 2 (AT2) receptors (losartan and PD 123319, respectively), we confirm that activation of brain angiotensin is essential for the expression of adrenalectomy-induced NaCl intake. Moreover, we show that (a) AT1 but not AT2 receptor blockade alone suppresses NaCl intake and (b) doses of AT1 and AT2 receptor antagonists that separately have no effect on NaCl intake, suppress the behavior when combined. It is proposed that AT1 receptors mediate the natriorexigenic effect of Ang II and that AT2 receptors have a permissive role on AT1 receptor stimulation.

Neuronal responses to iontophoretically applied angiotensin II, losartan and aldosterone, as well as gustatory stimuli, in non-anesthetized control and desoxycorticosterone acetate-pretreated rats.

The neuronal mechanism of the sodium appetite initiated in rats by priming with a mineralocorticoid (desoxycorticosterone acetate (DOCA)) treatment and subsequent central angiotensin II (Ang II) was investigated using electrophysiological-iontophoretic techniques and sapid salt stimulation of the tongue in non-anesthetized restrained, DOCA-pretreated (0.5 mg/day s.c. for 3 days) or non-pretreated male Wistar rats. The rats were trained to drink water and a 1.6% NaCl solution while their heads were painlessly held in a stereotaxic apparatus with an attachment fixed to the skull. A total of 634 neurons (375 in non-pretreated and 259 in DOCA-pretreated rats) were recorded in the medial septum and median preoptic area during iontophoretic application of Ang II, aldosterone or losartan, or tongue application of the salty solution or water. Of the 151 neurons recorded in control rats during the application of the solutions on the tongue, one (0.7%) was found specifically excited and 16 (10.6%) inhibited by the sapid sodium. Similarly, of the 110 neurons tested in the DOCA-pretreated rats, 5 (4.5%) were found specifically excited and 8 (7.3%) inhibited by the sapid sodium. The number of neurons responding to the iontophoretically applied agents was not significantly changed by the DOCA pretreatment. Thus, the DOCA pretreatment significantly increased the number of preoptic neurons that were specifically excited by a salty solution applied on the tongue. These results suggest that hormonally induced changes in the gustatory responsiveness of ventral forebrain neurons may be part of the sequence that alters the hedonic valence of NaCl during sodium appetite.

Effects of DOCA pretreatment on neuronal sensitivity and cell responsiveness to angiotensin II, in the bed nucleus of the stria terminalis in the rat.

A previous study has shown that DOCA pretreatment altered the responsiveness of neurons to microiontophoretic administration of angiotensin II (AII) and aldosterone (Aldo). This result coincided with an increase in activity in the septo-preoptic region and a decrease in activity of the central nucleus of the amygdala. The latter region is anatomically linked to the bed nucleus of the stria terminalis (BNST). Single unit activity was recorded in the BNST in response to iontophoretic application of AII, non-peptide AII-receptor antagonists or Aldo in DOCA-pretreated and in non-pretreated rats. DOCA-pretreatment significantly decreased the responsiveness to AII (28 cells (18.5%) vs. 8 cells (14.0%) u = 0.018 for excitation and 3 cells (8.6%) vs. 0 cells 0%, u = 0.011 for inhibition, P < 0.05) and to Aldo (24 cells (21.4%) vs. 4 cells (10.2%), u = 0.026 for excitation, and 3 cells (2.6%) vs. 0 cells, u = 0.009 for inhibition, P < 0.05) of the neurons localised in the BNST. A significant decrease was found in the inhibitory responses to iontophoretic application of losartan, an AII type-1 receptor (AT-1) antagonist (u = 0.042, P < 0.05). No significant differences were recorded with iontophoretic application of PD 123319, a specific AII-type-2 (AT-2) receptor antagonist. Therefore AT-1 receptors are likely responsible for the decreased responsiveness of the BNST correlated with the decrease in the activity within the amygdala.

Angiotensin II receptor subtype antagonists can both stimulate and inhibit salt appetite in rats.

In urethane-anaesthetised male Wistar rats iontophoretic application of the angiotensin II (Ang II) type 1 (AT-1) receptor specific nonpeptide antagonist losartan in the septo-preoptic continuum can produce neuronal excitation of short- and long-term duration which has been interpreted as removal of tonic Ang II-induced inhibition. Mineralocorticoid pretreatment, which increases neuronal sensitivity to Ang II to enhance salt appetite, also removes this losartan-induced long-term excitation. These results suggested steroid modulation of the AT-1 receptor and a complex involvement of Ang II in salt appetite. To investigate the role of the inhibitory action of central Ang II on salt appetite, we gave intracerebroventicular injections of a single, low dose (10 ng) of losartan in normal euhydrated rats and this produced, paradoxically, a progressive increase in salt intake (1.6 +/- 0.3 ml/day to 3.5 +/- 0.9 ml/day, n = 15, P < 0.05). Treatment of these salt enhanced rats with DOCA (0.5 mg/day, s.c., for 3 days) further increased the salt appetite, but then a second i.c.v. injection of the same dose of losartan significantly inhibited the enhanced salt appetite (4.7 +/- 0.7 to 1.3 +/- 0.4, n = 9, P < 0.05). These results provide evidence for a complex action of Ang II on the At-1 receptor mediating the generation of salt appetite that appears to involve either at least two functional subtypes of this AT-1 receptor, as already suggested by previous electrophysiological experiments, or one AT-1 receptor with several activation states.

Water versus salty taste and Iontophoretic ANGII responses of septopreoptic neurons in dehydrated and euhydrated awake rats.

Little is known of the influence of gustatory, particularly salt, input on neurons of the forebrain and if the same neurons are sensitive to hydromineral balance humoral stimuli. In awake, nonpremedicated rats we recorded the activity of spontaneously active neurons in the preoptic/anterior hypothalamic area of dehydrated and euhydrated rats while allowing them to ingest water or a hypertonic salt solution (1.6% NaCl) administered to the tongue. The hormones angiotensin and aldosterone, both implicated in hydromineral balance, were applied by iontophoresis to the same neurons. In the dehydrated rats, 27% (15/55) of the spontaneously active neurons responded to a liquid (either water or the NaCl) applied to the tongue; in the euhydrated rats 23% (18/78) responded to the same stimuli. In the dehydrated rats, however, 33% (5/15) of the responding neurons were inhibited when the NaCl solution was applied to the tongue compared with only 5% (1/18) in the euhydrated rats. Iontophoretic application of angiotensin increased the spontaneous activity in 21% of those neurons tested that responded to taste. These results suggest that the state of hydration of an animal is able to change the neuronal response to substances applied to the tongue. Furthermore, it appears that these gustatory-sensitive neurons may also be related to hydromineral balance regulation since they are able to respond to angiotensin.

Tonic neuronal inhibition by AII revealed by iontophoretic application of Losartan, a specific antagonist of AII type-1 receptors.

Short-term low-dose mineralocorticoid pretreatment enhances subsequent neuronal activity in the medial septum/preoptic region and in the stria terminalis/posterior amygdala of urethane anaesthetised male Wistar rats and sensitises these neurons to angiotensin II (AII). We have investigated the effect of iontophoretic application of Losartan, a specific nonpeptidergic AII type-1 receptor antagonist, on the background activity of spontaneously active neurons in these regions using a seven-barrelled microiontophoretic electrode sealed to a recording electrode. The influence of Losartan on the effects of iontophoretically applied AII in deoxycorticosterone acetate (DOCA) pretreated and nonpretreated rats was also investigated. Iontophoretically applied Losartan was observed to block the excitatory effect of AII in some neurons. In other spontaneously active neurons Losartan was seen to stimulate (or inhibit) immediately, this effect being greater in nonpretreated than in DOCA pretreated rats. Losartan was also observed to provoke persistent excitation of some spontaneously active neurons only in the nonpretreated rats. These results suggest that there exists a tonic inhibition by AII on the neurons in this area of the forebrain and that there may exist at least two subtypes of the AII type-1 receptor.