Search PubMed⌕ Search

Biomedical subjects

Catherine Chiron

Publications and source records attributed to Catherine Chiron.

At least 19 recordsLinked to original sources
PubMed2007

Stiripentol.

Stiripentol (STP) is a new antiepileptic compound made by Biocodex. It recently proved to increase the GABAergic transmission in vitro in an experimental model of immature rat. Clinical studies were based on the fact that STP also acts as an inhibitor of CYP3A4, CYP1A2, and CYP2C19 in vivo in epileptic patients. Whereas the studies in adult patients were disappointing, the trials conducted in pediatric populations demonstrated a specific efficacy of STP in severe myoclonic epilepsy in infancy, Dravet syndrome, when combined with valproate and clobazam. Based on these results, STP was granted orphan drug status in the European Union for the treatment of Dravet syndrome. The French experience in compassionate use suggests that STP might also be of benefit when combined with carbamazepine in pediatric patients with pharmacoresistant partial epilepsy. The interactions of STP with a large number of drugs need to be carefully taken into account, with doses of the combined antiepileptic drugs adjusted to improve the tolerability of the therapeutic association.

Animals↗
PubMed2007

Subependymal giant-cell astrocytomas in pediatric tuberous sclerosis disease: when should we operate?

OBJECTIVE: A small percentage of tuberous sclerosis patients will develop a subependymal giant-cell astrocytoma. Given the morbidity and mortality when such a lesion is left undiagnosed, successive follow-up imaging in pediatric patients has been recommended. Surgical removal of the lesion has become the procedure of choice; however, the timing of this surgery is still a controversial subject. By analyzing our own series of data, as well as other published series, we have attempted to reach a consensus on the benefits of early versus late surgery. METHODS: We retrospectively reviewed 19 patients treated surgically for intraventricular tumors in Foch Hospital and at the Fondation Adolphe de Rothschild in Paris, France, and we analyzed published pediatric reports from 1980 to 2006. RESULTS: The results from our own population, as well as from other published pediatric series (15 series), indicate that subependymal giant-cell astrocytomas have a good prognosis when a macroscopically total resection has been performed. In our series, residual lesions tended to enlarge, but residual tumors remaining stable have been reported. Careful follow-up examination should be undertaken because late recurrences do occur. Larger or symptomatic lesions tend to have a higher morbidity. CONCLUSION: We think that any lesion fulfilling the criteria for a subependymal giant-cell astrocytoma as previously described in the literature (lesion around the foramen of Monro, greater than 5 mm, with incomplete calcifications) should be removed as soon as clear evidence of growth has been confirmed.

Adolescent↗
PubMed2006

In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism.

A metabolic interaction between stiripentol (STP), an anticonvulsant agent that inhibits the activity of several cytochromes P450 (P450s), and clobazam (CLB), a 1,5-benzodiazepine, used in association with STP in severe myoclonic epilepsy in infancy was observed in vivo. This interaction was characterized in vitro using cDNA-expressed CYP3A4 and CYP2C19 (main P450 involved in CLB metabolism) to calculate K(i) and IC(50) of stiripentol in comparison with ketoconazole (CYP3A4 inhibitor) and omeprazole (CYP2C19 inhibitor). STP inhibited N-demethylation of CLB to N-desmethylclobazam (NCLB) mediated by CYP3A4 (noncompetitively) and CYP2C19 (competitively) with K(i) = 1.59 +/- 0.07 and 0.516 +/- 0.065 microM and IC(50) = 1.58 microM [95% confidence interval (CI95%) = 1.20-2.08] and 3.29 microM (CI95% = 1.87-5.79), respectively. STP inhibited also more strongly the 4'-hydroxylation of NCLB to 4'-hydroxy-N-desmethylclobazam by CYP2C19 [competitive interaction with K(i) = 0.139 +/- 0.025 microM and IC(50) = 0.276 microM (CI95% = 0.206-0.371)]. The inhibitory effect of STP on CLB demethylation by CYP3A4 was much weaker than that of ketoconazole [IC(50) = 0.023 microM (CI95% = 0.016-0.033)], whereas its effect on NCLB hydroxylation by CYP2C19 was much higher than that of omeprazole [IC(50) = 2.99 microM (CI95% = 2.11-4.24)]. The major in vitro inhibitory effect of STP on CLB metabolism and mostly on NCLB biotransformation is consistent with the changes in vivo in CLB and NCLB plasma concentrations in children treated by the association CLB/STP.

Anticonvulsants↗
PubMed2006

Misleading effects of clonazepam in symptomatic electrical status epilepticus during sleep syndrome.

Electrical status epilepticus during sleep syndrome and its variants are age-dependent epileptic encephalopathies associated with a sleep-related electroencephalographic pattern of continuous spike-waves, combined with motor or cognitive impairment. These epileptic encephalopathies are usually not responsive to conventional antiepileptic drugs. This report describes two children in whom clonazepam had no effect on cognitive and motor disorders but controlled spike activity, preventing a proper diagnosis. Withdrawal of clonazepam was accompanied by the recurrence of continuous spike-waves in slow sleep, permitting the diagnosis of electrical status epilepticus during sleep syndrome and appropriate therapeutic decisions. These two cases of the misleading effect of clonazepam in electrical status epilepticus during sleep syndrome illustrate the puzzling situation that can occur when therapeutic options only consider the electroencephalographic features without prior syndromic diagnosis.

Anticonvulsants↗
PubMed2006

Severe memory impairment in a child with bihippocampal injury after status epilepticus.

Epilepsy may contribute to memory deficits in children, but these deficits are generally mild. We describe the neuropsychological profile of a female who had prolonged status epilepticus at 5 years of age, and then developed temporal lobe epilepsy. Brain magnetic resonance imaging 1 month after the onset of status epilepticus showed marked bilateral hippocampal atrophy that seemed disproportionate to the mild cortico-subcortical atrophy. At the age of 7 years, this child had cognitive impairment (an IQ of 62), which particularly affected her memory. This included short-term memory, and immediate and delayed memory deficits for verbal and visual materials that had a profound impact on everyday life. This observation demonstrates that severe status epilepticus can cause predominant bilateral hippocampal atrophy in childhood. In contrast with children who develop such damage after anoxia, this may result in general cognitive impairment but also in more severe episodic memory deficit.

Atrophy↗
PubMed2006

Epilepsy in Menkes disease: analysis of clinical stages.

PURPOSE: Epilepsy is one of the main features of Menkes disease (MD), although it is not described in depth. To determine the spectrum of epilepsy, we studied its main characteristics. METHODS: Based on clinical charts, we retrospectively analyzed the evolution of electroclinical features of 12 patients with confirmed MD. RESULTS: Epilepsy could be divided into three periods: (a) an early stage (median age, 3 months), characterized by focal clonic status epilepticus, usually triggered by fever (10 patients). Ictal EEG showed runs of slow spike-waves and slow waves in the posterior regions, and interictal EEG multifocal and polymorphic slow waves (three cases), or mixed slow spike-waves and slow waves (seven cases). Partial seizure control was obtained in nine patients during 5.9 months; (b) an intermediate stage (median age, 10 months) with intractable infantile spasms (11 patients) in which interictal EEG demonstrated modified hypsarrhythmia (seven cases), diffuse irregular slow waves and spike-waves (four cases). Six patients died at the median age of 15 months; and (c) a late stage in the six remaining patients (median age, 25 months), with multifocal seizures, tonic spasms, and myoclonus in four patients, whereas two patients became seizure free. Interictal EEG showed multifocal high-amplitude activity, mixed with irregular slow waves in all six cases. These patients died at the median age of 3.6 years. CONCLUSIONS: Based on a relatively large series of MD patients with a quite prolonged survival, we individualized three successive periods in the course of epilepsy: early focal status, then infantile spasms, and then myoclonic and multifocal epilepsy after age 2 years.

Adult↗
PubMed2006

Early pattern of epilepsy in the ring chromosome 20 syndrome.

PURPOSE: The characteristics of epilepsy in ring chromosome 20 have been reported in adolescents and adults. The mode of onset most often remains imprecise. To clarify this onset period, we studied the early-onset features in our personal series and in the reported pediatric cases. METHODS: Our series comprises one child with an onset of epilepsy in the neonatal period and five others with an onset before age 8 years. The cases in the literature with an epilepsy onset before 8 years also were reviewed. RESULTS: Seizures in the neonatal period were described as motor seizures. Our personal patient with a neonatal onset had severe psychomotor delay. In both infancy and early childhood, the EEG showed no interictal frontal localization of the anomalies, and no long-lasting seizure was recorded. Seizures with terror and hallucinations usually appeared from about age 4 years. It is not before the age of 8 years that the usual interictal EEG pattern appeared of rhythmic theta slow-waves activity with spikes predominating in frontal areas described in adolescence and adulthood. The interictal EEG showed 1- to 2-Hz delta slow waves and spike-and-waves predominating in frontal areas, but no physiologic activity. CONCLUSIONS: In ring 20 chromosome, specific epilepsy features are lacking in the neonate, but the whole phenotype shows a more severe expression in terms of mental delay. The characteristic frontal EEG pattern and ictal terror do not appear before age 4 to 5 years.

Adolescent↗
PubMed2006

Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels.

PURPOSE: Stiripentol (STP) is currently an efficient drug for add-on therapy in infantile epilepsies because it improves the efficacy of antiepileptic drugs (AEDs) through its potent inhibition of liver cytochromes P450. In addition, STP directly reduces seizures in several animal models of epilepsy, suggesting that it might also have anticonvulsive effects of its own. However, its underlying mechanisms of action are unknown. METHODS: We examined the interactions of STP with gamma-aminobutyric acid (GABA) transmission by using patch-clamp methods in CA3 pyramidal neurons in the neonatal rat. RESULTS: STP markedly increased miniature inhibitory postsynaptic current (mIPSC) decay-time constant in a concentration-dependent manner. The prolongation of mIPSC duration does not result from an interaction with GABA transporters because it persisted in the presence of GAT-1 inhibitors (SKF-89976A and NO-711). An interaction with benzodiazepine or neurosteroid binding sites also was excluded because STP-mediated increase of decay time was still observed when these sites were initially saturated (by clobazam, zolpidem, or pregnanolone) or blocked (by flumazenil or dehydroepiandrosterone sulfate), respectively. In contrast, saturating barbiturate sites with pentobarbital clearly occluded this effect of STP, suggesting that STP and barbiturates interact at the same locus. This was directly confirmed by using outside-out patches, because STP increased the duration and not the frequency of opening of GABAA channels. CONCLUSIONS: At clinically relevant concentrations, STP enhances central GABA transmission through a barbiturate-like effect, suggesting that STP should possess an antiepileptic effect by itself.

Animals↗
PubMed2006

Cryptogenic late-onset epileptic spasms: an overlooked syndrome of early childhood?

PURPOSE: Few reports detailing late-onset epileptic spasms have been published. To determine whether this condition merely represents a late variant of classic West syndrome or exhibits specific features distinct from the latter and related to a later stage of brain maturation, we analyzed the whole population with this specific seizure type, excluding symptomatic cases to avoid the effect of brain lesion. METHODS: We reviewed the files of the 56 children evaluated for epileptic spasms in clusters having begun at age 12 months or later and analyzed clinical and video-EEG data of the 22 patients (4-17 years; mean, 8.5 years) without obvious cause. RESULTS: Interictal EEG did not show classic hypsarrhythmia. A temporal or temporofrontal slow wave and/or spike focus could be identified in all cases. Twelve children showed spasms with a tonic component. Ictal EEG revealed generalized high-voltage slow wave followed by diffuse voltage attenuation with superimposed fast activity. All children also exhibited other types of recorded seizures consisting of bursts of spike-waves with temporofrontal predominance, reminiscent of "atypical absences." In contrast with the occurrence of tonic components within a cluster of spasms, no tonic seizure stricto sensu was recorded or reported by the caregivers. In 10 children, treatment (two vigabatrin, seven hydrocortisone, one adrenocorticotropic hormone) achieved complete cessation of seizures and disappearance of focal EEG anomalies, but spasms persisted in 12 children. CONCLUSIONS: The cryptogenic group in our series without recognized cause and temporal or temporofrontal EEG anomalies seems to represent a type of epileptic encephalopathy intermediary between West and Lennox-Gastaut syndromes, in terms of seizure types and interictal EEG, and could correspond to dysfunction of the maturation process of the temporal lobe, possibly due to an undisclosed lesion.

Adolescent↗
PubMed2006

Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design.

Stiripentol, a new antiepileptic drug inhibiting cytochrome P450-enzymes, suggested some efficacy when combined with carbamazepine in an open trial in refractory partial epilepsy of childhood. Our objective was to test these results in a placebo-controlled trial. To limit the number of patients included, we used an enrichment and withdrawal design. Among the 67 children entered in a 4-month open add-on stiripentol study following a 1-month single-blind placebo baseline, the 32 responders were randomized for 2 months either to continue stiripentol (n = 17) or to withdraw to placebo (n = 15). If seizures increased by at least 50% after randomization compared with baseline, the patients dropped out (primary end point): there were six patients on stiripentol and eight patients on placebo (not significant). However, a decrease in seizure frequency compared with baseline (secondary end point) was greater on stiripentol (-75%) than on placebo (-22%) (P < .025). Twelve patients experienced at least one adverse event on stiripentol (71%) compared with four patients on placebo (27%); none were reported as severe. The combination of stiripentol and carbamazepine proved to reduce seizure frequency in children with refractory partial epilepsy, although it failed to show a significant impact according to the escape criteria selected as the primary end point in the present study, for ethical reasons.

Adolescent↗
PubMed2005

Atypical case of hemiconvulsions-hemiplegia-epilepsy syndrome revealing contralateral focal cortical dysplasia.

Hemiconvulsions-hemiplegia-epilepsy syndrome (HH/HHE) is a rare epileptic syndrome consisting of a prolonged unilateral convulsion producing a persisting hemiplegia, sometimes followed by epilepsy. We report on a 13-month-old male who presented with febrile left-sided HH syndrome with right hemispheric unilateral cytotoxic oedema followed by hemispheric atrophy on magnetic resonance imaging (MRI). Six months later the child progressively developed refractory focal epilepsy, including right hemiclonic seizures, and nearly continuous left frontal rhythmic spikes, suggesting the presence of a focal cortical dysplasia (FCD). A repeat MRI at 2 years of age showed left frontal FCD. This unusual case of dual pathology--right HH syndrome and left FCD--suggests that some other factor than the malformation determined the prolonged status and brain atrophy. The kinetics of regional cortical maturation could explain this unusual condition.

Brain Diseases↗
PubMed2005

Stiripentol.

Stiripentol (STP) is a new antiepileptic compound produced by Biocodex. It is not structurally related to any of the other currently marketed antiepileptic products as it belongs to the group of aromatic allylic alcohols. It has recently been proved to increase GABAergic transmission in experimental models. It has been studied and used in France and Canada for > 10 years, but its clinical development was delayed due to the inhibitory effect of STP on hepatic cytochrome P450 (CYP). Clinical studies were based on the fact that STP also acts as an inhibitor of CYP3A4, CYP1A2 and CYP2C19 in vivo in epileptic patients. Although the studies in adult patients were disappointing, the trials conducted in paediatric populations demonstrated a specific efficacy of STP in a severe form of early childhood epilepsy, Dravet syndrome (severe myoclonic epilepsy in infancy), when combined with valproate and clobazam. Based on these results, STP was granted orphan drug status in the European Union for the treatment of Dravet syndrome. The French experience in compassionate use suggests that STP might also be of benefit when combined with carbamazepine in paediatric patients with pharmacoresistant partial epilepsy. Nevertheless, two controlled adjunctive-therapy trials were recently completed in paediatric populations with epilepsy. The interactions of STP with a large number of drugs need to be carefully taken into account by adjusting the doses of the combined antiepileptic drugs in order to improve the tolerability of the therapeutic association.

Anticonvulsants↗
PubMed2004

Topiramate pharmacokinetics in children with epilepsy aged from 6 months to 4 years.

PURPOSE: To study the pharmacokinetics of topiramate (TPM) at steady state in children younger than 4 years comedicated with other antiepileptic drugs (AEDs). METHODS: Twenty-two children aged 6 months to 4 years with pharmacoresistant partial or generalized epilepsy were enrolled in an open-label prospective study. Children were assigned to different groups according to comedication with enzyme-inducing AEDs (n = 8), valproic acid (VPA) (n = 6), or other AEDs not known to affect drug metabolism (neutral AEDs, n = 7). One child was receiving treatment with both enzyme-inducing AEDs and VPA. After dose titration, blood samples were collected at steady state just before and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after the morning dose of TPM. Pharmacokinetic parameters were determined by a noncompartmental method. RESULTS: TPM apparent oral clearance (CL/F) was significantly higher in children taking enzyme-inducing AEDs (85.4 +/- 34.0 ml/h/kg) than in those receiving VPA (49.6 +/- 13.6 ml/h/kg) or neutral AEDs (46.5 +/- 12.8 ml/h/kg). Conversely, dose-normalized areas under the plasma TPM concentration curves (0-12 h) were significantly lower in enzyme-induced patients than in patients receiving VPA or other AEDs. CONCLUSIONS: Compared with children not receiving enzyme inducers, children younger than 4 years who receive concomitant enzyme-inducing AEDs need higher doses (milligrams per kilogram) to achieve comparable plasma TPM concentrations.

Age Factors↗
PubMed2004

The nonmalformed hemisphere is secondarily impaired in young children with hemimegalencephaly: a pre- and postsurgery study with SPECT and EEG.

PURPOSE: To study separately the functional value of each cerebral hemisphere in hemimegalencephaly (HME). HME is a unique model of unilateral hemispheric lesion, but one suspects that the non-HME hemisphere also could be functionally impaired because the postsurgery outcome is less favorable than expected. METHODS: We performed simultaneous prolonged EEG and 133-xenon SPECT (single-photon emission computed tomography); we measured the absolute values of cerebral blood flow (CBF) in both hemispheres and compared them with the normal values previously acquired. Thirteen patients (aged 5-38 months) underwent 31 examinations, 20 before surgery (hemispherotomy) and 11 after. RESULTS: In the HME hemisphere, we confirmed the presurgical mixture of increased and decreased CBF due to intermittent ictal discharges. After surgery, CBF was decreased in most cases. In the non-HME hemisphere, presurgery CBF was abnormal in 60% of the patients, increased and related mostly to diffuse interictal spikes on the same side, whereas normal CBF cases had focal spikes. After surgery, CBF was normal in 82% of cases, corresponding to an EEG without diffuse spikes. In the six patients longitudinally studied, CBF dramatically decreased after surgery in the HME hemisphere, whereas in the non-HME hemisphere, CBF was mostly normal very early (three fourths before 2 months), increased as soon as 3 months, and normalized only after hemispherotomy, the more rapidly the child was operated on, the earlier it was. CONCLUSIONS: This study shows that the function of the nonmalformed hemisphere is impaired as soon as the first months of the course of HME but can be restored after surgery. Our data support the recommendations to operate on the children as early as possible.

Brain↗
PubMed2003

Topiramate: efficacy and tolerability in children according to epilepsy syndromes.

To evaluate the efficacy and tolerability of topiramate (TPM) as add-on therapy in children less than 12 years of age with refractory epilepsy, according to epilepsy syndromes, we conducted an open, prospective, pragmatic and multicenter study in France. Efficacy was assessed, especially according to epilepsy syndromes, as well as tolerability. We included 207 children (41 of whom were less than 4 years of age). TPM was effective (responders with >50% decrease in seizure frequency) in 50% of 128 patients with partial epilepsy, and in 44% of 79 patients with generalized epilepsy. In case of generalized epilepsy, responders more frequently had generalized symptomatic epilepsy, severe myoclonic epilepsy and myoclono-astatic epilepsy, whereas response rate was mild in both infantile spasms and Lennox-Gastaut syndrome (LGS). Improvement was well maintained in all patients during the treatment period (median 5.6 months). Seizure frequency/severity increased (worsening) in 13% of patients with partial epilepsy and 17% with generalized epilepsy (particularly in those with infantile spasms), and resulted in withdrawal of TPM for 8%. The most frequently reported adverse events were moderate neurobehavioral and gastrointestinal disorders. Adverse events led to withdrawal of TPM from 13.5% of patients. Children less than 4 years of age had particularly good tolerability. Results confirm that TPM is effective and well tolerated in children under 12 years of age in a broad range of epilepsy syndromes, including refractory partial epilepsy, and symptomatic and myoclonic generalized epilepsy. Use of TPM should be considered in children under 4 years of age, and slow and progressive titration is important.

Anticonvulsants↗
PubMed2003

Effects of antiepileptic drugs on refractory seizures in the intact immature corticohippocampal formation in vitro.

PURPOSE: We developed a new in vitro preparation of immature rats, in which intact corticohippocampal formations (CHFs) depleted in magnesium ions become progressively epileptic. The better to characterize this model, we examined the effects of 14 antiepileptic drugs (AEDs) currently used in clinical practice. METHODS: Recurrent ictal-like seizures (ILEs, four per hour) were generated in intact CHFs of P7-8 rats, and extracellular recordings were performed in the hippocampus and neocortex. AEDs were applied at clinically relevant concentrations (at least two), during 30 min after the third ILE. Their ability to prevent or to delay the next ILE was examined. RESULTS: Valproic acid and benzodiazepines (clobazam and midazolam) but also phenobarbital and levetiracetam prevent the occurrence of seizures. In contrast, usual concentrations of carbamazepine (CBZ), phenytoin, vigabatrin, tiagabine, gabapentin, lamotrigine (LTG), topiramate, felbamate, and ethosuximide did not suppress ILEs. In addition, LTG and CBZ aggravate seizures in one third of the cases. CONCLUSIONS: This intact in vitro preparation in immature animals appears to be quite resistant to most AEDs. Blockade of seizures was achieved with drugs acting mainly at the gamma-aminobutyric acid (GABA)A-receptor site but not with those that increase the amount of GABA. Drugs with a broad spectrum of activity are efficient but not those preferentially used in partial seizures or absences. We suggest that this preparation may correspond to a model of epilepsy with generalized convulsive seizures and could be helpful to develop new AEDs for refractory infantile epilepsies.

Age Factors↗
PubMed2002

Drug therapy for West's syndrome.

West's syndrome resists most of the standard anticonvulsants. It may respond, however, to steroids or to some of the newer drugs like vigabatrin.

Anticonvulsants↗