Cannabidiol for the treatment of Lennox-Gastaut syndrome and Dravet syndrome: experts' recommendations for its use in clinical practice in Spain. / Cannabidiol para el tratamiento del síndrome de Lennox-Gastaut y del síndrome de Dravet: recomendaciones de expertos sobre su uso en la práctica clínica en España.

INTRODUCTION: Cannabidiol (CBD) is one of the main components of the cannabis plant that has demonstrated anti-epileptic seizure effect. Following its clinical development, in September 2019 the European Medicines Agency approved its indication for the adjunctive therapy of epileptic seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), combined with clobazam (CLB), in patients of 2 years of age and older. AIM: To establish recommendations on the use of plant-derived highly purified CBD on which Spanish experts have reached consensus for the treatment of epilepsy in patients with DS and LGS based on their clinical experience and the scientific evidence. DEVELOPMENT: Consensus meeting with the participation of four Spanish neurologists and neuropediatric who are experts in epilepsy secondary to DS and LGS and with clinical experience in the use and management of CBD. They discussed on several topics, including posology (starting dose, dose escalation schema), efficacy (assessment of outcomes and indications for treatment withdrawal), and safety (evaluation, drug-drug interactions, adverse events management). CONCLUSIONS: In order to optimise CBD treatment, a slow dose escalation (= 4 weeks) is recommended until the maximum recommended dose or the desire effect is reached. It is also recommended that the concomitant antiseizure medications (ASMs) be reduced in case of adverse events due to interactions, and that the treatment continues for at least 6 months if it is well tolerated. The efficacy and safety of CBD must be assessed individually, considering the benefits and risks for individual patients.

TITLE: Cannabidiol para el tratamiento del síndrome de Lennox-Gastaut y del síndrome de Dravet: recomendaciones de expertos sobre su uso en la práctica clínica en España.Introducción. El cannabidiol (CBD) es uno de los componentes principales de la planta del cannabis que ha demostrado efecto ante las crisis epilépticas. Tras su desarrollo clínico, obtuvo su aprobación por la Agencia Europea del Medicamento en septiembre de 2019 para el tratamiento de las crisis epilépticas asociadas con el síndrome de Lennox-Gastaut (SLG) y el síndrome de Dravet (SD), en combinación con el clobazam (CLB), en pacientes a partir de los dos años. Objetivo. Establecer unas recomendaciones de manejo del CBD derivado de la planta altamente purificado consensuadas por expertos españoles en el tratamiento de la epilepsia para su uso en pacientes con SD y SLG, basándose en su experiencia clínica y en la evidencia científica. Desarrollo. Reunión de consenso de un grupo de cuatro neurólogos y neuropediatras españoles expertos en el manejo de la epilepsia asociada al SD y el SLG y con experiencia clínica en el uso de CBD. Se debatió sobre diferentes áreas, incluyendo la posología (dosis de inicio, pauta de escalada), la eficacia (valoración de resultados e indicaciones para la suspensión del tratamiento) y la seguridad (evaluación, interacciones entre fármacos, manejo de efectos adversos). Conclusiones. Para optimizar el tratamiento con CBD, se recomienda una pauta lenta de escalada de dosis (de cuatro semanas o más) hasta alcanzar la dosis máxima recomendada o el efecto deseado, reducir los fármacos anticrisis epilépticas concomitantes si aparecen efectos adversos por interacciones y mantener el tratamiento al menos seis meses si se tolera. La eficacia y la seguridad del CBD deben evaluarse de forma individual, considerando el beneficio y el riesgo para cada paciente.

Pharmacokinetic Drug-Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients.

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

Interaction of cannabidiol with other antiseizure medications: A narrative review.

OBJECTIVE: Cannabidiol is efficacious as an adjunctive treatment in children with epilepsy associated with Dravet and Lennox-Gastaut syndromes. As its role is currently adjunctive, we reviewed the interactions of cannabidiol with other antiseizure medications (ASMs). METHODS: A search of Cochrane, Pubmed and Embase databases from January 2015 to April 2020 was performed. All original research papers discussing interactions between cannabidiol and ASMs were included. Bibliographies of review articles were searched to identify further papers. Adverse events and side effects were excluded. RESULTS: Cannabidiol interacts with ASMs through both pharmacokinetic and pharmacodynamic mechanisms. Thirty studies were identified (eighteen observational cohort studies, two randomised-control trials, three case reports/series, three animal studies, two briefing reports, an analysis of cohort data and a clinical trial simulation). There is potential for pharmacokinetic interactions between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide. Pharmacodynamic interactions were identified for clobazam, valproate and levetiracetam. An animal study identified that the brain concentration of ASMs may be altered while the serum concentration remains the same. CONCLUSION: Pharmacokinetic and pharmacodynamic interactions exist between cannabidiol and ASMs. The cytochrome p450 system in particular has been implicated in pharmacokinetic interactions, although not exclusively. The existing literature is limited for some ASMs by studies having relatively small cohorts. As increasing numbers of patients use cannabidiol, specialists need to monitor closely for interactions clinically and with blood levels when required.

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.

OBJECTIVE: Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. METHODS: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a+/- mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a+/- mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together. RESULTS: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation. SIGNIFICANCE: Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.

Perampanel chronic treatment does not induce tolerance and decreases tolerance to clobazam in genetically epilepsy prone rats.

Tolerance to some therapeutic effects of antiepileptic drugs may account for the development of pharmacoresistance in patients with epilepsy. In the present study, following oral acute pretreatment with the new antiepileptic drug perampanel (0.1, 0.3, 1 or 3 mg/kg), we observed that the drug significantly and dose-dependently attenuated the seizure phases (clonus and tonus) of audiogenic seizures in genetically epilepsy prone rats (GEPR-9 s), a genetic model of reflex generalized epilepsy. In addition, the GEPR-9 s were administered orally with perampanel (1 or 3 mg/kg) once daily for 10 weeks in order to study the possible development of tolerance, and when animals were subjected to auditory stimulation we observed that the ED50 values against clonus or tonus were not significantly different from those observed after single administration. Furthermore, the duration of anticonvulsant effects observed between 60 min and 9 h following oral administration of perampanel (1 mg/kg) were similar in acute and after chronic treatment. In another group of experiments, clobazam (0.75, 1.5, 3, 6, 9, 12 and 15 mg/kg) after acute administration was able to dose-dependently reduce the severity of the audiogenic seizures in GEPR-9 s. When clobazam (6 or 12 mg/kg) was administered alone for 10 consecutive weeks a clear development of tolerance to its anticonvulsant effects within approximately seven weeks was observed. In addition, we observed that when clobazam (6 mg/kg) was co-administered with perampanel (1 mg/kg), the latter drug was able to attenuate the development of tolerance to the antiseizure activity of clobazam. The present data indicate that both perampanel and clobazam are effective against audiogenic seizures, however, clobazam effects are hampered by the development of tolerance. Furthermore, concomitant treatment with perampanel slows development of tolerance to the anticonvulsant effects of clobazam in GEPR-9 s.

Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center.

Medically refractory epilepsy continues to be a challenge worldwide, and despite an increasing number of medical therapies, approximately 1 in 3 patients continues to have seizures. Cannabidiol (CBD), one of many constituents of the Cannabis sativa or marijuana plant, has received renewed interest in the treatment of epilepsy. While highly purified CBD awaits Food and Drug Administration (FDA) approval, artisanal formulations of CBD are readily available and are seeing increased use in our patient population. Although randomized controlled trials of CBD are ongoing and promising, data regarding artisanal formulations of CBD are minimal and largely anecdotal. Here, we report a retrospective study to define the efficacy of artisanal CBD preparations in children with epilepsy. Given the known interaction between CBD and clobazam, we also conducted a subgroup comparison to determine if clobazam use was related to any beneficial effects of CBD. Additionally, we compared response rates with CBD and with clobazam alone within an overlapping patient cohort. A pediatric cohort with epilepsy of 108 patients was identified through a medical record search for patients using CBD oil. The addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The responder rate for clobazam was similar. No patients achieved CBD monotherapy, although the weaning of other antiepileptic drugs (AEDs) became possible in 22% of patients. A comparable proportion had AED additions during CBD therapy. With concomitant use of clobazam, 44% of patients had a 50% reduction in seizures upon addition of CBD compared with 33% in the population not taking clobazam; this difference was not statistically significant. The most common reported side effect of CBD was sedation in less than 4% of patients, all of whom were also taking clobazam. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. Benefits were more marked in the CBD alone group, in contrast to the CBD and clobazam group, but this difference was not statistically significant. In summary, these findings support efficacy of artisanal CBD preparations in seizure reduction with few significant side effects. The response to CBD was independent of concurrent clobazam use, although clobazam may contribute to the sedation seen with concurrent CBD use.

Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy.

OBJECTIVE: Nocturnal frontal lobe epilepsy (NFLE) is an idiopathic partial epilepsy with a family history in about 25% of cases, with autosomal dominant inheritance (autosomal dominant NFLE [ADNFLE]). Traditional antiepileptic drugs are effective in about 55% of patients, whereas the rest remains refractory. One of the key pathogenetic mechanisms is a gain of function of neuronal nicotinic acetylcholine receptors (nAChRs) containing the mutated α4 or ß2 subunits. Fenofibrate, a common lipid-regulating drug, is an agonist at peroxisome proliferator-activated receptor alpha (PPARα) that is a ligand-activated transcription factor, which negatively modulates the function of ß2-containing nAChR. To test clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant ADNFLE\NFLE patients, we first demonstrated the effectiveness of fenofibrate in a mutated mouse model displaying both disease genotype and phenotype. METHODS: We first tested the efficacy of fenofibrate in transgenic mice carrying the mutation in the α4-nAChR subunit (Chrna4S252F) homologous to that found in humans. Subsequently, an add-on protocol was implemented in a clinical setting and fenofibrate was administered to pharmacoresistant NFLE patients. RESULTS: Here, we show that a chronic fenofibrate diet markedly reduced the frequency of large inhibitory postsynaptic currents (IPSCs) recorded from cortical pyramidal neurons in Chrna4S252F mice, and prevented nicotine-induced increase of IPSC frequency. Moreover, fenofibrate abolished differences between genotypes in the frequency of sleep-related movements observed under basal conditions. Patients affected by NFLE, nonresponders to traditional therapy, by means of adjunctive therapy with fenofibrate displayed a reduction of seizure frequency. Furthermore, digital video-polysomnographic recordings acquired in NFLE subjects after 6 months of adjunctive fenofibrate substantiated the significant effects on control of motor-behavioral seizures. SIGNIFICANCE: Our preclinical and clinical studies suggest PPARα as a novel disease-modifying target for antiepileptic drugs due to its ability to regulate dysfunctional nAChRs.

Hot Water Epilepsy Successfully Treated With Daily Clobazam.

Hot water epilepsy (HWE) is a rare form of reflex epilepsy precipitated by a bath or shower in hot water. Although the condition is benign and a decreased bath temperature will help, antiepileptic drugs may be needed in some cases. Prophylactic clobazam is currently the first choice treatment option. Here we report the case of a 10-year-old boy with HWE successfully treated with daily doses of clobazam. Daily clobazam was preferred over prophylactic clobazam because of the patient's frequent bathing and parental concern. Daily clobazam is a novel treatment option for HWE and seems to be a good choice where antiepileptic drugs are necessary.

Clobazam higher-evening differential dosing as an add-on therapy in refractory epilepsy.

PURPOSE: Clobazam treatment tailored to the timing of patient's seizures may improve seizure control. We aim to describe the safety and efficacy of higher-evening differential dose of clobazam as add-on therapy in patients with night-time/early morning seizures. METHOD: Differential dosing with higher evening dosing was started based on a high proportion of seizures (>80%) at nighttime (6p.m. to 6a.m.). Differential dosing was defined as providing more than 50% of the total daily dose of clobazam after 6p.m. RESULTS: Twenty-seven patients were treated with clobazam differential dosing as an add-on therapy. The median age was 9.1 years, with 11 (40.7%) females and median of the first follow-up was 2.7 months. Patients with differential dosing tolerated a higher median total clobazam dose of 0.8mg/kg/d at first follow-up, as compared to 0.6mg/kg/d in controls. In differential dose, the median percentage of the total clobazam dose administered in the evening was 66.7%. Differential dose patients exhibited a median seizure reduction of 75% as compared to 50% in controls (p<0.005). Patients with generalized seizures benefited the most from differential dosing with a 77.5% median seizure reduction, as compared to 50% in controls (p=0.017). CONCLUSION: Higher-evening differential dose of clobazam improved seizure control in patients with predominantly nighttime and early-morning seizures. Chronotherapy tailored to the patients' seizure susceptibility patterns may improve care in epilepsy patients as differential dosing may allow for higher overall treatment doses at times of greatest seizure susceptibility without increased side effects at other times.

Aggravation of atonic seizures by rufinamide: A case report.

BACKGROUND: Rufinamide is a novel antiepileptic drug used as adjunctive therapy in patients with Lennox-Gastaut syndrome and provides seizure control especially in tonic and atonic seizures. Rufinamide is expected to be effective in intractable epilepsy when atonic and tonic seizures exist. However, rufinamide induced seizure aggravation has been reported in a few patients, which was not associated with a specific type of seizure. CASE: A 12-year-old boy with intractable epilepsy had tonic and atonic seizures despite treatment with valproic acid (3000mg/day), levetiracetam (3000mg/day) and clobazam (40mg/day). Rufinamide was administered as adjuvant therapy. After 2weeks on rufinamide, he experienced atonic seizure worsening, and the frequency of epileptic discharges increased. The deterioration in seizure frequency and epileptiform discharges resolved when rufinamide was discontinued. CONCLUSION: Rufinamide may aggravate atonic seizures in patients with intractable epilepsy.

Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.

OBJECTIVE: Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article. METHODS: Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. RESULTS: We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction. SIGNIFICANCE: Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.

Ammonia encephalopathy and awake craniotomy for brain language mapping: cause of failed awake craniotomy.

We report the case of an aborted awake craniotomy for a left frontotemporoinsular glioma due to ammonia encephalopathy on a patient taking Levetiracetam, valproic acid and clobazam. This awake mapping surgery was scheduled as a second-stage procedure following partial resection eight days earlier under general anesthesia. We planned to perform the surgery with local anesthesia and sedation with remifentanil and propofol. After removal of the bone flap all sedation was stopped and we noticed slow mentation and excessive drowsiness prompting us to stop and control the airway and proceed with general anesthesia. There were no post-operative complications but the patient continued to exhibit bradypsychia and hand tremor. His ammonia level was found to be elevated and was treated with an infusion of l-carnitine after discontinuation of the valproic acid with vast improvement. Ammonia encephalopathy should be considered in patients treated with valproic acid and mental status changes who require an awake craniotomy with patient collaboration.

Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: a prospective study.

PURPOSE: To evaluate the role of intermittent prophylaxis with clobazam in the management of HWE in a long-term prospective study. MATERIAL AND METHODS: Two hundred and sixty patients [M:F - 194:66] with HWE were recruited. Patients were divided into: (a) 'HWE alone' (n=198) - received intermittent clobazam prophylaxis, 1-1½h prior to hot water head bath (group A); (b) 62 patients (20.4%) with 'HWE with spontaneous seizures were treated with continuous AEDs along with intermittent clobazam therapy (group B). RESULTS: Patients (n=198) in group A was followed for mean of 17.6 ± 10.6 months (range: 3-57). One hundred and forty seven patients (74.2%) had excellent response with complete seizure freedom with clobazam therapy while 12 (6.1%) had >75% reduction in seizure frequency. Remaining 39 (19.7%) required additional standard AED along with clobazam and 18 patients among them developed spontaneous/unprovoked seizure at follow up of 6.7 ± 4.1 months. Forty five patients in group B were seizure free while on continuous AEDs. CONCLUSIONS: Intermittent clobazam prophylaxis prior to head water bath might be a preferred mode of treatment of pure HWE. Additional AEDs are required if they have associated non-reflex unprovoked seizure.

Effect of pregabalin add-on treatment on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy: a pilot study.

OBJECTIVE: An open pilot study to evaluate the effect of pregabalin (PGB) as add-on therapy on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy (BTRE). MATERIALS AND METHODS: We recruited 25 consecutive patients with BTRE and uncontrolled seizures. At baseline and during follow-up, patients underwent a complete physical and neurological examination and were evaluated using the QOLIE 31P (V2), EORTC QLQ C30, Adverse Events Profile, and Hamilton Anxiety Rating Scale (HAM-A). At baseline, a seizure diary was given. RESULTS: During follow-up, 17 patients underwent chemotherapy, none underwent radiotherapy, 9 had disease progression, and 3 died. Mean duration of follow-up was 4.1 months. Mean PGB dosage was 279 mg/day. At baseline, mean weekly seizure frequency was 5.3 (±10) and at last available follow-up visit was 2.8±5. This difference was statistically significant (p=0.016). The responder rate was 76%. Ten patients dropped out; 4 as a result of seizure worsening, 1 as a result of unchanged seizure frequency, 3 as a result of a lack of compliance, and 2 as a result of side effects. Based on the QOLIE-31-P, a significant improvement of the subscale "seizure worry" (p=0.004) and a significant decrease in distress scores related to AEDs and social life (p=0.009 and p=0.008, respectively) were observed. A significant decrease in HAM-A score (p=0.002) was documented. CONCLUSIONS; These data indicate that PGB may represent a valid alternative as add-on treatment in this patient population, based on its efficacy on seizure control and anxiety.

Efficacy of stiripentol in hyperthermia-induced seizures in a mouse model of Dravet syndrome.

PURPOSE: We previously reported a mutant mouse carrying a severe myoclonic epilepsy in infancy (SMEI) mutation in Scn1a. In this study, we examined the susceptibility to hyperthermia-induced seizures of heterozygous Scn1a mutant mice (Scn1a(RX/+)) and wild-type (Scn1a(+/+) ) mice. Then we assessed the efficacy of stiripentol (STP) monotherapy versus STP and clobazam (CLB) combination therapy to prevent hyperthermia-induced seizures in Scn1a(RX/+) mice. METHODS: The seizure-inducing body temperatures in Scn1a(RX/+) mice and age-matched Scn1a(+/+) mice were compared in three age groups (1 month, 3-5 months, > 6 months). Then STP, CLB, or STP + CLB was administered intraperitoneally to Scn1a(RX/+) mice of two age groups (p1M, aged 1 month; p5M, aged 5-10 months). The efficacy of medications was assessed by comparing the seizure-inducing body temperature and the duration of seizures. KEY FINDINGS: The seizure-inducing body temperature was significantly lower in Scn1a(RX/+) than in Scn1a(+/+) mice for all age groups (p < 0.01). The seizure-inducing body temperature was significantly elevated after administration of STP in p1M (p < 0.05) but not in p5M (p > 0.05), and it was significantly elevated after administration of CLB in both age groups (p < 0.05). The seizure-inducing body temperature was significantly higher after administration of STP + CLB than after administration of CLB in p5M (p < 0.05). SIGNIFICANCE: Scn1a (RX/+) mice have increased susceptibility to hyperthermia-induced seizure in all age groups. STP monotherapy is effective in preventing hyperthermia-induced seizures in Scn1a(RX/+) mice aged 1 month, but not in those aged 5 months and older. When used in combination therapy with CLB, STP inhibits the metabolism of CLB and probably synergistically enhances the anticonvulsant effect in mice aged 1 month.

[A case of intractable epilepsy showing frequent gelastic seizures by administration of clobazam].

A 13-year-old boy patient had severe mental retardation and spastic quadriplegia due to fetal distress and hypoxic-ischemic brain damage in the perinatal period. He suffered from West syndrome at the age of 7 months, and subsequently was diagnosed as having symptomatic localization-related epilepsy. His intractable epileptic seizures were not controlled by combination of various antiepileptic drugs. After prescribing nitrazepam and zonisamide for more than 1 year, we added clobazam (CLB), which has been marketed in Japan since 2000, to this combination therapy. After the introduction of CLB, tonic seizures disappeared. However, gelastic seizures laughing with a stiff face and a wry mouth appeared frequently before falling asleep, and sleep disturbance worsened subsequently. It has not been reported previously that gelastic seizures are a side effect of CLB, although irritability and sleep disturbance have been described.

Prophylactic use of clobazam in hot water epilepsy.

OBJECTIVE: To assess the efficacy of intermittent administration of clobazam to prevent hot water epilepsy. MATERIAL AND METHODS: Ten adults with 1:1 ratio of hot water epilepsy were administered 10 mg of clobazam about one and half hour before each hot water head bath. They were followed up for nine months. RESULTS: Nine out of 10 patients did not develop recurrence of seizure following regular hot water head bath during nine month follow up period. One continued to get mild giddiness. The adverse effects observed were sleepiness in two and fall in memory in one on the day of drug intake. CONCLUSION: Intermittent oral administration of clobazam before hot water bath alone is effective in preventing hot water epilepsy with 1:1 ratio.