Safety and efficacy of intravenous valproate in pediatric status epilepticus and acute repetitive seizures

Summary: Purpose: To evaluate the safety and efficacy of intravenous valproate (VPA) loading in children with status epilepticus (SE) or acute repetitive seizures. Methods: Retrospective review was performed on 40 pediatric patients with intravenous VPA loading. Patients were classified into two groups: SE (n = 18) and acute repetitive seizures (n = 22). Thirty‐one patients were VPA naïve and received a full loading dose of 25 mg/kg; nine had subtherapeutic plasma VPA levels and received a partial loading dose. Average infusion rate was 2.8 mg/kg/min. Heart rate and blood pressure were measured before, during, and after infusion. Results: Intravenous VPA loading stopped seizures in 18 patients with SE within 20 min. All 18 patients regained baseline mental status within 1 h of seizure cessation. Among 22 patients with acute repetitive seizures, only one had further seizures after VPA infusion. One patient in the SE group complained of transient tremors. No significant changes in blood pressure or heart rate were found in either group. Postinfusion plasma VPA levels ranged from 51 to 138 μg/ml (mean ± SD = 88 ± 21.5 μg/ml). Conclusions: Intravenous VPA loading is safe and effective for treating acute seizure emergencies in children.     

Epilepsy outcomes in elderly treated with topiramate

Objectives –  To explore effectiveness, tolerability and quality of life in elderly patients with epilepsy treated with topiramate.
Methods –  One year, open-label, flexible-dosing clinical trial.
Results –  One hundred and seven patients (mean age 69 years, 53% men) were studied during 273 ± 141 days. The average final dose in monotherapy was 98 mg/day vs 153 mg/day in adjunctive treatment. Mean monthly cumulative seizure frequency decreased from 3.7 ± 15 to 1.6 ± 7.7 ( n  = 101, P  < 0.0001), 78% of patients with seizures at baseline ( n  = 102) achieved at least 50% reduction in seizure frequency, 44% were seizure-free throughout the trial. Total scores on the quality of life in epilepsy inventory (QOLIE-31) improved from 57 ± 17 to 68 ± 18 ( n  = 64, P  < 0.0001). The most frequently reported adverse events included convulsions, dizziness and tiredness.
Conclusions –  Elderly patients treated with topiramate showed marked reductions in seizures, good tolerability and significant improvements in several aspects of quality of life.     

Encephalopathy induced by levetiracetam added to valproate

Background –  We report on the manifestation of a levetiracetam (LEV)-induced encephalopathy.
Findings –  A 28-year-old man suffering from idiopathic epilepsy with generalized seizures was treated with LEV (3000 mg) added to valproate (VPA) (2000 mg). Frequency of generalized tonic-clonic seizures increased from one per 6 months to two per month. Neuropsychological testing showed impaired word fluency, psychomotor speed and working memory. The interictal electroencephalogram (EEG) showed a generalized slowing to 5 per second theta rhythms with bilateral generalized high-amplitude discharges.
Outcome –  Following discontinuation of LEV, EEG and neuropsychological findings improved and seizure frequency decreased.     

Assessment of seizure susceptibility in pilocarpine epileptic and nonepileptic Wistar rats and of seizure reinduction with pentylenetetrazole and electroshock models

Purpose:   Pentylenetetrazole (PTZ) and maximal electroshock (MES) models are often used to induce seizures in nonepileptic control animals or naive animals. Despite being widely used to screen antiepileptic drugs (AEDs), both models have so far failed to detect potentially useful AEDs for treating drug-resistant epilepsies. Here we investigated whether the acute induction of MES and PTZ seizures in epileptic rats might yield a distinct screening profile for AEDs.
Methods:   Status epilepticus (SE) was induced in adult male Wistar rats by intraperitoneal pilocarpine injection (Pilo, 320 mg/kg, i.p.). One month later, controls or naive animals (Cont) that did not develop SE postpilocarpine (N-Epi) and pilocarpine-epileptic rats (Epi) received one of the following: phenobarbital (PB, 40 mg/kg), phenytoin (PHT, 50 mg/kg), or valproic acid (VPA, 400 mg/kg). Thirty min later the animals were challenged with either subcutaneous MES or PTZ (50 mg/kg, s.c.).
Results:   VPA, PB, and PHT were able to prevent MES in all groups tested (Cont, N-Epi, and Epi groups), whereas for the PTZ model, only the Cont group (naive animals) had seizure control with the same AEDs. In addition, Epi and N-Epi groups when challenged with PTZ exhibited a higher incidence of severe seizures (scores IV-IX) and SE (p   <   0.05, Fisher's exact test).
Conclusions:   Our findings suggest that the induction of acute seizures with PTZ, but not with MES, in animals pretreated with pilocarpine (regardless of SE induction) might constitute an effective and valuable method to screen AEDs and to study mechanisms involved in pharmacoresistant temporal lobe epilepsy (TLE).     

Inflammation contributes to seizure-induced hippocampal injury in the neonatal rat brain

Objective –  The extent of neuronal injury in the hippocampus produced by experimental status epilepticus (SE) is age dependent and is not readily demonstrable in many models of neonatal seizures. Neonatal seizures often occur in clinical settings that include an inflammatory component. We examined the potential contributory role of pre-existing inflammation as an important variable in mediating neuronal injury.
Materials and methods –  Postnatal day 7 (P7) and P14 rat pups were injected with lipopolysaccharide (LPS), 2 h prior to SE induced by lithium–pilocarpine (LiPC). Neuronal injury was assessed by well-described histologic methods.
Results –  While LPS by itself did not produce any discernible cell injury at either age, this treatment exacerbated hippocampal damage induced by LiPC–SE. The effect was highly selective for the CA1 subfield.
Conclusions –  Inflammation can contribute substantially to the vulnerability of immature hippocampus to seizure-induced neuronal injury. The combined effects of inflammation and prolonged seizures in early life may impact long-term outcomes of neonatal seizures.     

Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin

Objective – To evaluate the efficacy and tolerability of the treatment with valproic acid (VPA) in patients with status epilepticus (SE) or acute repetitive seizures (ARS) comparing it with phenytoin (PHT) treatment. Materials and methods – Patients with SE or ARS were treated in a consecutive manner with either VPA or PHT intravenously. The primary endpoint was defined as clinical seizure cessation; the secondary endpoint was evaluation of drug tolerability. Results – Seventy‐four adult patients with SE or ARS participated in the study, 49 with VPA i.v. and 25 PHT i.v. In 43 (87.8%) of the VPA patients, the seizures discontinued, and no rescue medication was needed. Similar results were found in the PHT group in which seizures of 22 (88%) patients were well controlled. Side effects were found in 12% of the PHT group, and in none of the VPA group. Conclusions – VPA i.v. seems to be effective and well tolerated in adult patients with SE or ARS.     

Lamotrigine versus valproic acid as first-line monotherapy in newly diagnosed typical absence seizures: an open-label, randomized, parallel-group study

PURPOSE: To compare the efficacy of lamotrigine (LTG) and valproic acid (VPA) in newly diagnosed children and adolescents with typical absence seizures. METHODS: A randomized, open-label parallel-group design was used. After undergoing an awake video-EEG recording, which included one to two trials of 3 min of hyperventilation and intermittent photic stimulation, eligible patients were randomized to receive LTG or VPA. LTG was initiated at a daily dose of 0.5 mg/kg for 2 weeks in two divided doses, followed by 1.0 mg/kg/day for an additional 2 weeks. Thereafter, doses were increased in 1-mg/kg/day increments every 5 days until seizures were controlled, intolerable adverse effects occurred, or a maximum dose of 12 mg/kg/day had been reached. VPA was equally uptitrated according to clinical response, starting at 10 mg/kg and increasing by 5 mg/kg/24 h every 3 days, if required, to a maximum of 30 mg/kg/day in three divided doses. Patients were seen in the clinic every month for < or = 12 months.The primary efficacy end point at each visit was seizure freedom, defined as lack of clinically observed seizures since the previous visit and lack of electroclinical seizures during ambulatory 24-h EEG testing and a video-EEG session with hyperventilation. RESULTS: Thirty-eight children (17 boys, 21 girls), aged from 3 to 13 years (mean, 7.5 years), all newly diagnosed with childhood or juvenile typical absence seizures, were enrolled. After 1 month of treatment, 10 (52.6%) of 19 children taking VPA and one (5.3%) of 19 taking LTG were seizure free (p = 0.004). By the 3-month follow-up, 12 (63.1%) children taking VPA and seven (36.8%) taking LTG were controlled (p = 0.19). After 12 months, 13 children taking VPA (dose range, 20-30 mg/kg/day; mean serum level, 76.8 mg/L; range, 51.4-91 mg/L) and 10 taking LTG (dose range, 2-11 mg/kg/day; mean serum level, 8.1 mg/L; range, 1.1-18 mg/L) were seizure free (p = 0.51). Side effects were mostly mild and transient and were recorded in two (10.6%) children treated with VPA and in six (31.8%) treated with LTG. CONCLUSIONS: Both VPA and LTG can be efficacious against absence seizures, although VPA shows a much faster onset of action, at least in part because of its shorter titration schedule.     

Pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western subjects

Purpose:   To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations.
Methods:   An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5–8; subsequently, 500 mg on days 9–12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry.
Results:   Following a single dose, carisbamate C_max and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80–125% limits, which are considered not to be of clinical significance. With dose–body weight normalization, C_max and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80–125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1–41.4 ml/h/kg and 11.5–12.8 h.
Discussion:   Carisbamate plasma exposure (AUC) and C_max in Japanese subjects is ∼20–25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality.     

Lamotrigine–valproic acid combination therapy for medically refractory epilepsy

Purpose:   A retrospective study of lamotrigine (LTG)–valproic acid (VPA) combination therapy in medically refractory epilepsy.
Methods:   Patients were identified with an adult epilepsy clinic database and were included if they had been on LTG–VPA combination therapy for at least 6 months. Patient demographics and information about epilepsy type, severity, and degree of medical intractability were obtained by retrospective chart review. The primary outcome measure was change in baseline seizure frequency, and patients were stratified into three groups: (i) seizure-free, (ii) improved (at least 50% reduction in baseline seizure frequency), and (iii) not improved.
Results:   Thirty-five patients met all inclusion–exclusion criteria. Epilepsy type was generalized in 25 patients (71%) and partial in 10 patients (29%). Before LTG–VPA treatment, 27 of 35 (77%) experienced disabling seizures on a monthly basis, and 17 of 35 (49%) of patients had at least one disabling seizure per week. Patients had previously failed treatment with a median of five antiepileptic drugs (AEDs), alone or in combination. With LTG–VPA therapy, 18 (51.4%) remained completely seizure-free, four (11.4%) were improved, and 13 (37.1%) were unimproved. Median follow-up was 42 months. Of the 22 patients who improved, 11 had previously failed LTG and VPA monotherapy. There was no significant difference between improved and unimproved patients with respect to demographics, epilepsy type or severity, or number of previously failed AEDs.
Discussion:   The combination of LTG and VPA should be considered in patients with medically refractory epilepsy. The effectiveness of this combination appears to be independent of epilepsy type or patient demographics.     

Lithium prevents colchicine-induced apoptosis in rat cerebellar granule neurons

Objectives:  Here we evaluated the neuroprotective effects of two well-known mood stabilizers, lithium and valproic acid (VPA), against colchicine neurotoxicity in cerebellar granule cells (CGNs).
Methods:  The CGNs were differentiated for 7 days, pretreated with lithium or VPA for 24 h and after colchicine 1  μ M was added. Cellular damage was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) method and apoptosis in CGNs was characterized by chromatin condensation and DNA fragmentation.
Results:  Incubation with lithium (1–5 mM) attenuated this apoptosis markedly, in a dose–dependent way however, the addition of VPA (0.5–2 mM) did not protect CGNs. Colchicine-induced apoptosis is mediated through the activation of caspase-3. An increase in caspase-3 activity was detected within 18 h and was blocked in presence of lithium 5 mM.
Conclusions:  Our data indicate that lithium treatment is selectively neuroprotective; however, in our experimental conditions VPA did not protect CGNs from apoptosis induced by colchicine. Our results support the hypothesis that distinct pathways mediate the neuroprotective effects of lithium and VPA.     

Rapid onset of seizure suppression with pregabalin adjunctive treatment in patients with partial seizures

Purpose:  To determine the time at which pregabalin demonstrates seizure-suppressing activity when given as adjunctive treatment to patients with refractory partial seizures.
Methods:  Data from four similar 12-week, randomized, double-blind, placebo-controlled, parallel-group trials in patients with refractory partial seizures were pooled to provide an adequate sample to compare the proportion of patients free of seizures on each study day between pregabalin (combined 150–600 mg/day groups) and placebo (combined groups). A generalized estimating equation (GEE) statistical model was used to perform pairwise comparisons on each study day. In several pregabalin dosage groups the dosage was escalated during days 1–7, whereas in others pregabalin was initiated at a fixed dosage without escalation.
Results:  The proportion of patients free of seizures on any treatment day was greater in the combined pregabalin groups compared with baseline. Differences were not observed between the placebo group and baseline. A significantly greater proportion of patients were free of seizures in the combined pregabalin 150–600 mg/day and the pregabalin 600 mg/day fixed-dosage groups compared with the placebo groups from treatment day 2 onward (p < 0.05). From day 8 (coinciding with completion of the 1-week dosage-escalation period in two studies) onward, the proportion of patients free of seizures per day in the pregabalin groups remained relatively constant.
Discussion:  This exploratory analysis of a refractory population using a rigorous endpoint demonstrates that pregabalin rapidly reduced the frequency of partial seizures. At the dosing schemes most commonly used in placebo-controlled trials, significant seizure-suppressing activity was observed after only 2 days of treatment.     

Clinical features of convulsive status epilepticus: a study of 220 cases in western China

Background and purpose:  Convulsive status epilepticus (CSE) is the most common and life-threatening form of status epilepticus (SE). The aim of this study was to describe the clinical features of CSE in western China.
Methods:  Convulsive status epilepticus patients hospitalized from January 1996 to October 2007 were prospectively observed. Logistic regression was used to identify predictors of prognosis.
Results:  The average age of CSE patients ( n  = 220) was 37.5 years (SD 20.31), 50% of the patients had a history of epilepsy. The primary cause of CSE was central nervous system infection (32.7%), followed by discontinuation or reduction of antiepileptic drugs (AEDs; 15.5%). The median duration of CSE was 5 h and median duration of seizures before treatment was 2 h; both were longer in rural patients than in urban patients ( P  < 0.05). The fatality rate on discharge was 15.9%. Logistic regression analysis showed the duration of CSE [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.03–1.07], a history of epilepsy (OR 0.35, 95% CI 0.14–0.89), and respiratory depression (OR 5.96, 95% CI 2.49–14.24) were independent predictors of CSE prognosis.
Discussion:  Central nervous system infection and AEDs withdrawal in epilepsy patients were the most important causes of CSE. There is a large gap between antiepileptic therapy in China and European Status Epilepticus guidelines.     

Plastic Changes and Disease-modifying Effects of Scopolamine in the Pilocarpine Model of Epilepsy in Rats

Summary:  Purpose: We describe the use of a clinically relevant pharmacological intervention that alters the clinical history of status epilepticus (SE)-induced spontaneous recurrent seizures (SRS) in the pilocarpine model and the possible plastic changes underlying such an effect.
Methods: Two hours after pilocarpine-induced SE (320–350 mg/kg, i.p.), rats received scopolamine 1–2 mg/kg i.p. or saline, every 6 h for 3 days. After that, osmotic minipumps were implanted for continuous delivery of scopolamine or saline for an additional 14 days. Animals were video-monitored for 12 h/week during the following 3-month period for the occurrence of SRS and, thereafter, were perfused, processed, and coronal brain sections were stained for acetylcholinesterase (AChE) and for the presence of supragranular mossy fibers (Timm).
Results: Treatment with scopolamine led to significantly fewer SRS. Staining for AChE in the dentate gyrus was significantly more intense in naïve animals. The scopolamine group had the least intense AChE staining of all groups. However, regression analysis of the AChE staining for this group did not correlate with the presence or absence of SRS, or the latency or frequency of SRS. Supragranular mossy fiber sprouting developed in all animals experiencing pilocarpine-induced SE, irrespective of whether or not they were treated with scopolamine.
Conclusions: Pilocarpine-induced SE in the presence of scopolamine might produce animals that, despite mossy fiber sprouting, were not seen to exhibit spontaneous seizures. In addition, our data suggest that the encountered changes in the AChE staining in the dentate gyrus that followed treatment with scopolamine do not help to explain its disease-modifying effects.     

Effectiveness of the ketogenic diet in a broad range of seizure types and EEG features for severe childhood epilepsies

Background –  Ketogenic diet (KD) is an effective treatment for pharmacoresistant epilepsy: more than half of the patients show a greater than 50% reduction in seizures.
Objective –  To identify clinical or electroencephalogram (EEG) variables predicting the response to KD.
Methods –  Clinical and EEG data were retrospectively analysed from 50 consecutive patients treated by KD for severe, pharmacoresistant epilepsy. Most of the patients (70%) had retarded mental and motor development.
Results –  Three months after the start of the KD two-thirds (33) of the patients were responders (had a more than 50% reduction in seizure frequency). The presence of epileptiform EEG discharges in the temporal region correlated with an unfavourable response ( P  = 0.03). The presence of bilateral synchronous epileptiform discharges, and the presence of complex partial seizures approached significance but all other variables did not.
Conclusions –  Our results further support that KD is efficient in a wide variety of epileptic patients with a broad range of EEG features. However, patients with epileptiform discharges in the temporal region are less likely to achieve therapeutic response.     

Is vagus nerve stimulation a treatment option for patients with drug-resistant idiopathic generalized epilepsy?

Background –   The value of vagus nerve stimulation (VNS) for treating patients with drug-resistant idiopathic generalized epilepsy (IGE) is not well documented.
Patients and methods –   Twelve patients (2 males, 10 females) with a mean age of 31 years (11–48 years) and with drug-resistant IGE had VNS implanted in the period 1995–2006. All had generalized seizures documented by video-electroencephalogram. Mean follow-up period was 23 months (9–54 months).
Results –   There was a total seizure reduction of 61% (P = 0.0002). There was 62% reduction of generalized tonic-clonic seizures (P = 0.0020), 58% of absences (P = 0.0003) and 40% of myoclonic seizures (P = 0.0156). Eight patients were considered responders (>50% seizure reduction); two of these patients became seizure-free. Five out of seven patients with juvenile myoclonic epilepsy were responders. At the last follow-up visit, the patients had reduced the anti-epileptic drug (AED) usage from an average of 2.3 to 1.7 AED per patient (P = 0.0625). Two patients are currently being treated with VNS therapy only. Nine patients reported side effects, which were mostly mild and tended to diminish over time.
Conclusion –   Our results indicate that adjunctive VNS therapy is a favourable treatment option for patients with drug-resistant IGE. Rapid cycling seems worth trying in some of the non-responders.     

Successful initiation of combined therapy with valproate sodium injection and divalproex sodium extended-release tablets in the epilepsy monitoring unit

Summary: Purpose: Patients in epilepsy monitoring units (EMUs) often require aggressive initiation or reinitiation of therapy before discharge. We developed a simple dosing scheme using valproate sodium injection (VPA‐IV) and divalproex sodium extended‐release (VPA‐ER) tablets to minimize the time required for initiation of therapy, without increasing the likelihood of seizures and adverse effects. Methods: We identified 42 patients in the EMU, naïve to VPA‐IV and VPA‐ER, for whom one of the discharge AEDs included divalproex sodium. On the day of discharge, patients were loaded with 20 mg/kg VPA‐IV at 6 mg/kg/min, followed by ～20 mg/kg VPA‐ER within 1 h. The discharge daily dose of VPA‐ER was identical to the dose given after the IV load. We assessed tolerability and seizure occurrence during infusion, at 1 h, 4 h, and 1 week after discharge. Results: All patients tolerated the VPA‐IV dose followed by VPA‐ER. Four patients reported mild nausea, and two patients reported mild dizziness within 4 h. No seizures or significant changes in heart rate or blood pressure occurred within 4 h, and all patients were discharged the same day. All patients denied systemic complaints at 1 week, and five had seizures during the week after discharge. All patients had improved seizure frequencies at the end of the first week. Conclusions: VPA‐IV is well tolerated and convenient for rapid loading in the EMU. When promptly followed by VPA‐ER, seizure control remains excellent.     

Use of levetiracetam in hospitalized patients

PURPOSE: The objective of the study was to analyze the short-term efficacy and safety of levetiracetam (LEV) to treat repetitive seizures in hospitalized patients. METHODS: During admission to a tertiary hospital, we retrospectively identified patients with repetitive seizures who were treated for the first time with LEV during a hospital stay. LEV was considered effective if seizure cessation or >75% seizure reduction occurred in the 24 h after starting LEV (compared with the previous 48 h), requiring no further antiepileptic drug (AED) treatment. RESULTS: Thirty patients (12 men, 18 women) were included. Mean age was 59.7 years. Most frequent seizure type was focal motor in 12 (40%) of 30 patients. Most frequent etiology was stroke: nine (30%) of 30 patients. Relevant medical conditions included atrial fibrillation (three) and hepatic disease (three). Concomitant medications included oral anticoagulants (seven), corticosteroids (two), and chemotherapy (two). Four patients received LEV as the only AED. Six patients with focal SE and 20 (66.6%) patients with clusters of seizures but not in SE received LEV as add-on treatment after lack of response to first-line AEDs. Mean LEV dose during first day was 1,119 mg. Mean daily maintenance dose was 1,724 mg. LEV was effective in 24 (80%) patients, all four patients who received it as the only AED, four of six patients with focal SE, and 16 of 20 patients with clusters of seizures. Three (10%) elderly patients with seizures secondary to stroke and chronic obstructive pulmonary disease (COPD) reported moderate/severe somnolence and dizziness, leading to treatment discontinuation in one. On discharge, 20 (66.7%) patients continued on LEV, nine (30%) as the only AED. CONCLUSIONS: LEV is effective and safe to treat repetitive seizures in hospitalized patients, including patients in focal SE.     

Long-term assessment of oxcarbazepine in a naturalistic setting: a retrospective study

Background –  New antiepileptics seem to be better tolerated by patients. The retention rate of an antiepileptic would be a useful indicator of its practical usefulness.
Aims –  To assess the long-term outcome of oxcarbazepine (OXC) in a naturalistic setting by determining the retention rate.
Methods –  This is a retrospective study. All epilepsy patients treated with OXC at a tertiary care epilepsy center during a period of 3.5 years were included in this study. Retention rates of OXC at 1 and 3 years were estimated for each cohort group using Kaplan–Meier estimates and corresponding 95% confidence intervals.
Results –  A total of 98 patients were studied. OXC was used as monotherapy in 14 (14.3%) and as add-on therapy in 84 (85.7%). The mean daily dose was 947 ± 492 mg and 60% received ≤900 mg/day. Using the Kaplan–Meier survival analysis, the retention rates of OXC at 1 and 3 years were estimated to be 0.853 (0.749–0.956) and 0.737 (0.570–0.904), respectively.
Conclusions –  OXC is well tolerated by patients as both monotherapy and add-on therapy.     

Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice

Purpose:   Acetone is the principal ketone body elevated in the ketogenic diet (KD), with demonstrated robust anticonvulsant properties across a variety of seizure tests and models of epilepsy. Because the majority of patients continue to receive antiepileptic drugs (AEDs) during KD treatment, interactions between acetone and AEDs may have important clinical implications. Therefore, we investigated whether acetone could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs against maximal electroshock (MES)–induced seizures in mice.
Methods:   Effects of acetone given in subthreshold doses were tested on the anticonvulsant effects of carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA) against MES-induced seizures in mice. In addition, acute adverse effects of acetone–AEDs combinations were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). Pharmacokinetic interactions between acetone and AEDs were also studied in the mouse brain tissue.
Results:   Acetone (5 or 7.5 mmol/kg, intraperitoneally [i.p.]) enhanced the anticonvulsant activity of CBZ, LTG, PB, and VPA against MES-induced seizures; effects of OXC, PHT, and TPM were not changed. Acetone (7.5 mmol/kg) did not enhance the acute adverse-effect profiles of the studied AEDs. Acetone (5 or 7.5 mmol/kg, i.p.) did not affect total brain concentrations of the studied AEDs. In contrast, VPA, CBZ, LTG, OXC, and TPM significantly decreased the concentration of free acetone in the brain; PB and PHT had no effect.
Conclusions:   Acetone enhances the anticonvulsant effects of several AEDs such as VPA, CBZ, LTG, and PB without affecting their pharmacokinetic and side-effect profiles.     

Stiripentol open study in Japanese patients with Dravet syndrome

Purpose:   To survey the treatment situation of Dravet syndrome in Japan and to compare this result with effectiveness of stiripentol (STP) add-on therapy in an open-label multicenter study.
Methods:   Medical records of patients with Dravet syndrome who visited the study institutions during 2006 were surveyed to examine the effect of antiepileptic drugs (AEDs) on clonic or tonic–clonic seizures (GTCS). Patients older than 1 year of age treated with at least one conventional AED and more than four GTCS per month were invited to participate in the STP study. Seizure status and adverse effects during the first 4 weeks of STP (50 or 1,000 mg/day) add-on therapy (early period) and during long-term treatment were compared with baseline.
Results:   Only 15% of the treatment trials with 15 conventional AEDs in 112 patients succeeded in reducing seizures by more than 50%. With STP, GTCS were reduced more than 50% in 14 of 23 patients (61%), including 2 who became seizure-free, in the early period. Moreover, duration of seizures was shortened in 10 patients and status epilepticus decreased in 6. These effects continued in the long-term although to a lesser degree. Adverse effects (loss of appetite, sleep disturbance, ataxia, hyperactivity/irritability) disappeared after dose modification in most cases. STP was effective at a lower than initial dose in five patients. Some patients benefited from STP added on clobazam despite mutation in CYP2C19 .
Conclusion:   Our data suggest that an early introduction of STP into Japan will result in substantial patient benefit.