- Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment-resistant status epilepticus. [Journal Article]
- EEpilepsia 2018 Feb 17
- Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA)Areceptors that e...
Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA)Areceptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE. The objective of this study was to assess the efficacy of intramuscular allopregnanolone and ganaxolone in the treatment of SE induced by the chemical threat agent tetramethylenedisulfotetramine (TETS). The test agents were administered 40 minutes after the onset of SE when mice are refractory to treatment. Allopregnanolone and ganaxolone (each at 3 mg/kg) terminated SE in, respectively, 92% and 75% of animals, and prevented mortality in 85% and 50% of animals; the mean times to termination of behavioral seizures were, respectively, 172 ± 16 and 447 ± 52 seconds. In a separate series of experiments, mice were dosed with the neuroactive steroids by intramuscular injection, and plasma and brain levels were sampled at various time points following injection to estimate pharmacokinetic parameters. Plasma Cmax(maximum concentration) values for allopregnanolone and ganaxolone were 645 and 550 ng/mL, respectively. Brain exposure of both steroids was approximately 3-fold the plasma exposure. Two-compartment pharmacokinetic analysis revealed that the central compartment Vd(volume of distribution), CL (clearance), t½(terminal half-life), and F (intramuscular bioavailability) values for allopregnanolone and ganaxolone were, respectively, 4.95 L/kg 12.88 L/kg/h,16 minutes, 97%, and 5.07 L/kg, 8.35 L/kg/h, 25 minutes, 95%. Allopregnanolone and ganaxolone are effective in the treatment of TETS-induced SE when administered by the intramuscular route. Allopregnanolone is more rapidly acting and modestly more effective, possibly because it has greater potency on GABAAreceptors.
- Assessment of the correlations of lacosamide concentrations in saliva and serum in patients with epilepsy. [Journal Article]
- EEpilepsia 2018 Feb 16
- Therapeutic drug monitoring of antiepileptic drugs is based on patient serum samples. In this study, we evaluated the correlation between lacosamide (LCM) steady state concentrations in serum and sal...
Therapeutic drug monitoring of antiepileptic drugs is based on patient serum samples. In this study, we evaluated the correlation between lacosamide (LCM) steady state concentrations in serum and saliva samples. Additionally, we investigated the relation with daily dose, and assessed the feasibility of saliva collection. This was an open-label, single center study including data from 25 patients at the Bethel Epilepsy Center treated with LCM (50-650 mg/d). Samples were collected in the morning (fasting values) and in selected cases at 50 minutes to 5 hours after the morning dose. Nonsignificant differences in the mean LCM morning (trough) concentration in serum and saliva were observed. Serum and saliva concentrations across all samples were highly correlated, (r = .874), with a slightly lower correlation when only fasting values were analyzed (r = .860). Higher correlation with daily dosages was observed in serum samples (r = .773) than in saliva samples (r = .604). Serum and saliva concentrations increased significantly after intake of the LCM morning dose (P < .001). The median absolute and percentage increase of LCM in serum were moderately lower than in saliva samples, with a few outliers in saliva samples. Consequently, saliva could offer great clinical potential to monitor drug concentrations and guide LCM treatment in epileptic patients.
- Efficacy and safety of eslicarbazepine acetate monotherapy in patients converting from carbamazepine. [Journal Article]
- EEpilepsia 2018 Feb 16
- CONCLUSIONS: Baseline use of CBZ or other major putative VGSC inhibitors did not appear to significantly increase the risk of study exit due to worsening seizure control, or to increase the frequency of side effects when converting to ESL monotherapy. However, bigger improvements in efficacy may be possible in patients converting to ESL monotherapy from an AED regimen that does not include a VGSC inhibitor.
- Individualized prediction of seizure relapse and outcomes following antiepileptic drug withdrawal after pediatric epilepsy surgery. [Journal Article]
- EEpilepsia 2018 Feb 15
- The objective of this study was to create a clinically useful tool for individualized prediction of seizure outcomes following antiepileptic drug withdrawal after pediatric epilepsy surgery. We used ...
The objective of this study was to create a clinically useful tool for individualized prediction of seizure outcomes following antiepileptic drug withdrawal after pediatric epilepsy surgery. We used data from the European retrospective TimeToStop study, which included 766 children from 15 centers, to perform a proportional hazard regression analysis. The 2 outcome measures were seizure recurrence and seizure freedom in the last year of follow-up. Prognostic factors were identified through systematic review of the literature. The strongest predictors for each outcome were selected through backward selection, after which nomograms were created. The final models included 3 to 5 factors per model. Discrimination in terms of adjusted concordance statistic was 0.68 (95% confidence interval [CI] 0.67-0.69) for predicting seizure recurrence and 0.73 (95% CI 0.72-0.75) for predicting eventual seizure freedom. An online prediction tool is provided on www.epilepsypredictiontools.info/ttswithdrawal. The presented models can improve counseling of patients and parents regarding postoperative antiepileptic drug policies, by estimating individualized risks of seizure recurrence and eventual outcome.
- Increased neuronal synchrony prepares mesial temporal networks for seizures of neocortical origin. [Journal Article]
- EEpilepsia 2018 Feb 14
- CONCLUSIONS: These results suggest a mechanism of spreading seizures whereby the seizure focus first synchronizes local field potentials in downstream networks to the seizure activity. This change in local field coherence modifies the activity of interneuron populations in these downstream networks, which leads to the attenuation of interneuronal firing rate, effectively shutting down local interneuron populations prior to the spread of seizure. Therefore, regional synchrony may influence the failure of downstream interneurons to prevent the spread of the seizures during generalization.
- The immediate and short-term effects of bilateral intrahippocampal depth electrodes on verbal memory. [Journal Article]
- EEpilepsia 2018 Feb 07
- In contrast to previous studies, Ljung et al. provide evidence of permanent cognitive consequences of bilateral intrahippocampal depth electrodes for verbal memory in patients who were not operated o...
In contrast to previous studies, Ljung et al. provide evidence of permanent cognitive consequences of bilateral intrahippocampal depth electrodes for verbal memory in patients who were not operated or operated in the right temporal lobe. Stimulated by this, we provide historical confirmatory and supplementary evidence of the detrimental effect of bilateral depth electrodes implanted along the longitudinal axis of the hippocampus on verbal learning and especially on delayed verbal memory and recognition performance. This is demonstrated in 31 patients with memory assessments before implantation, after explantation, and 3 months later after left/right temporal lobe surgery. After surgery, significant recovery from postimplantation impairment is found in right temporal patients. Left temporal resection patients stay on the level seen after implantation and do not recover. Surgery, however, has its own effects in addition to the implantation. Intracranial electrodes for electroencephalographic monitoring or electrical stimulation are commonly and increasingly used for diagnosis or treatment in pharmacoresistant epilepsies. Thus, the monitoring of invasive stereotactic approaches is recommended to find safe procedures for the patients. In response to the findings, we restricted indications and used different implantation schemes, different trajectories, and targets to minimize the risk of additional damage.
- Response: Memory decline from hippocampal electrodes? Let's not forget statistics and study design. [Letter]
- EEpilepsia 2018; 59(2):503-504
- Memory decline from hippocampal electrodes? Let's not forget statistics and study design. [Letter]
- EEpilepsia 2018; 59(2):502-503
- Erratum. [Published Erratum]
- EEpilepsia 2018; 59(2):507
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- Risk of pharmacokinetic interactions between antiepileptic and other drugs in older persons and factors associated with risk. [Journal Article]
- EEpilepsia 2018 Feb 07
- CONCLUSIONS: A substantial portion of older epilepsy patients received NED-AED combinations that could cause important PK interactions. The lower frequency among incident vs. prevalent cases may reflect changes in prescribing practices. Avoidance of interacting AEDs is feasible for most persons because of the availability of newer drugs.