Early vigabatrin to augment GABAergic pathways in post-anoxic status epilepticus.

The outcomes of patients who experience status epilepticus during the post-cardiac arrest period, or post-anoxic status epilepticus (PASE), remain dismal despite advances in resuscitation. The combination of therapeutic nihilism and the refractoriness of seizures in a setting where pessimistic prognostic impressions prevail is likely the main driver of such poor outcomes. The resulting pervasive vicious cycle perpetuates this knowledge gap, whereby hypoxic-ischemic insults as the etiology for seizures remain a ubiquitous exclusion criterion for clinal trials in status epilepticus. Effective therapies targeting hyperexcitability resulting from hypoxic-ischemic brain injury are urgently needed. Early inhibition of gamma-aminobutyric acid (GABA) transaminase with vigabatrin holds potential as an effective adjunctive therapy for PASE. This scientific premise is based on the resulting halted GABA catabolism thereby promoting synergistic augmentation of GABAergic pathway when used in combination with positive GABAergic allosteric modulators. This paper is based on a lecture presented at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures, in London 8-10 April 2024.

Secondary hypothermia in patients with super-refractory status epilepticus managed with propofol and ketamine.

BACKGROUND: Therapeutic hypothermia as a potent nonpharmacologic antiseizure therapy has been investigated experimentally in animal models and humans. Although induced hypothermia has been shown to be neuroprotective in acute convulsive status epilepticus, whether its use will translate into improved outcomes for patients with super-refractory nonconvulsive status epilepticus (SRNCSE) has been debated. No clinical data are available on the occurrence and prognostic impact of secondary hypothermia (s-HT) in patients with SRNCSE. With the possibility of core to periphery redistribution of heat with propofol and a centrally mediated dose-dependent fall in body temperature with ketamine, we aimed to investigate the incidence of s-HT events in patients with SRNCSE managed with propofol and ketamine and their impact on clinical outcomes. METHODS: We performed a retrospective observational analysis of consecutive patients with SRNCSE managed with propofol and/or ketamine in a single-center neurological intensive care unit between December 1, 2012 and December 31, 2015. Patients were divided according to the occurrence of hypothermia (temperature < 35.0 °C) into an s-HT group and a nonhypothermia (n-HT) group. Patients who received targeted temperature management therapy were excluded. We compared the demographics, comorbidities, treatment characteristics, and outcomes between groups. RESULTS: Ninety-nine consecutive patients with SRNCSE managed with propofol and/or ketamine were identified during the study period. Twenty patients who received targeted temperature management were excluded, leaving a total of 79 patients for analysis. Hypothermia was observed in 52% (41/79) of the study population. Ketamine was used in 63/79 patients (80%). Ketamine infusion rates were higher and of longer duration among patients who developed s-HT compared with those who did not (mean dosage: 57.35 ±â€¯26.6 mcg/kg/min vs 37.17 ±â€¯15 mcg/kg/min, P = 0.001; duration: 116.36 ±â€¯81.9 h vs 88 ±â€¯89.7 h, P = 0.048). Propofol was used in 78/79 patients (99%), with no significant differences in characteristics between groups (mean dosage: 46.44 ±â€¯20.2 mcg/kg/min vs 36.9 ±â€¯12.9 mcg/kg/min, P = 0.058; duration: 125.43 ±â€¯96.4 h vs 102.3 ±â€¯87.1 h, P = 0.215). No significant differences in demographics, comorbidities, status epilepticus duration and resolution rates, and outcomes were observed between groups. CONCLUSION: In this single-center retrospective analysis of patients whose SRNCSE is being treated, higher doses and longer durations of ketamine were associated with the occurrence of s-HT. Further investigation is warranted to clarify the thermogenic effects of ketamine and its effect on status epilepticus outcomes.

Propofol-ketamine combination therapy for effective control of super-refractory status epilepticus.

Retrospective analysis was conducted of patients with SRSE who were treated simultaneously with propofol and ketamine. Sixty-seven patients were identified from 2012 to 2015, and outcomes documented were resolution and mortality. The duration of combined ketamine and propofol use ranged from 1 to 28 days (mean - 3.6 days). Infusion rates ranged up to 145 and 175 mcg/kg/min. Vasopressors were used in 53 patients (79%), and were given within the first 5 days of the ICU admission in 48 (91%) patients. The overall SRSE resolution rate was 91%, and the overall mortality including patients with anoxic brain injury was 39%. Of the 13 patients with SRSE as a result of anoxic brain injury, SRSE was controlled in 5 (56%). The primary determinant of mortality was family withdrawing care related to the presence of severe medical/neurological diseases.

Population pharmacokinetics of carbamazepine in elderly patients.

BACKGROUND: Carbamazepine is a commonly used antiepileptic drug in elderly patients. This study analyzed prospective data collected as part of a randomized, double-blinded trial of newly diagnosed epilepsy patients. The aims of this study were to determine the pharmacokinetic parameters and their variability of carbamazepine in elderly patients and to quantify the effect of covariates on these parameters. METHODS: Prospectively collected carbamazepine concentrations from 121 patients aged 60 years or older were used to develop a population pharmacokinetic model. Data were analyzed by a nonlinear mixed effects model (NONMEM). A 1-compartment model with first-order absorption and elimination was used to characterize the time course of carbamazepine concentration. Model evaluation and the predictive performance of the final model were assessed using the nonparametric bootstrap approach. RESULTS: The apparent clearance (CL/F) of carbamazepine in this community-dwelling elderly population was estimated to be 3.59 L/h with an interindividual variability of 18.1%. The CL/F increases 23% in patients comedicated with phenytoin. The volume of distribution (V/F) was estimated to be 102 L with an interindividual variability of 74.7%. CONCLUSIONS: Carbamazepine clearance was not associated with body weight or any parameterization of body size nor was age or race or any marker of hepatic or renal function in community dwelling elderly patients. Elderly patients on concurrent phenytoin therapy may require a smaller 23% higher dose on average, about half that reported for younger patients.

Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in patients with new-onset epilepsy: a randomized double-blind clinical trial.

PURPOSE: To evaluate topiramate (TPM) and phenytoin (PHT) monotherapy following rapid oral initiation in new-onset epilepsy. METHODS: Randomized, double-blind, 28-day trial of TPM (100 mg/day beginning on day 1) versus PHT (1,000 mg on day 1 followed by 300 mg/day maintenance dosing) in 261 patients with new-onset epilepsy. The primary end point was time to seizure, and the primary objective was to establish noninferiority of TPM to PHT in the risk of seizure. RESULTS: At day 28, the estimated seizure-free rate was 81.1% for TPM treatment in comparison with 90.3% for PHT treatment. Noninferiority of TPM to PHT (primary objective) could not be established [hazard ratio (HR) 2.0, 95% confidence interval (CI), 0.98 to 4.12, p = 0.366), and PHT could not be shown to be superior to TPM. A higher percentage discontinued with PHT compared to TPM for all reasons (21.1 vs. 12.8%) and due to adverse events (13.4 vs. 6.8%). The most common treatment-related adverse events in both groups were dizziness, paresthesia, and somnolence. A post hoc analysis showed that TPM was superior to PHT in time to discontinuation (retention rate) for all causes (89.4% vs. 80.3%, p = 0.047). CONCLUSION: This study was inconclusive in establishing noninferiority of TPM 100 mg/day compared to a standard regimen of oral PHT in seizure risk in this population of patients with new-onset epilepsy. Given the superiority of TPM in overall retention and favorable tolerability without titration, it may nonetheless be an appropriate option in some patients with new-onset epilepsy requiring rapid treatment initiation.

MicroRNA Regulatory Network as Biomarkers of Late Seizure in Patients with Spontaneous Intracerebral Hemorrhage.

Approximately 15% of patients experience seizures after spontaneous intracerebral hemorrhage (ICH). The pathogenesis of seizures post-ICH is not well-known; however, iron deposition-related neuronal injury following hemoglobin breakdown may contribute. Profiling known miRNAs to identify biomarkers for post-ICH late seizures, we found 64 differentially expressed miRNA: 32 upregulated and 32 downregulated in seizure vs. non-seizure. Functional classification of upregulated miRNA for KEGG pathways and biological processes identified enrichment for cell cycle, protein modifications, and FoxO neurotrophin signaling pathways. No significant enrichment was found for downregulated miRNA. Molecular functions Gene Ontology (GO) terms enriched for upregulated miRNA are numerous, while downregulated miRNAs were associated with ion channel activity. RT-PCR confirmed two miRNAs, 4317 and 4325, were differentially expressed in patients who developed seizures at 1 year. MiR-4317 regulates SLC38A1, a glutamine-glutamate transporter. Integrated miRNA-mRNA network analysis identified COMMD6, APOBEC2, and RASSF6-involved in NF-kB regulation. Two miRNAs (miR-4317 and 4325) differentiated post-ICH late seizures vs. non-seizures at 1 year. The results suggest functional and miRNA-mRNA networks as potential biomarkers for post-ICH late seizures.

A multicenter, outpatient, open-label study to evaluate the dosing, effectiveness, and safety of topiramate as monotherapy in the treatment of epilepsy in clinical practice.

This 24-week, multicenter, open-label trial was designed to evaluate the dosing, effectiveness, and safety of topiramate monotherapy for epilepsy and to identify patient and clinical characteristics predictive of optimally effective stabilized monotherapy doses. Of 406 randomized patients, 244 comprised the evaluable-for-efficacy population (12 weeks of treatment and stabilized topiramate dose during final 28 days); 213 were on topiramate monotherapy at the end of the trial. The mean stabilized daily dose of topiramate over the last 28 days of treatment (primary endpoint) was significantly lower for patients reporting one to three seizures (low seizure frequency, n=147) than for those reporting more than three seizures (high seizure frequency, n=66) during a 3-month retrospective baseline period (191 mg vs 239 mg, P=0.003). Patients in the low-seizure-frequency group reached a stable topiramate dose after a median of 36 days, compared with 53 days for patients in the high-seizure-frequency group. Linear and stepwise regression analyses showed baseline seizure frequency and lifetime seizure count to be significant (P<0.05) predictors of the stabilized dosage. Most treatment-emergent adverse events (TEAEs) were mild to moderate; those occurring with cumulative incidence rates >10% in either seizure frequency group were paresthesia, fatigue, anorexia, dizziness, somnolence, headache, and hypoesthesia; 18.2% of patients discontinued topiramate because of a TEAE, 5.1% reported serious TEAEs, and no deaths were reported during the study.

Lamotrigine therapy in elderly patients with epilepsy, bipolar disorder or dementia.

INTRODUCTION: In spite of circumstances that precipitate high use of anticonvulsants in geriatric populations, there is a paucity of data on the use of antiepileptic drugs in elderly patients with psychiatric and neurological disorders. METHODS: Reports of lamotrigine therapy in elderly patients with epilepsy, bipolar disorder (BD), or dementia were identified by conducting an electronic search of major publication databases. Abstracts and presentations from professional meetings were searched as were the bibliographies of relevant articles. RESULTS: Fourteen reports were identified, and included well-controlled prospective trials, retrospective analyses, and case reports of lamotrigine treatment. Controlled trials in elderly patients with epilepsy demonstrate efficacy and tolerability comparable to gabapentin. Improvement in bipolar depressive symptoms, improvement in core manic symptoms, and delay in mood relapse was reported in geriatric patients with BD. Preliminary case studies in patients with dementia note improvement in cognition and symptoms of agitation and depression. CONCLUSION: Review of the available literature suggests lamotrigine is effective and well tolerated in elderly patients with epilepsy and relatively well-tolerated and may be effective in delaying mood relapse, particularly in the depressive pole, in patients with BD. While very limited literature suggests that lamotrigine may be effective and relatively well-tolerated in patients with dementia, further studies are needed.