Faculty Bibliography

BACKGROUND:There are limited data to guide antiseizure medication (ASM) prophylaxis in patients with aneurysmal subarachnoid hemorrhage (SAH). This results in practice variation in the use and duration of ASM prophylaxis. METHODS:We conducted a systematic review and meta-analysis of articles assessing ASM prophylaxis in adults with aneurysmal SAH. The population, intervention, comparator, and outcome (PICO) questions were as follows: (1) Should ASM or no ASM be used in patients hospitalized for aneurysmal subarachnoid hemorrhage who have no history of clinical or electrographic seizures? (2) If an ASM is used, should levetiracetam or phenytoin/fosphenytoin be preferentially used? (3) If an ASM is used, should a long (> 3 days) or short (≤ 3 days) duration of prophylaxis be used? The main outcomes were early seizure (≤ 14 days), late seizures (> 14 days), adverse events, mortality, and functional outcomes. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to generate recommendations. RESULTS:The initial literature search yielded 1988 articles, of which 10 formed the basis of the recommendations: Regarding PICO 1, we did not find a significant difference in outcomes of early seizure, adverse events, mortality, or functional outcomes when comparing ASM to no ASM. In regard to PICO 2, we found fewer early seizures with phenytoin/fosphenytoin and lower risk for neurologic decline with levetiracetam; however, there was low certainty of evidence. There was no significant difference in mortality between the different treatment types. Regarding PICO 3, we found extended use of ASM may be associated with lower seizure risk, but at the same time be associated with higher risk for adverse effects. CONCLUSIONS:Overall, the quality of evidence is low, precluding strong recommendations. We suggest that ASM or no ASM may be used in patients hospitalized with aneurysmal subarachnoid hemorrhage (conditional recommendation, low quality of evidence). If used, we suggest either levetiracetam or phenytoin/fosphenytoin (conditional recommendation, very low quality of evidence) for a short or long duration (conditional recommendation, moderate quality of evidence).

INTRODUCTION/BACKGROUND:In patients with tuberous sclerosis complex (TSC), seizure onset can be as early as in the neonatal period. Recent studies showed that earlier treatment of TSC positively improves epilepsy and neurodevelopmental outcomes. METHODS:This is an international retrospective study on neonates with TSC monitored with long-term video-EEG. RESULTS:Six of ten neonates with a perinatal diagnosis of TSC were found to have electrographic-only seizures within the first 10 days of life on long-term video-EEG. All patients in this series were found to have TSC2 variants and, except for 1 patient, had difficult-to-treat seizures requiring multiple anti-seizure medications. CONCLUSION/CONCLUSIONS:Our study suggests that early video-EEG for electrographic-only seizures may be valuable in neonates with TSC who otherwise would go untreated.

In the phase 3 randomized controlled trial (RCT; NCT03355209) of fenfluramine in Lennox-Gastaut syndrome (LGS), patients in fenfluramine treatment groups (0.2 mg/kg/day, 0.7 mg/kg/day) experienced greater reduction from baseline in frequency of seizures associated with a fall versus placebo, which was sustained in the open-label extension (OLE) study (NCT03355209). In this post hoc analysis, trajectories of fenfluramine effectiveness and safety, along with dose changes over time, are described for patients with LGS randomized to placebo in RCT who switched to fenfluramine in OLE (PBO-FFA) and those who received fenfluramine in both RCT/OLE (FFA-FFA). Among patients who completed 12 months in OLE (N = 151), numerical improvements in effectiveness outcomes were seen in the PBO-FFA group (n = 59) after initiating fenfluramine and were similar to those in the FFA-FFA group (n = 92). Regression to the mean was not observed in the PBO-FFA group, suggesting that changes were due to fenfluramine. Incidence of the most commonly reported treatment-emergent adverse events increased in the PBO-FFA group after fenfluramine initiation but decreased in the FFA-FFA group in OLE. These data demonstrate rapid improvement in seizure frequency and global functioning in both groups with continued clinical improvement as the mean fenfluramine dose was increased. These results confirm that sustained fenfluramine treatment is effective and tolerable. PLAIN LANGUAGE SUMMARY: This study assessed the change over time in the number of seizures, overall improvement, and side effects in patients with LGS receiving placebo (no active medicine) or fenfluramine in a 14-week study; all patients later received fenfluramine in the extension study. Overall, the number of seizures (associated with a fall) decreased once patients initially receiving placebo changed to fenfluramine (optimal effect around Month 4 while receiving a higher dose), but as expected, common side effects were reported more frequently once patients began fenfluramine treatment. Patients, parents, and doctors should be aware of this time course to allow fenfluramine enough time to work.

[This corrects the article DOI: 10.7759/cureus.113024.].

BACKGROUND:The United States-based Early Access Program (US EAP) provided access to arimoclomol for individuals with Niemann-Pick disease Type C (NPC) ineligible or unable to enroll in clinical trials, generating 4 years of real-world safety and effectiveness data. METHODS:Participants were enrolled at 14 US sites. Investigators collected adverse events (AEs) and assessed disease severity using the 5-domain NPC Clinical Severity Scale (5DNPCCSS) at Baseline and follow-up visits as part of routine clinical care. RESULTS:Among 109 participants, 53 (48.6%) were adults (≥18 years) and 71 (65.1%) received miglustat alongside arimoclomol. Mean (SD) arimoclomol exposure was 820 (539) days. Of 248 reported AEs, 17 events in 13 participants (12.8%) were treatment related. 5DNPCCSS scores remained relatively stable throughout the program, with mean (SD) total scores of 11.0 (6.15) at Baseline (n = 100) and 12.0 (7.32) at Year 4 (n = 22). Among participants with Baseline and Year 1 assessments, mean (SD) scores were 11.2 (6.33) at Baseline and 11.1 (6.63) at Year 1 (n = 78). Similar patterns were observed for those with Baseline and Year 2, Year 3, or Year 4 assessments. Rescored 4-domain NPCCSS (R4DNPCCSS) scores (calculated based on 5DNPCCSS data) showed comparable longitudinal trends. CONCLUSION/CONCLUSIONS:The US EAP provides robust real-world evidence data up to 4 years, supporting the tolerability and effectiveness of arimoclomol in a broad NPC population, including adults and those not treated with miglustat. These findings complement and extend clinical trials results, reinforcing the role of arimoclomol, especially in combination with miglustat, as an important therapeutic option in routine clinical practice.

In mesial temporal lobe epilepsy, resection or ablation-typically of anterior temporal structures-is highly successful in achieving seizure freedom. However, in a substantial proportion of patients, seizures recur for unclear reasons. Invasive hippocampal recordings suggest that, in some patients, hippocampal seizures are highly focal, often restricted to the anterior or posterior hippocampus. This led us to hypothesize that resection or ablation limited to the hippocampal subregion(s) involved at seizure onset is more likely to control seizures than surgery that does not address the specific onset locations. We present a case in which seizures were successfully controlled after posterior hippocampal ablation, as well as a retrospective case series of 18 patients in which 10 cases demonstrated focal onsets within the anterior or posterior hippocampus. Better outcomes occurred when surgery was concordant with the onset region(s) versus discordant (n = 7 concordant vs. 11 discordant patients, P = 0.046, Barnard Exact test). These data suggest that mesial temporal lobe epilepsy can be subdivided according to whether the hippocampal onset pattern is focal or nonfocal, and that targeting localized seizure onset zones within the hippocampus can be effective for seizure control, while limiting surgical morbidity and potentially the risk of adverse cognitive outcomes.

PURPOSE OF REVIEW/OBJECTIVE:This article reviews the existing literature on non-LDL biomarkers in atherosclerotic cardiovascular disease (ACSVD), atherogenesis, and ischemic stroke risk, including a discussion of potential future applications for secondary prevention of stroke. RECENT FINDINGS/RESULTS:Although foundational studies established the strong link between elevated low-density lipoprotein-cholesterol (LDL-C) with the development of atherosclerosis and increased cardiovascular risk, a growing number of recent studies have shown that more precise cerebrovascular disease (CVD) risk stratification can be achieved by using other components of the traditional lipid panel along with additional lipoprotein assays. The specific relationship between these non-traditional markers of atherosclerosis and ischemic stroke risk remains incompletely defined. Lipid measures beyond LDL-C including updated interpretations of the standard lipid panel, such as the triglyceride-to-high density lipoprotein ratio (TG:HDL) as well as testing for lipoprotein (a) (Lp(a)) and apolipoprotein B (ApoB), play a important respective roles in estimating metabolic health as well as atherogenic particle burden. These measures should therefore be considered in the context of stroke risk assessment, monitoring, and secondary prevention.