The efficacy and safety of third-generation antiseizure medications and non-invasive brain stimulation to treat refractory epilepsy: a systematic review and network meta-analysis study.

Background: The new antiseizure medications (ASMs) and non-invasive brain stimulation (NIBS) are controversial in controlling seizures. So, this network meta-analysis aimed to evaluate the efficacy and safety of five third-generation ASMs and two NIBS therapies for the treatment of refractory epilepsy. Methods: We searched PubMed, EMBASE, Cochrane Library and Web of Science databases. Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM), perampanel (PER), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) were selected as additional treatments for refractory epilepsy in randomized controlled studies and other cohort studies. Randomized, double-blind, placebo-controlled, add-on studies that evaluated the efficacy or safety of medication and non-invasive brain stimulation and included patients with seizures were uncontrolled by one or more concomitant ASMs were identified. A random effects model was used to incorporate possible heterogeneity. The primary outcome was the change in seizure frequency from baseline, and secondary outcomes included the proportion of patients with ≥50% reduction in seizure frequency, and the rate of treatment-emergent adverse events. Results: Forty-five studies were analyzed. The five ASMs and two NIBS decreased seizure frequency from baseline compared with placebo. The 50% responder rates of the five antiseizure drugs were significantly higher than that of placebo, and the ASMs were associated with fewer adverse events than placebo (p < 0.05). The surface under the cumulative ranking analysis revealed that ESL was most effective in decreasing the seizure frequency from baseline, whereas CNB provided the best 50% responder rate. BRV was the best tolerated. No significant publication bias was identified for each outcome index. Conclusion: The five third-generation ASMs were more effective in controlling seizures than placebo, among which CNB, ESL, and LCM were most effective, and BRV exhibited better safety. Although rTMS and tDCS did not reduce seizure frequency as effectively as the five drugs, their safety was confirmed. Systematic review registration: PROSPERO, https://www.crd.york.ac.uk/prospero/ (CRD42023441097).

Cognitive features of white matter lesions accompanied by different risk factors of cerebrovascular diseases.

BACKGROUND: The relationship between different risk factors and the cognitive impairment of white matter lesions (WML) remains poorly understood. OBJECTIVES: To investigate the features of cognitive impairment of patients diagnosed with WML accompanied by different risk factors of cerebrovascular diseases. MATERIAL AND METHODS: A total of 157 cases of WML patients were divided into no risk factor group (n = 26), hypertension group (n = 35), diabetes mellitus group (n = 27), dyslipidemia group (n = 30), and mixed factors group (n = 39). RESULTS: The severity of WML (Fazekas score) in the hypertension and mixed factors groups was higher than in the non-risk factors group. The Montreal Cognitive Assessment (MoCA) scores in the hypertension and mixed factors groups were lower than in the non-risk factors group. The scores of MoCA, immediate memory and delayed recall in the hypertension and mixed factors groups with Fazekas score ≥3 were lower than in the peer group with Fazekas score <3. The scores of MoCA and immediate memory in the hypertension and mixed factors groups with Fazekas score ≥3 were lower than in the non-risk factors group with Fazekas score ≥3. CONCLUSIONS: Hypertension aggravates the severity of WML and cognitive impairment. The severity of WML is positively correlated with the severity of cognitive impairment accompanied by these risk factors.

CNTNAP4 Impacts Epilepsy Through GABAA Receptors Regulation: Evidence From Temporal Lobe Epilepsy Patients and Mouse Models.

Epilepsy is a serious neurological condition characterized by recurrent unprovoked seizures. The exact etiology of epilepsy is not fully understood. Here, we demonstrated that the expression of contactin-associated protein-like 4 (CNTNAP4) was decreased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. Lentivirus-mediated knock-down of CNTNAP4 in the hippocampus increased mice susceptibility to epilepsy. Conversely, lentivirus-mediated overexpression of CNTNAP4 decreased epileptic behavior in mice. CNTNAP4 affected neuronal excitability and inhibitory synaptic transmission via postsynaptic receptors in Mg2+-free epilepsy cell model. Down-regulation or overexpression of CNTNAP4 in the hippocampus influenced the expression of gamma-aminobutyric acid A receptor ß2/3 (GABAARß2/3) membrane protein, without affecting total GABAARß2/3 protein concentration in epileptic mice. Protein interactions between CNTNAP4, GABAARß2/3 and gamma-aminobutyric acid receptor-associated protein (GABARAP) were observed in the hippocampus of epileptic mice. These findings suggest CNTNAP4 may be involved in the occurrence and development of epilepsy through the regulation of GABAAR function, and may be a promising target for the development of epilepsy treatment.

Tubulin ß-III modulates seizure activity in epilepsy.

Tubulin ß-III (TUBB3) is the most dynamic ß-tubulin isoform expressed in neurons, and is highly expressed in the central nervous system. However, the relationship between TUBB3 and epileptic seizures has not been thoroughly investigated. The aims of this study were to investigate the expression of TUBB3 in patients with temporal lobe epilepsy and two different rat models of chronic epilepsy, and to determine the specific roles of TUBB3 in epilepsy. TUBB3 expression was upregulated in human and rat epileptic tissue. Moreover, TUBB3 expression was associated with inhibitory GABAergic neurons and the inhibitory postsynaptic scaffold protein gephyrin. TUBB3 downregulation attenuated the behavioural phenotypes of epileptic seizures during the pilocarpine-induced chronic phase of epileptic seizures and the pentylenetetrazole kindling process, whereas TUBB3 overexpression had the opposite effect. Whole-cell clamp recordings and western blotting revealed that the amplitude of GABA-A receptor-mediated miniature inhibitory postsynaptic currents and the surface expression of the GABA-A receptor were increased in rats in which TUBB3 expression was downregulated. Importantly, TUBB3 interacted with GABA-A receptor-associated protein, which is known to be involved in GABA-A receptor trafficking. These results indicate that TUBB3 plays a critical role in the regulation of epileptic seizures via GABA-A receptor trafficking, suggesting a molecular mechanism for new therapeutic strategies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Clonazepam in the treatment of status epilepticus.

Status epilepticus (SE) is a common and serious neurological disorder. The prognosis of SE may be improved by effectively treating the disorder as early as possible. Clonazepam (CZP) has rarely been included in treatment guidelines for SE; however, this drug has been widely used in the treatment of SE patients and has unique advantages. Here, we elaborate on the clinical application of CZP in the treatment of SE and provide an effective and alternative treatment method for this disorder. We review selected literature, summarize action mechanisms, pharmacokinetics and clinical applications of CZP in the treatment of SE. We found that the effects of CZP are rapid and reliable and that adverse reactions are mild and transient. We conclude that CZP may be safely used to treat SE.