Seizure Outcomes After Interventional Treatment in Cerebral Arteriovenous Malformation-Associated Epilepsy: A Systematic Review and Meta-Analysis.

BACKGROUND: Seizures are the second most common presenting symptom of cerebral arteriovenous malformations (AVMs). Evidence supporting different treatment modalities is continuously evolving and it remains unclear which modality offers better seizure outcomes. OBJECTIVE: To compare various interventional treatment modalities (i.e., microsurgery, radiosurgery, endovascular embolization, or multimodality treatment), regarding outcomes in AVM-associated epilepsy. METHODS: PubMed, Embase, and Web of Science were searched on December 31, 2020 for studies that evaluated outcomes in patients with AVM-associated epilepsy after undergoing different treatment modalities. Pooled analysis was performed using a random-effects model and stratified by different modalities. RESULTS: Forty-nine studies including 2668 patients were included. Interventional management was associated with a 56.0% probability of seizure freedom and a 73.0% probability of seizure improvement. The probability of discontinuing antiepileptic drugs was estimated at 38.0%. The stratified analysis showed that microsurgery was associated with a higher probability of seizure freedom and seizure improvement than was radiosurgery, endovascular, or multimodality treatment. The probability of antiepileptic drug cessation was also higher after microsurgery compared with radiation therapy; however, only clinical but not statistical significance could be inferred because of the lack of comparative analyses. CONCLUSIONS: Interventional management of AVM-related epilepsy was associated with seizure freedom and seizure improvement in 56% and 73% of cases. Microsurgery seemed to be associated with a higher incidence of seizure freedom and seizure improvement than did other modalities. Future well-designed comparative studies are needed to draw definitive conclusions regarding each modality.

Postnatal expression of the lysine methyltransferase SETD1B is essential for learning and the regulation of neuron-enriched genes.

In mammals, histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Among these enzymes, SETD1B (SET domain containing 1b) has been linked to syndromic intellectual disability in human subjects, but its role in the mammalian postnatal brain has not been studied yet. Here, we employ mice deficient for Setd1b in excitatory neurons of the postnatal forebrain, and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that Setd1b controls the expression of a set of genes with a broad H3K4me3 peak at their promoters, enriched for neuron-specific genes linked to learning and memory function. Comparative analyses in mice with conditional deletion of Kmt2a and Kmt2b histone methyltransferases show that SETD1B plays a more pronounced and potent role in regulating such genes. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-dependent regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

Epigenetic gene expression links heart failure to memory impairment.

In current clinical practice, care of diseased patients is often restricted to separated disciplines. However, such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age-associated dementias. The underlying molecular mechanisms are presently unknown, and thus, corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms, we show that heart failure leads to specific changes in hippocampal gene expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.