PAC-FOS: A novel translational concordance framework identifies preclinical seizure models with highest predictive validity for clinical focal onset seizures.

Objective: Central to the development of novel antiseizure medications (ASMs) is testing of antiseizure activity in preclinical models. Although various well-established models exist, their predictive validity across the spectrum of clinical epilepsies has been less clear. We sought to establish the translational concordance of commonly used preclinical models to define models with the highest predictive clinical validity for focal onset seizures (FOS).

Same-Day Hospital Discharge Is Feasible for a Variety of Urologic Surgeries When Using a Virtual Hybrid Care Hotel.

Introduction: To determine postoperative outcomes of same-day discharge to a patient Care Hotel after select urologic surgeries.

Methods: The Care Hotel is a hybrid-care model where patients, who historically would have been admitted, are discharged after surgery. In the Care Hotel, patients have access to an on-call nurse, paramedic team, and virtual access to the Command Center for medical questions or concerns.

Antisense oligonucleotide treatment in a preterm infant with early-onset SCN2A developmental and epileptic encephalopathy.

Early-onset SCN2A developmental and epileptic encephalopathy is caused by SCN2A gain-of-function variants. Here we describe the clinical experience with intrathecally administered elsunersen, a gapmer antisense oligonucleotide targeting SCN2A, in a female preterm infant with early-onset SCN2A developmental and epileptic encephalopathy, in an expanded access program. Before elsunersen treatement, the patient was in status epilepticus for 7 weeks with a seizure frequency of 20-25 per hour.

Sleep links hippocampal propensity for epileptiform activity to its viscerosensory inputs.

The development of a seizure relies on two factors. One is the existence of an overexcitable neuronal network and the other is a trigger that switches normal activity of that network into a paroxysmal state. While mechanisms of local overexcitation have been the focus of many studies, the process of triggering remains poorly understood.

Greater Familiarity Between Surgeon and Operating Room Allied Health Staff is Associated with Shorter Case Duration - A Multi-Institutional Study.

Objective: To characterize the relationship between surgeon-staff familiarity and the time required to perform an operation.

Summary Background Data: The clinical and operational efficiency of operating rooms (ORs) is a driver of hospital finances and patient outcomes. Surgeon-staff familiarity is an important focus for quality improvement and process optimization.

Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy.

Background: Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides no benefits to the patients' developmental and cognitive outcomes. Genetic variants are the most common cause of DEE with KCNQ2 being one of the most frequently identified disease-causing genes.

Brain-wide circuitry underlying altered auditory habituation in zebrafish models of autism.

Auditory processing is widely understood to occur differently in autism, though the patterns of brain activity underlying these differences are not well understood. The diversity of autism also means brain-wide networks may change in various ways to produce similar behavioral outputs. We used larval zebrafish to investigate auditory habituation in four genetic lines relevant to autism: , , and .

Variant-specific in vitro neuronal network phenotypes and drug sensitivity in SCN2A developmental and epileptic encephalopathy.

De novo variants in the Na1.2 voltage-gated sodium channel gene SCN2A are among the major causes of developmental and epileptic encephalopathies (DEE). Based on their biophysical impact on channel conductance and gating, SCN2A DEE variants can be classified into gain-of-function (GoF) or loss-of-function (LoF).

Established and emerging GABA receptor pharmacotherapy for epilepsy.

Drugs that modulate the GABA receptor are widely used in clinical practice for both the long-term management of epilepsy and emergency seizure control. In addition to older medications that have well-defined roles for the treatment of epilepsy, recent discoveries into the structure and function of the GABA receptor have led to the development of newer compounds designed to maximise therapeutic benefit whilst minimising adverse effects, and whose position within the epilepsy pharmacologic armamentarium is still emerging. Drugs that modulate the GABA receptor will remain a cornerstone of epilepsy management for the foreseeable future and, in this article, we provide an overview of the mechanisms and clinical efficacy of both established and emerging pharmacotherapies.

Cortical Tonic Inhibition Gates the Expression of Spike-and-Wave Discharges Associated with Absence Epilepsy.

Objective: Absence seizures result from aberrant thalamocortical processing that confers synchronous, bilateral spike-and-wave discharges (SWDs) and behavioral arrest. Previous work has demonstrated that SWDs can result from enhanced thalamic tonic inhibition, consistent with the mechanism of first-line antiabsence drugs that target thalamic low-voltage-activated calcium channels. However, nearly half of patients with absence epilepsy are unresponsive to first-line medications.

Distinctive In Vitro Phenotypes in iPSC-Derived Neurons From Patients With Gain- and Loss-of-Function Developmental and Epileptic Encephalopathy.

encodes Na1.2, an excitatory neuron voltage-gated sodium channel and a major monogenic cause of neurodevelopmental disorders, including developmental and epileptic encephalopathies (DEE) and autism. Clinical presentation and pharmocosensitivity vary with the nature of variant dysfunction and can be divided into gain-of-function (GoF) cases with pre- or peri-natal seizures and loss-of-function (LoF) patients typically having infantile spasms after 6 months of age.

Generation of a stably transfected mouse embryonic stem cell line for inducible differentiation to excitatory neurons.

In vitro differentiation of stem cells into various cell lineages is valuable in developmental studies and an important source of cells for modelling physiology and pathology, particularly for complex tissues such as the brain. Conventional protocols for in vitro neuronal differentiation often suffer from complicated procedures, high variability and low reproducibility. Over the last decade, the identification of cell fate-determining transcription factors has provided new tools for cellular studies in neuroscience and enabled rapid differentiation driven by ectopic transcription factor expression.

The Q/R editing site of AMPA receptor GluA2 subunit acts as an epigenetic switch regulating dendritic spines, neurodegeneration and cognitive deficits in Alzheimer's disease.

Background: RNA editing at the Q/R site of GluA2 occurs with ~99% efficiency in the healthy brain, so that the majority of AMPARs contain GluA2(R) instead of the exonically encoded GluA2(Q). Reduced Q/R site editing infcreases AMPA receptor calcium permeability and leads to dendritic spine loss, neurodegeneration, seizures and learning impairments. Furthermore, GluA2 Q/R site editing is impaired in Alzheimer's disease (AD), raising the possibility that unedited GluA2(Q)-containing AMPARs contribute to synapse loss and neurodegeneration in AD.

Conversion to Disposable Cystoscopes Decreased Post-procedure Encounters and Infections Compared to Reusable Cystoscopes.

Introduction: We evaluated for differences in post-procedure 30-day encounters or infections following office cystoscopy using disposable vs reusable cystoscopes.

Methods: Cystoscopies performed from June to September 2020 and from February to May 2021 in our outpatient practice were retrospectively reviewed. The 2020 cystoscopies were performed with reusable cystoscopes, and the 2021 cystoscopies were performed with disposable cystoscopes.

channelopathies: Navigating from genotype to neural circuit dysfunction.

The gene is strongly associated with epilepsy and plays a central role for supporting cortical excitation-inhibition balance through the expression of Na1.1 within inhibitory interneurons. The phenotype of disorders has been conceptualized as driven primarily by impaired interneuron function that predisposes to disinhibition and cortical hyperexcitability.

Beyond CBD: Inhibitory effects of lesser studied phytocannabinoids on human voltage-gated sodium channels.

Cannabis contains cannabidiol (CBD), the main non-psychoactive phytocannabinoid, but also many other phytocannabinoids that have therapeutic potential in the treatment of epilepsy. Indeed, the phytocannabinoids cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA) and cannabichromene (CBC) have recently been shown to have anti-convulsant effects in a mouse model of Dravet syndrome (DS), an intractable form of epilepsy. Recent studies demonstrate that CBD inhibits voltage-gated sodium channel function, however, whether these other anti-convulsant phytocannabinoids affect these classic epilepsy drug-targets is unknown.

Biophysical characterization and modelling of SCN1A gain-of-function predicts interneuron hyperexcitability and a predisposition to network instability through homeostatic plasticity.

SCN1A gain-of-function variants are associated with early onset developmental and epileptic encephalopathies (DEEs) that possess distinct clinical features compared to Dravet syndrome caused by SCN1A loss-of-function. However, it is unclear how SCN1A gain-of-function may predispose to cortical hyper-excitability and seizures. Here, we first report the clinical features of a patient carrying a de novo SCN1A variant (T162I) associated with neonatal-onset DEE, and then characterize the biophysical properties of T162I and three other SCN1A variants associated with neonatal-onset DEE (I236V) and early infantile DEE (P1345S, R1636Q).

Carbogen-Induced Respiratory Acidosis Blocks Experimental Seizures by a Direct and Specific Inhibition of Na1.2 Channels in the Axon Initial Segment of Pyramidal Neurons.

Brain pH is a critical factor for determining neuronal activity, with alkalosis increasing and acidosis reducing excitability. Acid shifts in brain pH through the breathing of carbogen (5% CO/95% O) reduces seizure susceptibility in animal models and patients. The molecular mechanisms underlying this seizure protection remain to be fully elucidated.

Fundamental Neurochemistry Review: GABA receptor neurotransmission and epilepsy: Principles, disease mechanisms and pharmacotherapy.

Epilepsy is a common neurological disorder associated with alterations of excitation-inhibition balance within brain neuronal networks. GABA receptor neurotransmission is the most prevalent form of inhibitory neurotransmission and is strongly implicated in both the pathophysiology and treatment of epilepsy, serving as a primary target for antiseizure medications for over a century. It is now established that GABA exerts a multifaceted influence through an array of GABA receptor subtypes that extends far beyond simply negating excitatory activity.

Antisense oligonucleotide therapy for KCNT1 encephalopathy.

Developmental and epileptic encephalopathies (DEEs) are characterized by pharmaco-resistant seizures with concomitant intellectual disability. Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe of these syndromes. De novo variants in ion channels, including gain-of-function variants in KCNT1, which encodes for sodium activated potassium channel protein KNa1.

A nutraceutical product, extracted from Cannabis sativa, modulates voltage-gated sodium channel function.

Background: Purified cannabidiol (CBD), a non-psychoactive phytocannabinoid, has gained regulatory approval to treat intractable childhood epilepsies. Despite this, artisanal and commercial CBD-dominant hemp-based products continue to be used by epilepsy patients. Notably, the CBD doses used in these latter products are much lower than that found to be effective in reducing seizures in clinical trials with purified CBD.