Preclinical common data elements for general pharmacological studies (pharmacokinetic sample collection, tolerability, and drug administration). A report of the TASK3-WG1A General Pharmacology Working Group of the ILAE/AES Joint Translational Task Force.

Growing concerns over rigor and reproducibility of preclinical studies, including consistency across laboratories and translation to clinical populations, have triggered efforts to harmonize methodologies. This includes the first set of preclinical common data elements (CDEs) for epilepsy research studies, as well as Case Report Forms (CRFs) for widespread use in epilepsy research. The General Pharmacology Working Group of the ILAE/AES Task Force (TASK3-WG1A) has continued in this effort by adapting and refining CDEs/CRFs to address specific study design areas as they relate to preclinical drug screening: general pharmacology, pharmacokinetics (PK) and pharmacodynamics (PD), and tolerability. This work has expanded general pharmacology studies to include dose records, PK/PD, tolerability, and elements of rigor and reproducibility. Tolerability testing CRFs included rotarod and Irwin/Functional Observation Battery (FOB) assays. The material provided in the form of CRFs can be delivered for widespread use within the epilepsy research community.

A companion to the preclinical common data elements for rodent models of pediatric acquired epilepsy: A report of the TASK3-WG1B, Pediatric and Genetic Models Working Group of the ILAE/AES Joint Translational Task Force.

Epilepsy syndromes during the early years of life may be attributed to an acquired insult, such as hypoxic-ischemic injury, infection, status epilepticus, or brain trauma. These conditions are frequently modeled in experimental rodents to delineate mechanisms of epileptogenesis and investigate novel therapeutic strategies. However, heterogeneity and subsequent lack of reproducibility of such models across laboratories is an ongoing challenge to maintain scientific rigor and knowledge advancement. To address this, as part of the TASK3-WG1B Working Group of the International League Against Epilepsy/American Epilepsy Society Joint Translational Task Force, we have developed a series of case report forms (CRFs) to describe common data elements for pediatric acquired epilepsy models in rodents. The "Rodent Models of Pediatric Acquired Epilepsy" Core CRF was designed to capture cohort-general information; while two Specific CRFs encompass physical induction models and chemical induction models, respectively. This companion manuscript describes the key elements of these models and why they are important to be considered and reported consistently. Together, these CRFs provide investigators with the tools to systematically record critical information regarding their chosen model of acquired epilepsy during early life, for improved standardization and transparency across laboratories. These outcomes will support the ultimate goal of such research; that is, to understand the childhood onset-specific biology of epileptogenesis after acquired insults, and translate this knowledge into therapeutics to improve pediatric patient outcomes and minimize the lifetime burden of epilepsy.

A companion to the preclinical common data elements for rodent genetic epilepsy models. A report of the TASK3-WG1B: Paediatric and genetic models working group of the ILAE/AES joint translational TASK force.

Rodent models of epilepsy remain the cornerstone of research into the mechanisms underlying genetic epilepsy. Reproducibility of experiments using these rodent models, occurring across a diversity of laboratories and commercial vendors, remains an issue impacting the cost-effectiveness and scientific rigor of the studies performed. Here, we present two case report forms (CRFs) describing common data elements (CDE) for genetic rodent models, developed by the TASK3-WG1B Working Group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Joint Translational Task Force. The first CRF relates to genetic rodent models that have been engineered based on variants described in epilepsy patients. The second CRF encompasses both spontaneous and inbred rodent models. This companion piece describes the elements and discusses the important factors to consider before documenting each required element. These CRFs provide tools that allow investigators to more uniformly describe core experimental data on different genetic models across laboratories, with the aim of improving experimental reproducibility and thus translational impact of such studies.

Acquired parvalbumin-selective interneuronopathy in the multiple-hit model of infantile spasms: A putative basis for the partial responsiveness to vigabatrin analogs?

West syndrome, an age-specific epileptic encephalopathy, manifests with infantile spasms (IS) and impaired neurodevelopmental outcomes and epilepsy. The multiple-hit rat model of IS is a chronic model of IS due to structural etiology, in which spasms respond partially to vigabatrin analogs. Using this model, we investigated whether IS due to structural etiology may have deficits in parvalbumin (PRV) and somatostatin (SST) immunoreactive (-ir) interneurons, and calretinin-ir (CR-ir) neurons of the primary somatosensory cortex of postnatal day (PN) 20-24 rats, using specific immunohistochemical assays. PN3 Sprague-Dawley male rats underwent the multiple-hit induction protocol, were monitored until PN20-24, and were transcardially perfused to collect brains for histology. Age-matched sham and naive control male rats were also used. Coronal brain cryosections were stained with anti-PRV, anti-CR, and anti-SST antibodies, and regions of interest (ROIs) from the primary somatosensory cortices were selected to determine PRV-, CR-, and SST-ir cell counts and cortical ROI volumes, with blinding to experimental group. Statistical analyses were done using a linear mixed model accounting for repeated measures. We found PRV-ir interneuronal selective reduction, sparing of the CR-ir and SST-ir neurons, and bilateral cortical atrophy. Our findings provide evidence for acquired PRV-selective interneuronopathy, possibly underlying the pathogenesis of IS, neurodevelopmental deficits, and epilepsy, and potentially contributing to the partial response to vigabatrin analogs in this model.

Epileptogenesis in neonatal brain.

Epilepsy is a chronic neurological disorder affecting 65 million people worldwide. The etiologies of seizures can often be identified as genetic, metabolic, structural, immunologic or infectious, but in many cases the cause is unknown with the current diagnostic tools. Epileptogenesis is a process during which genetic or other acquired etiologies/insults lead to functional, structural, or network reorganization changes in the brain that may lead to the development of, or progression of, spontaneous seizures. During development, there are continuous changes in the structure, function, and network operation that also show sex specificity, which may alter the mechanisms underlying the generation of seizures (ictogenesis) and epileptogenesis. Understanding the mechanisms of early life epileptogenesis will enable the development of rationally designed age- and sex-appropriate therapies that would improve the overall quality of patients' lives. Here, we discuss some of these processes that may affect seizure generation and epileptogenesis in the neonatal brain.

INTERNEURONOPATHIES AND THEIR ROLE IN EARLY LIFE EPILEPSIES AND NEURODEVELOPMENTAL DISORDERS.

GABAergic interneurons control the neural circuitry and network activity in the brain. The advances in genetics have identified genes that control the development, maturation and integration of GABAergic interneurons and implicated them in the pathogenesis of epileptic encephalopathies or neurodevelopmental disorders. For example, mutations of the Aristaless-Related homeobox X-linked gene (ARX) may result in defective GABAergic interneuronal migration in infants with epileptic encephalopathies like West syndrome (WS), Ohtahara syndrome or X-linked lissencephaly with abnormal genitalia (XLAG). The concept of "interneuronopathy", i.e. impaired development, migration or function of interneurons, has emerged as a possible etiopathogenic mechanism for epileptic encephalopathies. Treatments that enhance GABA levels, may help seizure control but do not necessarily show disease modifying effect. On the other hand, interneuronopathies can be seen in other conditions in which epilepsy may not be the primary manifestation, such as autism. In this review, we plan to outline briefly the current state of knowledge on the origin, development, and migration and integration of GABAergic interneurons, present neurodevelopmental conditions, with or without epilepsy, that have been associated with interneuronopathies and discuss the evidence linking certain types of interneuronal dysfunction with epilepsy and/or cognitive or behavioral deficits.