Machine learning models reveal distinct disease subgroups and improve diagnostic and prognostic accuracy for individuals with pathogenic SCN8A gain-of-function variants.

Distinguishing clinical subgroups for patients suffering with diseases characterized by a wide phenotypic spectrum is essential for developing precision therapies. Patients with gain-of-function (GOF) variants in the SCN8A gene exhibit substantial clinical heterogeneity, viewed historically as a linear spectrum ranging from mild to severe. To test for hidden clinical subgroups, we applied two machine-learning algorithms to analyze a dataset of patient features collected by the International SCN8A Patient Registry.

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy.

Background: Epilepsy is a common neurological disease; however, few if any of the currently marketed antiseizure medications prevent or cure epilepsy. Discovery of pathological processes in the early stages of epileptogenesis has been challenging given the common use of preclinical models that induce seizures in physiologically normal animals. Moreover, despite known sex dimorphism in neurological diseases, females are rarely included in preclinical epilepsy models.

Clinical severity is correlated with age at seizure onset and biophysical properties of recurrent gain of function variants associated with SCN8A-related epilepsy.

Objective: Genetic variants in the SCN8A gene underlie a wide spectrum of neurodevelopmental phenotypes including several distinct seizure types and a host of comorbidities. One of the major challenges facing clinicians and researchers alike is to identify genotype-phenotype (G-P) correlations that may improve prognosis, guide treatment decisions, and lead to precision medicine approaches.

Methods: We investigated G-P correlations among 270 participants harboring gain-of-function (GOF) variants enrolled in the International SCN8A Registry, a patient-driven online database.

The International SCN8A Patient Registry: A Scientific Resource to Advance the Understanding and Treatment of a Rare Pediatric Neurodevelopmental Syndrome.

Genetic variants in the gene underlie a wide spectrum of neurodevelopmental phenotypes that range from severe epileptic encephalopathy to benign familial infantile epilepsy to neurodevelopmental delays with or without seizures. A host of additional comorbidities also contribute to the phenotypic spectrum. As a result of the recent identification of the genetic etiology and the length of time it often takes to diagnose patients, little data are available on the natural history of these conditions.

Distinguishing Loss-of-Function and Gain-of-Function Variants Using a Random Forest Classification Model Trained on Clinical Features.

Background And Objectives: Pathogenic variants at the voltage-gated sodium channel gene, , are associated with a wide spectrum of clinical disease outcomes. A critical challenge for neurologists is to determine whether patients carry gain-of-function (GOF) or loss-of-function (LOF) variants to guide treatment decisions, yet in vitro studies to infer channel function are often not feasible in the clinic. In this study, we develop a predictive modeling approach to classify variants based on clinical features present at initial diagnosis.

Quantifying endodermal strains during heart tube formation in the developing chicken embryo.

In the early avian embryo, the developing heart forms when bilateral fields of cardiac progenitor cells, which reside in the lateral plate mesoderm, move toward the embryonic midline, and fuse above the anterior intestinal portal (AIP) to form a straight, muscle-wrapped tube. During this process, the precardiac mesoderm remains in close contact with the underlying endoderm. Previous work has shown that the endoderm around the AIP actively contracts to pull the cardiac progenitors toward the midline.

Clinical and radiologic outcomes after stereotactic radiosurgery for meningiomas in direct contact with the optic apparatus: an international multicenter study.

Objective: Resection of meningiomas in direct contact with the anterior optic apparatus carries risk of injury to the visual pathway. Stereotactic radiosurgery (SRS) offers a minimally invasive alternative. However, its use is limited owing to the risk of radiation-induced optic neuropathy.

Dose to neuroanatomical structures surrounding pituitary adenomas and the effect of stereotactic radiosurgery on neuroendocrine function: an international multicenter study.

Objective: Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS.

Stereotactic radiosurgery for clinoid meningiomas: a multi-institutional study.

Purpose: Resection of clinoid meningiomas can be associated with significant morbidity. Experience with stereotactic radiosurgery (SRS) for clinoid meningiomas remains limited. We studied the safety and effectiveness of SRS for clinoid meningiomas.

Stereotactic Radiosurgery for Perioptic Meningiomas: An International, Multicenter Study.

Background: Stereotactic radiosurgery (SRS) is increasingly used for management of perioptic meningiomas.

Objective: To study the safety and effectiveness of SRS for perioptic meningiomas.

Methods: From 12 institutions participating in the International Radiosurgery Research Foundation (IRRF), we retrospectively assessed treatment parameters and outcomes following SRS for meningiomas located within 3 mm of the optic apparatus.

Dose homogeneity analysis of adjuvant radiation treatment in surgically resected brain metastases: Comparison of IORT, SRS, and IMRT indices.

Purpose: Although surgery remains a treatment option for symptomatic brain metastases, the need for adjuvant radiation after surgery is widely accepted as standard. Despite a multitude of randomized trials aimed at identifying the ideal radiation treatment plan for surgically resected metastases, the development of new delivery regiments necessitates a periodic re-evaluation of dosimetric performance/outcome. Here, we compare the homogeneity index (HI) across three platforms: single-session stereotactic radiosurgery (SRS), multisession stereotactic radiotherapy, and intraoperative radiotherapy (IORT).

ECM Stiffness Controls the Activation and Contractility of Corneal Keratocytes in Response to TGF-β1.

After surgery or traumatic injury, corneal wound healing can cause a scarring response that stiffens the tissue and impairs ocular function. This fibrosis is caused in part by the activation of corneal keratocytes from a native mechanically quiescent state to an activated myofibroblastic state. This transformation is tied to signaling downstream of transforming growth factor-β1 (TGF-β1).

Intraoperative radiotherapy (IORT) for surgically resected brain metastases: outcome analysis of an international cooperative study.

Background And Objective: The ideal delivery of radiation to the surgical cavity of brain metastases (BMs) remains the subject of debate. Risks of local failure (LF) and radiation necrosis (RN) have prompted a reappraisal of the timing and/or modality of this critical component of BM management. IORT delivered at the time of resection for BMs requiring surgery offers the potential for improved local control (LC) afforded by the elimination of delay in time to initiation of radiation following surgery, decreased uncertainty in target delineation, and the possibility of dose escalation beyond that seen in stereotactic radiosurgery (SRS).

Tumor Cavity Recurrence after Stereotactic Radiosurgery of Surgically Resected Brain Metastases: Implication of Deviations from Contouring Guidelines.

Background: Significant heterogeneity exists in target volumes for postoperative stereotactic radiosurgery (SRS) for brain metastases. A set of contouring guidelines was recently published, and we investigated the impact of deviations.

Methods: Patients (n = 41) undergoing single-fraction Gamma Knife SRS following surgical resection of brain metastases from 2011 to 2017 were retrospectively reviewed.

Gamma Knife Radiosurgery for Arteriovenous Malformations Using a Four-Dimensional Dynamic Volume Computed Tomography Angiography Planning System as an Alternative to Traditional Catheter Angiogram.

Background Gamma knife radiosurgery (GKRS) remains a critical intervention in the long-term management of arteriovenous malformations (AVMs). For planning a treatment, identification of the nidus is essential, and it is dependent on high-resolution blood flow imaging, usually in the form of a traditional angiogram. The development of dynamic 320-slice computed tomography (CT) angiography has offered a noninvasive alternative to intra-arterial fluoroscopic imaging, and it is capable of providing equivalent temporal resolution.

Feasibility of dose escalation using intraoperative radiotherapy following resection of large brain metastases compared to post-operative stereotactic radiosurgery.

Background And Purpose: Post-operative SRS (stereotactic radiosurgery) for large brain metastases is challenged by risks of radiation necrosis that limit SRS dose. Intraoperative radiotherapy (IORT) is a potential alternative, however standard dose recommendations are lacking.

Methods And Materials: Twenty consecutive brain metastases treated with post-operative SRS were retrospectively compared to IORT plans generated for 10-30 Gy in 1 fraction to 0-5 mm by estimating the applicator size and distance from critical organs using pre-operative and post-operative MRI.

Efficacy of Stereotactic Radiosurgery in Patients with Multiple Metastases: Importance of Volume Rather Than Number of Lesions.

The role of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases is controversial. While whole brain radiation therapy (WBRT) has historically been the mainstay of treatment, its value is increasingly being questioned as emerging data supports that SRS alone can provide comparable therapeutic outcomes for limited (one to three) intracranial metastases with fewer adverse effects, including neurocognitive decline. Multiple recent studies have also demonstrated that patients with multiple (> 3) intracranial metastases with a low overall tumor volume have a favorable therapeutic response to SRS, with no significant difference compared to patients with limited metastases.

Stereotactic Radiosurgery for Brainstem Metastases: An International Cooperative Study to Define Response and Toxicity.

Purpose: To pool data across multiple institutions internationally and report on the cumulative experience of brainstem stereotactic radiosurgery (SRS).

Methods And Materials: Data on patients with brainstem metastases treated with SRS were collected through the International Gamma Knife Research Foundation. Clinical, radiographic, and dosimetric characteristics were compared for factors prognostic for local control (LC) and overall survival (OS) using univariate and multivariate analyses.