Multiparameter quantitative analyses of diagnostic cells in brain tissues from tuberous sclerosis complex.

The advent of high-dimensional imaging offers new opportunities to molecularly characterize diagnostic cells in disorders that have previously relied on histopathological definitions. One example case is found in tuberous sclerosis complex (TSC), a developmental disorder characterized by systemic growth of benign tumors. Within resected brain tissues from patients with TSC, detection of abnormally enlarged balloon cells (BCs) is pathognomonic for this disorder. Though BCs can be identified by an expert neuropathologist, little is known about the specificity and broad applicability of protein markers for these cells, complicating classification of proposed BCs identified in experimental models of this disorder. Here, we report the development of a customized machine learning pipeline (BAlloon IDENtifier; BAIDEN) that was trained to prospectively identify BCs in tissue sections using a histological stain compatible with high-dimensional cytometry. This approach was coupled to a custom 36-antibody panel and imaging mass cytometry (IMC) to explore the expression of multiple previously proposed BC marker proteins and develop a descriptor of BC features conserved across multiple tissue samples from patients with TSC. Here, we present a modular workflow encompassing BAIDEN, a custom antibody panel, a control sample microarray, and analysis pipelines-both open-source and in-house-and apply this workflow to understand the abundance, structure, and signaling activity of BCs as an example case of how high-dimensional imaging can be applied within human tissues.

Dobbs Versus Jackson: Epilepsy, Reproductive Health, and Abortion.

On June 24, 2022, Dobbs vs Jackson Women's Health Organization was decided by the Supreme Court effectively overturning the former precedent of Roe v. Wade. This ruling has direct consequences for the care of persons with epilepsy of childbearing potential. Now more than ever we need to provide informed and comprehensive care to our patients with epilepsy who are particularly vulnerable to the impact of this legislation on their reproductive decision-making. Important areas to understand include (1) the current state of affairs on abortion in the United States; (2) contraception options, their effectiveness, and interactions with anti-seizure medications (ASM); (3) teratogenic effects and adverse neurocognitive outcomes of ASMs; (4) folic acid supplementation; (5) the effect on perinatal and pediatric care; and (6) unique issues related to people of color.

Acute seizure therapies in people with epilepsy: Fact or fiction? A U.S. Perspective.

Patients with epilepsy (PWE) may experience seizure emergencies including acute repetitive seizures despite chronic treatment with daily antiseizure medications. Seizures may adversely impact routine daily activities and/or healthcare utilization and may impair the quality of life of patients with epilepsy and their caregivers. Seizures often occur at home, school, or work in a community setting. Appropriate treatment that is readily accessible for patients with seizure urgencies and emergencies is essential outside the hospital setting. When determining the best acute antiseizure therapy for PWE, clinicians need to consider all of the available rescue medications and their routes of administration including the safety and efficacy profiles. Benzodiazepines are a standard of care as a rescue therapy, yet there are several misconceptions about their use and safety. Reevaluating potential misconceptions and formulating best practices are necessary to maximize usage for each available option of acute therapy. We examine common beliefs associated with traditional use of acute seizure therapies to refute or support them based on the current level of evidence in the published literature.

Image-guided TMS is safe in a predominately pediatric clinical population.

OBJECTIVE: The safety of transcranial magnetic stimulation (TMS) has been previously evaluated in healthy volunteers and clinical adult populations. We sought to fill the gap in safety of TMS functional mapping in a clinical, predominately pediatric cohort. METHODS: In a retrospective chart review, we assessed TMS motor and language mapping studies in persons with epilepsy or brain tumor for adverse events and safety of TMS, and in patients with cranial metal. RESULTS: Out of 500 TMS sessions attempted in 429 individual patients (51% males, 82% ≤ 18 y), seizures occurred in 29 sessions (5.8%) during or after TMS with semiology consistent with their typical presentation and 53 patients (10.6%) experienced pain during stimulation. TMS was completed safely in 276 patients with cranial metal. CONCLUSIONS: Most TMS-related adverse events were benign and transient; the most serious safety events were seizures that could not be conclusively attributed to TMS. However, useful mapping results were obtained in almost all patients. Presence of cranial metal did not adversely affect TMS mapping. We show that TMS functional mapping is safe in a largely pediatric clinical cohort. SIGNIFICANCE: This study demonstrates the safety of TMS functional mapping in patients with refractory epilepsy, brain tumor or cranial metal and fills a gap in knowledge for TMS safety in pediatric clinical population.

Clinical Utility of Transcranial Magnetic Stimulation (TMS) in the Presurgical Evaluation of Motor, Speech, and Language Functions in Young Children With Refractory Epilepsy or Brain Tumor: Preliminary Evidence.

Accurate presurgical mapping of motor, speech, and language cortices, while crucial for neurosurgical planning and minimizing post-operative functional deficits, is challenging in young children with neurological disease. In such children, both invasive (cortical stimulation mapping) and non-invasive functional mapping imaging methods (MEG, fMRI) have limited success, often leading to delayed surgery or adverse post-surgical outcomes. We therefore examined the clinical utility of transcranial magnetic stimulation (TMS) in young children who require functional mapping. In a retrospective chart review of TMS studies performed on children with refractory epilepsy or a brain tumor, at our institution, we identified 47 mapping sessions in 36 children 3 years of age or younger, in whom upper and lower extremity motor mapping was attempted; and 13 children 5-6 years old in whom language mapping, using a naming paradigm, was attempted. The primary hand motor cortex was identified in at least one hemisphere in 33 of 36 patients, and in both hemispheres in 27 children. In 17 children, primary leg motor cortex was also successfully identified. The language cortices in temporal regions were successfully mapped in 11 of 13 patients, and in six of them language cortices in frontal regions were also mapped, with most children (n = 5) showing right hemisphere dominance for expressive language. Ten children had a seizure that was consistent with their clinical semiology during or immediately following TMS, none of which required intervention or impeded completion of mapping. Using TMS, both normal motor, speech, and language developmental patterns and apparent disease induced reorganization were demonstrated in this young cohort. The successful localization of motor, speech, and language cortices in young children improved the understanding of the risk-benefit ratio prior to surgery and facilitated surgical planning aimed at preserving motor, speech, and language functions. Post-operatively, motor function was preserved or improved in nine out of 11 children who underwent surgery, as was language function in all seven children who had surgery for lesions near eloquent cortices. We provide feasibility data that TMS is a safe, reliable, and effective tool to map eloquent cortices in young children.

Noninvasive Localization of Language Cortex in an Awake 4-Year-Old Child with Rasmussen Encephalitis: A Case Report.

BACKGROUND AND IMPORTANCE: Presurgical mapping of eloquent cortex in young patients undergoing neurosurgery is critical for timely intervention, surgical planning, and minimizing postoperative deficits. However, invasive direct cortical stimulation has limited success in young children and noninvasive modalities, such as magnetoencephalography and functional MRI, require sedation, often precluding localization of critical language cortices. Transcranial magnetic stimulation (TMS), a noninvasive brain stimulation technique, is well suited to evaluate language areas in young children because it does not require the patient to remain still during mapping. CLINICAL PRESENTATION: A 4-yr and 11-mo-old female patient diagnosed with epilepsia partialis continua of the right arm and face and right-sided weakness was evaluated at our institution. MRI findings and clinical examination led to the diagnosis of Rasmussen encephalitis involving left frontal lobe and insula. Language cortices were successfully identified in both hemispheres using TMS. The TMS findings aided in discussing with the family the risks of postsurgical deficits of left functional hemispherectomy, the definitive treatment for Rasmussen encephalitis. Postoperatively, the patient had intact speech and was seizure free. CONCLUSION: We illustrate the feasibility and utility of TMS as a noninvasive functional mapping tool in this young child. The preoperative demonstration of bilateral language organization indicated a greater likelihood of preserved language functions postsurgery. We demonstrate that TMS is a safe and noninvasive tool to map language cortices in young children with serious epilepsy syndromes.

Emerging Antiepileptic Drugs for Severe Pediatric Epilepsies.

The medical management of the epilepsy syndromes of early childhood (eg, infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome) is challenging; and requires careful evaluation, classification, and treatment. Pharmacologic therapy continues to be the mainstay of management for these children, and as such it is important for the clinician to be familiar with the role of new antiepileptic drugs. This article reports the clinical trial data and personal experience in treating the severe epilepsies of childhood with the recently Food and Drug Administration-approved new antiepileptic drugs (vigabatrin, rufinamide, perampanel, and clobazam) and those in clinical trials (cannabidiol, stiripentol, and fenfluramine). Genetic research has also identified an increasing number of pediatric developmental and seizure disorders that are possibly treatable with targeted drug therapies, focused on correcting underlying neural dysfunction. We highlight recent genetic advances, and how they affect our treatment of some of the genetic epilepsies, and speculate on the use of targeted genetic treatment (precision medicine) in the future.