An Initial Experience of Completion Hemispherotomy via Magnetic Resonance-Guided Laser Interstitial Therapy.

INTRODUCTION: In carefully selected patients with medically refractory epilepsy, disconnective hemispherotomy can result in significant seizure freedom; however, incomplete disconnection can result in ongoing seizures and poses a significant challenge. Completion hemispherotomy provides an opportunity to finish the disconnection. We describe the use of magnetic resonance-guided laser interstitial thermal ablation (MRgLITT) for completion hemispherotomy. METHODS: Patients treated with completion hemispherotomy using MRgLITT at our institution were identified. Procedural and seizure outcomes were evaluated retrospectively. RESULTS: Five patients (3 males) underwent six MRgLITT procedures (one child treated twice) for completion hemispherotomy at a median age of 6 years (range 1.8-12.9). Two children had hemimegalencephaly, two had Rasmussen encephalitis, and one had polymicrogyria. All five children had persistent seizures likely secondary to incomplete disconnection after their functional hemispherotomy. The mean time from open hemispherotomy to MRgLITT was 569.5 ± 272.4 days (median 424, range 342-1,095). One patient underwent stereoelectroencephalography before MRgLITT. The mean number of ablation targets was 2.3 ± 0.47 (median 2, range 2-3). The mean length of the procedure was 373 min ± 68.9 (median 374, range 246-475). Four of the five patients were afforded improvement in their neurocognitive functioning and speech performance after ablation, with mean daily seizure frequency at 1 year of 1.03 ± 1.98 (median 0, range 0-5). Two patients achieved Engel Class I outcomes at 1 year after ablation, one was Engel Class III, and two were Engel Class IV. The mean follow-up time was 646.8 ± 179.5 days (median 634, range 384-918). No MRgLITT-related complications occurred. Delayed retreatment (>1 year) occurred in three patients: one child underwent redo ablation and two underwent anatomic hemispherectomy. CONCLUSION: We have demonstrated the feasibility of a minimally invasive approach for completion hemispherotomy using MRgLITT. Delayed retreatment was needed in three patients; thus, further study of this technique with comparison to other surgical techniques is warranted.

PAK1 c.1409 T > a (p. Leu470Gln) de novo variant affects the protein kinase domain, leading to epilepsy, macrocephaly, spastic quadriplegia, and hydrocephalus: Case report and review of the literature.

The p-21-activated kinase 1 (PAK1) protein, encoded by the PAK1 gene, is an evolutionarily conserved serine/threonine-protein kinase that regulates key cellular developmental processes. To date, seven de novo PAK1 variants have been reported to cause the Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). In addition to the namesake features, other common characteristics include structural brain anomalies, delayed development, hypotonia, and dysmorphic features. Here, we report a de novo PAK1 NM_002576.5: c.1409 T > A variant (p.Leu470Gln) identified by trio genome sequencing (GS) in a 13-year-old boy with postnatal macrocephaly, obstructive hydrocephalus, medically refractory epilepsy, spastic quadriplegia, white matter hyperintensities, profound developmental disabilities, and a horseshoe kidney. This is the first recurrently affected residue identified in the protein kinase domain. Combined assessment of the eight pathogenic PAK1 missense variants reveal that the variants cluster in either the protein kinase or autoregulatory domains. Although interpretation of the phenotypic spectrum is limited by the sample size, neuroanatomical alterations were found more often in individuals with PAK1 variants in the autoregulatory domain. In contrast, non-neurological comorbidities were found more often in individuals with PAK1 variants in the protein kinase domain. Together, these findings expand the clinical spectrum of PAK1-associated IDDMSSD and reveal potential correlations with the affected protein domains.

Epilepsy Surgery in Young Children With Tuberous Sclerosis Complex: A Novel Hybrid Multimodal Surgical Approach.

BACKGROUND: Surgery has become integral in treating children with tuberous sclerosis complex (TSC)-related drug-resistant epilepsy (DRE). OBJECTIVE: To describe outcomes of a multimodal diagnostic and therapeutic approach comprising invasive intracranial monitoring and surgical treatment and compare the complementary techniques of open resection and magnetic resonance-guided laser interstitial thermal therapy. METHODS: Clinical and radiographic data were prospectively collected for pediatric patients undergoing surgical evaluation for TSC-related DRE at our tertiary academic hospital. Seizure freedom, developmental improvement, and Engel class were compared. RESULTS: Thirty-eight patients (20 females) underwent treatment in January 2016 to April 2019. Thirty-five underwent phase II invasive monitoring with intracranial electrodes: 24 stereoencephalography, 9 craniotomy for grid/electrode placement, and 2 grids + stereoencephalography. With the multimodal approach, 33/38 patients (87%) achieved >50% seizure freedom of the targeted seizure type after initial treatment; 6/9 requiring secondary treatment and 2/2 requiring a third treatment achieved >50% freedom. The median Engel class was II at last follow-up (1.65 years), and 55% of patients were Engel class I/II. The mean age was lower for children undergoing open resection (2.4 vs 4.9 years, P = .04). Rates of >50% reduction in seizures (86% open resection vs 88% laser interstitial thermal therapy) and developmental improvement (86% open resection vs 83% magnetic resonance-guided laser interstitial thermal therapy) were similar. CONCLUSION: This hybrid approach of using both open surgical and minimally invasive techniques is safe and effective in treating DRE secondary to TSC. Clinical trials focused on treatment method with longer follow-up are needed to determine the optimal candidates for each approach and compare the treatment modalities more effectively.

Epilepsy Surgery: Monitoring and Novel Surgical Techniques.

Drug-resistant epilepsy warrants referral to an epilepsy surgery center for consideration of alternative treatments including epilepsy surgery. Advances in technology now allow for minimally invasive neurophysiologic monitoring and surgical interventions, approaches that are attractive to families because large craniotomies and associated morbidity are avoided. This work reviews the presurgical evaluation process and discusses the use of invasive stereo-electroencephalography monitoring to localize seizure onset zones. Minimally invasive surgical techniques are described for the treatment of focal and generalized epilepsies. These approaches have expanded our capacity to palliate and cure epilepsy in the pediatric population.

A Genetic Screen for Genes That Impact Peroxisomes in Drosophila Identifies Candidate Genes for Human Disease.

Peroxisomes are subcellular organelles that are essential for proper function of eukaryotic cells. In addition to being the sites of a variety of oxidative reactions, they are crucial regulators of lipid metabolism. Peroxisome loss or dysfunction leads to multi-system diseases in humans that strongly affect the nervous system. In order to identify previously unidentified genes and mechanisms that impact peroxisomes, we conducted a genetic screen on a collection of lethal mutations on the X chromosome in Drosophila Using the number, size and morphology of GFP tagged peroxisomes as a readout, we screened for mutations that altered peroxisomes based on clonal analysis and confocal microscopy. From this screen, we identified eighteen genes that cause increases in peroxisome number or altered morphology when mutated. We examined the human homologs of these genes and found that they are involved in a diverse array of cellular processes. Interestingly, the human homologs from the X-chromosome collection are under selective constraint in human populations and are good candidate genes particularly for dominant genetic disease. This in vivo screening approach for peroxisome defects allows identification of novel genes that impact peroxisomes in vivo in a multicellular organism and is a valuable platform to discover genes potentially involved in dominant disease that could affect peroxisomes.

High-frequency oscillations detected in ECoG recordings correlate with cavernous malformation and seizure-free outcome in a child with focal epilepsy: A case report.

Epilepsy associated with cavernous malformation (CM) often requires surgical resection of seizure focus to achieve seizure-free outcome. High-frequency oscillations (HFOs) in intracranial electroencephalogram (EEG) are reported as potential biomarkers of epileptogenic regions, but to our knowledge there are no data on the existence of HFOs in CM-caused epilepsy. Here we report our experience of the identification of the seizure focus in a 3-year-old pediatric patient with intractable epilepsy associated with CM. The electrocorticographic recordings were obtained from a 64-contact grid over 2 days in the epilepsy monitoring unit (EMU). The spatial distribution of HFOs and epileptic spikes were estimated from recording segments right after the electrode placement, during sleep and awake states separately. The HFO distribution showed consistency with the perilesional region; the location of spikes varied over days and did not correlate with the lesion. The HFO spatial distribution was more compact in sleep state and pinpointed the contacts sitting on the CM border. Following the resection of the CM and the hemosiderin ring, the patient became seizure-free. This is the first report describing HFOs in a pediatric patient with intractable epilepsy associated with CM and shows their potential in identifying the seizure focus.

Dataset for a case report of a homozygous PEX16 F332del mutation.

This dataset provides a clinical description along with extensive biochemical and molecular characterization of a patient with a homozygous mutation in PEX16 with an atypical phenotype. This patient described in Molecular Genetics and Metabolism Reports was ultimately diagnosed with an atypical peroxisomal disorder on exome sequencing. A clinical timeline and diagnostic summary, results of an extensive plasma and fibroblast analysis of this patient׳s peroxisomal profile is provided. In addition, a table of additional variants from the exome analysis is provided.

A homozygous mutation in PEX16 identified by whole-exome sequencing ending a diagnostic odyssey.

We present a patient with a unique neurological phenotype with a progressive neurodegenerative phenotype. An 18-year diagnostic odyssey for the patient ended when exome sequencing identified a homozygous PEX16 mutation suggesting an atypical peroxisomal biogenesis disorder (PBD). Interestingly, the patient's peroxisomal biochemical abnormalities were subtle, such that plasma very-long-chain fatty acids initially failed to provide a diagnosis. This case suggests next-generation sequencing may be diagnostic in some atypical peroxisomal biogenesis disorders.

Dopamine dynamics and signaling in Drosophila: an overview of genes, drugs and behavioral paradigms.

Changes in dopamine (DA) signaling have been implicated in a number of human neurologic and psychiatric disorders. Similarly, defects in DA signaling in the fruit fly, Drosophila melanogaster, have also been associated with several behavioral defects. As most genes involved in DA synthesis, transport, secretion, and signaling are conserved between species, Drosophila is a powerful genetic model organism to study the regulation of DA signaling in vivo. In this review, we will provide an overview of the genes and drugs that regulate DA biology in Drosophila. Furthermore, we will discuss the behavioral paradigms that are regulated by DA signaling in flies. By analyzing the genes and neuronal circuits that govern such behaviors using sophisticated genetic, pharmacologic, electrophysiologic, and imaging approaches in Drosophila, we will likely gain a better understanding about how this neuromodulator regulates motor tasks and cognition in humans.

Internalization is required for proper Wingless signaling in Drosophila melanogaster.

The Wnt-Wingless (Wg) pathway regulates development through precisely controlled signaling. In this study, we show that intracellular trafficking regulates Wg signaling levels. In Drosophila melanogaster cells stimulated with Wg media, dynamin or Rab5 knockdown causes reduced Super8XTOPflash activity, suggesting that internalization and endosomal transport facilitate Wg signaling. In the wing, impaired dynamin function reduces Wg transcription. However, when Wg production is unaffected, extracellular Wg levels are increased. Despite this, target gene expression is reduced, indicating that internalization is also required for efficient Wg signaling in vivo. When endosomal transport is impaired, Wg signaling is similarly reduced. Conversely, the expression of Wg targets is enhanced by increased transport to endosomes or decreased hepatocyte growth factor-regulated tyrosine kinase substrate- mediated transport from endosomes. This increased signaling correlates with greater colocalized Wg, Arrow, and Dishevelled on endosomes. As these data indicate that endosomal transport promotes Wg signaling, our findings suggest that the regulation of endocytosis is a novel mechanism through which Wg signaling levels are determined.

The ins and outs of Wingless signaling.

Signaling through the highly conserved Wingless/Wnt pathway plays a crucial role in a diverse array of developmental processes, many of which depend upon the precise regulation of Wingless/Wnt signaling levels. Recent evidence has indicated that the intracellular trafficking of Wingless/Wnt signaling components can result in significant changes in the level of signaling. Here, we examine three mechanisms through which intracellular trafficking might regulate Wingless signaling--the degradation of Wingless, its transport and the transduction of its signal. The intracellular trafficking of several Wingless/Wnt signaling components, including LRP5, LRP6, Dishevelled and Axin, as well as the functional implications of protein localization on Wingless/Wnt signaling, will be discussed.