Laser interstitial thermal therapy (LITT) for pediatric low-grade glioma-case presentations and lessons learned.

BACKGROUND: The surgical treatment of brain tumors has developed over time, offering customized strategies for patients and their specific lesions. One of the most recent advances in pediatric neuro-oncological surgery is laser interstitial thermal therapy (LITT). However, its effectiveness and indications are still being evaluated. The aim of this work is to review the current literature on LITT for pediatric low-grade gliomas (pLGG) and evaluate our initial results in this context. METHODS: We retrospectively reviewed our pediatric neurosurgery database for patients who received LITT treatment between November 2019 and December 2023. We collected data on the indications for LITT, technical issues during the procedure, and clinical and radiological follow-up. RESULTS: Three patients underwent 5 LITT procedures for pLGG. The lesion was thalamo-peduncular in one patient, cingulate in one, and deep parietal in one patient. Two patients had a previous open resection done and were diagnosed with pLGG. One patient underwent a stereotaxic biopsy during the LITT procedure that was non-diagnostic. The same patient underwent a later open resection of the tumor in the cingulate gyrus. There were no surgical complications and all patients were discharged home on the first post-operative day. The follow-up period was between 20 and 40 months. Radiological follow-up showed a progressive reduction of the tumor in patients with LGG. CONCLUSION: Laser interstitial thermal therapy is a minimally invasive treatment that shows promise in treating deep-seated pLGG in children. The treatment has demonstrated a reduction in tumor volume, and the positive results continue over time. LITT can be used as an alternative treatment for tumors located in areas that are difficult to access surgically or in cases where other standard treatment options have failed.

Increased hepatoprotective effects of the novel farnesoid X receptor agonist INT-787 versus obeticholic acid in a mouse model of nonalcoholic steatohepatitis.

The nuclear farnesoid X receptor (FXR), a master regulator of bile acid and metabolic homeostasis, is a key target for treatment of nonalcoholic steatohepatitis (NASH). This study compared efficacy of FXR agonists obeticholic acid (OCA) and INT-787 by liver histopathology, plasma biomarkers of liver damage, and hepatic gene expression profiles in the Amylin liver NASH (AMLN) diet-induced and biopsy-confirmed Lepob/ob mouse model of NASH. Lepob/ob mice were fed the AMLN diet for 12 weeks before liver biopsy and subsequent treatment with vehicle, OCA, or INT-787 for 8 weeks. Hepatic steatosis, inflammation, and fibrosis (liver lipids, galectin-3, and collagen 1a1 [Col1a1], respectively), as well as plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, were assessed. Hepatic gene expression was assessed in Lepob/ob mice that were fed the AMLN diet for 14 weeks then treated with vehicle, OCA, or INT-787 for 2 weeks. INT-787, which is equipotent to OCA but more hydrophilic, significantly reduced liver lipids, galectin-3, and Col1a1 compared with vehicle, and to a greater extent than OCA. INT-787 significantly reduced plasma ALT and AST levels, whereas OCA did not. INT-787 modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA in hepatic tissue. These findings demonstrate greater efficacy of INT-787 treatment compared with OCA in improving liver histopathology, decreasing liver enzyme levels, and enhancing gene regulation, suggesting superior clinical potential of INT-787 for the treatment of NASH and other chronic liver diseases.

Functional hemispheric disconnection procedures for chronic epilepsy: history, indications, techniques, complications and current practice in Europe. A consensus statement on behalf of the EANS functional neurosurgery section.

Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure. Research question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy. Material and methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines. Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported. Discussion and conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe.

The prepontine block and its relevance for the development and treatment of hydrocephalus.

OBJECTIVE: Pulsatile CSF flow patterns include flow through the ventricles to the subarachnoid space and cisterns and from the infra- to the supratentorial subarachnoid space. In this study, we demonstrate how an obstruction at the level of the prepontine space may lead to obstructive hydrocephalus with specific radiological characteristics, as well as the implications for treatment options. METHODS: We retrospectively collected data of patients who underwent surgery between February 2010 and December 2022 for hydrocephalus secondary to a suspected prepontine block. One additional patient diagnosed with prepontine block who did not undergo surgery was also included. We excluded patients with a background of previous unrelated neurosurgical procedures or CNS infections. RESULTS: Six children and two adults were included. Three presented with hydrocephalus on imaging, without any other underlying pathology. Five had a suprasellar arachnoid cyst, with its lower border abating the pons and occluding the spinal subarachnoid space (SAS). All cases had an open aqueduct on T2 sagittal sequences, as well as an infracerebellar or retrocerebellar CSF collection. In most cases, a horizontal web was identified in the prepontine region. Seven cases were treated with an endoscopic fenestration. One patient subsequently underwent a shunt surgery. All the operated children reached normal developmental milestones after surgery. CONCLUSIONS: This paper describes a rather small series of cases where clear obstruction was observed at the level of the prepontine subarachnoid space. We believe this anatomical subtlety adds to a better understanding of CSF pathways and the role of ETV in treating hydrocephalus, focusing on a small subgroup of patients without a clear obstruction.

Development of small-molecule Tau-SH3 interaction inhibitors that prevent amyloid-ß toxicity and network hyperexcitability.

Alzheimer's disease (AD) is the leading cause of dementia and lacks highly effective treatments. Tau-based therapies hold promise. Tau reduction prevents amyloid-ß-induced dysfunction in preclinical models of AD and also prevents amyloid-ß-independent dysfunction in diverse disease models, especially those with network hyperexcitability, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau binds several SH3 domain-containing proteins implicated in AD via its central proline-rich domain. We previously used a peptide inhibitor to demonstrate that blocking Tau interactions with SH3 domain-containing proteins ameliorates amyloid-ß-induced dysfunction. Here, we identify a top hit from high-throughput screening for small molecules that inhibit Tau-FynSH3 interactions and describe its optimization with medicinal chemistry. The resulting lead compound is a potent cell-permeable Tau-SH3 interaction inhibitor that binds Tau and prevents amyloid-ß-induced dysfunction, including network hyperexcitability. These data support the potential of using small molecule Tau-SH3 interaction inhibitors as a novel therapeutic approach to AD.

The Pediatric Epilepsy Surgery Interest Group (PESIG) under the auspice of the ISPN Research Committee: Availability of relevant technology and geographical distribution.

PURPOSE: Epilepsy surgery for pediatric drug-resistant epilepsy has been shown to improve seizure control, enhance patient and family QoL, and reduce mortality. However, diagnostic tools and surgical capacity are less accessible worldwide. The International Society Pediatric Neurosurgery (ISPN) has established a Pediatric Epilepsy Surgery Interest Group (PESIG), aiming to enhance global collaboration in research and educational aspects. The goals of this manuscript are to introduce PESIG and analyze geographical differences of epilepsy surgery and technology availability. METHODS: PESIG was established (2022) following an ISPN executive board decision. Using a standardized form, we surveyed the PESIG members, collecting and analyzing data regarding geographical distribution, and availability of various epilepsy treatment-related technologies. RESULTS: Two hundred eighty-two members registered in PESIG from 70 countries, over 6 continents, were included. We categorized the countries by GDP as follows: low, lower-medium, upper-medium, and high income. The most commonly available technology was vagus nerve stimulation 68%. Stereoelectroencephalography was available for 58%. North America had statistically significant greater availability compared to other continents. Europe had greater availability compared to Africa, Asia, and South (Latin) America. Asia had greater availability compared to Africa. High-income countries had statistically significant greater availability compared to other income groups; there was no significant difference between the other income-level subgroups. CONCLUSION: There is a clear discrepancy between countries and continents regarding access to epilepsy surgery technologies. This strengthens the need for collaboration between neurologists and neurosurgeons from around the world, to enhance medical education and training, as well as to increase technological availability.

Positional shunt assist for slit ventricle syndrome.

PURPOSE: Hydrocephalus is one of the most common pathologies in pediatric neurosurgery. One of the causes of recurring events of headaches among shunted children is "slit ventricle syndrome" (SVS). Several potential treatments have been proposed, yet SVS often represents a treatment challenge. The goal of the current series is to present our experience with adding a positional shunt-assist (SA) (Miethke, Aesculap) for the treatment of SVS. METHODS: Clinical data was retrospectively collected from all consecutive children with SVS that were treated with SA (Miethke, Aesculap) at our center. Surgical and clinical outcomes as expressed by hospital visits, or need for additional surgery, were evaluated. RESULTS: Nine cases were included. Hydrocephalus etiology included IVH (6), postinfectious (1), and congenital syndromes (2). Average age at first shunt was 4 months. Primary shunt type was differential-pressure-valve in all. Average age at SVS onset was 4 years. Average age at SA placement was 5.5 years. There were no perioperative complications besides a single stich abscess. A 6-month follow-up period after SA was compared to a 6-month period prior to the SA: average hospital visits decreased from 2.4 to 0.6 per patient (p < 0.0002). 4/9 patients needed an LP or shunt revision before the SA surgery, while no procedure was indicated during the immediate 6-month follow-up. At the last follow-up, there was a significant reduction in the rate of ER visits compared to prior to surgery; however, the number of neurosurgical procedures did not significantly differ. CONCLUSION: Using a SA for SVS was associated with a short-term improvement of symptoms in the majority of cases, reduction in hospital visits, and reduced need for SVS-related procedures.

Systematic analysis of alternative exon-dependent interactome remodeling reveals multitasking functions of gene regulatory factors.

Alternative splicing significantly expands biological complexity, particularly in the vertebrate nervous system. Increasing evidence indicates that developmental and tissue-dependent alternative exons often control protein-protein interactions; yet, only a minor fraction of these events have been characterized. Using affinity purification-mass spectrometry (AP-MS), we show that approximately 60% of analyzed neural-differential exons in proteins previously implicated in transcriptional regulation result in the gain or loss of interaction partners, which in some cases form unexpected links with coupled processes. Notably, a neural exon in Chtop regulates its interaction with the Prmt1 methyltransferase and DExD-Box helicases Ddx39b/a, affecting its methylation and activity in promoting RNA export. Additionally, a neural exon in Sap30bp affects interactions with RNA processing factors, modulating a critical function of Sap30bp in promoting the splicing of <100 nt "mini-introns" that control nuclear RNA levels. AP-MS is thus a powerful approach for elucidating the multifaceted functions of proteins imparted by context-dependent alternative exons.

Fluctuating hearing loss secondary to spontaneous intracranial hypotension: A case report and review of the literature.

OBJECTIVE: Fluctuating sensorineural hearing loss (SNHL) has multiple etiologies, most commonly Ménière's disease (MD), recurrent sudden SNHL, and autoimmune inner ear disorders. Fluctuating SNHL has rarely been described as a symptom of spontaneous intracranial hypotension (SIH). PATIENT: A 39-year-old previously healthy female presented with "Ménière's like" symptoms responsive to steroid treatment, which worsened during the day and improved in the supine position. Conservative treatment for MD consisting of low salt and caffeine diet and betahistine medication yielded no improvement. Secondary revision of brain imaging scans showed signs indicative of SIH, and a spinal cerebrospinal fluid leak was ultimately found and treated by a novel technique of transvenous fistula embolization by means of Onyx® glue, leading to gradual clinical improvement and near-complete resolution of symptoms. CONCLUSION: SIH should be considered as part of the differential diagnosis of fluctuating SNHL. Clinical and radiological features should be known and sought. We suspect that early diagnosis and treatment can lead to cure and prevent permanent auditory damage.

Shifting Strategies in the Treatment of Pediatric Craniopharyngioma.

PURPOSE OF REVIEW: Craniopharyngiomas represent one of the most challenging diseases to treat. Despite their benign histology, and after many decades of surgical experience and technological advancements, there is still no clear consensus regarding the most effective management for this tumor. Due to their location and aggressive local characteristics, purely surgical approaches all too often result in unacceptable morbidity. RECENT FINDINGS: Partial resection combined with radiation therapy results in similar control rates when compared to aggressive surgery, while also minimalizing the neuro-endocrinological morbidity. In this manuscript, we describe the historical progression of the shifting strategies in the management of pediatric craniopharyngioma. Time has also altered our expectations for outcomes, evolving from purely morbidity and mortality to simple Glasgow Outcomes Scales, now to formal neuro-psychometric and quality of life data.

Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila.

Huntington's disease (HD) is a neurodegenerative disease characterized by movement and cognitive dysfunction. HD is caused by a CAG expansion in exon 1 of the HTT gene that leads to a polyglutamine (PQ) repeat in the huntingtin protein, which aggregates in the brain and periphery. Previously, we used Drosophila models to determine that Htt-PQ aggregation in the heart causes shortened lifespan and cardiac dysfunction that is ameliorated by promoting chaperonin function or reducing oxidative stress. Here, we further study the role of neuronal mutant huntingtin and how it affects peripheral function. We overexpressed normal (Htt-PQ25) or expanded mutant (Htt-PQ72) exon 1 of huntingtin in Drosophila neurons and found that mutant huntingtin caused age-dependent Htt-PQ aggregation in the brain and could cause a loss of synapsin. To determine if this neuronal dysfunction led to peripheral dysfunction, we performed a negative geotaxis assay to measure locomotor performance and found that neuronal mutant huntingtin caused an age-dependent decrease in locomotor performance. Next, we found that rapamycin reduced Htt-PQ aggregation in the brain. These results demonstrate the role of neuronal Htt-PQ in dysfunction in models of HD, suggest that brain-periphery crosstalk could be important to the pathogenesis of HD, and show that rapamycin reduces mutant huntingtin aggregation in the brain.

Added value of corpus callosotomy following vagus nerve stimulation in children with Lennox-Gastaut syndrome: A multicenter, multinational study.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe form of epileptic encephalopathy, presenting during the first years of life, and is very resistant to treatment. Once medical therapy has failed, palliative surgeries such as vagus nerve stimulation (VNS) or corpus callosotomy (CC) are considered. Although CC is more effective than VNS as the primary neurosurgical treatment for LGS-associated drop attacks, there are limited data regarding the added value of CC following VNS. This study aimed to assess the effectiveness of CC preceded by VNS. METHODS: This multinational, multicenter retrospective study focuses on LGS children who underwent CC before the age of 18 years, following prior VNS, which failed to achieve satisfactory seizure control. Collected data included epilepsy characteristics, surgical details, epilepsy outcomes, and complications. The primary outcome of this study was a 50% reduction in drop attacks. RESULTS: A total of 127 cases were reviewed (80 males). The median age at epilepsy onset was 6 months (interquartile range [IQR] = 3.12-22.75). The median age at VNS surgery was 7 years (IQR = 4-10), and CC was performed at a median age of 11 years (IQR = 8.76-15). The dominant seizure type was drop attacks (tonic or atonic) in 102 patients. Eighty-six patients underwent a single-stage complete CC, and 41 an anterior callosotomy. Ten patients who did not initially have a complete CC underwent a second surgery for completion of CC due to seizure persistence. Overall, there was at least a 50% reduction in drop attacks and other seizures in 83% and 60%, respectively. Permanent morbidity occurred in 1.5%, with no mortality. SIGNIFICANCE: CC is vital in seizure control in children with LGS in whom VNS has failed. Surgical risks are low. A complete CC has a tendency toward better effectiveness than anterior CC for some seizure types.

Chiari Type 1 Malformation and Syringomyelia in Children: Classification and Treatment Options.

Chiari type 1 malformation (CIM) is defined as tonsillar ectopia of >5 mm, while syringomyelia (SM) is defined as a cerebrospinal fluid (CSF)-filled cavity larger than 3 mm dissecting the spinal cord. Over the last decades, our understanding of these pathologies has grown; however, many controversies still exist almost in every aspect of CIM and SM, including etiology, indication for treatment, timing of treatment, surgical technique, follow-up regime, and outcome. This chapter provides a comprehensive overview on different aspects of CIM and SM and on the still existing controversies, based on the evidence presently available. Future directions for clinical research concerning CIM and SM treatment and outcome are elaborated and discussed as well.

[EPILEPSY SURGERY IN CHILDREN: A SUMMARY OF A DECADE AT THE SOURASKY TEL AVIV MEDICAL CENTER].

INTRODUCTION: Drug-resistant epilepsy in children is associated with morbidity, developmental regression and mortality. Over recent years, there is an increase in awareness regarding the role of surgery in the treatment of refractory epilepsy, both in the diagnostic phase and for treatment, reducing the number and magnitude of seizures. Technological advancements have enabled a minimalization of surgery, with reduction in surgical associated morbidity. METHODS: In this retrospective study, we review our experience with cranial surgery for epilepsy between the years 2011-2020. Collected data included information regarding the epileptic disorder, surgery, surgical-related complications and epilepsy outcome. RESULTS: A total of 93 children underwent 110 cranial surgeries over a decade. The main etiologies included cortical dysplasia (29), Rasmussen encephalitis (10), genetic disorders (9), tumors (7) and tuberous sclerosis (7). The main surgeries included lobectomies (32), focal resections (26), hemispherotomies (25), and callosotomies (16). Two children underwent MRI-guided laser interstitial thermal treatment (LITT). The most significant improvements following surgery were following hemispherotomy or tumor resection (100% of children, each). Following resections for cortical dysplasia led to a significant improvement in 70%. In 83% of children undergoing callosotomy, there were no additional drop seizures; 14% of the entire group underwent additional epilepsy surgery; 23% of children had an unexpected complication, in the vast majority with no permanent sequela. There was not mortality. CONCLUSIONS: Epilepsy surgery may lead to significant improvement and even cure of epilepsy. There is a wide span of epilepsy surgical procedures. Ealy referral of children with refractory epilepsy for surgical evaluation may significantly reduce the developmental injury, and improve functional outcomes.

Neurosurgical aspects of Noonan syndrome.

PURPOSE: Noonan syndrome (NS) is a rare neurodevelopmental syndrome characterized by dysmorphic features, congenital heart defects, neurodevelopmental delay, and bleeding diathesis. Though rare, several neurosurgical manifestations have been associated with NS, such as Chiari malformation (CM-I), syringomyelia, brain tumors, moyamoya, and craniosynostosis. We describe our experience in treating children with NS and various neurosurgical conditions, and review the current literature on neurosurgical aspects of NS. METHODS: Data were retrospectively collected from the medical records of children with NS who were operated at a tertiary pediatric neurosurgery department, between 2014 and 2021. Inclusion criteria were clinical or genetic diagnosis of NS, age < 18 years at treatment, and need for a neurosurgical intervention of any kind. RESULTS: Five cases fulfilled the inclusion criteria. Two had tumors, one underwent surgical resection. Three had CM-I, syringomyelia, and hydrocephalus, of whom one also had craniosynostosis. Comorbidities included pulmonary stenosis in two patients and hypertrophic cardiomyopathy in one. Three patients had bleeding diathesis, two of them with abnormal coagulation tests. Four patients were treated preoperatively with tranexamic acid, and two with Von Willebrand factor or platelets (1 each). One patient with a clinical bleeding predisposition developed hematomyelia following a syringe-subarachnoid shunt revision. CONCLUSIONS: NS is associated with a spectrum of central nervous system abnormalities, some of which with known etiology, while in others a pathophysiological mechanism has been suggested in the literature. When operating on a child with NS, a meticulous anesthetic, hematologic, and cardiac evaluation should be conducted. Neurosurgical interventions should then be planned accordingly.

Postoperative coagulopathy among otherwise healthy pediatric patients undergoing open craniosynostosis repair: a retrospective study.

Significant blood loss and resultant transfusion may lead to coagulopathy. The need for routine transfusion of non-RBC blood products in healthy pediatric patients suffering significant, yet controlled, intra-operative blood loss is controversial. Open craniosynostosis surgery is often associated with significant intra-operative blood loss and transfusion, and routinely preformed on otherwise healthy pediatric patients. Therefore, we found it as a useful model for our study, which aimed to assess the need for routine transfusion of non-RBC blood products in healthy pediatric patients suffering significant intra-operative blood loss. We conducted a retrospective cohort study of otherwise healthy pediatric patients, undergoing open craniosynostosis surgery and transfused solely with packed red blood cells (pRBCs) in a single large-volume tertiary surgical center, between January 2010 and December 2021. Among 457 eligible patients, 34 (7.4%) developed significant postoperative coagulopathy. Median [IQR] intra-operative pRBC transfusion volume was 17.4 ml kg-1 [13.3, 23.1]. Patients who developed coagulopathy did not have higher postoperative pRBC transfusion rate (8.8% vs 3.8%, P = 0.16) or volume (median [IQR], 0 [0, 0] vs 0 [0, 0] ml, P = 0.15), nor higher hospital LOS (5 [4, 5] vs 5 [4, 5] days, P = 0.66). ICU LOS was 0.8 [0.7, 1] vs 0.7 [0.6, 0.8] days (P = 0.02), a difference of no clinical significance.  Conclusions: The incidence of significant coagulopathy after craniosynostosis surgery was low, and not associated with clinically important complications. In otherwise healthy pediatric patients, even significant intra-operative blood loss can be safely managed solely with intravenous fluids and pRBC transfusion. What is Known: • Significant intra-operative blood loss and resultant transfusion may lead to postoperative coagulopathy. • There are potential deleterious effects from both coagulopathy and administration of blood products. What is New: • Open craniosynostosis corrective surgery is a useful model for studying coagulopathy after significant intra-operative blood loss and transfusion in otherwise healthy children. • Under certain conditions, in otherwise healthy pediatric patients, even significant intra-operative blood loss can be safely treated with intravenous fluids and pRBC transfusion alone, with no clinically significant postoperative coagulopathy or its complications.

Circadian-mediated regulation of cardiometabolic disorders and aging with time-restricted feeding.

Circadian rhythms are present throughout biology, from the molecular level to complex behaviors such as eating and sleeping. They are driven by molecular clocks within cells, and different tissues can have unique rhythms. Circadian disruption can trigger obesity and other common metabolic disorders such as aging, diabetes, and cardiovascular disease, and circadian genes control metabolism. At an organismal level, feeding and fasting rhythms are key drivers of circadian rhythms. This underscores the bidirectional relationship between metabolism and circadian rhythms, and many metabolic disorders have circadian disruption or misalignment. Therefore, studying circadian rhythms may offer new avenues for understanding the etiology and management of obesity. This review describes how circadian rhythm dysregulation is linked with cardiometabolic disorders and how the lifestyle intervention of time-restricted feeding (TRF) regulates them. TRF reinforces feeding-fasting rhythms without reducing caloric intake and ameliorates metabolic disorders such as obesity and associated cardiac dysfunction, along with reducing inflammation. TRF optimizes the expression of genes and pathways related to normal metabolic function, linking metabolism with TRF's benefits and demonstrating the molecular link between metabolic disorders and circadian rhythms. Thus, TRF has tremendous therapeutic potential that could be easily adopted to reduce obesity-linked dysfunction and cardiometabolic disorders.