Differential gene expression underlying epileptogenicity in patients with gliomas.

Background: Seizures are a common sequela for patients suffering from gliomas. Molecular properties are known to influence the initiation of seizures that may influence tumor growth. Different levels of gene expression with seizures related to gliomas remain unclear. We analyzed RNA sequencing of gliomas to further probe these differences. Methods: Total RNA sequencing was obtained from The Cancer Genome Atlas-Lower-Grade Glioma project, comprised of 2021 World Health Organization classification low-grade gliomas, including IDH-mutant and IDH-wild type, to distinguish differential expression in patients who did and did not experience seizures. Utilizing QIAGEN Ingenuity Pathways Analysis, we identified canonical and functional pathways to characterize differential expression. Results: Of 289 patients with gliomas, 83 (28.7%) had available information regarding seizure occurrence prior to intervention and other pertinent variables of interest. Of these, 50 (60.2%) were allocated to the seizure group. When comparing the level of RNA expression from these tumors between the seizure and non-seizure groups, 52 genes that were significantly differentially regulated were identified. We found canonical pathways that were altered, most significantly RhoGDI and semaphorin neuronal repulsive signaling. Functional gene analysis revealed tumors that promoted seizures had significantly increased functional gene sets involving neuronal differentiation and synaptogenesis. Conclusions: In the setting of gliomas, differences in tumor gene expression exist between individuals with and without seizures, despite similarities in patient demographics and other tumor characteristics. There are significant differences in gene expression associated with neuron development and synaptogenesis, ultimately suggesting a mechanistic role of a tumor-neuron synapse in seizure initiation.

Characterization of cerebral radiation necrosis following the treatment of sinonasal malignancies.

Objectives: Our study aims to determine the incidence and potential risk factors for cerebral radiation necrosis (CRN) following treatment of sinonasal malignancies. Methods: One hundred thirty-two patients diagnosed with sinonasal malignancies over an 18-year period were identified at two institutions. Forty-six patients meeting inclusion criteria and treated with radiation therapy were included for analysis. Demographic and clinical-pathologic characteristics were collected and reviewed. Post-treatment magnetic resonance imaging (MRI) at least 1 year following treatment was reviewed to determine presence or absence of CRN. Results: CRN was identified on MRI in 8 of 46 patients (17.4%) following radiation treatment. Patients with a history of reirradiation were more likely to develop CRN (50% vs. 10.5%, p < .05). The BEDs of radiation were also higher in CRN patients compared to non-CRN patients, but this difference was not significant (p > .05). CRN patients had a higher proportion of tumors with skull base involvement than non-CRN patients (100% vs. 57.9%, p = .037). Demographics, comorbidities, pathology, primary tumor subsite, chemotherapy use, and stage of disease demonstrated no significant increase in risk of CRN. Conclusions: Reirradiation and tumor skull base involvement were significant risk factors associated with CRN. Higher average total prescribed and BEDs of radiation were seen in the CRN groups, but these differences were not statistically significant. Gender, comorbidities, tumor subsite, tumor location, and treatment type were not significantly different between groups. Level of evidence: Level 3.

Multicenter comparison of Chiari malformation type I presentation in children versus adults.

OBJECTIVE: Treatment for Chiari malformation type I (CM-I) often includes surgical intervention in both pediatric and adult patients. The authors sought to investigate fundamental differences between these populations by analyzing data from pediatric and adult patients who required CM-I decompression. METHODS: To better understand the presentation and surgical outcomes of both groups of patients, retrospective data from 170 adults and 153 pediatric patients (2000-2019) at six institutions were analyzed. RESULTS: The adult CM-I patient population requiring surgical intervention had a greater proportion of female patients than the pediatric population (p < 0.0001). Radiographic findings at initial clinical presentation showed a significantly greater incidence of syringomyelia (p < 0.0001) and scoliosis (p < 0.0001) in pediatric patients compared with adult patients with CM-I. However, presenting signs and symptoms such as headaches (p < 0.0001), ocular findings (p = 0.0147), and bulbar symptoms (p = 0.0057) were more common in the adult group. After suboccipital decompression procedures, 94.4% of pediatric patients reported symptomatic relief compared with 75% of adults with CM-I (p < 0.0001). CONCLUSIONS: Here, the authors present the first retrospective evaluation comparing adult and pediatric patients who underwent CM-I decompression. Their analysis reveals that pediatric and adult patients significantly differ in terms of demographics, radiographic findings, presentation of symptoms, surgical indications, and outcomes. These findings may indicate different clinical conditions or a distinct progression of the natural history of this complex disease process within each population, which will require prospective studies to better elucidate.

Differential metabolic alterations in IDH1 mutant vs. wildtype glioma cells promote epileptogenesis through distinctive mechanisms.

Glioma-related epilepsy (GRE) is a hallmark clinical presentation of gliomas with significant impacts on patient quality of life. The current standard of care for seizure management is comprised of anti-seizure medications (ASMs) and surgical resection. Seizures in glioma patients are often drug-resistant and can often recur after surgery despite total tumor resection. Therefore, current research is focused on the pro-epileptic pathological changes occurring in tumor cells and the peritumoral environment. One important contribution to seizures in GRE patients is metabolic reprogramming in tumor and surrounding cells. This is most evident by the significantly heightened seizure rate in patients with isocitrate dehydrogenase mutated (IDHmut) tumors compared to patients with IDH wildtype (IDHwt) gliomas. To gain further insight into glioma metabolism in epileptogenesis, this review compares the metabolic changes inherent to IDHmut vs. IDHwt tumors and describes the pro-epileptic effects these changes have on both the tumor cells and the peritumoral environment. Understanding alterations in glioma metabolism can help to uncover novel therapeutic interventions for seizure management in GRE patients.

Chronic neuronal activation leads to elevated lactate dehydrogenase A through the AMP-activated protein kinase/hypoxia-inducible factor-1α hypoxia pathway.

Recent studies suggest that changes in neuronal metabolism are associated with epilepsy. High rates of ATP depletion, lactate dehydrogenase A and lactate production have all been found in epilepsy patients, animal and tissue culture models. As such, it can be hypothesized that chronic seizures lead to continuing elevations in neuronal energy demand which may lead to an adapted metabolic response and elevations of lactate dehydrogenase A. In this study, we examine elevations in the lactate dehydrogenase A protein as a long-term cellular adaptation to elevated metabolic demand from chronic neuronal activation. We investigate this cellular adaptation in human tissue samples and explore the mechanisms of lactate dehydrogenase A upregulation using cultured neurones treated with low Mg2+, a manipulation that leads to NMDA-mediated neuronal activation. We demonstrate that human epileptic tissue preferentially upregulates neuronal lactate dehydrogenase A, and that in neuronal cultures chronic and repeated elevations in neural activity lead to upregulation of neuronal lactate dehydrogenase A. Similar to states of hypoxia, this metabolic change occurs through the AMP-activated protein kinase/hypoxia-inducible factor-1α pathway. Our data therefore reveal a novel long-term bioenergetic adaptation that occurs in chronically activated neurones and provide a basis for understanding the interplay between metabolism and neural activity during epilepsy.

Reliability of Home Sleep Apnea Testing for Diagnosing Obstructive Sleep Apnea in Patients With Spontaneous Cerebrospinal Fluid Leaks.

STUDY OBJECTIVES:  To establish the prevalence of obstructive sleep apnea (OSA) in patients with spontaneous cerebrospinal fluid (sCSF) leaks and demonstrate the reliability of home sleep apnea testing (HSAT) to screen for OSA in this population. METHODS: A literature review was performed to assess data on OSA prevalence in sCSF leaks. An institutional retrospective review was performed of 20 patients with sCSF leaks who met inclusion criteria. Patients without prior sleep studies were prospectively administered sleep studies, either HSAT or polysomnogram (PSG). RESULTS: Twenty patients met the inclusion criteria. Two patients had prior sleep studies while 18 patients obtained prospective sleep studies following diagnosis and prior to management of sCSF leaks. Nineteen patients (95%) had evidence of mild or greater OSA. CONCLUSIONS:  This study re-demonstrates the high prevalence of OSA in patients with sCSF leaks, consistent with current literature, and investigates the reliability of HSAT for diagnosis of OSA in this population.

IDH-mutated gliomas promote epileptogenesis through d-2-hydroxyglutarate-dependent mTOR hyperactivation.

BACKGROUND: Uncontrolled seizures in patients with gliomas have a significant impact on quality of life and morbidity, yet the mechanisms through which these tumors cause seizures remain unknown. Here, we hypothesize that the active metabolite d-2-hydroxyglutarate (d-2-HG) produced by the IDH-mutant enzyme leads to metabolic disruptions in surrounding cortical neurons that consequently promote seizures. METHODS: We use a complementary study of in vitro neuron-glial cultures and electrographically sorted human cortical tissue from patients with IDH-mutant gliomas to test this hypothesis. We utilize micro-electrode arrays for in vitro electrophysiological studies in combination with pharmacological manipulations and biochemical studies to better elucidate the impact of d-2-HG on cortical metabolism and neuronal spiking activity. RESULTS: We demonstrate that d-2-HG leads to increased neuronal spiking activity and promotes a distinct metabolic profile in surrounding neurons, evidenced by distinct metabolomic shifts and increased LDHA expression, as well as upregulation of mTOR signaling. The increases in neuronal activity are induced by mTOR activation and reversed with mTOR inhibition. CONCLUSION: Together, our data suggest that metabolic disruptions in the surrounding cortex due to d-2-HG may be a driving event for epileptogenesis in patients with IDH-mutant gliomas.

Anterior lumbar interbody fusion: single institutional review of complications and associated variables.

BACKGROUND CONTEXT: As more patients undergo anterior lumbar interbody fusion (ALIF) procedures and more devices are created for that purpose, it is important to understand the complications that can arise and the variables that mitigate risk for major and minor complications. PURPOSE: To assess complication rates after ALIF with or without posterior instrumentation and variables associated with increased likelihood of postoperative complications. We aim to provide this data as benchmarking to improve patient safety and surgical care. STUDY DESIGN: A single-center retrospective cohort study. PATIENT SAMPLE: All adult patients who underwent ALIF between 2017 and 2019 was performed OUTCOME MEASURES: Post-operative major and minor complications were evaluated. METHODS: Complications were recorded and presented as percentages. Patient demographics, perioperative, and postoperative data were also collected and analyzed between patients who had no complications and those that had any complication. Subgroup analysis of surgical complications were performed by nonparametric Chi-square tests. Continuous variables were compared using Mann-Whitney U tests. RESULTS: Ninty-five of three hundred sixty-two (26.2%) of patients experienced a minor or major complication. Among the most common complications found were surgical site infections (5.8%), neurological complications (4.1%), vascular complications (3.6%), and urinary tract infections (3.3%). Patients undergoing ALIF alone with post-operative complications had higher mean age, higher BMI, higher ASA status, and experienced higher estimated blood loss. Patients undergoing ALIF and posterior instrumentation with post-operative complications were more likely to have diabetes and had a higher ASA status. Patients with any complications from both groups had longer length of stay, discharge to a non-home setting and were more likely to be readmitted or return to the operating room. CONCLUSION: Our study reveals variables associated with complications at our institution, including age of the patient, BMI, and ASA status leading to higher complications and greater LOS, higher readmission rates, and disposition to skilled facilities.

Responsive neurostimulation for the treatment of medically refractory epilepsy in pediatric patients: strategies, outcomes, and technical considerations.

OBJECTIVE: Children with medically refractory partial-onset epilepsy arising from eloquent cortex present a therapeutic challenge, as many are not suitable for resective surgery. For these patients, responsive neurostimulation may prove to be a potential tool. Although responsive neurostimulation has demonstrated utility in adults, little has been discussed regarding its utility in the pediatric population. In this study, the authors present their institution's experience with responsive neurostimulation via the RNS System through a case series of 5 pediatric patients. METHODS: A single-center retrospective study of patients who underwent RNS System implantation at Children's National Hospital was performed. RESULTS: Five patients underwent RNS System implantation. The mean patient age at treatment was 16.8 years, and the average follow-up was 11.2 months. All patients were considered responders, with a seizure frequency reduction of 64.2% without adverse events. CONCLUSIONS: All 5 patients experienced medium-term improvements in seizure control after RNS System implantation with decreases in seizure frequency > 50% from baseline preoperative seizure frequency. The authors demonstrated two primary configurations of electrode placement: hippocampal or amygdala placement via an occipitotemporal trajectory, as well as infratemporal surface electrodes and surface electrodes on the primary motor cortex. No adverse events were experienced in this case series.

The Retroauricular Incision as an Effective and Safe Alternative Incision for Decompressive Hemicraniectomy.

BACKGROUND: The reverse question mark (RQM) incision has been traditionally utilized to perform decompressive hemicraniectomies (DHC) to relieve refractory intracranial hypertension. Alternative incisions have been proposed in the literature but have not been compared directly. OBJECTIVE: To present the retroauricular (RA) incision as an alternative incision that we hypothesize will increase calvarium exposure to maximize the removal of the hemicranium and will decrease wound-related complications compared to the RQM incision. METHODS: This study is a retrospective review of all DHCs performed at our institution over a span of 34 mo, stratified based on the type of scalp incision. The surface areas of the cranial defects were calculated, normalizing to their respective skull diameters. For those patients surviving beyond 1 wk, complications were examined from both cohorts. RESULTS: A total of 63 patients in the RQM group and 43 patients in the RA group were included. The average surface area for the RA and RQM incisions was 117.0 and 107.8 cm2 (P = .0009), respectively. The ratio of average defect size to skull size for RA incision was 0.81 compared to 0.77 for the RQM group (P = .0163). Of those who survived beyond 1 wk, the absolute risk for surgical site complications was 14.0% and 8.3% for RQM and RA group (P = .5201), respectively. CONCLUSION: The RA incision provides a safe and effective alternative incision to the traditional RQM incision used for DHC. This incision affords a potentially larger craniectomy while mitigating postoperative wound complications.

Multiple VHL-related hemangioblastomas and holocord syrinx: identifying the causative lesion. Illustrative case.

BACKGROUND: Brainstem and spinal cord hemangioblastomas are a common manifestation of von Hippel-Lindau (VHL) disease. Cysts and associated syringes are the most common cause of significant morbidity in these patients. Surgical treatment of symptomatic hemangioblastomas are often complicated by the presence of multiple potential lesions, leading to cyst and syrinx formation. OBSERVATIONS: The authors present a case of a patient with multiple VHL-related hemangioblastomas who presented with syringobulbia and holocord syrinx. Resection of two cyst wall hemangioblastomas and one cervical hemangioblastoma only transiently improved syringobulbia. Eventual resolution of syringobulbia and collapse of the holocord syrinx only occurred following removal of a large lower thoracic hemangioblastoma. LESSONS: Surgical management of hemangioblastomas and associated cysts in patients with VHL should only target lesions most likely contributing to neurological deficits as excess surgical intervention risks treatment-related morbidity. The authors illustrate how anatomical and pathophysiological considerations as well as patient symptoms are key to identifying target lesions for resection and developing deliberate treatment plans.

Transmembrane Helix Integrity versus Fraying To Expose Hydrogen Bonds at a Membrane-Water Interface.

Transmembrane helices dominate the landscape for many membrane proteins. Often flanked by interfacial aromatic residues, these transmembrane helices also contain loops and interhelix segments, which could help in stabilizing a transmembrane orientation. Using 2H nuclear magnetic resonance spectroscopy to monitor bilayer-incorporated model GWALP23 family peptides, we address systematically the issue of helix fraying in relation to the dynamics and orientation of highly similar individual transmembrane helices. We inserted aromatic (Phe, Trp, Tyr, and His) or non-aromatic residues (Ala and Gly) into positions 4 and 5 adjacent to a core transmembrane helix to examine the side-chain dependency of the transmembrane orientation, dynamics, and helix integrity (extent and location of unraveling). Incorporation of [2H]alanine labels enables one to assess the helicity of the core sequence and the peptide termini. For most of the helices, we observed substantial unwinding involving at least three residues at both ends. For the unique case of histidine at positions 4 and 5, an extended N-terminal unwinding was observed up to residue 7. For further investigation of the onset of fraying, we employed A4,5GWALP23 with 2H labels at residues 4 and 5 and found that the number of terminal residues involved in the unwinding depends on bilayer thicknesses and helps to govern the helix dynamics. The combined results enable us to compare and contrast the extent of fraying for each related helix, as reflected by the deviation of experimental 2H quadrupolar splitting magnitudes of juxta-terminal alanines A3 and A21 from those represented by an ideal helix geometry.

Juxta-terminal Helix Unwinding as a Stabilizing Factor to Modulate the Dynamics of Transmembrane Helices.

Transmembrane helices of integral membrane proteins often are flanked by interfacial aromatic residues that can serve as anchors to aid the stabilization of a tilted transmembrane orientation. Yet, physical factors that govern the orientation or dynamic averaging of individual transmembrane helices are not well understood and have not been adequately explained. Using solid-state (2) H NMR spectroscopy to examine lipid bilayer-incorporated model peptides of the GWALP23 (acetyl-GGALW(LA)6 LWLAGA-amide) family, we observed substantial unwinding at the terminals of several tilted helices spanning the membranes of DLPC, DMPC, or DOPC lipid bilayers. The fraying of helix ends might be vital for defining the dynamics and orientations of transmembrane helices in lipid bilayer membranes.