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 in order 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.

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.

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.

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 neurons 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 neurons and provide a basis for understanding the interplay between metabolism and neural activity during epilepsy.