Responsive Neurostimulation Targeting the Anterior, Centromedian and Pulvinar Thalamic Nuclei and the Detection of Electrographic Seizures in Pediatric and Young Adult Patients.

Background: Responsive neurostimulation (RNS System) has been utilized as a treatment for intractable epilepsy. The RNS System delivers stimulation in response to detected abnormal activity, via leads covering the seizure foci, in response to detections of predefined epileptiform activity with the goal of decreasing seizure frequency and severity. While thalamic leads are often implanted in combination with cortical strip leads, implantation and stimulation with bilateral thalamic leads alone is less common, and the ability to detect electrographic seizures using RNS System thalamic leads is uncertain. Objective: The present study retrospectively evaluated fourteen patients with RNS System depth leads implanted in the thalamus, with or without concomitant implantation of cortical strip leads, to determine the ability to detect electrographic seizures in the thalamus. Detailed patient presentations and lead trajectories were reviewed alongside electroencephalographic (ECoG) analyses. Results: Anterior nucleus thalamic (ANT) leads, whether bilateral or unilateral and combined with a cortical strip lead, successfully detected and terminated epileptiform activity, as demonstrated by Cases 2 and 3. Similarly, bilateral centromedian thalamic (CMT) leads or a combination of one centromedian thalamic alongside a cortical strip lead also demonstrated the ability to detect electrographic seizures as seen in Cases 6 and 9. Bilateral pulvinar leads likewise produced reliable seizure detection in Patient 14. Detections of electrographic seizures in thalamic nuclei did not appear to be affected by whether the patient was pediatric or adult at the time of RNS System implantation. Sole thalamic leads paralleled the combination of thalamic and cortical strip leads in terms of preventing the propagation of electrographic seizures. Conclusion: Thalamic nuclei present a promising target for detection and stimulation via the RNS System for seizures with multifocal or generalized onsets. These areas provide a modifiable, reversible therapeutic option for patients who are not candidates for surgical resection or ablation.

Molecular Stratification of Medulloblastoma: Clinical Outcomes and Therapeutic Interventions.

Medulloblastoma (MB) is the most common malignant pediatric posterior fossa tumor. Recent genetic, epigenetic, and transcriptomic analyses have classified MB into three subgroups, Wingless Type (WNT), Sonic Hedgehog (SHH), and non-WNT/non-SHH (originally termed Group 3 and Group 4), with discrete patient profiles and prognoses. WNT is the least common subgroup with the best prognosis, characterized by nuclear ß-catenin expression, mutations in Catenin beta-1 (CTNNB1), and chromosome 6 monosomy. SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway. Originally, the presence of TP53 gene alterations and/or MYC amplifications was considered the most reliable prognostic factor. However, recent molecular analyses have subdivided SHH MB into several subtypes with distinct characteristics such as age, TP53 mutation, MYC amplification, presence of metastases, TERT promoter alterations, PTEN loss, and other chromosomal alterations as well as SHH pathway-related gene mutations. The third non-WNT/non-SHH MB (Group3/4) subgroup is genetically highly heterogeneous and displays several molecular patterns, including MYC and OTX2 amplification, GFI1B activation, KBTBD4 mutation, GFI1 rearrangement, PRDM6 enhancer hijacking, KDM6A mutation, LCA histology, chromosome 10 loss, isochromosome 17q, SNCAIP duplication, and CDK6 amplification. However, based on molecular profiling and methylation patterns, additional non-WNT/non-SHH MB subtypes have been described. Recent WHO (2021) guidelines stratified MB into four molecular subgroups with four and eight further subgroups for SHH and non-WNT/non-SHH MB, respectively. In this review, we discuss advancements in genetics, epigenetics, and transcriptomics for better characterization, prognostication, and treatment of MB using precision medicine.

Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma.

Aberrant signaling of mechanistic target of rapamycin (mTOR aka mammalian target of rapamycin) is shown to be linked to tumorigenesis of numerous malignancies including glioblastoma (GB). mTOR is a serine threonine kinase that functions by forming two multiprotein complexes. These complexes are named mTORC1 and mTORC2 and activate downstream substrates that execute cellular and metabolic functions. This signaling cascade of PI3K/AKT/mTOR is often upregulated due to frequent loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. Since rapamycin and its analogue are less effective in treatment of GB, we used novel ATP-competitive dual inhibitors of mTORC1 and mTORC2, namely, Torin1, Torin2, and XL388. Torin2 caused a concentration dependent pharmacodynamic effects on inhibition of phosphorylation of the mTORC1 substrates S6KSer235/236 and 4E-BP1Thr37/46 as well as the mTORC2 substrate AKTSer473 resulting in suppression of tumor cell proliferation and migration. Torin1 showed similar effects only at higher doses. Another small molecule compound, XL388 suppressed cell proliferation at a higher dose but failed to inhibit cell migration. Torin1 suppressed phosphorylation of PRAS40Thr246, however, Torin2 completely abolished it. XL388 treatment inhibited the phosphorylation of PRAS40Thr246 at higher doses only. These findings underscore the use of novel compounds in treatment of cancer. In addition, formulation of third generation mTOR inhibitor "Rapalink-1" may provide new aspects to target mTOR pathways. Numerous inhibitors are currently being used in clinical trials that are aimed to target activated mTOR pathways.

Porencephalic cyst after endoscopic third ventriculostomy and Ommaya reservoir placement: case report and review of the literature.

BACKGROUND: A 13-year-old female patient was diagnosed with a tectal glioma (TG), a subgroup of astrocytoma that can result in obstructive hydrocephalus secondary to aqueductal stenosis. Endoscopic third ventriculostomy (ETV) is used to treat this type of hydrocephalus with a good success rate. Our institution performs ETV and Ommaya reservoir (OR) placement in these cases. The OR allows measurement of intracranial pressure (ICP) and cerebrospinal fluid (CSF) access and a method for performing ventricular dye studies to evaluate third ventricular stoma (TVS) patency. In this case, a porencephalic cyst (PC) developed around the OR's ventricular catheter (OVC) two and a half months after surgery. CONCLUSION: The PC is thought to have developed in association with TVS stoma closure and resolved after ETV revision.

Decompressive craniectomy with scalp expansion graft using a temporary synthetic skin substitute in the pediatric population: case series and review of the literature.

INTRODUCTION: The use of decompressive craniectomy in children is controversial and often reserved for patients with refractory intracranial hypertension. Following decompression, skin closure in select cases can be challenging due to brain herniation and swelling through the craniectomy defect. In these cases, partial cortical debridement is sometimes performed. METHODS: We describe two cases in which a synthetic skin substitute was used to facilitate a tension-free closure, rather than performing a partial lobectomy. RESULTS: At 6-month follow-up, both patients are at preoperative cognitive baseline, with some residual hemiparesis. DISCUSSION: We believe that use of a synthetic skin substitute for skin closure after decompression is a suitable option for closure of traumatic scalp wounds and may contribute to improved functional outcome in patients with severe intraoperative brain swelling.

Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship.

Activation of Mechanistic target of rapamycin (mTOR) signaling plays a crucial role in tumorigenesis of numerous malignancies including glioblastoma (GB). The Canonical PI3K/Akt/mTOR signaling cascade is commonly upregulated due to loss of the tumor suppressorm PTEN, a phosphatase that acts antagonistically to the kinase (PI3K) in conversion of PIP2 to PIP3. mTOR forms two multiprotein complexes, mTORC1 and mTORC2 which are composed of discrete protein binding partners to regulate cell growth, motility, and metabolism. These complexes are sensitive to distinct stimuli, as mTORC1 is sensitive to nutrients while mTORC2 is regulated via PI3K and growth factor signaling. The main function of mTORC1 is to regulate protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. On the other hand, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK and it also plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. mTORC1 and mTORC2 regulate each other, as shown by the fact that Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin1 to modulate mTORC2 activity. Allosteric inhibitors of mTOR, rapamycin and rapalogs, remained ineffective in clinical trials of Glioblastoma (GB) patients, in part due to their incomplete inhibition of mTORC1 as well as unexpected activation of mTOR via the loss of negative feedback loops. In recent years, novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6KSer235/236, while effectively suppressing mTORC2 activity, as demonstrated by complete dephosphorylation of pAKTSer473. Furthermore by these novel combined mTORC1/mTORC2 inhibitors reduced the proliferation and self-renewal of GB cancer stem cells. However, a search of more effective way to target mTOR has generated a third generation inhibitor of mTOR, "Rapalink", that bivalently combines rapamycin with an ATP-binding inhibitor, which effectively abolishes the mTORC1 activity. All in all, the effectiveness of inhibitors of mTOR complexes can be judged by their ability to suppress both mTORC1/mTORC2 and their ability to impede both cell proliferation and migration along with aberrant metabolic pathways.

An unusual case of hemophagocytic lymphohistiocytosis diagnosed by spinal nerve root biopsy.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease process characterized by aberrant immune system activation and an exaggerated inflammatory response. Establishing the diagnosis may be challenging and is achieved by satisfying a number of clinical criteria, in addition to demonstrating tissue hemophagocytosis. This syndrome is rapidly fatal if prompt diagnosis and treatment are not achieved. The authors present the case of a 17-year-old male patient with CNS HLH involving both the brain and spinal cord, highlighting the variable CNS manifestations in pediatric patients with HLH and the challenges that accompany establishing diagnosis.

Molecular Sequence of Events and Signaling Pathways in Cerebral Metastases.

Brain metastases are the leading cause of morbidity and mortality among cancer patients, and are reported to occur in about 40% of cancer patients with metastatic disease in the United States of America. Primary tumor cells appear to detach from the parent tumor site, migrate, survive and pass through the blood brain barrier in order to establish cerebral metastases. This complex process involves distinct molecular and genetic mechanisms that mediate metastasis from these primary organs to the brain. Furthermore, an interaction between the invading cells and cerebral milieu is shown to promote this process as well. Here, we review the mechanisms by which primary cancer cells metastasize to the brain via a mechanism called epithelial-to-mesenchymal transition, as well as the involvement of certain microRNA and genetic aberrations implicated in cerebral metastases from the lung, breast, skin, kidney and colon. While the mechanisms governing the development of brain metastases remain a major hindrance in treatment, understanding and identification of the aforementioned molecular pathways may allow for improved management and discovery of novel therapeutic targets.

International teleconsultation on conjoined twins leading to a successful separation: a case report.

Conjoined twins are identical twins that have incompletely separated in utero. The prognosis for conjoined twins is poor and management in a skilled tertiary care centre is paramount for definitive care. We describe our experience with a telemedical consultation on conjoined twins in The Dominican Republic from our eHealth centre in Valhalla, NY. The patients were two month old, female, pygopagus conjoined twins. A multidisciplinary teleconference was initiated with the patients, their family, the referring paediatrician and our team. Based on this teleconsultation, the team felt as though the twins may be amenable to a surgical separation. They presented to our centre in Valhalla, NY, for a detailed physical examination and series of imaging studies. Soon after, the patients underwent a successful 21 h separation procedure and were discharged 12 weeks later. To our knowledge, this is one of the first reports of an international teleconsultation leading to a successful conjoined twin separation procedure.

A Novel Approach Using Electromagnetic Neuronavigation and a Flexible Neuroendoscope for Placement of Ommaya Reservoirs.

OBJECTIVE: Placement of intraventricular catheters in oncology patients can be associated with morbidity given their small to slit-like ventricles and underlying hematologic disorders. We studied the accuracy of placing Ommaya reservoirs using neuronavigation and a flexible neuroendoscope to verify catheter positioning. METHODS: Ommaya reservoirs placed in 25 oncology patients between 2013 and 2015 were retrospectively reviewed. Twenty-five ventricular catheters were placed using the AxiEM stealth frameless neuronavigation system and a flexible neuroendoscope. Postoperative catheter accuracy, operative complications, and postoperative complications were assessed. We discuss surgical protocol and technical nuances. RESULTS: All ventricular catheters were successfully placed into the ipsilateral (84%) or contralateral (16%) foramen of Monro. A single ventricular catheter pass was needed to cannulate the ventricle in 96% of patients. The mean accuracy was 4.09 ± 3.47 mm from the target, the ipsilateral foramen of Monro. One patient had a catheter tract hemorrhage seen on postoperative imaging related to thrombocytopenia. No postoperative neurologic deficits were seen. CONCLUSIONS: A combined neuronavigation and neuroendoscopic approach improved catheter tip accuracy compared with accuracy rates described in the literature using other techniques. This approach can be adapted toward routine clinical practice of placing ventricular shunt catheters and Ommaya reservoirs.

All-trans retinoic acid modulates cancer stem cells of glioblastoma multiforme in an MAPK-dependent manner.

Glioblastoma multiforme (GBM), a grade IV glioma, appears to harbor therapy-resistant cancer stem cells (CSCs) that are the major cause of recurrence. All-trans retinoic acid (ATRA), a derivative of retinoid, is capable of differentiating a variety of stem cells, as well as normal neural progenitor cells, and down-regulates expression of the stem cell marker nestin. This study investigated the effects of ATRA on differentiation, proliferation, self-renewal, and signaling pathways of CSCs in GBM. CSCs differentiated into glial and neuronal lineages at low concentrations of ATRA (10 µM). Proliferation and self renewal of neurospheres were reduced following ATRA, although ATRA induced apopotsis at higher (40 µM) concentrations. Analysis of mitogen-activated protein kinase signaling pathways, specifically extracellular signal-regulated kinases (ERK1/2), showed that ATRA-induced alterations in ERK1/2 were associated with regulation of differentiation, proliferation and apoptosis. These results emphasize that low doses of ATRA may have therapeutic potential by differentiating GBM CSCs and rendering them sensitive to targeted therapy.

Passive range of motion functional magnetic resonance imaging localizing sensorimotor cortex in sedated children.

OBJECT: In this study, the authors examined whether passive range of motion (ROM) under conscious sedation could be used to localize sensorimotor cortex using functional MR (fMR) imaging in children as part of their presurgical evaluation. METHODS: After obtaining institutional review board approval (for retrospective analysis of imaging data acquired for clinical purposes) and informed consent, 16 children underwent fMR imaging. All 16 had lesions; masses were found in 9 patients and cortical dysplasia was found in 4; the lesions in 3 patients were not diagnosed. Passive ROM was performed during blood oxygen level-dependent MR imaging sequences. Three of the patients also performed active motor tasks during the fMR imaging study. All patients were evaluated using passive ROM of the hand and/or foot; 3 patients were evaluated for passive touch of the face. In 9 cases, intraoperative electrocorticography (ECoG) was used. Five of the patients underwent intraoperative ECoG to evaluate for seizure activity. Four patients had intraoperative ECoG for motor mapping. Five of the patients had subdural grids placed for extraoperative monitoring. RESULTS: In 3 cases, the active and passive ROMs colocalized. In 4 patients ECoG was used to identify motor cortex, and in all 4 motor ECoG yielded results consistent with the passive ROM localization. Thirteen of 16 children have undergone resection based on passive ROM fMR imaging findings with no unanticipated deficits. CONCLUSIONS: These preliminary data suggest that passive ROM fMR imaging can accurately detect functional hand, leg, and face regions of the sensorimotor cortex in the sedated child. This extends current extraoperative mapping capabilities to patients unable or unwilling to cooperate for active motor tasks.

Temporal variation of induction neurogenesis in a rat model of transient middle cerebral artery occlusion.

OBJECTIVE: The adult brain is capable of neurogenesis after cerebral ischemia. We investigated the presence of new neural precursors after transient middle cerebral artery ischemia adult rats. METHODS: Transient middle cerebral artery ischemia was induced in adult Wistar rats (n=13) using the monofilament method. In the experimental group (n=8), animals were harvested at days 3, 7, 10, 17 and 21 after ischemia. Five animals served as controls. Sagittal sections through the ischemic cortex were double-stained for neural (nestin and beta-tubulin, nestin and PCNA), glial (nestin and GFAP) and oligodendroglial (nestin and O4, CNP and PCNA) precursors. Double-stained cells were also counted under high-power view and tabulated over time. RESULTS: In the subventricular zone (SVZ), there was positive double-staining starting at day 3 showing proliferating astrocytic precursors (nestin + GFAP, 5-20% of cells), neuronal stem cells (nestin + PCNA, 95% of cells) and neuronal precursors (nestin + beta-tubulin, 50% of cells). Within the penumbra, a more robust response showed more astrocytic precursors (50-80% of cells), premature and differentiated oligodendrocytes, neuronal stem cells (85% of cells) and neuronal precursors (15% of cells). In the area of the stroke, there was an intermediate response consisting of more astrocytic precursors (10-20% of cells), premature oligodendrocytes (45-100% of cells), neuronal stem cells (95% of cells) and neuronal precursors (25% of cells). Results were confirmed with cell counting analysis. DISCUSSION: Our results show that not only do neural precursors proliferate in the SVZ, there is definite and real response in the penumbra and ischemic cortex, suggesting the ability of repair in the central nervous system.

Extent of surgical resection of malignant astrocytomas of the spinal cord: outcome analysis of 35 patients.

OBJECTIVE: The optimal management of malignant intramedullary spinal cord astrocytomas remains controversial. Although radiotherapy has become the standard of care, the relationship between extent of resection and survival remains unclear. We report the outcomes of the surgical management of 35 malignant spinal cord astrocytomas and assess the association of extent of resection with survival after aggressive resection of these tumors. METHODS: An institutional intramedullary spinal cord tumor database (1990-2002) was reviewed to identify all patients treated for malignant astrocytomas of the spinal cord (anaplastic astrocytoma [AA] or glioblastoma multiforme [GBM]). Length of survival from surgery was charted by Kaplan-Meier plots, and association of extent of resection with survival was assessed via log rank analysis for stratified covariates and Cox proportional-hazards model for continuous covariates. RESULTS: Twenty-seven (77%) and eight (23%) patients underwent resection of AA and GBM, respectively. Mean age was 29 +/-16 years (range, 2-61 yr). Tumor involved six +/- four vertebral levels. For AA cases, radical resection (no residual postoperative magnetic resonance enhancement) was achieved in 12 (44%) patients and subtotal resection (residual postoperative magnetic resonance enhancement) was achieved in 15 (56%). No GBM patients underwent radical resection (mean estimated resection, 70%). After surgery, two (6%) patients improved neurologically by modified McCormick score, 19 (54%) remained stable, and 14 (40%) declined. Median overall survival for AA patients was 72 months (85% at 1 yr; 59% at 5 yr). Median overall survival for GBM patients was 9 months (31% at 1 yr; 0% at 5 yr). Subtotal versus radical resection of AA was associated with decreased overall survival (38 versus 78% at 4 yr, P = 0.028). Postoperative tumor dissemination was associated with decreased survival (P = 0.004). When adjusting for multiple comparisons (P < 0.006 needed for significance), a trend of increased survival was observed with radical resection (P = 0.023). CONCLUSION: Neurological function can be preserved with aggressive resection of malignant intramedullary spinal astrocytomas; however, motor decline may be observed in many cases. Radical resection of AA was associated with a trend of increased overall survival in nondisseminated AA cases. Radical surgery and radiotherapy of GBM was associated with poor survival, similar to historical controls of diagnostic biopsy and radiotherapy. A markedly shorter survival may be expected in cases in which AA disseminates along the neuraxis. Biopsy alone may not provide the best outcomes for patients with malignant spinal cord tumors.

Surgical management of long intramedullary spinal cord tumors.

OBJECT: Spinal cord tumors represent approximately 10-20% of primary central nervous system tumors. Only 20-30% of primary intradural tumors are intramedullary. The incidence of longitudinally extensive tumors involving the cervical, thoracic, and lumbar spine is very low (<1% of intramedullary lesions); hence, little literature exists on the management of this entity. MATERIALS AND METHODS: We retrospectively reviewed all patients undergoing surgical resection of longitudinally extensive intramedullary spinal cord tumors involving the majority of the spinal cord between 1990 and 2002. Clinical, radiographic, operative, and outcome variables were retrospectively recorded and reported. RESULTS: Thirteen patients (eight male, five female) were included in the study. Mean age was 15 years (range, 3-45) at the time of the initial resection. Gross total resection was achieved in eight cases and subtotal resection in five cases. Pathology revealed astrocytoma in six cases (two pilocytic, four grade II), gangliogliomas in four cases, oligodendroglioma in two cases (one anaplastic), and lipoma in one case. One (8%) patient died from progression of anaplastic oligodendroglioma, and two (15%) underwent reoperation for recurrent tumor (ganglioglioma, grade II astrocytoma). With a mean of 3.4 years (range, 1-12) after surgery, the modified McCormick score (MMS) had worsened in only two (15%) patients, improved in three (23%) patients, and remained stable in seven (54%) patients compared to preoperative MMS. Five (38%) patients required fusion for progressive spinal deformity. CONCLUSION: Gross total resection of holocord and longitudinally extensive intramedullary spinal cord tumors can be achieved with preservation of long-term neurological function in many cases. Serial imaging is recommended to guide subsequent resection for tumor recurrence and stabilization of progressive spinal deformity.