Deep Brain Stimulation of Bilateral Centromedian Thalamic Nuclei in Pediatric Patients with Lennox-Gastaut Syndrome: An Institutional Experience.

BACKGROUND: Surgical management of pediatric patients with nonlesional, drug-resistant epilepsy, including patients with Lennox-Gastaut syndrome (LGS), remains a challenge given the lack of resective targets in most patients and shows seizure freedom rates <50% at 5 years. The efficacy of deep brain stimulation (DBS) is less certain in children than in adults. This study examined clinical and seizure outcomes for pediatric patients with LGS undergoing DBS targeting of the centromedian thalamic nuclei (CMTN). METHODS: An institutional review board-approved retrospective analysis was performed of patients aged ≤19 years with clinical diagnosis of LGS undergoing bilateral DBS placement to the CMTN from 2020 to 2021 by a single surgeon. RESULTS: Four females and 2 males aged 6-19 years were identified. Before surgery, each child experienced at least 6 years of refractory seizures; 4 children had experienced seizures since infancy. All took antiseizure medications at the time of surgery. Five children had previous placement of a vagus nerve stimulator and 2 had a previous corpus callosotomy. The mean length of stay after DBS was 2 days. No children experienced adverse neurologic effects from implantation; the mean follow-up time was 16.3 months. Four patients had >60% reduction in seizure frequency after surgery, 1 patient experienced 10% reduction, and 1 patient showed no change. No children reported worsening seizure symptoms after surgery. CONCLUSIONS: Our study contributes to the sparse literature describing CMTN DBS for children with drug-resistant epilepsy from LGS. Our results suggest that CMTN DBS is a safe and effective therapeutic modality that should be considered as an alternative or adjuvant therapy for this challenging patient population. Further studies with larger patient populations are warranted.

A Comparison of Clinical Outcomes for Subependymal Giant Cell Astrocytomas Treated with Laser Interstitial Thermal Therapy, Open Surgical Resection, and mTOR Inhibitors.

INTRODUCTION: Subependymal giant cell astrocytoma (SEGA) is the most common CNS tumor in patients with tuberous sclerosis complex (TSC). Although these are benign, their proximity to the foramen of Monroe frequently causes obstructive hydrocephalus, a potentially fatal complication. Open surgical resection has been the mainstay of treatment; however, this can cause significant morbidity. The development of mTOR inhibitors has changed the treatment landscape, but there are limitations to their use. Laser interstitial thermal therapy (LITT) is an emerging treatment modality that has shown promise in treatment of a variety of intracranial lesions, including SEGAs. We present a single institution, retrospective study of patients treated for SEGAs with LITT, open resection, mTOR inhibitors, or a combination of these modalities. The primary study outcome was tumor volume at most recent follow-up compared with volume at treatment initiation. The secondary outcome was clinical complications associated with treatment modality. METHODS: Retrospective chart review was performed to identify patients with SEGAs treated at our institution from 2010 to 2021. Demographics, treatment information, and complications were collected from the medical record. Tumor volumes were calculated from imaging obtained at initiation of treatment and at most recent follow-up. Kruskal-Wallis nonparametric testing was used to assess differences in tumor volume and follow-up duration between groups. RESULTS: Four patients underwent LITT (3 with LITT only), three underwent open surgical resection, and four were treated with mTOR inhibitors only. Mean percent tumor volume reduction for each group was 48.6 ± 13.8, 90.7 ± 39.8, and 67.1 ± 17.2%, respectively. No statistically significant difference was identified comparing percent tumor volume reduction between the three groups (p = 0.0513). Additionally, there was no statistically significant difference in follow-up duration between groups (p = 0.223). Only 1 patient in our series required permanent CSF diversion and 4 discontinued or decreased the dose of mTOR inhibitor due to either cost or side effects. CONCLUSIONS: Our study suggests that LITT could be considered as a treatment option for SEGAs as it was effective in reducing tumor volume with very few complications. This modality is less invasive than open resection and may be an alternative for patients who are not candidates for mTOR inhibitors. We recommend an updated paradigm for SEGA treatment which includes LITT in select cases after consideration of patient-specific factors.

Large Adult Spinal Diffuse Midline Histone H3 Lysine27-to-Methionine-Mutant Glioma With Intramedullary and Extramedullary Components Presenting With Progressive Hydrocephalus: A Case Report Highlighting Unique Imaging Findings and Treatment.

Diffuse midline glioma with histone H3 lysine27-to-methionine mutation (H3 K27M mutation) is a rare, aggressive tumor that is designated as World Health Organization (WHO) grade IV regardless of histologic features. Preoperative diagnosis remains challenging due to limited evidence regarding distinctive clinical and imaging characteristics. We describe the case of a young woman who presented with progressively worsening headaches due to communicating hydrocephalus. MR imaging with contrast of the cervical and thoracic spine revealed diffuse leptomeningeal enhancement with focal areas of intramedullary and subarachnoid T2 hyperintensity and enhancement, suggestive of a potential infectious process. Intraoperatively, no epidural pathology was identified, and with the differential diagnosis remaining broad, a second procedure was conducted involving intradural exploration and biopsy of a lesion. This was then identified as a diffuse midline glioma with H3 K27M mutation. The nonfocal clinical presentation in the setting of communicating hydrocephalus as well as the significant exophytic tumor growth and imaging findings made the initial diagnosis unique and challenging. This case, therefore, emphasizes the rare presentation of this tumor, and the need for further understanding of the clinical and imaging characteristics of this disease as well as the need for effective therapeutics.

Asleep Speech Mapping Using Orofacial Muscles as Surrogates for Motor Speech in Patients Who Cannot Tolerate Awake Surgery: A Case Series.

Background Bi-polar electrical cortical stimulation during awake craniotomy has been the gold standard for mapping eloquent cortex to preserve speech. Unfortunately, not all patients can tolerate awake surgery. Monopolar hi-frequency electrical stimulation can be conducted while a patient is under general anesthesia. Utilizing this technique and targeting the orofacial muscles as surrogates for motor speech may provide a limited alternative to awake cortical mapping in patients unable to undergo surgery awake. Objective To evaluate the utility of asleep motor speech mapping during dominant hemisphere craniotomy for lesion resection in patients who cannot tolerate awake surgery. Methods We describe a series of seven patients who underwent craniotomy for resection of intra-axial lesion in eloquent cortex for whom a novel "asleep speech" cortical stimulation paradigm was used for motor speech preservation. Results Compound muscle action potentials (CMAPs) from orofacial muscles involved in motor speech were recorded during direct cortical stimulation of eloquent cortex prior to and during lesion resection. Planned resections proceeded in all cases with no adverse neuromonitoring events. Speech was preserved in all patients. Conclusions To preserve motor speech functionality in patients unable to tolerate awake speech mapping, we employed a technique in which asleep neurophysiological mapping is specifically applied to motor cortex controlling the orofacial muscles of phonation and articulation. Further study is necessary regarding the safety and efficacy of this technique for motor speech preservation when awake surgery cannot be performed.

Laser interstitial thermal therapy for gyrus rectus cortical dysplasia in a child: a technical note.

Laser interstitial thermal therapy (LITT) has become a popular tool in the treatment of tumors and epilepsy. While most commonly used for the treatment of mesial temporal lobe epilepsy, it can be used as a minimally invasive option for the treatment of any seizure focus but has very rarely been discussed in the setting of cortical dysplasia. Here, we discuss the case of a 5-year-old girl with medically refractory epilepsy secondary to a right medial orbital gyrus and gyrus rectus cortical dysplasia successfully treated with LITT. After confirmation of seizure focus using stereo electroencephalography (SEEG), the patient underwent thermal ablation of the focus through an eyebrow incision with use of a single laser fiber. She has been seizure-free 6 months postoperatively, only on one anti-seizure medication, with normal EEG. The use of LITT in this case was successful because of the cylindrical shape of the cortical dysplasia, making it easily accessible via a single laser fiber in the absence of a yet to develop fontal sinus. While open resection would have also been appropriate, the use of LITT provided a minimally invasive alternative approach that allowed for an excellent outcome with limited risks.

Neuropsychological outcomes following supratotal resection for high-grade glioma: a review.

PURPOSE: Supratotal resection (SpTR) of high-grade glioma (HGG), in which surgical removal of the tumor is extended outside the margins of the preoperative radiographic abnormality, has been suggested to improve overall survival (OS) and progression free survival (PFS) in patients harboring tumors of non-eloquent cortex when compared to gross total resection (GTR). While current literature demonstrates these findings without an increase in post-operative complications or neurological deficits, there remains a paucity of data examining the neuropsychological outcomes of SpTR for HGG. As quality of life dramatically influences survival rates in these patients, it is crucial for neurosurgeons, neuro-oncologists, and neuropsychiatrists to understand the behavioral and cognitive outcomes following SpTR, such that optimal treatment strategies can be tailored for each patient. METHODS: We performed a comprehensive review of the available literature regarding survival, neuropsychological, and quality of life (QOL) outcomes following SpTR for HGG. We also review neuropsychological and QOL outcomes following GTR for HGG to serve as a framework for better understanding potential implications of SpTR. RESULTS: While results are limited following SpTR for HGG, available data suggests similar outcomes to those seen in patients undergoing GTR of HGG, as well as low-grade glioma. These include a short-term decline in neuropsychological functioning post-surgically with a return to baseline across most neurocognitive domains occurring within several months. Memory and attention remain relatively diminished at long term follow-up. CONCLUSIONS: Limited data exist examining postoperative cognitive and behavioral outcomes following SpTR for HGG. While the available data suggests a return to baseline for many neurocognitive domains, attention and memory deficits may persist. However, sample sizes are relatively small and have not been examined in the context of QOL and OS/PFS. More rigorous pre- and post-surgical neuropsychological assessment will help shed light on the long-term cognitive and behavioral effects of SpTR in the setting of HGG and inform clinical care and counseling when SpTR is considered.

Robotic Surgical Assistant Rehearsal: Combining 3-Dimensional-Printing Technology With Preoperative Stereotactic Planning for Placement of Stereoencephalography Electrodes.

BACKGROUND: The use of frameless stereotactic robotic technology has rapidly expanded since the Food and Drug Administration's approval of the Robotic Surgical Assistant (ROSA) in 2012. Although the use of the ROSA robot has greatly augmented stereotactic placement of intracerebral stereoelectroencephalography (sEEG) for the purposes of epileptogenic focus identification, the preoperative planning stages remain limited to computer software. OBJECTIVE: To describe the use of a 3-dimensionally (3D)-printed patient model in the preoperative planning of ROSA-assisted depth electrode placement for epilepsy monitoring in a pediatric patient. METHODS: An anatomically accurate 3D model was created and registered in a preoperative rehearsal session using the ROSA platform. After standard software-based electrode trajectory planning, sEEG electrodes were sequentially placed in the 3D model. RESULTS: Utilization of the 3D-printed model enabled workflow optimization and increased staff familiarity with the logistics of the robotic technology as it relates to depth electrode placement. The rehearsal maneuvers enabled optimization of patient head positioning as well as identification of physical conflicts between 2 electrodes. This permitted revision of trajectory planning in anticipation of the actual case, thereby improving patient safety and decreasing operative time. CONCLUSION: Use of a 3D-printed patient model enhanced presurgical positioning and trajectory planning in the placement of stereotactic sEEG electrodes for epilepsy monitoring in a pediatric patient. The ROSA rehearsal decreased operative time and increased efficiency of electrode placement.

Robotic Surgical Assistant (ROSA™) Rehearsal: Using 3-Dimensional Printing Technology to Facilitate the Introduction of Stereotactic Robotic Neurosurgical Equipment.

BACKGROUND: The use of frameless stereotactic robotic technology has rapidly expanded since the Food and Drug Administration's approval of the Robotic Surgical Assistant (ROSA™) in 2012. Although the safety and accuracy of the ROSA platform has been well-established, the introduction of complex robotic technology into an existing surgical practice poses technical and logistical challenges particular to a given institution. OBJECTIVES: To better facilitate the integration of new surgical equipment into the armamentarium of a thriving pediatric neurosurgery practice by describing the use of a three-dimensional (3D)-printed patient model with in situ 3D-printed tumor for presurgical positioning and trajectory optimization in the stereotactic biopsy of a pontine lesion in a pediatric patient. METHODS: A 3D model was created with an added silicone mock tumor at the anatomical position of the lesion. In a preoperative rehearsal session, the patient model was pinned and registered using the ROSA platform, and a mock biopsy was performed targeting the in Situ silicone tumor. RESULTS: Utilization of the 3D-printed model enabled workflow optimization and increased staff familiarity with the logistics of the robotic technology. Biopsy trajectory successfully reached intralesional tissue on the 3D-printed model. The rehearsal maneuvers decreased operative and intubation time for the patient and improved operative staff familiarity with the robotic setup. CONCLUSION: Use of a 3D-printed patient model enhanced presurgical positioning and trajectory planning in the biopsy of a difficult to reach pontine lesion in a pediatric patient. The ROSA rehearsal decreased operative time and increased staff familiarity with a new complex surgical equipment.

The X-chromosome instability phenotype in Alzheimer's disease: a clinical sign of accelerating aging?

Premature centromere division, or premature centromere separation (PCS), occurs when chromatid separation is dysfunctional, occurring earlier than usual during the interphase stage of mitosis. This phenomenon, seen in Robert's syndrome and various cancers, has also been documented in peripheral as well as neuronal cells of Alzheimer's disease (AD). In the latter instances, fluorescent in situ hybridization (FISH), applied to the centromere region of the X-chromosome in interphase nuclei of lymphocytes from peripheral blood in AD patients, demonstrated premature chromosomal separation before mitotic metaphase directly after completion of DNA replication in G(2) phase of the cell cycle. Furthermore, and perhaps unexpectedly given the presumptive post-mitotic status of terminally differentiated neurons, neurons in AD patients also showed significantly increased levels of PCS of the X-chromosome. Taken together with other phenomena such as cell cycle re-activation and ectopic re-expression of cyclins and cyclin dependent proteins, we propose that AD is an oncogenic phenotype leading to accelerated aging of the affected brain.

Retinoblastoma protein phosphorylation at multiple sites is associated with neurofibrillary pathology in Alzheimer disease.

The re-expression of multiple cell cycle markers representing various cell cycle phases in postmitotic pyramidal neurons suggests that neurons in Alzheimer disease (AD) attempt to re-enter the cell cycle. Entry into the cell cycle requires activation of G1 to S phase cell cycle proteins, among which retinoblastoma protein (pRb) is a key regulator. pRb inhibits the transcription of cell cycle proteins in the nucleus of healthy cells by interaction and consequent blocking of the active site of E2F, dependent upon the phosphate stoichiometry and combination of the locations of their 16 potential phosphorylation sites on pRb. Therefore, to determine whether pRb is involved in the aberrant cell cycle phenotype in AD neurons, a systematic immunocytochemical evaluation of the phosphorylation status of pRb protein using antibodies specific for multiple phosphorylation sites (i.e., pSpT249/252, pS612, pS795, pS807, pS811 and pT821) was carried out in the hippocampal regions of brains from AD patients. Increased levels of phospho-pRb (ppRb) for all these phosphorylation sites were noted in the brains of AD patients as compared to control cases. More importantly, redistribution of ppRb from the nucleus to the cytoplasm of susceptible neurons, with significant localization in neurofibrillary tangles and neuritic plaques, was observed. Additional studies revealed extensive co-localization between phospho-p38 and ppRb, implicating that p38 activation may contribute to cell cycle abnormalities through pRb phosphorylation. Taken together, these data supports the concept of neuronal cell cycle re-entry in AD and indicates a crucial role for pRb in this process.