Accuracy and Utility of Frameless Stereotactic Placement of Stereoelectroencephalography Electrodes.

BACKGROUND: Successful surgery for epilepsy hinges on identification of the epileptogenic focus. Stereoelectroencephalography (sEEG) is the most effective way to identify most seizure foci. There are multiple methods of inserting depth electrodes, including frame-based, frameless, and robot-assisted techniques. Studies have shown the accuracy of frame-based and robotic-assisted techniques to be statistically similar, while only one study has detailed the frameless sEEG insertion technique. METHODS: Patients underwent placement of sEEG depth electrodes using frameless stereotaxy from September 2019 to September 2021 at Geisinger Medical Center by a single surgeon. Seizure history, electrode placement accuracy relative to the planned trajectories, surgical times, success rate of identifying the epileptogenic focus, and subsequent seizure control rates after surgical treatment were documented. RESULTS: Data were available for 21 patients and 181 electrodes inserted using the VarioGuide frameless stereotactic system. Each insertion took an average of 14.5 minutes per lead. Average entry variance was 2.7 mm with an average target variance of 4.6 mm. The epileptogenic focus was identified in 19 of 21 patients, and further surgical treatment was performed in 18 of 21 patients (85.7%). CONCLUSIONS: VarioGuide frameless stereotaxy for sEEG placement is comparable to frame-based and robotic-assisted techniques with statistically similar rates of epileptic focus identification. Lead placement accuracy is slightly lower and time per lead is slightly higher relative to robot-assisted surgeries. When a robot system is unavailable, surgeons can consider using a frameless stereotactic technique for sEEG insertion, allowing patients to benefit from a similarly high rate of epileptic zone identification.

Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors.

BACKGROUND: Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target. METHODS: We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing. RESULTS: We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2-4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed. CONCLUSION: Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.

Case series review of neuroradiologic changes associated with immune checkpoint inhibitor therapy.

While immuno-oncotherapy (IO) has significantly improved outcomes in the treatment of systemic cancers, various neurological complications have accompanied these therapies. Treatment with immune checkpoint inhibitors (ICIs) risks multi-organ autoimmune inflammatory responses with gastrointestinal, dermatologic, and endocrine complications being the most common types of complications. Despite some evidence that these therapies are effective to treat central nervous system (CNS) tumors, there are a significant range of related neurological side effects due to ICIs. Neuroradiologic changes associated with ICIs are commonly misdiagnosed as progression and might limit treatment or otherwise impact patient care. Here, we provide a radiologic case series review restricted to neurological complications attributed to ICIs, anti-CTLA-4, and PD-L-1/PD-1 inhibitors. We report the first case series dedicated to the review of CNS/PNS radiologic changes secondary to ICI therapy in cancer patients. We provide a brief case synopsis with neuroimaging followed by an annotated review of the literature relevant to each case. We present a series of neuroradiological findings including nonspecific parenchymal and encephalitic, hypophyseal, neural (cranial and peripheral), meningeal, cavity-associated, and cranial osseous changes seen in association with the use of ICIs. Misdiagnosis of radiologic abnormalities secondary to neurological immune-related adverse events can impact patient treatment regimens and clinical outcomes. Rapid recognition of various neuroradiologic changes associated with ICI therapy can improve patient tolerance and adherence to cancer therapies.

Hemifacial Spam: Endoscopic Assistance in Facial Nerve Decompression With Lateral Spread Response Corroboration: 2-Dimensional Operative Video.

This video depicts the case of a 48-yr-old female with 3 yr of progressive left hemifacial spasm (HFS) refractory to medication. Magnetic resonance imaging showed a large anterior inferior cerebellar artery (AICA) and also a labyrinthine artery loop around the facial nerve (FN) root exit zone. A large bony eminence was also noted in the superior and lateral aspects of the porous acousticus (PA). She preferred surgery if "cure" was possible in lieu of Botox injections. A left retro sigmoid craniotomy was performed with brainstem auditory evoked responses (BAERs) and FN monitoring along with lateral spread response (LSR) assessment. The large bony prominence was drilled in its lateral aspect. Despite this, visualization was still limited and therefore we utilized a 30-degree-angled endoscope to observe the vessels caudal and cranial to the FN. This view prompted us to then drill further at the PA to decompress the FN as well as mobilize the labyrinthine artery away from the nerve. The LSR showed a dramatic improvement when FN decompression was accomplished, and then a further improvement with arterial mobilization and Teflon pledget placement. The BAERS remained at baseline throughout. FN function and hearing were intact on postoperative clinical assessment. Her symptomatic improvement was recorded at 12 mo after surgery. This video illustrates a more complex case of microvascular decompression with skull base concepts and techniques. The patient provided consent for the procedure and use of her images and operative video for publication.

Aventricular hemispherotomy: technical note.

Hemispheric disconnection in the form of hemispherectomy or hemispherotomy is the most effective way of treating intractable hemispheric epilepsy. Anatomical hemispherectomy approaches have largely been abandoned in most cases due to a higher risk of superficial hemosiderosis, intraoperative blood loss, hydrocephalus, prolonged hospital stay, and mortality compared to the variety of tissue-sparing hemispherotomy techniques. Disconnective hemispherotomy approaches utilize the lateral ventricle as a key component of the surgical corridor. Without a lateral ventricle, disconnective surgery becomes significantly challenging, typically leading to a hemispherectomy. The authors present the case of a patient with severe hemispheric dysplasia without a lateral ventricle on the pathologic side and detail a novel surgical technique for a prone, occipital interhemispheric, tissue-sparing, purely disconnective aventricular hemispherotomy with an excellent surgical outcome.

Moyamoya Syndrome in a Patient With Klippel-Trenaunay Syndrome.

Moyamoya syndrome consists of internal carotid artery stenosis with development of collateral vasculature responsible for ischemic events and cerebral hemorrhage. Moyamoya vasculopathy is commonly treated with external carotid artery to internal carotid artery bypass, either through direct or indirect anastomosis. Klippel-Trenaunay Syndrome (KTS) is a tissue hyper-proliferation disorder known to have a significant angio-dysplastic component to the pathology. No other instances of a patient with both KTS and Moyamoya syndrome are presently reported in the literature. We present a patient who had been diagnosed with KTS as a child who was found to have Moyamoya vasculopathy after experiencing frequent cerebral ischemic events. He underwent a left direct superficial temporal artery to middle cerebral artery bypass with subsequent significant improvement of his stroke symptoms. This case report demonstrates an association between KTS and Moyamoya syndrome with a possible shared pathophysiology. Patients with KTS may benefit from screening for cerebral ischemic events and monitoring for development of Moyamoya syndrome.

Acute Development and Rupture of a Basilar Tip Mycotic Aneurysm.

BACKGROUND: Infectious intracranial aneurysms are rare but encountered when associated with rupture or detected on screening of high-risk patients. The time course of the development of these aneurysms is unknown. Ultimately, the data published on mycotic aneurysms are in the form of case series, retrospective studies, with one recent systematic review, all of which have difficulty defining specifics regarding aneurysmal formation in these patients. We present a case that may help define the time frame of mycotic aneurysm growth. CASE DESCRIPTION: A patient with endocarditis, first identified to have a distal middle cerebral artery aneurysm treated with Onyx embolization, and an otherwise-unremarkable cerebral angiogram experienced significant subarachnoid hemorrhage 5 days later. Within that short time frame on appropriate antibiotic therapy, she developed and ruptured a basilar tip aneurysm, which was subsequently treated with coil embolization. CONCLSUSIONS: The time course of infectious intracranial aneurysm development is not known and difficult to define. This case illustrates an example of the development of a new infectious intracranial aneurysm and subsequent rupture over the course of 5 days, showing that these types of aneurysms and subsequent neurologic sequelae can happen acutely.

Multimodality 3D Superposition and Automated Whole Brain Tractography: Comprehensive Printing of the Functional Brain.

Whole brain tractography using diffusion tensor imaging (DTI) sequences can be used to map cerebral connectivity; however, this can be time-consuming due to the manual component of image manipulation required, calling for the need for a standardized, automated, and accurate fiber tracking protocol with automatic whole brain tractography (AWBT). Interpreting conventional two-dimensional (2D) images, such as computed tomography (CT) and magnetic resonance imaging (MRI), as an intraoperative three-dimensional (3D) environment is a difficult task with recognized inter-operator variability. Three-dimensional printing in neurosurgery has gained significant traction in the past decade, and as software, equipment, and practices become more refined, trainee education, surgical skills, research endeavors, innovation, patient education, and outcomes via valued care is projected to improve. We describe a novel multimodality 3D superposition (MMTS) technique, which fuses multiple imaging sequences alongside cerebral tractography into one patient-specific 3D printed model. Inferences on cost and improved outcomes fueled by encouraging patient engagement are explored.

Surgical Treatment of Vestibular Schwannoma: Does Age Matter?

OBJECTIVE: For older patients (>65 years) who undergo surgical treatment of vestibular schwannoma (VS), the reported rates of facial nerve preservation, hearing preservation, and complications are inconsistent. Many surgeons believe that older patients have worse outcomes than their younger counterparts and advise against surgical treatment. We analyzed a consecutive series of patients with VS treated with surgery to determine whether age was a factor in outcome. METHODS: We retrospectively reviewed all patients treated for VS at our institution from January 1, 2000, to July 1, 2012. We examined how sex, age (≥65 years and <65 years), race, tumor size, tumor laterality, body mass index, Charlson Comorbidity Index, smoking status, surgical approach, and preoperative hearing and symptoms were associated with outcomes. RESULTS: Two-hundred forty-three patients underwent resection of VS, including 23 patients ≥65 years (mean 68 ± 4 years) and 220 patients <65 years (mean 47 ± 11 years). The average tumor size was 16.5 mm. Older patients had a significantly lower body mass index of 26.6 vs. 29.8 (P = 0.03) and were more likely to have a CCI ≥2 (52.2% vs. 18.2%, P ≤ 0.00, preoperative facial numbness (34.8% vs. 10.1%, P = 0.03), and dizziness (78.3% vs. 49.3%, P = 0.03). There were no significant differences after surgery in facial nerve outcome, hearing preservation outcome, or general surgical complications between the 2 cohorts. CONCLUSIONS: With no difference in surgical complications, facial nerve outcome, or hearing preservation rates between older and younger patients in our series, age alone may not be an absolute contraindication to surgical management of VS.

Middle Fossa Approach for Vestibular Schwannoma: Good Hearing and Facial Nerve Outcomes with Low Morbidity.

OBJECTIVE: The middle fossa approach (MFA) is not used as frequently as the traditional translabyrinthine and retrosigmoid approaches for accessing vestibular schwannomas (VSs). Here, MFA was used to remove primarily intracanalicular tumors in patients in whom hearing preservation is a goal of surgery. METHODS: A retrospective chart review was performed to identify consecutive adult patients who underwent MFA for VS. Demographic profile, perioperative complications, pre- and postoperative hearing, and facial nerve outcomes were analyzed with linear regression analysis to identify factors predicting hearing outcome. RESULTS: Among 78 identified patients (mean age, 49 years; 53% female; mean tumor size, 7.5 mm), 78% had functional hearing preoperatively (American Academy of Otolaryngology-Head and Neck Surgery class A/B). Follow-up audiologic data were available for 60 patients overall (mean follow-up, 15.1 months). The hearing preservation rate was 75.5% (37/49) at last known follow-up for patients with functional hearing preoperatively. Other than preoperative hearing status (P < 0.001), none of the factors assessed, including demographic profile, size of tumor, and fundal fluid cap, predicted hearing preservation (P > 0.05). Good functional preservation of the facial nerve (House-Brackmann class I/II) was achieved in 90% of patients. The only operative complications were 3 wound infections (3.8%). CONCLUSIONS: Preliminary results from this single-center retrospective study of patients undergoing MFA for resection of VS showed that good hearing preservation and facial nerve outcomes could be achieved with few complications. These results suggest that resection via the MFA is a rational alternative to watchful waiting or stereotactic radiosurgery.

Minimizing bone gaps when using custom pediatric cranial implants is associated with implant success.

OBJECT: Occasionally after a craniotomy, the bone flap is discarded (as in the case of osteomyelitis) or is resorbed (especially after trauma), and an artificial implant must be inserted in a delayed fashion. Polyetheretherketone (PEEK) implants and hard-tissue replacement patient-matched implants (HTR-PMI) are both commonly used in such cases. This study sought to compare the failure rate of these 2 implants and identify risk factors of artificial implant failure in pediatric patients. METHODS: This was a retrospective cohort study examining all pediatric patients who received PEEK or HTR-PMI cranioplasty implants from 2000 to 2013 at a single institution. The authors examined the following variables: age, sex, race, mechanism, surgeon, posttraumatic hydrocephalus, time to cranioplasty, bone gap width, and implant type. The primary outcome of interest was implant failure, defined as subsequent removal and replacement of the implant. These variables were analyzed in a bivariate statistical fashion and in a multivariate logistic regression model for the significant variables. RESULTS: The authors found that 78.3% (54/69) of implants were successful. The mean patient age was 8.2 years, and a majority of patients were male (73%, 50/69); the mean follow-up for the cohort was 33.3 months. The success rate of the 41 HTR-PMI implants was 78.1%, and the success rate of the 28 PEEK implants was 78.6% (p = 0.96). Implants with a bone gap of > 6 mm were successful in 33.3% of cases, whereas implants with a gap of < 6 mm had a success rate of 82.5% (p = 0.02). In a multivariate model with custom-type implants, previous failed custom cranial implants, time elapsed from previous cranioplasty attempt, and bone gap size, the only independent risk factor for implant failure was a bone gap > 6 mm (odds ratio 8.3, 95% confidence interval 1.2-55.9). CONCLUSIONS: PEEK and HTR-PMI implants appear to be equally successful when custom implantation is required. A bone gap of > 6 mm with a custom implant in children results in significantly higher artificial implant failure.

AlloDerm for duraplasty in Chiari malformation: superior outcomes.

BACKGROUND: Autologous pericranium, fascia lata (either as autograft or allograft), bovine pericardium (DuraGuard), fetal bovine tissue (Durepair), processed collagen matrix (DuraGen), and synthetic fabrics (e.g., synthetic Goretex graft) have all been used for duraplasty in Chiari decompression surgery, and no consensus exists as to the optimal material. We reviewed our experience to compare the incidence of graft-related complications associated with using acellular human dermis allograft (AlloDerm) with those of DuraGuard, DuraGen, and Durepair. METHODS: In a retrospective cohort chart review, our cohort included 119 patients who underwent 128 Chiari decompression procedures by a single surgeon from January 1, 1997, through July 31, 2012. Age, sex, smoking status, weight, and the type of dural graft used were analyzed with univariate statistical tests. Dural grafts were selected based on the commercial products available at the time of surgery during this 15-year period. RESULTS: The reoperation rate for cerebrospinal fluid leak causing pseudomeningocele was 2.2 % (1/46 cases) with the AlloDerm graft and 17.1 % (14/82 cases) with other materials (p = 0.01). Each of the non-AlloDerm grafts had a higher reoperation rate than AlloDerm when analyzed separately. Not using AlloDerm was the only statistically significant factor for the need for reoperation (p = 0.01). CONCLUSIONS: The use of the AlloDerm dural graft for duraplasty in Chiari decompressions resulted in a significantly lower pseudomeningocele formation than the use of any other type of dural graft. There was no association between patient age, sex, extra weight, or smoking status and the need for reoperation.

National variation in costs and mortality for leukodystrophy patients in US children's hospitals.

BACKGROUND: Inherited leukodystrophies are progressive, debilitating neurological disorders with few treatment options and high mortality rates. Our objective was to determine national variation in the costs for leukodystrophy patients and to evaluate differences in their care. METHODS: We developed an algorithm to identify inherited leukodystrophy patients in deidentified data sets using a recursive tree model based on International Classification of Disease, 9th Edition, Clinical Modification, diagnosis and procedure charge codes. Validation of the algorithm was performed independently at two institutions, and with data from the Pediatric Health Information System (PHIS) of 43 US children's hospitals, for a 7-year period between 2004 and 2010. RESULTS: A recursive algorithm was developed and validated, based on six International Classification of Disease, 9th Edition, Clinical Modification, codes and one procedure code that had a sensitivity up to 90% (range 61-90%) and a specificity up to 99% (range 53-99%) for identifying inherited leukodystrophy patients. Inherited leukodystrophy patients comprise 0.4% of admissions to children's hospitals and 0.7% of costs. During 7 years, these patients required $411 million of hospital care, or $131,000/patient. Hospital costs for leukodystrophy patients varied at different institutions, ranging from two to 15 times more than the average pediatric patient. There was a statistically significant correlation between higher volume and increased cost efficiency. Increased mortality rates had an inverse relationship with increased patient volume that was not statistically significant. CONCLUSIONS: We developed and validated a code-based algorithm for identifying leukodystrophy patients in deidentified national datasets. Leukodystrophy patients account for $59 million of costs yearly at children's hospitals. Our data highlight potential to reduce unwarranted variability and improve patient care.

Determinants of health care use in a population-based leukodystrophy cohort.

OBJECTIVES: To determine the costs for children with leukodystrophies and whether high costs are associated with characteristic clinical features or resources use. STUDY DESIGN: We determined health care costs in a population cohort of 122 patients with leukodystrophies, including inpatient, outpatient, and emergency department use, during a 9-year period. We analyzed differences in patients with high costs (>85th percentile) and their health care use. RESULTS: Patients with leukodystrophy had significant variability in resource use, with the top 15th percentile of patients accounting for 73% of costs ($9.6 million). The majority of costs, 81% ($10.8 million), arose from inpatient hospitalization. High-cost patients had more and longer hospitalizations, increased requirements for intensive unit care and mechanical ventilation, and significantly more infections. Importantly, bone marrow transplantation did not solely account for the difference between high-cost and low-cost groups. CONCLUSION: Inpatient hospitalization is the greatest source of health care resource use in patients with leukodystrophies. A minority of patients account for the majority of costs, primarily attributable to an increased volume of hospitalization. Strategies to improve care and reduce costs will need to reduce inpatient stays and target modifiable reasons for hospitalization.

Hypoxia disruption of vertebrate CNS pathfinding through ephrinB2 Is rescued by magnesium.

The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium.

Gal80 intersectional regulation of cell-type specific expression in vertebrates.

Characterization and functional manipulation of specific groups of neurons in the vertebrate central nervous system (CNS) remains a major hurdle for understanding complex circuitry and functions. In zebrafish, the Gal4/UAS system has permitted expression of transgenes and enhancer trap screens, but is often limited by broad expression domains. We have developed a method for cell-type specific expression using Gal80 inhibition of Gal4-dependent expression. We show that native Gal4 is able to drive strong expression, that Gal80 can inhibit this expression, and that overlapping Gal4 and Gal80 expression can achieve "intersectional" expression in spatially and genetically defined subsets of neurons. We also optimize Gal80 for expression in vertebrates, track Gal80 expression with a co-expressed fluorescent marker, and use a temperature-sensitive allele of Gal80 to temporally regulate its function. These data demonstrate that Gal80 is a powerful addition to the genetic techniques available to map and manipulate neural circuits in zebrafish.