A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus.

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.

Differentiating radiation necrosis from tumor recurrence: a systematic review and diagnostic meta-analysis comparing imaging modalities.

PURPSOSE: Cerebral radiation necrosis (RN) is often a delayed phenomenon occurring several months to years after the completion of radiation treatment. Differentiating RN from tumor recurrence presents a diagnostic challenge on standard MRI. To date, no evidence-based guidelines exist regarding imaging modalities best suited for this purpose. We aim to review the current literature and perform a diagnostic meta-analysis comparing various imaging modalities that have been studied to differentiate tumor recurrence and RN. METHODS: A systematic search adherent to PRISMA guidelines was performed using Scopus, PubMed/MEDLINE, and Embase. Pooled sensitivities and specificities were determined using a random-effects or fixed-effects proportional meta-analysis based on heterogeneity. Using diagnostic odds ratios, a diagnostic frequentist random-effects network meta-analysis was performed, and studies were ranked using P-score hierarchical ranking. RESULTS: The analysis included 127 studies with a total of 220 imaging datasets, including the following imaging modalities: MRI (n = 10), MR Spectroscopy (MRS) (n = 28), dynamic contrast-enhanced MRI (n = 7), dynamic susceptibility contrast MRI (n = 36), MR arterial spin labeling (n = 5), diffusion-weighted imaging (n = 13), diffusion tensor imaging (DTI) (n = 2), PET (n = 89), and single photon emission computed tomography (SPECT) (n = 30). MRS had the highest pooled sensitivity (90.7%). DTI had the highest pooled specificity (90.5%). Our hierarchical ranking ranked SPECT and MRS as most preferable, and MRI was ranked as least preferable. CONCLUSION: These findings suggest SPECT and MRS carry greater utility than standard MRI in distinguishing RN from tumor recurrence.

Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.

Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation (P = 4.0 × 10-8); additionally, a rare damaging mutation in SOX11, which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B, a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (P = 8.2 × 10-12). Three probands had rare damaging mutations in GLI2, SOX11, or GPC4, which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier KAT6A, and CTNNA1, encoding catenin α-1. These findings establish TFAP2B as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

Trends in medical device company payments in neurosurgery: a nationwide, multidatabase, geospatial analysis.

OBJECTIVE: Industry partnerships help advance the field of neurosurgery. Given the nature of the field and its close relationship with innovation, neurosurgeons frequently partner with the medical device industry to advance technology and improve outcomes. However, this can create important ethical concerns for patients. In this paper, the authors sought to comprehensively study how physician payments from medical device companies have changed and what geographic parameters influence the trends observed over the years. METHODS: The authors queried and merged several large databases, including Medicare and Medicaid provider usage data and databases from the Open Payments Program, National Plan and Provider Enumeration System, and US Census Bureau. Geospatial analysis was performed using Moran's I and II clustering. Univariate and multivariable analyses were performed using the Mann-Whitney U-test and geospatially weighted multivariable regression for hot spot and cold spot membership. RESULTS: Data for 952 counties across the continental United States were analyzed. Ninety-seven counties constituted geographic hot spots. These hot spots were primarily concentrated in Florida, the New York-Pennsylvania region, central Colorado, and southwestern United States. Independent predictors of hot spot membership included greater unemployment rates, the percentage of White patients, the presence of mobile homes, and the percentage of county Hispanic and Black populations. Company-based differences were examined. The vast majority of Medtronic's payments were in the form of royalties and licensing (86.6%). Royalties and licensing accounted for the majority of payments for DePuy (69.4%), Globus Medical (62%), and NuVasive (77.1%). In contrast, other companies, such as Boston Scientific, opted to pay physicians in the form of ownership and investment interests (42.1%). The impact of the COVID-19 pandemic was also assessed. During the onset of the pandemic in 2020, physician payments fell or remained the same across all regions with the exception of the South Atlantic region. However, it was observed that nearly all regions rebounded, with stark elevations in physician payments immediately in 2021. CONCLUSIONS: This analysis demonstrates that there are national hot spots and cold spots of physician payments, and offers some social, economic, and company-dependent predictors that may influence the magnitude of payments. Further analysis is needed to better understand this clinical-commercial partnership in healthcare, specifically within neurosurgical practice.

Reciprocal Changes in Sagittal Spinal Alignment After L5-S1 Anterior Lumbar Interbody Fusion.

OBJECTIVE: Degenerative diseases of the lumbar spine decrease lumbar lordosis (LL). Anterior lumbar interbody fusion (ALIF) at the L5-S1 disc space improves segmental lordosis, LL, and sagittal balance. This study investigated reciprocal changes in spinopelvic alignment after L5-S1 ALIF. METHODS: A retrospective chart review identified patients who underwent L5-S1 ALIF with or without posterior fixation at a single institution (November 1, 2016 to October 1, 2021). Changes in pelvic tilt, sacral slope, proximal LL (L1-L4), distal LL (L4-S1), total LL (L1-S1), segmental lordosis, pelvic incidence-LL mismatch, thoracic kyphosis, cervical lordosis, and sagittal vertical axis were measured on preoperative and postoperative radiographs. RESULTS: Forty-eight patients were identified. Immediate postoperative radiographs were obtained at a mean (SD) of 17 (20) days after surgery; delayed radiographs were obtained 184 (82) days after surgery. After surgery, patients had significantly decreased pelvic tilt (15.71° [7.25°] vs. 17.52° [7.67°], P = 0.003) and proximal LL (11.86° [10.67°] vs. 16.03° [10.45°], P < 0.001) and increased sacral slope (39.49° [9.27°] vs. 36.31° [10.39°], P < 0.001), LL (55.35° [13.15°] vs. 51.63° [13.38°], P = 0.001), and distal LL (43.17° [9.33°] vs. 35.80° [8.02°], P < 0.001). Segmental lordosis increased significantly at L5-S1 and decreased significantly at L2-3, L3-4, and L4-5. Lordosis distribution index increased from 72.55 (19.53) to 81.38 (22.83) (P < 0.001). CONCLUSIONS: L5-S1 ALIF was associated with increased L5-S1 segmental lordosis accompanied by pelvic anteversion and a reciprocal decrease in proximal LL. These changes may represent a reversal of compensatory mechanisms, suggesting an overall relaxation of spinopelvic alignment after L5-S1 ALIF.

Intraoperative confocal laser endomicroscopy for interpretation of a sellar hemangioblastoma: illustrative case.

BACKGROUND: Intraoperative frozen sections play a critical role in surgical strategy because of their ability to provide rapid histopathological information. In cases in which intraoperative biopsy carries a significant risk of bleeding, intraoperative confocal laser endomicroscopy (CLE) can assist in decision-making. OBSERVATIONS: The authors present a rare case of a large sellar hemangioblastoma. Preoperative radiographic imaging and normal pituitary function suggested a differential diagnosis that included hemangioblastoma. The patient underwent partial preoperative embolization and a right-sided pterional craniotomy for resection of the lesion. Gross intraoperative examination revealed a highly vascular sellar lesion requiring circumferential dissection to minimize blood loss. The serious vascularity precluded intraoperative frozen section analysis, and CLE imaging was performed. CLE imaging provided excellent visualization of the remarkable vascular structure and characteristic histoarchitecture with microvasculature, intracytoplasmic vacuoles, and atypical cells consistent with hemangioblastoma. Resection and decompression of the chiasm was accomplished, and the patient was discharged with improved vision. The final histopathological diagnosis was hemangioblastoma. LESSONS: When the benefits of obtaining intraoperative frozen sections greatly outweigh the associated risks, CLE imaging can aid in decision-making. CLE imaging offers real-time, on-the-fly evaluation of intraoperative tissue without the need to biopsy a vascular lesion.

Thoracic laminectomy and midline myelotomy for resection of a spinal ependymoma.

Spinal cord ependymomas comprise 25% of all intramedullary tumors and are typically treated with resection. A man in his mid-60s presented with imbalance and sensory deficits in both lower extremities, and a spinal thoracic intramedullary ependymoma spanning the levels T2 and T3 was diagnosed. After a laminectomy was performed, the tumor was microsurgically resected, and the patient demonstrated no neurological deficits on postoperative examination. Subsequent MRI showed complete resection of the tumor. This video showcases a thoracic intramedullary ependymoma resected using careful microdissection into the median raphe as a safe entry zone to preserve neurological function.

Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts.

Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10-33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease.

A novel SMARCC1 -mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus.

Importance: Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery. A few familial forms of congenital hydrocephalus (CH) have been identified, but the cause of most sporadic cases of CH remains elusive. Recent studies have implicated SMARCC1 , a component of the B RG1- a ssociated factor (BAF) chromatin remodeling complex, as a candidate CH gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, CH-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo . Objectives: The aims of this study are to (i) assess the extent to which rare, damaging de novo mutations (DNMs) in SMARCC1 are associated with cerebral ventriculomegaly; (ii) describe the clinical and radiographic phenotypes of SMARCC1 -mutated patients; and (iii) assess the pathogenicity and mechanisms of CH-associated SMARCC1 mutations in vivo . Design setting and participants: A genetic association study was conducted using whole-exome sequencing from a cohort consisting of 2,697 ventriculomegalic trios, including patients with neurosurgically-treated CH, totaling 8,091 exomes collected over 5 years (2016-2021). Data were analyzed in 2023. A comparison control cohort consisted of 1,798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents sourced from the Simons simplex consortium. Main outcomes and measures: Gene variants were identified and filtered using stringent, validated criteria. Enrichment tests assessed gene-level variant burden. In silico biophysical modeling estimated the likelihood and extent of the variant impact on protein structure. The effect of a CH-associated SMARCC1 mutation on the human fetal brain transcriptome was assessed by analyzing RNA-sequencing data. Smarcc1 knockdowns and a patient-specific Smarcc1 variant were tested in Xenopus and studied using optical coherence tomography imaging, in situ hybridization, and immunofluorescence microscopy. Results: SMARCC1 surpassed genome-wide significance thresholds in DNM enrichment tests. Six rare protein-altering DNMs, including four loss-of-function mutations and one recurrent canonical splice site mutation (c.1571+1G>A) were detected in unrelated patients. DNMs localized to the highly conserved DNA-interacting SWIRM, Myb-DNA binding, Glu-rich, and Chromo domains of SMARCC1 . Patients exhibited developmental delay (DD), aqueductal stenosis, and other structural brain and heart defects. G0 and G1 Smarcc1 Xenopus mutants exhibited aqueductal stenosis and cardiac defects and were rescued by human wild-type SMARCC1 but not a patient-specific SMARCC1 mutant. Hydrocephalic SMARCC1 -mutant human fetal brain and Smarcc1 -mutant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2 . Conclusions: SMARCC1 is a bona fide CH risk gene. DNMs in SMARCC1 cause a novel human BAFopathy we term " S MARCC1- a ssociated D evelopmental D ysgenesis S yndrome (SaDDS)", characterized by cerebral ventriculomegaly, aqueductal stenosis, DD, and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodeling complex for human brain morphogenesis and provide evidence for a "neural stem cell" paradigm of human CH pathogenesis. These results highlight the utility of trio-based WES for identifying risk genes for congenital structural brain disorders and suggest WES may be a valuable adjunct in the clinical management of CH patients. KEY POINTS: Question: What is the role of SMARCC1 , a core component of the B RG1- a ssociated factor (BAF) chromatin remodeling complex, in brain morphogenesis and congenital hydrocephalus (CH)? Findings: SMARCC1 harbored an exome-wide significant burden of rare, protein-damaging de novo mutations (DNMs) (p = 5.83 × 10 -9 ) in the largest ascertained cohort to date of patients with cerebral ventriculomegaly, including treated CH (2,697 parent-proband trios). SMARCC1 contained four loss-of-function DNMs and two identical canonical splice site DNMs in a total of six unrelated patients. Patients exhibited developmental delay, aqueductal stenosis, and other structural brain and cardiac defects. Xenopus Smarcc1 mutants recapitulated core human phenotypes and were rescued by the expression of human wild-type but not patient-mutant SMARCC1 . Hydrocephalic SMARCC1 -mutant human brain and Smarcc1 -mutant Xenopus brain exhibited similar alterationsin the expression of key transcription factors that regulate neural progenitor cell proliferation. Meaning: SMARCC1 is essential for human brain morphogenesis and is a bona fide CH risk gene. SMARCC1 mutations cause a novel human BAFopathy we term " S MARCC1- a ssociated D evelopmental D ysgenesis S yndrome (SaDDS)". These data implicate epigenetic dysregulation of fetal neural progenitors in the pathogenesis of hydrocephalus, with diagnostic and prognostic implications for patients and caregivers.

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP ( RASA1 ) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79×10 -7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 ( EPHB4 ) (p=1.22×10 -5 ), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1 , NOTCH1 , ITGB1 , and PTPN11 . ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

The "Binder Ring" Bypass: Transection, Rerouting, and Reanastomosis as an Alternative to Macrovascular Decompression of a Dolichoectatic Vertebral Artery.

BACKGROUND: In cases of extreme vertebrobasilar dolichoectasia, padding the cranial nerves (CNs) (microvascular decompression [MVD]) and clip-assisted sling transposition of the tortuous artery (macrovascular decompression [MaVD]) may be ineffective because the sling does not reduce the redundancy. Transposition may not decompress the nerves or may kink the artery. An alternative solution is needed. OBJECTIVE: To introduce the "binder ring" bypass as a novel solution to this unusual macrovascular compression problem. METHODS: The binder ring denotes the opening and closing of the offending vascular loop with standard bypass techniques with the artery transected, rerouted lateral to the CNs, and reanastomosed. An example case study is presented for a 72-year-old man whose severe vertebral artery tortuosity could not be relieved by MVD or MaVD. His pathology was exposed with an extended retrosigmoid craniotomy, the V4 segment was transected, the free ends were mobilized lateral to CN VII/VIII, and an end-to-end reanastomosis was performed with intraluminal suturing. RESULTS: The example binder ring bypass was patent angiographically, and the patient experienced immediate and lasting symptom relief without complications. CONCLUSION: The binder ring bypass applies standard bypass techniques to macrovascular compression but represents a significant escalation in technical challenges relative to traditional techniques. Patient tolerance to temporary arterial occlusion during reanastomosis depends on the location of the compressive arterial loop and the anatomy of collateral circulation. The binder ring bypass should be used as a last resort after medical therapy and MaVD techniques fail and performed only by neurosurgeons with advanced bypass skills.

Magnetic Resonance-Guided Laser Interstitial Thermal Therapy for Management of Low-Grade Gliomas and Radiation Necrosis: A Single-Institution Case Series.

BACKGROUND: Laser interstitial thermal therapy (LITT) has emerged as a minimally invasive treatment modality for ablation of low-grade glioma (LGG) and radiation necrosis (RN). OBJECTIVE: To evaluate the efficacy, safety, and survival outcomes of patients with radiographically presumed recurrent or newly diagnosed LGG and RN treated with LITT. METHODS: The neuro-oncological database of a quaternary center was reviewed for all patients who underwent LITT for management of LGG between 1 January 2013 and 31 December 2020. Clinical data including demographics, lesion characteristics, and clinical and radiographic outcomes were collected. Kaplan-Meier analyses comprised overall survival (OS) and progression-free survival (PFS). RESULTS: Nine patients (7 men, 2 women; mean [SD] age 50 [16] years) were included. Patients underwent LITT at a mean (SD) of 11.6 (8.5) years after diagnosis. Two (22%) patients had new lesions on radiographic imaging without prior treatment. In the other 7 patients, all (78%) had surgical resection, 6 (67%) had intensity-modulated radiation therapy and chemotherapy, respectively, and 4 (44%) had stereotactic radiosurgery. Two (22%) patients had lesions that were wild-type IDH1 status. Volumetric assessment of preoperative T1-weighted contrast-enhancing and T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences yielded mean (SD) lesion volumes of 4.1 (6.5) cm3 and 26.7 (27.9) cm3, respectively. Three (33%) patients had evidence of radiographic progression after LITT. The pooled median (IQR) PFS for the cohort was 52 (56) months, median (IQR) OS after diagnosis was 183 (72) months, and median (IQR) OS after LITT was 52 (60) months. At the time of the study, 2 (22%) patients were deceased. CONCLUSIONS: LITT is a safe and effective treatment option for management of LGG and RN, however, there may be increased risk of permanent complications with treatment of deep-seated subcortical lesions.

Residual Tumor Volume and Tumor Progression after Subtotal Resection and Observation of WHO Grade I Skull Base Meningiomas.

Objective This study investigated the impact of residual tumor volume (RTV) on tumor progression after subtotal resection and observation of WHO grade I skull base meningiomas. Study Design This study is a retrospective volumetric analysis. Setting This study was conducted at a single institution. Participants Patients who underwent subtotal resection of a WHO grade I skull base meningioma and postsurgical observation (July 1, 2007-July 1, 2017). Main Outcome Measure The main outcome was radiographic tumor progression. Results Sixty patients with residual skull base meningiomas were analyzed. The median (interquartile range) RTV was 1.3 (5.3) cm 3 . Tumor progression occurred in 23 patients (38.3%) at a mean duration of 28.6 months postsurgery. The 1-, 3-, and 5-year actuarial progression-free survival (PFS) rates were 98.3, 58.6, and 48.7%, respectively. The Cox multivariate analysis identified increasing RTV ( p = 0.01) and history of more than 1 previous surgery ( p = 0.03) as independent predictors of tumor progression. In a Kaplan-Meier analysis for PFS, the RTV threshold of 3 cm 3 maximized log-rank testing significance between groups of patients dichotomized at 0.5 cm 3 thresholds ( p < 0.01). The 3-year actuarial PFS rates for meningiomas with RTV ≤3 cm 3 and >3 cm 3 were 76.2 and 32.1%, respectively. When RTV >3 cm 3 was entered as a covariate in the Cox model, it was the only factor independently associated with tumor progression ( p < 0.01). Conclusion RTV was associated with tumor progression after subtotal resection of WHO grade I skull base meningioma in this cohort. An RTV threshold of 3 cm 3 was identified that minimized progression of the residual tumor when gross total resection was not safe or feasible.

Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

Case Report: Internal Carotid Artery Thrombosis: A Rare Complication After Fibrin Glue Injection for Cavernous Sinus Hemostasis.

Background: Fibrin glue injection within the cavernous sinus (CS) is a demonstrably safe and simple technique to control venous bleeding with a low complication rate. However, this technique does have inherent risks. We illustrate 2 cases of internal carotid artery (ICA) thrombosis after fibrin glue injection in the CS for hemostasis. Methods: After encountering this complication recently, we conducted a retrospective review of the surgical database of 2 senior neurosurgeons who specialize in cerebrovascular and skull base surgery to identify patients with any complications associated with the use of fibrin glue injection for hemostasis. Approval was given by respective institutional review boards, and patient consent was obtained. Results: Of more than 10,000 microsurgery procedures performed by 2 senior neurosurgeons with a combined experience of 40 years, including procedures for aneurysms and skull base tumors, 2 cases were identified involving ICA thrombosis after fibrin glue injection in the CS for hemostasis. Both cases involved severe ischemic complications as a result of the ICA thrombosis. In this article, we present their clinical presentation, characteristics, management, and outcomes. Conclusion: Direct injection of fibrin glue into the CS for hemostasis can effectively control venous bleeding and facilitate complex dissections. However, it can be associated with ICA thrombosis, with subsequent serious ischemia and poor prognosis. Although this complication appears to be rare, increased awareness of this problem should temper the routine use of fibrin glue in anterior clinoidectomy and transcavernous approaches.

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

Trim71/lin-41 Links an Ancient miRNA Pathway to Human Congenital Hydrocephalus.

Tripartite motif 71 (Trim71)/lineage defective 41 (lin-41) is the primary target of the ancient lethal 7 (let-7) miRNA that is essential for survival and development across animal phylogeny. Recent work identified Trim71 as a critical regulator of mammalian neural stem cell (NSC) fate and a bona fide human disease gene in congenital hydrocephalus (CH). Studying TRIM71 as a paradigm of NSC involvement in CH is a remarkable opportunity to better understand the mechanisms that regulate the timing of brain development and the pathogenesis of the most common pediatric neurosurgical disorder.

SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus.

BACKGROUND: Congenital hydrocephalus (CH) is a highly morbid disease that features enlarged brain ventricles and impaired cerebrospinal fluid homeostasis. Although early linkage or targeted sequencing studies in large multigenerational families have localized several genes for CH, the etiology of most CH cases remains unclear. Recent advances in whole exome sequencing (WES) have identified five new bona fide CH genes, implicating impaired regulation of neural stem cell fate in CH pathogenesis. Nonetheless, in the majority of CH cases, the pathological etiology remains unknown, suggesting more genes await discovery. METHODS: WES of family members of a sporadic and familial form of severe L1CAM mutation-negative CH associated with aqueductal stenosis was performed. Rare genetic variants were analyzed, prioritized, and validated. De novo copy number variants (CNVs) were identified using the XHMM algorithm and validated using qPCR. Xenopus oocyte experiments were performed to access mutation impact on protein function and expression. RESULTS: A novel inherited protein-damaging mutation (p.Pro605Leu) in SLC12A6, encoding the K+ -Cl- cotransporter KCC3, was identified in both affected members of multiplex kindred CHYD110. p.Pro605 is conserved in KCC3 orthologs and among all human KCC paralogs. The p.Pro605Leu mutation maps to the ion-transporting domain, and significantly reduces KCC3-dependent K+ transport. A novel de novo CNV (deletion) was identified in SLC12A7, encoding the KCC3 paralog and binding partner KCC4, in another family (CHYD130) with sporadic CH. CONCLUSION: These findings identify two novel, related genes associated with CH, and implicate genetically encoded impairments in ion transport for the first time in CH pathogenesis.