Faculty Bibliography

OBJECTIVE:NF2-related schwannomatosis (NF2-SWN) is an autosomal dominant genetic disorder characterized by the development of schwannomas, meningiomas, and spinal ependymomas. Treatment with bevacizumab, a monoclonal antibody against VEGF, has been shown to result in decreased vestibular schwannoma size and hearing improvement in ~50% of NF2-SWN patients. It is unknown whether the same degree of benefit is seen in younger patients compared with older patients. The objective of this study is to determine the association between age and bevacizumab treatment outcomes in NF2-SWN. STUDY DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Thirty-seven patients with NF2-SWN. INTERVENTIONS/METHODS:Bevacizumab. MAIN OUTCOME MEASURES/METHODS:Change in tumor size of 20% or more. RESULTS:This study includes 37 patients with NF2-SWN who were treated with bevacizumab at our institution between 2014 and 2024. They were divided into 2 groups: 22 adults over the age of 25 (26 to 71 y) and 15 adolescent and young adult (AYA) patients under the age of 25 (12 to 24 y). The median treatment duration was 2.1 years. A significantly higher proportion of AYA schwannomas (37.5%, n=9) exhibited radiographic tumor progression during the treatment period compared with those of the older patient group (11.9%, n=5) (P=0.026), despite similar pre-treatment growth rates. There was no significant difference in the proportion of older and younger patients with hearing decline, improvement, or stability (P>0.05). CONCLUSIONS:AYA patients were significantly more likely to exhibit progression of tumor growth during bevacizumab treatment compared with older patients, though no significant differences were detected in hearing outcomes.

OBJECTIVE:To characterize patient outcomes after primary stereotactic radiosurgery (SRS) for the management of sporadic facial nerve schwannoma. STUDY DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Six tertiary referral centers across the United States and United Kingdom. PATIENTS/METHODS:Adults undergoing SRS from 2000 through 2023 for sporadic facial nerve schwannoma along any segment of the facial nerve were included. Patients with NF2-related schwannomatosis were excluded. INTERVENTION/METHODS:Stereotactic radiosurgery. MAIN OUTCOME MEASURE/METHODS:Long-term tumor control. RESULTS:Among 60 patients meeting inclusion, the median age at SRS was 52 years (IQR: 41 to 64) with a median tumor size of 19.5 mm (IQR: 14.7 to 22.8). Tumors commonly involved the internal auditory canal (73%), cisternal (49%), geniculate/labyrinthine (47%), and tympanic segments (22%). Two patients experienced SRS failure and underwent salvage treatment; salvage-free survival rates (95% CI; number still at risk) at 1, 3, 5, and 10 years after SRS were 100% (100 to 100; 55), 100% (100 to 100; 36), 100% (100 to 100; 18), and 87% (72 to 100; 9), respectively. Among 31 (52%) patients with House-Brackmann (HB) grade I facial function at presentation, only 6 demonstrated worse facial function at a median of 3.2 years (IQR: 1.7 to 6.6) after SRS. Of 18 patients with serviceable hearing (AAO-HNS class A/B) at SRS, 13 maintained serviceable hearing at a median of 1.0 years (IQR: 0.5 to 4.9) of post-SRS audiometric follow-up. CONCLUSIONS:Durable tumor control after primary SRS for sporadic facial nerve schwannoma is achieved in most patients. Among those with HB grade I facial function at presentation, treatment with SRS harbors limited additional risk of facial paresis beyond observation alone.

INTRODUCTION/UNASSIGNED:Skull base surgery is a highly innovative, multidisciplinary field that brings together teams of neurosurgeons, otolaryngology-head and neck surgeons (OHNS), plastic surgeons, ophthalmologists, radiation oncologists, and others. However, not long ago, the nascent field was instead characterized by isolated individual brilliance. METHODS/UNASSIGNED:This paper explores the contributions of several key players toward breaking silos and transforming the field into what it is today. Our analysis centers on the formation of the North American Skull Base Society (NASBS), and the instrumental role that it played in the development of skull base surgery. We interviewed 12 past presidents of the NASBS and 2 prominent figures in skull base surgery. The contents of those 20 hours and 38 minutes of interviews and documents from initial NASBS meetings were analyzed. Key moments were segmented into short video clips, which complement this manuscript and are available on the NASBS website. RESULTS/UNASSIGNED:A compelling narrative of collaboration, mentorship, and tenacity emerged from our analysis. In the 20th century, the field of skull base surgery was characterized mainly by courageous but isolated efforts by neurosurgeons and OHNS surgeons. Through mentorship, collaboration, and incredible innovation, it has since grown into a multidisciplinary, cutting-edge specialty that utilizes the strengths of several medical specialties. This transformation was largely facilitated by the formation of the NASBS in 1989, which enabled worldwide communication and collaboration among those dedicated to advancing the field. CONCLUSION/UNASSIGNED:The growth of skull base surgery in North America and the instrumental role of the NASBS highlight the power of collaboration and innovation. It is important to recognize and celebrate the key players who facilitated the creation and success of the NASBS, which continues to unite young members across countless disciplines under one banner.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Unruptured intracranial aneurysms (UIAs) are increasingly detected and require careful management to prevent rupture. No externally validated score currently predicts procedural risk to guide treatment decisions. We developed and validated 2 predictive scores for complications after endovascular treatment (EVT) or neurosurgical treatment (NT) of UIA using routinely collected clinical and aneurysmal features. METHODS:We conducted a multicenter retrospective study including patients with UIA treated with EVT or NT across 15 neurovascular centers (2014-2024). Predictive models were built using multivariable logistic regression, with variables derived from Delphi consensus. The primary outcome was a composite safety end point: new neurological deficits, modified Rankin Scale (mRS) worsening (≥1 point or mRS 2-5 within 30 days), or procedural death. Internal validation used bootstrapping, and external validation was performed temporally and institutionally. Model performance was assessed using area under the receiver operating characteristic curve (AUROC) and calibration. Final scores, named Morbidity and Mortality Associated Risk in the Treatment of UIAs (MARTA)-EVT and MARTA-NT, were compared with existing models identified through systematic review. RESULTS:Among 2647 patients (1907 EVT and 740 NT), procedural complications occurred in 6.3% (EVT) and 12.8% (NT). Independent predictors included age, baseline mRS, aneurysm location, size, morphology, and procedural factors. MARTA-EVT (AUROC = 0.68, 95% CI = 0.57-0.78) and MARTA-NT (AUROC = 0.65, 95% CI = 0.54-0.77) showed moderate discrimination and good calibration. MARTA-EVT outperformed existing models; MARTA-NT performed similarly to SAFETEA. Predictive models are available open-source: https://martascoreapp.shinyapps.io/martascoreapp/. CONCLUSION/CONCLUSIONS:MARTA-EVT and MARTA-NT are validated tools for predicting procedural risks in UIA treatment and may support patient counseling and clinical decision making.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Stereotactic radiosurgery (SRS) has been increasingly employed in the multimodal management of primary central nervous system lymphoma. Here, we evaluate the outcomes of SRS for the treatment of primary central nervous system lymphoma through a multicenter, international cohort study. METHODS:A multicenter, retrospective cohort study was conducted through the International Radiosurgery Research Foundation. Subgroups were defined according to treatment setting: up-front (primary treatment), boost (SRS after consolidative chemotherapy with or without whole-brain radiotherapy), and relapsed/refractory (recurrent/progressive disease after first-line therapy). The primary end point was local tumor control. Time-to-event analysis was conducted using the Kaplan-Meier method. Variables associated with local control were assessed using the Cox proportional hazard modeling. RESULTS:Fifty-four patients with 127 tumor sites were included in this analysis. Actuarial 12-month local and distant control rates for the entire cohort were 75.7% and 63.7%, respectively, with a median overall survival (OS) of 18 months (range: 1-176). Actuarial 12-month local control rates were significantly different at 95.6%, 78.3%, and 42.1% (P < .0001) for the up-front, relapsed/refractory groups, and boost cohorts, respectively. OS across all cohorts were similar with 12-month OS rates of 55.2%, 51.3%, and 53.5% for the up-front, relapsed/refractory, and boost cohorts, respectively. Rates of radiation necrosis were 18.5%, 20.8%, 15.4%, and 11.8% for the entire cohort, relapsed/refractory, boost, and up-front cohorts, respectively. Diminished OS was significantly associated with treatment volumes >27 cm3 (hazard ratio: 2.5, P = .04). CONCLUSION/CONCLUSIONS:SRS shows promising local tumor control rates for up-front and relapsed cohorts. Despite this, distant tumor progression limits total tumor control and may adversely affect OS.

OBJECTIVE:CDKL5 deficiency disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy caused by loss-of-function variants in the CDKL5 gene. Preclinical experiments using enzyme replacement or gene therapies show promise and could be transformative therapies. This precompetitive consortium sought to harmonize nonseizure clinical endpoint selection for efficacy trials. Clinical Assessment of Neurodevelopmental Measures in CDD (CANDID) is an ongoing study evaluating the feasibility and suitability of neurocognitive tests and functioning scales in CDD patients. METHODS:CANDID is a 3-year, longitudinal, noninterventional global study involving children and adults with CDD. On-site and remote visits include clinical, behavioral, developmental, and quality of life assessments. RESULTS:We enrolled 112 patients (111 included in analyses); mean age = 8.3 years (range <1-28); 93% female; 10 participants were ≥18 years old. In the first 28 days, 82% had >16 seizures; six were seizure-free. Median seizure onset was at 1.5 months (range = 0-66). Patients used an average of 2.6 antiseizure medications at baseline. The most frequent comorbidities included gastrointestinal hypomotility, muscle tone abnormalities, and sleep disorders. Gross Motor Function Measure-88 (GMFM-88) scores indicated a floor effect in crawling, standing, and walking across all ages. Vineland-3 and Bayley-4 scores could be derived in most, with receptive language, interpersonal relationships, and fine and gross motor scores increasing with age. Bruni sleep questionnaire identified sleep initiation, sleep-awake transition, and excessive somnolence as the most disrupted components across all age groups. The mean Quality of Life Inventory-Disability total scores ranged from 53% to 64%, the independence domain being the most impacted. SIGNIFICANCE/CONCLUSIONS:The scales in the CANDID study capture disease-related deficits and phenotype variability in CDD. Floor effects in subdomains aligned with disease severity. The GMFM-88 lacks granularity, and its operational limitations make it unsuitable for CDD trials. Baseline analyses demonstrate the feasibility and potential value of most selected scales, supporting their use in optimizing trial design and endpoint selection for future CDD clinical trials.

Study DesignNarrative Review.ObjectivesTo summarize the scientific contributions generated from the AO Spine Knowledge Forum Tumor (AOSKFT) databases, focusing on primary spine tumors, and highlight key findings, research trends, and future directions.MethodsData from the Primary Tumor Retrospective (PT-Retro) and Primary Tumor Research Outcome Network (PTRON) registries were analyzed. The nineteen studies included were peer-reviewed manuscripts focused on primary spine tumors, excluding abstracts, book chapters, systematic reviews, and metastatic studies.ResultsThe PT-Retro registry compiled data from 1495 patients across 18 primary tumor histologies, offering insights into recurrence, survival, and treatment paradigms. Key findings emphasize the importance of Enneking-appropriate (EA) resection in improving survival and reducing recurrence in tumors such as chordoma, chondrosarcoma, and osteosarcoma. Genetic markers, including hTERT promoter mutations and rs2305089 SNP, were linked to prognosis in specific histologies. Benign tumors, such as giant cell tumors and aneurysmal bone cysts, demonstrated variable outcomes with different surgical approaches and selective arterial embolization.ConclusionsThe AOSKFT registries have significantly advanced knowledge in primary spine tumor management, emphasizing preoperative staging, surgical margins, and multidisciplinary approaches. International, multicentric registries are essential for studying rare diseases like primary spine tumors, enabling robust data collection, improved statistical power, and broader applicability of findings across diverse clinical settings. Ongoing prospective data collection through PTRON will further refine evidence-based care for these rare and challenging conditions.

BACKGROUND AND PURPOSE/OBJECTIVE:Accurate localization of the ventral intermediate nucleus (VIM) within the dentatorubrothalamic tract (DRTT) is critical for effective neurosurgical treatment of essential tremor (ET). This study evaluated the feasibility and anatomical specificity of quantitative susceptibility mapping (QSM) for direct VIM/DRTT visualization, comparing it with conventional diffusion tractography-based reconstructions. MATERIALS AND METHODS/METHODS:Twenty-seven participants (10 healthy controls, 17 ET patients) were enrolled across two institutions and imaged on 3T MRI systems. QSM-defined VIM/DRTT regions were manually segmented based on characteristic hypointense susceptibility contrast. Whole-brain diffusion tractography was performed to reconstruct the DRTT, pyramidal tract (PT), and medial lemniscus (ML) tracts. Spatial overlap between QSM-and tractography-defined VIM/DRTT regions was calculated, as well as overlap with neighboring PT and ML tracts to assess specificity. RESULTS:Two participants were excluded due to insufficient VIM/DRTT streamlines in tractography reconstruction. In healthy controls, QSM-and tractography-defined VIM/DRTT showed high spatial correspondence (left: 87.6 ± 5.1%; right: 85.3 ± 6.5%). ET patients exhibited slightly lower overlap (mean range: 71.5 - 85.1%). Overlap with neighboring PT and ML tracts was minimal (<3.3%), confirming high anatomical specificity of QSM-derived VIM/DRTT regions. CONCLUSIONS:QSM enables direct visualization of the VIM/DRTT with high spatial agreement to conventional tractography-based approaches while demonstrating minimal overlap with adjacent tracts. These findings support QSM as a complementary or standalone imaging modality for improved, patient-specific neurosurgical targeting in ET. ABBREVIATIONS/BACKGROUND:DBS = deep brain stimulation; DRTT = dentatorubrothalamic tract; ET = essential tremor; ML = medial lemniscus; MRgFUS = MR-guided focused ultrasound; VIM = ventral intermediate nucleus; PT = pyramidal tract; QSM = quantitative susceptibility mapping; WM = white matter.

IMPORTANCE/UNASSIGNED:Adjuvant radiotherapy can improve locoregional control and survival in patients with olfactory neuroblastoma (ONB), particularly with advanced-stage and histologic-grade disease. Standard radiotherapy treatment is with intensity-modulated radiotherapy (IMRT). Proton beam radiotherapy (PBRT) provides theoretical advantages in greater sparing of dose to uninvolved organs at risk. OBJECTIVE/UNASSIGNED:To investigate if there are differences in the effectiveness and radiation treatment-related adverse events (RTAEs) between adjuvant IMRT and PBRT for patients with ONB. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This propensity score-matched cohort study included patients with ONB treated between February 2005 and April 2021 with either IMRT or PBRT at 9 academic tertiary care centers in North America. Patients were matched 1:2 based on age, modified Kadish stage, and Hyams grade. Data were analyzed from July 2024 to January 2025. EXPOSURE/UNASSIGNED:Adjuvant IMRT or adjuvant PBRT. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Local recurrence-free survival (RFS), any RFS, and overall survival (OS). RTAEs, ie, grade 2 events or higher based on Common Terminology Criteria for Adverse Events, were recorded for both modalities. RESULTS/UNASSIGNED:Of 54 included patients, 27 (50%) were female, and the mean (SD) age was 46.2 (15.4) years. A total of 18 were treated with PBRT and 36 were treated with IMRT. Most patients had modified Kadish stage C disease (33 of 54 [61%]), and 24 patients (44%) had Hyams grade III or IV disease. The RTAE rate was 20% (8 of 40); IMRT had a rate of 21% (6 of 29), and PBRT had a rate of 18% (2 of 11). The difference in the point estimates for 10-year RFS showed a potential clinical benefit favoring IMRT, although the wide confidence interval indicates uncertainty (10-year RFS: IMRT, 63.3%; 95% CI, 44.6-89.8; PBRT, 37.8%; 95% CI, 14.2-100; difference, 25.5 percentage points; 95% CI, -17.6 to 68.6). There were no clinically meaningful differences in 10-year local RFS (IMRT, 75.6%; 95% CI, 59.8-95.4; PBRT, 72.7%; 95% CI, 45.2-100; difference, 2.9 percentage points; 95% CI, -35.9 to 41.7) or 10-year OS (IMRT, 61.8%; 95% CI, 42.8-89.1; PBRT, 57.1%; 95% CI, 24.3-100; difference, 4.7 percentage points; 95% CI, -49.2 to 58.6), although wide confidence intervals indicate considerable uncertainty. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Due to the imprecision of estimates, no definitive conclusions can be made regarding the comparative effectiveness of IMRT vs PBRT for patients with ONB. These preliminary data may inform the design of appropriately powered prospective studies evaluating the efficacy of PBRT vs IMRT in this population.