Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Gynecological cancers represent 10% to 15% of cancers in women, but brain metastases (BM) are uncommon, with limited evidence regarding their management. This study investigates the role of stereotactic radiosurgery (SRS) for BM from primary gynecological cancers. METHODS:Institutions of the International Radiosurgery Research Foundation participated in this study. Inclusion criteria required histological diagnosis of epithelial ovarian, cervical, or endometrial cancer, SRS between 2000 and 2020, and at least 1 imaging or clinical follow-up. RESULTS:A total of 276 patients having SRS for 977 BM were included. Median age at SRS was 62 years (IQR, 55-70). Primary cancer origin was ovarian in 128 (46%), cervical in 43 (16%), and endometrial in 105 patients (38%). Median Karnofsky Performance Scale was 80%, and systemic disease was active in 124 (45%) of patients. A median of 1 metastasis was treated (IQR, 1-3) per patient. Median individual metastasis volume was 0.27 cc (IQR, 0.05-1.59 cc). The majority (91%) received single-fraction SRS, using a median margin dose of 18 Gy (IQR, 16-20 Gy). Actuarial overall survival was 77%, 65%, and 44% at 6, 12, and 24 months, respectively. Predictors of worsened survival included older age, cervical and endometrial primary, previous whole-brain radiation therapy (WBRT), active systemic disease, worsened Karnofsky Performance Scale, absence of subsequent surgery, and increasing number of BM. Actuarial local control was 94% at 6 months, 89% at 12 months, and 78% at 24 months. Previous SRS or WBRT, tumor bed treatment, and cervical histology increased the risk of local failure. New remote BM and leptomeningeal dissemination occurred in 44% and 11% of patients, respectively. Adverse radiation effects (ARE) occurred in 13% of cases but were symptomatic in only 3%. Previous WBRT or SRS and increased tumor diameter increased the risk of ARE. CONCLUSION/CONCLUSIONS:SRS is an effective management for BM from gynecological cancers with low risks of symptomatic ARE.

OBJECTIVE:To better understand the distance relationship of the stapes to the round window, to assist in intraoperative round window identification. STUDY DESIGN/METHODS:Retrospective review of CT temporal bone imaging and multiplanar image reformat analysis. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Patients above 18 years of age who underwent cochlear implantation between January 2020 and April 2025 and had preoperative computed tomography (CT) imaging of the temporal bone. Patients were excluded if they had prior surgical procedures that could distort the stapes superstructure (eg, stapedectomy) or if image quality/resolution precluded adequate visualization of the stapes crus. INTERVENTION/METHODS:None. MAIN OUTCOME MEASURE/METHODS:Prediction accuracy of the stapes intercrural width to locate the level of the round window. RESULTS:There were 102 ears that were studied, including 51 (50%) left and 51 (50%) right ears. The average measured intercrural width was 2.1 mm (SD: 0.17 mm). The maximum intercrural distance was found to be 2.6 mm, and the minimum distance was 1.7 mm. In all 102 (100%) ears, the intercrural distance of the stapes accurately predicted the level of the RW on image analysis. CONCLUSION/CONCLUSIONS:The stapes intercrural width can be utilized as an accurate predictor of the round window level and is a simple and intuitive intraoperative tool surgeons can utilize to safely gain access to the cochlea.

BACKGROUND AND IMPORTANCE/BACKGROUND:Rhino-orbital cerebral mucormycosis (ROCM) is an aggressive fungal infection involving the paranasal sinuses, orbit, and intracranial cavity, with a propensity for vascular invasion. This can lead to complications such as internal carotid artery (ICA) thrombosis and occlusion, presenting major neurosurgical challenges. Although surgical debridement and antifungal therapy are the mainstays of treatment, cases with significant neurovascular involvement require specialized intervention. We report a case of ROCM with severe flow-limiting ICA stenosis treated by direct extracranial-intracranial bypass. CLINICAL PRESENTATION/METHODS:tA 65-year-old man with diabetes presented with progressive left-sided blindness and facial numbness. Imaging revealed a left orbital mass extending into the paranasal sinuses and intracranially. Empiric antifungal therapy was started. Pathology confirmed Rhizopus species. Despite extensive surgical debridement and antifungal therapy, the patient developed progressive severe cavernous ICA stenosis, leading to watershed territory strokes. To restore cerebral perfusion, protect from distal emboli, and prepare for potential aggressive debridement, a flow-replacing direct (superficial temporal artery-middle cerebral artery (M2)) bypass was performed, and the supraclinoid carotid was trapped. Intraoperative angiography confirmed robust flow through the bypass. The patient was discharged on antifungal therapy and aspirin. At 6-month follow-up, the patient was neurologically intact with an modified Rankin Scale score of 1. Computed tomography angiography and transcranioplasty Doppler ultrasonography confirmed good flow through the bypass. CONCLUSION/CONCLUSIONS:In addition to antifungal therapy and surgical debridement, superficial temporal artery-middle cerebral artery bypass can be a lifesaving intervention in the management of ROCM with severe cerebrovascular compromise. This case highlights the critical role of cranial bypass in preserving cerebral perfusion in patients with flow-limiting ROCM-associated ICA invasion.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Single-session stereotactic radiosurgery (SRS) has limited role for large arteriovenous malformations (AVM). Volume-staged SRS (VS-SRS) is used to optimize outcomes, but studies reporting results are limited. METHODS:This multicenter retrospective cohort of 378 patients from 21 centers reports results of VS-SRS for the entire AVM nidus. We report favorable outcome, obliteration, hemorrhage, and permanent symptomatic adverse radiation effect rates. RESULTS:The median age was 31 years (IQR: 19-44) at the first volume stage, with patients treated in 2-4 stages. The median total nidus volume was 21 cm3 (IQR: 13.9-30.1 cm3), and a median prescription dose of 17 Gy (IQR: 16-18 Gy) was used. The median radiographic and clinical follow-up were 48 and 55 months, respectively. Seventy-seven patients (20.4%) had a favorable outcome, with the 3-year and 5-year rates being 3.9% and 18%, respectively. 127 patients (33.6%) achieved obliteration, with the 3-year and 5-year rates being 6.8% and 26%, respectively. Obliteration rates of AVMs <15 cm3 were 81% and 31%, respectively. The latency period hemorrhage incidence rate was 3.02 cases per 100 patient-years; 52 patients (13.8%) had a bleed. Seventy-two patients (19%) had symptomatic adverse radiation effect; in 38 patients (10.1%), these were permanent. Total nidus volume, prescription dose at first stage, diffuse nidus, and prior hemorrhage were all independent affecting outcome rates. CONCLUSION/CONCLUSIONS:VS-SRS can be used to treat large AVMs as a standalone treatment. Obliteration rates and favorable outcomes are lower than that with smaller AVMs, and repeat treatment is often required. Optimizing treatment plans, by increasing prescription doses, reducing treatment volume at each stage, and increasing the number of stages, may lead to better outcomes.

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.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

STUDY DESIGN/METHODS:Delphi Consensus. OBJECTIVE:To define an optimal surgical composite outcome measure in patients with metastatic spine disease (OSCO-M) through international consensus among key opinion leaders. METHODS:Members of the AO Spine Knowledge Forum Tumor, an international group of dedicated spine oncology surgeons and oncologists, participated in a modified Delphi process between March 2023 and November 2024. The study was conducted in two parts. The first part aimed on identifying which outcome variables were deemed important to be included in the composite outcome. The second part focused on the definition of a successful outcome with regards to the agreed variables from Part 1. Each part consisted of a questionnaire and a consensus meeting. Consensus was achieved when a threshold of 70% agreement was reached. RESULTS:A total of 42 dedicated spine oncology surgeons and oncologists from North America, Latin America, Europe, and Asia participated. Over 87% of respondents agreed that composite measures reflect the multidimensional aspect of the surgical process more than an individual outcome variable. Most respondents (93%) agreed/strongly agreed that composite measures should be used to assess the quality of surgical care in spine oncology. Through consensus, the following three outcome variables were selected to define the OSCO-M: the absence of SAVES-V2 (Spinal Adverse Events Severity System, Version 2) Grade 3 adverse events or higher within 30 days of surgery, maintaining or improving ECOG (Eastern Cooperative Oncology Group) performance status at 90 days, and being ambulatory (with or without aid) at 90 days. CONCLUSION/CONCLUSIONS:This is the first study defining a composite outcome measure in oncologic surgery for spinal metastases derived from an international group of key opinion leaders in spine oncology. The OSCO-M may be useful for future research in spine tumor patients and serve as a benchmark to optimize outcomes.

OBJECTIVE:Sudden unexpected death in epilepsy (SUDEP) often follows generalized tonic-clonic seizures during sleep, likely resulting from impaired brainstem cardiorespiratory function. We used ictal electrocardiogram (ECG)-based cross-frequency phase-amplitude coupling (PAC) to detect cardiorespiratory disruptions, comparing SUDEP to non-SUDEP cohorts. Leveraging respiratory modulation of ECG signals can provide a robust indirect proxy of respiratory monitoring despite high-amplitude noise. METHODS:We analyzed ictal ECG and electroencephalographic recordings in 21 SUDEP cases and 21 non-SUDEP epilepsy controls. Ictal ECG segments from 76 seizures (38 SUDEP, 38 non-SUDEP) were processed using continuous wavelet transformation to compute PAC between respiratory (.1-.55 Hz, 6-33 breaths per minute) and cardiac (.7-3.7 Hz, 42-222 beats per minute) frequencies. Relative PAC coupling strength was evaluated for respiratory frequencies > .25 Hz (15 breaths per minute) and cardiac frequencies > 1.7 Hz (102 beats per minute). Furthermore, a 3 × 3 grid of PAC ranges was derived for each 20-s window, yielding 18 features (mean and SD) as inputs to a logistic regression model. RESULTS:Elevated ictal PAC at higher respiratory (>.25 Hz, p < .0001) and cardiac (>1.7 Hz, p < .0142) frequencies in SUDEP patients suggests ictal respiration modulates ictal tachycardia, leading to cardiorespiratory dysfunction, probably brainstem-mediated. The logistic model accurately distinguished 38 seizures in SUDEP cases from 38 seizures in non-SUDEP cases (receiver operating characteristic area under the curve = 91%). Seizures in SUDEP patients had higher propensity scores (p < .001) both per seizure and per patient. All six test seizures (three SUDEP, three non-SUDEP) were correctly classified using the optimal threshold. SIGNIFICANCE/CONCLUSIONS:Ictal ECG-based PAC analysis is a potential noninvasive biomarker for SUDEP risk, capturing cardiorespiratory dysregulation during seizures. Its integration into wearable ECG devices could enable real-time risk assessment, informing clinical interventions such as rescue medications, antiseizure medication adjustments, or surgical evaluations.

BACKGROUND:Lumbar fusion eliminates motion at the operative level and is associated with altered load transfer and adjacent segment degeneration. Total joint replacement (TJR) of the lumbar spine is a motion segment reconstruction procedure performed via a bilateral transforaminal approach that allows direct neural decompression and replacement of both disc and facet function. This prospective investigational device exemption clinical trial compared TJR with a concurrent, propensity-score-weighted real-world evidence cohort treated with either instrumented transforaminal lumbar interbody fusion (TLIF) or posterior lumbar interbody spine fusion (PLIF). METHODS:. RESULTS:= 0.04). CONCLUSIONS:Substantial decreases in back impairment and pain severity were realized in both study groups. However, longitudinal improvement in ODI significantly favored patients treated with TJR. CLINICAL RELEVANCE/CONCLUSIONS:Lumbar TJR combines decompression with motion preservation in a single procedure, potentially offering an alternative to fusion in selected patients. The advantage of utilizing a standard posterior operative approach with TJR is that it allows for direct decompression of the neural elements prior to implant placement. LEVEL OF EVIDENCE/METHODS:2b.

DNA methylation is a crucial epigenetic mechanism that regulates gene expression. Precise editing of DNA methylation has emerged as a promising tool for dissecting its biological function. However, challenges in delivery have limited most applications of DNA methylation editing to in vitro systems. Here, we develop two transgenic mouse lines harboring an inducible dCas9-DNMT3A or dCas9-TET1 editor to enable tissue-specific DNA methylation editing in vivo. We demonstrate that targeted methylation of the Psck9 promoter in the liver of dCas9-DNMT3A mice results in decreased Pcsk9 expression and a subsequent reduction in serum low-density lipoprotein cholesterol level. Targeted demethylation of the Mecp2 promoter in dCas9-TET1 mice reactivates Mecp2 expression from the inactive X chromosome and rescues neuronal nuclear size in Mecp2^+/- mice. Genome-wide sequencing analyses reveal minimal transcriptional off-targets, demonstrating the specificity of the system. These results demonstrate the feasibility and versatility of methylation editing, to functionally interrogate DNA methylation in vivo.