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David J. McCarthy, Dallas L. Sheinberg, Evan Luther, and Heather J. McCrea

OBJECTIVE

Myelomeningocele (MMC), the most severe form of spina bifida, is characterized by protrusion of the meninges and spinal cord through a defect in the vertebral arches. The management and prevention of MMC-associated hydrocephalus has evolved since its initial introduction with regard to treatment of MMC defect, MMC-associated hydrocephalus treatment modality, and timing of hydrocephalus treatment.

METHODS

The Nationwide Inpatient Sample (NIS) database from the years 1998–2014 was reviewed and neonates with spina bifida and hydrocephalus status were identified. Timing of hydrocephalus treatment, delayed treatment (DT) versus simultaneous MMC repair with hydrocephalus treatment (ST), and treatment modality (ETV vs ventriculoperitoneal shunt [VPS]) were analyzed. Yearly trends were assessed with univariable logarithmic regression. Multivariable logistic regression identified correlates of inpatient shunt failure. A PRISMA systematic literature review was conducted that analyzed data from studies that investigated 1) MMC closure technique and hydrocephalus rate, 2) hydrocephalus treatment modality, and 3) timing of hydrocephalus treatment.

RESULTS

A weighted total of 10,627 inpatient MMC repairs were documented in the NIS, 8233 (77.5%) of which had documented hydrocephalus: 5876 (71.4%) were treated with VPS, 331 (4.0%) were treated with ETV, and 2026 (24.6%) remained untreated on initial inpatient stay. Treatment modality rates were stable over time; however, hydrocephalic patients in later years were less likely to receive hydrocephalus treatment during initial inpatient stay (odds ratio [OR] 0.974, p = 0.0331). The inpatient hydrocephalus treatment failure rate was higher for patients who received ETV treatment (17.5% ETV failure rate vs 7.9% VPS failure rate; p = 0.0028). Delayed hydrocephalus treatment was more prevalent in the later time period (77.9% vs 69.5%, p = 0.0287). Predictors of inpatient shunt failure included length of stay, shunt infection, jaundice, and delayed treatment. A longer time between operations increased the likelihood of inpatient shunt failure (OR 1.10, p < 0.0001). However, a meta-analysis of hydrocephalus timing studies revealed no difference between ST and DT with respect to shunt failure or infection rates.

CONCLUSIONS

From 1998 to 2014, hydrocephalus treatment has become more delayed and the number of hydrocephalic MMC patients not treated on initial inpatient stay has increased. Meta-analysis demonstrated that shunt malfunction and infection rates do not differ between delayed and simultaneous hydrocephalus treatment.

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Roberto J. Perez-Roman, Vaidya Govindarajan, David J. Levi, Evan Luther, and Allan D. Levi

OBJECTIVE

With an increasing number of disease-modifying drugs available to manage rheumatoid arthritis (RA), spine surgeons have anecdotally noted decreased rates of cervical spine surgical procedures in this population. Although these medications have been shown to mitigate RA progression and its systemic effects on joint destruction, there are currently no large-scale studies of RA patients that suggest the use of these disease-modifying drugs has truly coincided with a decline in cervical spine surgery.

METHODS

Patients with RA who underwent cervical spinal fusion from 1998 to 2021 performed by the senior author were retrospectively reviewed. The cohort was stratified into 3 categories based on procedure level: 1) occipitocervical, 2) atlantoaxial, and 3) subaxial. The number of surgical procedures per year in each subgroup was evaluated to determine treatment trends over time. National (Nationwide) Inpatient Sample (NIS) data on both RA and non-RA patients who underwent cervical fusion were analyzed to assess for surgical trends over time and for differences in likelihood of surgical intervention between RA and non-RA patients over the epoch.

RESULTS

From 1998 to 2021, the number of overall cervical fusions performed in RA patients significantly declined (–0.13 procedures/year, p = 0.01) in this cohort, despite an overall significant increase in cervical fusions in non-RA patients over the same period. NIS analysis of cervical fusions across all patients similarly demonstrated a significant increase in cervical fusions over the same epoch (19,278 cases/year, p < 0.0001). When normalized for changes in population size, the incidence of new surgical procedures was lower in patients with RA regardless of surgical technique. Anterior cervical fusion was the most common approach used over the epoch in both RA and non-RA patients; correspondingly, RA patients were significantly less likely to undergo anterior cervical fusion (OR 0.655, 95% CI −0.4504 to −0.3972, p < 0.0001).

CONCLUSIONS

At the authors’ institution, there was a clear decline in the number of cervical fusions performed to treat the 3 most common forms of cervical spine pathology in RA patients (basilar impression, atlantoaxial instability, and subaxial cervical deformity). Although national trends suggest an increase in total cervical fusions in both RA and non-RA patients, the incidence of new procedures in patients with RA was significantly lower than in patients without RA, which supports the anecdotal results of spine surgeons nationally.

Free access

Victor M. Lu, Ashish H. Shah, Frederic A. Vallejo, Daniel G. Eichberg, Evan M. Luther, Sumedh S. Shah, Ricardo J. Komotar, and Michael E. Ivan

OBJECTIVE

Adult glioblastoma (GBM) has proven refractory to decades of innovation. Oncolytic viral therapy represents a novel therapy that uses viral vectors as both a delivery and therapeutic mechanism to target GBM cells. Despite the growing body of basic science data supporting the feasibility of viral therapy to treat GBM, the reporting of clinical trial results is heterogeneous. Correspondingly, the aim of this study was to present a contemporary summary of the progress all clinical trials have made to date.

METHODS

The ClinicalTrials.gov database was reviewed in August 2020 for all possible interventional clinical trials involving viral vector–based therapy to treat adult GBM. These were then screened against selection criteria to identify pertinent clinical trials.

RESULTS

A total of 29 oncolytic viral therapy trials treating adult GBM were identified. The median start and expected completion years were 2014 and 2020, respectively. At the time of this writing, 10 (35%) trials were reported to have completed recruitment, whereas 7 (24%) were actively recruiting. The median target enrollment number was 36 (range 13–108), with the majority of trials being phase I (n = 18, 62%), and involving secondary GBM among other malignant glioma (n = 19, 66%). A total of 10 unique viral vectors were used across all trials, with the most common being adenovirus (n = 16, 55%). Only 2 (7%) phase I trials to date have reported outcomes on the ClinicalTrials.gov portal. Results of 12 additional clinical trials were found in academic publications, with median progression-free and overall survival times of 3 and 15 months, respectively, after the first viral dose at recurrence. The coordination of the large majority of trials originated from the US (n = 21, 72%), and the median number of testing sites per trial was 1 (range 1–15), via industry funding (n = 18 trials, 62%).

CONCLUSIONS

There are multiple early-stage oncolytic viral therapy clinical trials for adult GBM currently active. To date, limited results and outcomes are promising but scarce. The authors expect this to change in the near future because many trials are scheduled to have either nearly or actually reached their expected recruitment completion time. How exactly oncolytic viral therapy will fit into the current treatment paradigms for primary and secondary GBM remains to be seen, and will not be known until safety and toxicity profiles are established by these clinical trials.

Free access

Dallas L. Sheinberg, David J. McCarthy, Omar Elwardany, Jean-Paul Bryant, Evan Luther, Stephanie H. Chen, John W. Thompson, and Robert M. Starke

Endothelial cell (EC) dysfunction is known to contribute to cerebral aneurysm (CA) pathogenesis. Evidence shows that damage or injury to the EC layer is the first event in CA formation. The mechanisms behind EC dysfunction in CA disease are interrelated and include hemodynamic stress, hazardous nitric oxide synthase (NOS) activity, oxidative stress, estrogen imbalance, and endothelial cell-to-cell junction compromise. Abnormal variations in hemodynamic stress incite pathological EC transformation and inflammatory zone formation, ultimately leading to destruction of the vascular wall and aneurysm dilation. Hemodynamic stress activates key molecular pathways that result in the upregulation of chemotactic cytokines and adhesion molecules, leading to inflammatory cell recruitment and infiltration. Concurrently, oxidative stress damages EC-to-EC junction proteins, resulting in interendothelial gap formation. This further promotes leukocyte traffic into the vessel wall and the release of matrix metalloproteinases, which propagates vascular remodeling and breakdown. Abnormal hemodynamic stress and inflammation also trigger adverse changes in NOS activity, altering proper EC mediation of vascular tone and the local inflammatory environment. Additionally, the vasoprotective hormone estrogen modulates gene expression that often suppresses these harmful processes. Crosstalk between these sophisticated pathways contributes to CA initiation, progression, and rupture. This review aims to outline the complex mechanisms of EC dysfunction in CA pathogenesis.

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Jamie E. Clarke, Evan Luther, Brooke Oppenhuizen, Jessica D. Leuchter, John Ragheb, Toba N. Niazi, and Shelly Wang

OBJECTIVE

Infantile intracranial aneurysms are exceedingly rare. The goal of this study was to evaluate an institutional case series of infantile intracranial aneurysms, as well as those reported in the contemporary literature, to determine their demographics, presentation, management, and long-term outcome.

METHODS

A comprehensive literature review from 1980 to 2020 was performed to identify individual cases of intracranial aneurysms in the infantile population ≤ 2 years of age. Additional cases from the authors’ institution were identified during the same time period. An individual participant data meta-analysis (IPDMA) was performed, abiding by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Patient demographic, radiographic, and clinical information was obtained. Descriptive statistical data were recorded, and multivariate logistic regression analyses were performed.

RESULTS

Patient data were obtained for 133 patients from 87 articles in the literature. Ten additional patients at the authors’ institution were also identified, for a total of 143 patients included in the IPDMA. The majority (72.7%) of this cohort consisted of idiopathic aneurysms, while 13.3% were posttraumatic pseudoaneurysms, 9.8% were infectious mycotic aneurysms, and 4.2% were aneurysms associated with a systemic connective tissue disorder or vasculitis. The mean age at presentation was 6.6 months. The majority of infants (97.9%) harbored only 1 aneurysm, and hemorrhage was the most common presenting feature (78.3%). The mean aneurysm size was 14.4 mm, and giant aneurysms ≥ 25 mm comprised 12.9% of the cohort. Most aneurysms occurred in the anterior circulation (80.9%), with the middle cerebral artery (MCA) being the most commonly affected vessel (51.8%). Management strategies included open surgical aneurysm ligation (54.0%), endovascular treatment (35.0%), surgical decompression without aneurysm treatment (4.4%), and medical supportive management only (13.9%). Surgical aneurysm ligation was more commonly performed for MCA and anterior cerebral artery aneurysms (p = 0.004 and p = 0.015, respectively), while endovascular techniques were favored for basilar artery aneurysms (p = 0.042). The mean follow-up period was 29.9 months; 12.4% of the cohort died, and 67.0% had a favorable outcome (Glasgow Outcome Scale score of 5).

CONCLUSIONS

This study is, to the authors’ knowledge, the largest analysis of infantile intracranial aneurysms to date. The majority were idiopathic aneurysms involving the anterior circulation. Surgical and endovascular techniques yielded equally favorable outcomes in this cohort. Long-term outcomes in the infantile population compared favorably to outcomes in adults.

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Victor M. Lu, Jessica D. Leuchter, Jamie E. Clarke, Evan M. Luther, Shelly Wang, and Toba N. Niazi

OBJECTIVE

The effect of congenital cardiac status on endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS) failure in hydrocephalic infants is unknown. Because cardiac status in infants can impact central venous pressure (CVP), it is possible that congenital heart disease (CHD) and congenital cardiac anomalies may render these cerebrospinal fluid diversion interventions more susceptible to failure. Correspondingly, the aim of this study was to determine how CHD and congenital cardiac anomalies may impact the failure of these initial interventions.

METHODS

A retrospective review of the Nationwide Inpatient Sample (NIS) database was conducted. Infants (aged < 1 year) with known congenital cardiac status managed with either ETV or VPS were included. Quantitative data were compared using either parametric or nonparametric methods, and failure rates were modeled using univariable and multivariable regression analyses.

RESULTS

A total of 18,763 infants treated with ETV or VPS for hydrocephalus were identified in our search, with ETV used to treat 7657 (41%) patients and VPS used to treat 11,106 (59%). There were 6722 (36%) patients who presented with CHD at admission, and a total of 25 unique congenital cardiac anomalies were detected across the cohort. Overall, the most common anomaly was patent ductus arteriosus (PDA) in 4990 (27%) patients, followed by atrial septal defect (ASD) in 2437 (13%) patients and pulmonary hypertension in 810 (4%) patients. With respect to initial intervention failure, 3869 (21%) patients required repeat surgical intervention during admission. This was significantly more common in the ETV group than the VPS group (36% vs 10%, p < 0.01). In both the ETV and VPS groups, CHD (p < 0.01), including all congenital cardiac anomalies, was an independent and significant predictor of failure. ASD (p < 0.01) and PDA (p < 0.01) both significantly predicted ETV failure, and PDA (p < 0.01) and pulmonary hypertension (p = 0.02) both significantly predicted VPS failure.

CONCLUSIONS

These results indicate that congenital cardiac status predicts ETV and VPS failure in patients with infantile hydrocephalus. The authors hypothesized that this finding was primarily due to changes in CVP; however, this may not be completely universal across both interventions and all congenital cardiac anomalies. Future studies about optimization of congenital cardiac status with ETV and VPS are required to understand the practical significance of these findings.

Free access

Michael E. Ivan, Daniel G. Eichberg, Long Di, Ashish H. Shah, Evan M. Luther, Victor M. Lu, Ricardo J. Komotar, and Timur M. Urakov

OBJECTIVE

Monitor and wand–based neuronavigation stations (MWBNSs) for frameless intraoperative neuronavigation are routinely used in cranial neurosurgery. However, they are temporally and spatially cumbersome; the OR must be arranged around the MWBNS, at least one hand must be used to manipulate the MWBNS wand (interrupting a bimanual surgical technique), and the surgical workflow is interrupted as the surgeon stops to “check the navigation” on a remote monitor. Thus, there is need for continuous, real-time, hands-free, neuronavigation solutions. Augmented reality (AR) is poised to streamline these issues. The authors present the first reported prospective pilot study investigating the feasibility of using the OpenSight application with an AR head-mounted display to map out the borders of tumors in patients undergoing elective craniotomy for tumor resection, and to compare the degree of correspondence with MWBNS tracing.

METHODS

Eleven consecutive patients undergoing elective craniotomy for brain tumor resection were prospectively identified and underwent circumferential tumor border tracing at the time of incision planning by a surgeon wearing HoloLens AR glasses running the commercially available OpenSight application registered to the patient and preoperative MRI. Then, the same patient underwent circumferential tumor border tracing using the StealthStation S8 MWBNS. Postoperatively, both tumor border tracings were compared by two blinded board-certified neurosurgeons and rated as having an excellent, adequate, or poor correspondence degree based on a subjective sense of the overlap. Objective overlap area measurements were also determined.

RESULTS

Eleven patients undergoing craniotomy were included in the study. Five patient procedures were rated as having an excellent correspondence degree, 5 had an adequate correspondence degree, and 1 had poor correspondence. Both raters agreed on the rating in all cases. AR tracing was possible in all cases.

CONCLUSIONS

In this small pilot study, the authors found that AR was implementable in the workflow of a neurosurgery OR, and was a feasible method of preoperative tumor border identification for incision planning. Future studies are needed to identify strategies to improve and optimize AR accuracy.

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Daniel G. Eichberg, Ashish H. Shah, Long Di, Alexa M. Semonche, George Jimsheleishvili, Evan M. Luther, Christopher A. Sarkiss, Allan D. Levi, Sakir H. Gultekin, Ricardo J. Komotar, and Michael E. Ivan

OBJECTIVE

In some centers where brain tumor surgery is performed, the opportunity for expert intraoperative neuropathology consultation is lacking. Consequently, surgeons may not have access to the highest quality diagnostic histological data to inform surgical decision-making. Stimulated Raman histology (SRH) is a novel technology that allows for rapid acquisition of diagnostic histological images at the bedside.

METHODS

The authors performed a prospective blinded cohort study of 82 consecutive patients undergoing resection of CNS tumors to compare diagnostic time and accuracy of SRH simulation to the gold standard, i.e., frozen and permanent section diagnosis. Diagnostic accuracy was determined by concordance of SRH-simulated intraoperative pathology consultation with a blinded board-certified neuropathologist, with official frozen section and permanent section results.

RESULTS

Overall, the mean time to diagnosis was 30.5 ± 13.2 minutes faster (p < 0.0001) for SRH simulation than for frozen section, with similar diagnostic correlation: 91.5% (κ = 0.834, p < 0.0001) between SRH simulation and permanent section, and 91.5% between frozen and permanent section (κ = 0.894, p < 0.0001).

CONCLUSIONS

SRH-simulated intraoperative pathology consultation was significantly faster and equally accurate as frozen section.