Cavernous sinus meningiomas (CSMs) are challenging lesions for the skull base neurosurgeon to manage given their close association with cranial nerves II–VI and the internal carotid artery. In the 1980s and early 1990s, with advancements in microsurgical techniques, increasing knowledge of the relevant microsurgical neuroanatomy, and the advent of advanced skull base surgical approaches, the treatment of CSMs involved attempts at gross-total resection (GTR). Initial fervor for a surgical cure waned, however, as skull base neurosurgeons demonstrated the limits of complete resection in this region, the ongoing issue of potential tumor recurrences, and the unacceptably high cranial nerve and vascular morbidity associated with this strategy. The advent of radiosurgery and its documented success for tumor growth control and limited morbidity in cavernous lesions has helped to shift the treatment goals for CSMs from GTR to tumor control and symptom relief while minimizing treatment- and lesion-associated morbidity. The authors review the relevant microanatomy of the cavernous sinus with anatomical and radiographic correlates, as well as the various treatment options. A modernized, multimodality treatment algorithm to guide management of these lesions is proposed.
Daniel R. Klinger, Bruno C. Flores, Jeremy J. Lewis and Samuel L. Barnett
Todd Hollon, Vincent Nguyen, Brandon W. Smith, Spencer Lewis, Larry Junck and Daniel A. Orringer
Survival rates and prognostic factors for supratentorial hemispheric ependymomas have not been determined. The authors therefore designed a retrospective study to determine progression-free survival (PFS), overall survival (OS), and prognostic factors for hemispheric ependymomas.
The study population consisted of 8 patients from our institution and 101 patients from the literature with disaggregated survival information (n = 109). Patient age, sex, tumor side, tumor location, extent of resection (EOR), tumor grade, postoperative chemotherapy, radiation, time to recurrence, and survival were recorded. Kaplan-Meier survival analyses and Cox proportional hazard models were completed to determine survival rates and prognostic factors.
Anaplastic histology/WHO Grade III tumors were identified in 62% of cases and correlated with older age. Three-, 5-, and 10-year PFS rates were 57%, 51%, and 42%, respectively. Three-, 5-, and 10-year OS rates were 77%, 71%, and 58%, respectively. EOR and tumor grade were identified on both Kaplan-Meier log-rank testing and univariate Cox proportional hazard models as prognostic for PFS and OS. Both EOR and tumor grade remained prognostic on multivariate analysis. Subtotal resection (STR) predicted a worse PFS (hazard ratio [HR] 4.764, p = 0.001) and OS (HR 4.216, p = 0.008). Subgroup survival analysis of patients with STR demonstrated a 5- and 10-year OS of 28% and 0%, respectively. WHO Grade III tumors also had worse PFS (HR 10.2, p = 0.004) and OS (HR 9.1, p = 0.035). Patients with WHO Grade III tumors demonstrated 5- and 10-year OS of 61% and 46%, respectively. Postoperative radiation was not prognostic for PFS or OS.
A high incidence of anaplastic histology was found in hemispheric ependymomas and was associated with older age. EOR and tumor grade were prognostic factors for PFS and OS on multivariate analysis. STR or WHO Grade III pathology, or both, predicted worse overall prognosis in patients with hemispheric ependymoma.
Todd Hollon, Spencer Lewis, Christian W. Freudiger, X. Sunney Xie and Daniel A. Orringer
Despite advances in the surgical management of brain tumors, achieving optimal surgical results and identification of tumor remains a challenge. Raman spectroscopy, a laser-based technique that can be used to nondestructively differentiate molecules based on the inelastic scattering of light, is being applied toward improving the accuracy of brain tumor surgery. Here, the authors systematically review the application of Raman spectroscopy for guidance during brain tumor surgery. Raman spectroscopy can differentiate normal brain from necrotic and vital glioma tissue in human specimens based on chemical differences, and has recently been shown to differentiate tumor-infiltrated tissues from noninfiltrated tissues during surgery. Raman spectroscopy also forms the basis for coherent Raman scattering (CRS) microscopy, a technique that amplifies spontaneous Raman signals by 10,000-fold, enabling real-time histological imaging without the need for tissue processing, sectioning, or staining. The authors review the relevant basic and translational studies on CRS microscopy as a means of providing real-time intraoperative guidance. Recent studies have demonstrated how CRS can be used to differentiate tumor-infiltrated tissues from noninfiltrated tissues and that it has excellent agreement with traditional histology. Under simulated operative conditions, CRS has been shown to identify tumor margins that would be undetectable using standard bright-field microscopy. In addition, CRS microscopy has been shown to detect tumor in human surgical specimens with near-perfect agreement to standard H & E microscopy. The authors suggest that as the intraoperative application and instrumentation for Raman spectroscopy and imaging matures, it will become an essential component in the neurosurgical armamentarium for identifying residual tumor and improving the surgical management of brain tumors.
Debayan Dasgupta, Linda D’Antona, Daniel Aimone Cat, Ahmed K. Toma, Carmel Curtis, Laurence D. Watkins and Lewis Thorne
Temporary CSF diversion through an external ventricular drain (EVD) comes with the risk of EVD-related infections (ERIs). The incidence of ERIs varies from 0.8% to 22%. ERIs increase mortality, morbidity, length of stay, and costs; require prolonged courses of antibiotics; and increase the need for subsequent permanent CSF diversion. The authors report the results of a quality improvement project designed to improve infection rates and EVD placement using simulation training in addition to a standardized perioperative care bundle. This project resulted not only in a decrease in ERIs, but also a significant improvement in surgical outcomes.
A best-practice standardized perioperative approach and care bundle was approved by consensus among the senior neurosurgeons at the authors’ institution, and a standardized operative note was designed to encourage adherence to policy and improve documentation. This approach was adapted from the bundle previously described by Kubilay et al. Simulation workshops were introduced to teach safe sampling technique, administration of intrathecal drugs, and a standardized operative technique using the Rowena head surgical model. Effects of the interventions on placement, infection rates, and displacement were measured at two distinct time points over a 2-year period.
Baseline audits demonstrated satisfactory EVD placement in 74%, an infection rate of 8.5%, and displacement occurring in 20%. In the 2 years following the interventions, satisfactory placement improved to 96%, infection rate fell to 4.8%, and inadvertent displacement occurred in only 1.7%.
Simulation training and standardizing the perioperative care of patients requiring EVDs dramatically improved placement accuracy, reduced infection rates, and reduced EVD displacement rate.
William G. B. Singleton, Alison S. Bienemann, Max Woolley, David Johnson, Owen Lewis, Marcella J. Wyatt, Stephen J. P. Damment, Lisa J. Boulter, Clare L. Killick-Cole, Daniel J. Asby and Steven S. Gill
The pan–histone deacetylase inhibitor panobinostat has preclinical efficacy against diffuse intrinsic pontine glioma (DIPG), and the oral formulation has entered a Phase I clinical trial. However, panobinostat does not cross the blood-brain barrier in humans. Convection-enhanced delivery (CED) is a novel neurosurgical drug delivery technique that bypasses the blood-brain barrier and is of considerable clinical interest in the treatment of DIPG.
The authors investigated the toxicity, distribution, and clearance of a water-soluble formulation of panobinostat (MTX110) in a small- and large-animal model of CED. Juvenile male Wistar rats (n = 24) received panobinostat administered to the pons by CED at increasing concentrations and findings were compared to those in animals that received vehicle alone (n = 12). Clinical observation continued for 2 weeks. Animals were sacrificed at 72 hours or 2 weeks following treatment, and the brains were subjected to neuropathological analysis. A further 8 animals received panobinostat by CED to the striatum and were sacrificed 0, 2, 6, or 24 hours after infusion, and their brains explanted and snap-frozen. Tissue-drug concentration was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). Large-animal toxicity was investigated using a clinically relevant MRI-guided translational porcine model of CED in which a drug delivery system designed for humans was used. Panobinostat was administered at 30 μM to the ventral pons of 2 juvenile Large White–Landrace cross pigs. The animals were subjected to clinical and neuropathological analysis, and findings were compared to those obtained in controls after either 1 or 2 weeks. Drug distribution was determined by LC-MS/MS in porcine white and gray matter immediately after CED.
There were no clinical or neuropathological signs of toxicity up to an infused concentration of 30 μM in both small- and large-animal models. The half-life of panobinostat in rat brain after CED was 2.9 hours, and the drug was observed to be distributed in porcine white and gray matter with a volume infusion/distribution ratio of 2 and 3, respectively.
CED of water-soluble panobinostat, up to a concentration of 30 μM, was not toxic and was distributed effectively in normal brain. CED of panobinostat warrants clinical investigation in patients with DIPG.
Michael J. Durkin, Kristen V. Dicks, Arthur W. Baker, Rebekah W. Moehring, Luke F. Chen, Daniel J. Sexton, Sarah S. Lewis and Deverick J. Anderson
The relationship between time of year and surgical site infection (SSI) following neurosurgical procedures is poorly understood. Authors of previous reports have demonstrated that rates of SSI following neurosurgical procedures performed during the summer months were higher compared with rates during other seasons. It is unclear, however, if this difference was related to climatological changes or inexperienced medical trainees (the July effect). The aim of this study was to evaluate for seasonal variation of SSI following spine surgery in a network of nonteaching community hospitals.
The authors analyzed 6 years of prospectively collected surveillance data (January 1, 2007, to December 31, 2012) from all laminectomies and spinal fusions from 20 hospitals in the Duke Infection Control Outreach Network of community hospitals. Surgical site infections were defined using National Healthcare Safety Network criteria and identified using standardized methods across study hospitals. Regression models were then constructed using Poisson distribution to evaluate for seasonal trends by month. Each analysis was first performed for all SSIs and then for SSIs caused by specific organisms or classes of organisms. Categorical analysis was performed using two separate definitions of summer: June through September (definition 1), and July through September (definition 2). The prevalence rate of SSIs during the summer was compared with the prevalence rate during the remainder of the year by calculating prevalence rate ratios and 95% confidence intervals.
The authors identified 642 SSIs following 57,559 neurosurgical procedures (overall prevalence rate = 1.11/100 procedures); 215 occurred following 24,466 laminectomies (prevalence rate = 0.88/100 procedures), and 427 following 33,093 spinal fusions (prevalence rate = 1.29/100 procedures). Common causes of SSI were Staphylococcus aureus (n = 380; 59%), coagulase-negative staphylococci (n = 90; 14%), and Escherichia coli (n = 41; 6.4%). Poisson regression models demonstrated increases in the rates of SSI during each of the summer months for all SSIs and SSIs due to gram-positive cocci, S. aureus, and methicillin-sensitive S. aureus. Categorical analysis confirmed that the rate of SSI during the 4-month summer period was higher than the rate during the remainder of the year, regardless of which definition for summer was used (definition 1, p = 0.008; definition 2, p = 0.003). Similarly, the rates of SSI due to grampositive cocci and S. aureus were higher during the summer months than the remainder of the year regardless of which definition of summer was used. However, the rate of SSI due to gram-negative bacilli was not.
The rate of SSI following fusion or spinal laminectomy/laminoplasty was higher during the summer in this network of community hospitals. The increase appears to be related to increases in SSIs caused by gram-positive cocci and, more specifically, S. aureus. Given the nonteaching nature of these hospitals, the findings demonstrate that increases in the rate of SSI during the summer are more likely related to ecological and/or environmental factors than the July effect.
Zarina S. Ali, Robert L. Bailey, Lawrence B. Daniels, Venus Vakhshori, Daniel J. Lewis, Alisha T. Hossain, Karlyndsay Y. Sitterley, John Y. K. Lee, Phillip B. Storm, Gregory G. Heuer and Sherman C. Stein
No clear treatment guidelines for pediatric craniopharyngiomas exist. The authors developed a decision analytical model to evaluate outcomes of 4 surgical approaches for craniopharyngiomas in children, including attempted gross-total resection (GTR), planned subtotal removal plus radiotherapy, biopsy plus radiotherapy, and endoscopic resections of all kinds.
Pooled data, including the authors' own experience, were used to create evidence tables, from which incidence, relative risks, and summary outcomes in quality-adjusted life years (QALYs) were calculated for the 4 management strategies.
Quality-adjusted life years at the 5-year follow-up were 2.3 ± 0.1 for attempted GTR, 2.9 ± 0.2 for planned subtotal removal plus radiotherapy, 3.9 ± 0.2 for biopsy plus radiotherapy, and 3.7 ± 0.2 for endoscopic resection (F = 17,150, p < 0.001). Similarly, QALYs at 10-year follow-up were 4.5 ± 0.2 for attempted GTR, 5.7 ± 0.5 for planned subtotal removal plus radiotherapy, and 7.8 ± 0.5 for biopsy plus radiotherapy (F = 6,173, p < 0.001). On post hoc pairwise comparisons, the differences between all pairs compared were also highly significant (p < 0.001). Since follow-up data at 10 years are lacking for endoscopic cases, this category was excluded from 10-year comparisons.
Biopsy with subsequent radiotherapy is the preferred approach with respect to improved overall quality of life. While endoscopic approaches also show promise in preserving quality of life at five-year follow-up, there are not sufficient data to draw conclusions about this comparison at 10 years.
Daniel Lewis, Carmine A. Donofrio, Claire O’Leary, Ka-loh Li, Xiaoping Zhu, Ricky Williams, Ibrahim Djoukhadar, Erjon Agushi, Cathal J. Hannan, Emma Stapleton, Simon K. Lloyd, Simon R. Freeman, Andrea Wadeson, Scott A. Rutherford, Charlotte Hammerbeck-Ward, D. Gareth Evans, Alan Jackson, Omar N. Pathmanaban, Federico Roncaroli, Andrew T. King and David J. Coope
Inflammation and angiogenesis may play a role in the growth of sporadic and neurofibromatosis type 2 (NF2)–related vestibular schwannoma (VS). The similarities in microvascular and inflammatory microenvironment have not been investigated. The authors sought to compare the tumor microenvironment (TME) in sporadic and NF2-related VSs using a combined imaging and tissue analysis approach.
Diffusion MRI and high-temporal-resolution dynamic contrast-enhanced (DCE) MRI data sets were prospectively acquired in 20 NF2-related and 24 size-matched sporadic VSs. Diffusion metrics (mean diffusivity, fractional anisotropy) and DCE-MRI–derived microvascular biomarkers (transfer constant [Ktrans], fractional plasma volume, tissue extravascular-extracellular space [ve], longitudinal relaxation rate, tumoral blood flow) were compared across both VS groups, and regression analysis was used to evaluate the effect of tumor size, pretreatment tumor growth rate, and tumor NF2 status (sporadic vs NF2-related) on each imaging parameter. Tissues from 17 imaged sporadic VSs and a separate cohort of 12 NF2-related VSs were examined with immunohistochemistry markers for vessels (CD31), vessel permeability (fibrinogen), and macrophage density (Iba1). The expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 was evaluated using immunohistochemistry, Western blotting, and double immunofluorescence.
Imaging data demonstrated that DCE-MRI–derived microvascular characteristics were similar in sporadic and NF2-related VSs. Ktrans (p < 0.001), ve (p ≤ 0.004), and tumoral free water content (p ≤ 0.003) increased with increasing tumor size and pretreatment tumor growth rate. Regression analysis demonstrated that with the exception of mean diffusivity (p < 0.001), NF2 status had no statistically significant effect on any of the imaging parameters or the observed relationship between the imaging parameters and tumor size (p > 0.05). Tissue analysis confirmed the imaging metrics among resected sporadic VSs and demonstrated that across all VSs studied, there was a close association between vascularity and Iba1+ macrophage density (r = 0.55, p = 0.002). VEGF was expressed by Iba1+ macrophages.
The authors present the first in vivo comparative study of microvascular and inflammatory characteristics in sporadic and NF2-related VSs. The imaging and tissue analysis results indicate that inflammation is a key contributor to TME and should be viewed as a therapeutic target in both VS groups.