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Contributing Author Samuel R. Browd, M.D., Ph.D. December 1, 2020 Journal of Experimental Neurology Research

A Protocol for the Generation of Treatment-naïve Biopsy-derived Diffuse Intrinsic Pontine Glioma and Diffuse Midline Glioma Models

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal tumor of the brainstem, most commonly affecting young children. Due to its location, surgical resection is not achievable, but consideration of a biopsy has become standard practice at children’s hospitals with the appropriate neurosurgical expertise. While the decision to obtain a biopsy should be directed by the presence of atypical radiographic features that call the diagnosis of DIPG into question or the requirement of biopsy tissue for clinical trial enrollment, once this precious tissue is available its use for research should be considered. The majority of DIPG and diffuse midline glioma, H3 K27M-mutant (DMG) models are autopsy-derived or genetically-engineered, each of which has limitations for translational studies, so the use of biopsy tissue for laboratory model development provides an opportunity to create unique model systems. Here, we present a detailed laboratory protocol for the generation of treatment-naïve biopsy-derived DIPG/DMG models.

Journal of Experimental Neurology
Contributing Author Samuel R. Browd, M.D., Ph.D. April 2, 2021 Journal of Neurosurgery: Pediatrics Research

Development of best practices in the utilization and implementation of pediatric cervical spine traction: a modified Delphi study

OBJECTIVE Cervical traction in pediatric patients is an uncommon but invaluable technique in the management of cervical trauma and deformity. Despite its utility, little empirical evidence exists to guide its implementation, with most practitioners employing custom or modified adult protocols. Expert-based best practices may improve the care of children undergoing cervical traction. In this study, the authors aimed to build consensus and establish best practices for the use of pediatric cervical traction in order to enhance its utilization, safety, and efficacy. METHODS A modified Delphi method was employed to try to identify areas of consensus regarding the utilization and implementation of pediatric cervical spine traction. A literature review of pediatric cervical traction was distributed electronically along with a survey of current practices to a group of 20 board-certified pediatric neurosurgeons and orthopedic surgeons with expertise in the pediatric cervical spine. Sixty statements were then formulated and distributed to the group. The results of the second survey were discussed during an in-person meeting leading to further consensus. Consensus was defined as ≥ 80% agreement on a 4-point Likert scale (strongly agree, agree, disagree, strongly disagree). RESULTS After the initial round, consensus was achieved with 40 statements regarding the following topics: goals, indications, and contraindications of traction (12), pretraction imaging (6), practical application and initiation of various traction techniques (8), protocols in trauma and deformity patients (8), and management of traction-related complications (6). Following the second round, an additional 9 statements reached consensus related to goals/indications/contraindications of traction (4), related to initiation of traction (4), and related to complication management (1). All participants were willing to incorporate the consensus statements into their practice. CONCLUSIONS In an attempt to improve and standardize the use of cervical traction in pediatric patients, the authors have identified 49 best-practice recommendations, which were generated by reaching consensus among a multidisciplinary group of pediatric spine experts using a modified Delphi technique. Further study is required to determine if implementation of these practices can lead to reduced complications and improved outcomes for children.

Journal of Neurosurgery: Pediatrics
Contributing Author Samuel R. Browd, M.D., Ph.D. June 16, 2020 Journal of Neuro-Oncology Research

Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children’s Hospital experience

Introduction Beyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation. Methods We retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children’s Hospital from 2009 to 2018 and analyzed survival using the Kaplan–Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated. Results Median age at diagnosis was 10.9 years (18 months–18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG. Conclusion Our single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.

Journal of Neuro-Oncology
Contributing Author Samuel R. Browd, M.D., Ph.D. October 17, 2020 Child's Nervous System Research

Issues of consent and assent in pediatric neurosurgery

Background Consent and assent are important concepts to understand in the care of pediatric neurosurgery patients. Recently it has been recommended that although pediatric patients generally do not have the legal capacity to make medical decisions, they be encouraged to be involved in their own care. Given the paucity of information on this topic in the neurosurgery community, the objective is to provide pediatric neurosurgeons with recommendations on how to involve their patients in medical decision-making. Methods We review the essential elements and current guidelines of consent and assent for pediatric patients using illustrative neurosurgical case vignettes. Results The pediatric population ranges widely in cognitive and psychological development making the process of consent and assent quite complex. The role of the child or adolescent in medical decision-making, issues associated with obtaining assent or dissent, and informed refusal of treatment are considered. Conclusion The process of obtaining consent and assent represents a critical yet often overlooked aspect to care of pediatric neurosurgical patients. The pediatric neurosurgeon must be able to distill immensely complex and high-risk procedures into simple, understandable terms. Furthermore, they must recognize when the child’s dissent or refusal to treatment is acceptable. In general, allowing children to be involved in their neurosurgical care is empowering and gives them both identity and agency, which is the vital first step to a successful neurosurgical intervention.

Child's Nervous System
Contributing Author Samuel R. Browd, M.D., Ph.D. December 18, 2020 Journal of Neurosurgery: Pediatrics Research

Predictors of fast and ultrafast shunt failure in pediatric hydrocephalus: a Hydrocephalus Clinical Research Network study

OBJECTIVE The primary objective of this study was to use the prospective Hydrocephalus Clinical Research Network (HCRN) registry to determine clinical predictors of fast time to shunt failure (≤ 30 days from last revision) and ultrafast time to failure (≤ 7 days from last revision). METHODS Revisions (including those due to infection) to permanent shunt placements that occurred between April 2008 and November 2017 for patients whose entire shunt experience was recorded in the registry were analyzed. All registry data provided at the time of initial shunt placement and subsequent revision were reviewed. Key variables analyzed included etiology of hydrocephalus, age at time of initial shunt placement, presence of slit ventricles on imaging at revision, whether the ventricles were enlarged at the time of revision, and presence of prior fast failure events. Univariable and multivariable analyses were performed to find key predictors of fast and ultrafast failure events. RESULTS A cohort of 1030 patients with initial shunt insertions experienced a total of 1995 revisions. Of the 1978 revision events with complete records, 1216 (61.5%) shunts remained functional for more than 1 year, and 762 (38.5%) failed within 1 year of the procedure date. Of those that failed within 1 year, 423 (55.5%) failed slowly (31–365 days) and 339 (44.5%) failed fast (≤ 30 days). Of the fast failures, 131 (38.6%) were ultrafast (≤ 7 days). In the multivariable analysis specified a priori, etiology of hydrocephalus (p = 0.005) and previous failure history (p = 0.011) were independently associated with fast failure. Age at time of procedure (p = 0.042) and etiology of hydrocephalus (p = 0.004) were independently associated with ultrafast failure. These relationships in both a priori models were supported by the data-driven multivariable models as well. CONCLUSIONS Neither the presence of slit ventricle syndrome nor ventricular enlargement at the time of shunt failure appears to be a significant predictor of repeated, rapid shunt revisions. Age at the time of procedure, etiology of hydrocephalus, and the history of previous failure events seem to be important predictors of fast and ultrafast shunt failure. Further work is required to understand the mechanisms of these risk factors as well as mitigation strategies.

Journal of Neurosurgery: Pediatrics
Contributing Author Samuel R. Browd, M.D., Ph.D. November 1, 2021 Neurosurgical Focus Research

Medicolegal issues in abusive head trauma for the pediatric neurosurgeon

The purpose of this article is to serve as a rational guide for the pediatric neurosurgeon in navigating common medicolegal issues that arise in the management of abusive head trauma (AHT). Many of these issues may be unfamiliar or unpleasant to surgeons focused on addressing disease. The authors begin with a brief history on the origins of the diagnosis of AHT and the controversy surrounding it, highlighting some of the facets of the diagnosis that make it particularly unique in pediatric neurosurgery. They then review some special medical considerations in these patients through the perspective of the neurosurgeon and provide several examples as illustration. The authors discuss how to appropriately document these cases in the medical record for expected legal review, and last, they provide an overview of the legal process through which the neurosurgeon may be called to provide testimony.

Neurosurgical Focus
Contributing Author Samuel R. Browd, M.D., Ph.D. November 4, 2021 Child's Nervous System Research

The role of intra-operative neuroelectrophysiological monitoring in single-level approach selective dorsal rhizotomy

Objective Selective dorsal rhizotomy via a single-level approach (SL-SDR) to treat spasticity 100% relies on the interpretation of results from the intra-operative neuroelectrophysiological monitoring. The current study is to investigate the role EMG interpretation plays during SL-SDR procedure with regard to the selection of nerve rootlets for partially sectioning in pediatric cases with spastic cerebral palsy (CP). Methods A retrospective study was conducted in pediatric patients with spastic CP undergone our modified rhizotomy protocol-guided SL-SDR from May 2016 to Mar. 2019 in our hospital. Our study focused on intra-operative EMG interpretation and its correlation with pre-op evaluation results, and dorsal rootlet selection difference when data of our intra-operative EMG recordings interpreted using different rhizotomy protocols. Results Clinical and intra-operative neuroelectrophysiological monitoring data of a total of 318 consecutive cases were reviewed, which include 231 boys and 87 girls with 32 hemiplegias, 161 diplegias, and 125 quadriplegias. Age at the time of SL-SDR in those cases was between 3.0–14.0 (5.9 ± 1.9) years. The number of targeted muscle ranged from 2 to 8 over these cases (the muscle in lower limbs with its pre-op muscle tone ≥ 2 grade, Modified Ashworth scale). Among 21,728 nerve rootlets tested (68.3 ± 8.2/case), 6272 (28.9%) were identified sphincter related by our intra-operative neuromonitoring. In the rest of 15,456 (48.6 ± 7.6/case) nerve rootlets which neuromonitoring suggested associated with lower limbs, 11,009 were taken as the dorsal ones (34.6 ± 7.4/case). A total of 3370 (10.6 ± 4.7/case) rootlets matched our rhizotomy criteria with 3061 (9.6 ± 4.1/case) sectioned 50% and 309 (1.0 ± 1.0/case) cut 75%. The rhizotomy ratio (partially transected nerve rootlets/all dorsal rootlets associated with lower limbs in a particular case) was 15.8%, 22.3%, 33.4%, 41.8%, and 45.7% across cases with their pro-op GMFCS level from I to V, respectively. Rootlets required 75% cut had a tendency to increase as well in our cases with their pro-op GMFCS level from I to V, which comprising 1.5%, 4.8%, 8.5%, 14.1%, and 15.2% of all rootlets transected, respectively. The muscle tone of 2068 targeted muscles in these cases at the time of 3 weeks after the SL-SDR was revealed a significant decrease when compared to pre-op (1.7 ± 0.5 vs. 2.7 ± 0.6). Further investigation to compare our rootlet selection with the one guided by the traditional rhizotomy criteria using our intro-operative EMG recordings in 318 cases, revealed that the overlap ratio had a tendency to increase in cases when their pre-op GMFCS level increased (39.5%, 41.3%, 52.2%, 54.1%, and 62.8% in cases with levels I–V, respectively). While our modified rhizotomy protocol successfully identified 2–23 rootlets for sectioning in all of our 318 cases, the traditional rhizotomy protocol failed to distinguish any for cutting in about 20% of cases with their pre-op GMFCS levels I and II. Conclusions The rhizotomy criteria fully rely on the EMG interpretation making intra-operative neuroelectrophysiological monitoring crucial when SDR is performed via a single-level approach. Our modified rhizotomy protocol is feasible, safe, and effective to guide SL-SDR to treat all types of spastic CP cases by decreasing muscle tone in particular spastic muscle groups in their lower limbs. Data of EMG responses during SL-SDR procedure and as well as the clinical outcomes based on their interpretation could help clinicians to further understand how neuronal circuits work in the spinal cord of these patients.

Child's Nervous System
Contributing Author Samuel R. Browd, M.D., Ph.D. December 18, 2020 Journal of Neurosurgery: Pediatrics Research

Temporal trends in surgical procedures for pediatric hydrocephalus: an analysis of the Hydrocephalus Clinical Research Network Core Data Project

Objective: Analysis of temporal trends in patient populations and procedure types may provide important information regarding the evolution of hydrocephalus treatment. The purpose of this study was to use the Hydrocephalus Clinical Research Network's Core Data Project to identify meaningful trends in patient characteristics and the surgical management of pediatric hydrocephalus over a 9-year period. Methods: The Core Data Project prospectively collected patient and procedural data on the study cohort from 9 centers between 2008 and 2016. Logistic and Poisson regression were used to test for significant temporal trends in patient characteristics and new and revision hydrocephalus procedures. Results: The authors analyzed 10,149 procedures in 5541 patients. New procedures for hydrocephalus (shunt or endoscopic third ventriculostomy [ETV]) decreased by 1.5%/year (95% CI -3.1%, +0.1%). During the study period, new shunt insertions decreased by 6.5%/year (95% CI -8.3%, -4.6%), whereas new ETV procedures increased by 12.5%/year (95% CI 9.3%, 15.7%). Revision procedures for hydrocephalus (shunt or ETV) decreased by 4.2%/year (95% CI -5.2%, -3.1%), driven largely by a decrease of 5.7%/year in shunt revisions (95% CI -6.8%, -4.6%). Concomitant with the observed increase in new ETV procedures was an increase in ETV revisions (13.4%/year, 95% CI 9.6%, 17.2%). Because revisions decreased at a faster rate than new procedures, the Revision Quotient (ratio of revisions to new procedures) for the Network decreased significantly over the study period (p = 0.0363). No temporal change was observed in the age or etiology characteristics of the cohort, although the proportion of patients with one or more complex chronic conditions significantly increased over time (p = 0.0007). Conclusions: Over a relatively short period, important changes in hydrocephalus care have been observed. A significant temporal decrease in revision procedures amid the backdrop of a more modest change in new procedures appears to be the most notable finding and may be indicative of an improvement in the quality of surgical care for pediatric hydrocephalus. Further studies will be directed at elucidation of the possible drivers of the observed trends.

Journal of Neurosurgery: Pediatrics
Contributing Author Samuel R. Browd, M.D., Ph.D. January 1, 2020 Neurosurgical Focus Research

Progress in diffuse intrinsic pontine glioma: advocating for stereotactic biopsy in the standard of care

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor affecting approximately 300 children in the US annually. Median survival is less than 1 year, and radiation therapy has been the mainstay of treatment for decades. Recent advances in the biological understanding of the disease have identified the H3K27M mutation in nearly 80% of DIPGs, leading to the 2016 WHO classification of diffuse midline glioma H3K27M-mutant, a grade IV brainstem tumor. Developments in epigenetic targeting of transcriptional tendencies have yielded potential molecular targets for clinical trials. Chimeric antigen receptor T cell therapy has also shown preclinical promise. Recent clinical studies, including prospective trials, have demonstrated the safety and feasibility of pediatric brainstem biopsy in the setting of DIPG and other brainstem tumors. Given developments in the ability to analyze DIPG tumor tissue to deepen biological understanding of this disease and develop new therapies for treatment, together with the increased safety of stereotactic brainstem biopsy, the authors present a case for offering biopsy to all children with suspected DIPG. They also present their standard operative techniques for image-guided, frameless stereotactic biopsy.

Neurosurgical Focus
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