- Brain Tumors
- Surgical epilepsy
- Arnold-Chiari Malformation
- Minimally invasive craniosynostosis
- Moya-moya disease
- Pediatric Neurological Surgery
Division Chief, Pediatric Neurosurgery (2014 - Present)
Boards, Advisory Committees, Professional Organizations
Section Editor, Neurosurgery (2014 - Present)
Education Chair, American Society of Pediatric Neurosurgery (2013 - Present)
Committee on Trauma, American College of Surgeons (2012 - Present)
Member at Large, Executive Commitee, Section of Pediatric Neurosurgery (2014 - Present)
Executive Committee, Congress of Neurological Surgeons (2014 - Present)
Board Certification: Pediatric Neurological Surgery, American Board of Pediatric Neurological Surgery (2008)
Fellowship:University of Washington (2002) WA
Residency:University of Washington (2001) WA
Internship:University of Washington (1995) WA
Board Certification: Neurological Surgery, American Board of Neurological Surgery (2005)
Medical Education:Stanford University School of Medicine (1994) CA
Bachelor of Sciences, Duke University, Neurosciences (1989)
Community and International Work
Stanford Neurosurgery in Uganda, Mulago Hospital
Opportunities for Student Involvement
Current Research and Scholarly Interests
Dr. Grant directs a Blood-brain Barrier Translational Laboratory focusing on enhancing drug delivery to brain tumors in children.
- Narratives in Neurosurgery
NSUR 200 (Spr)
- Independent Studies (5)
- Prior Year Courses
Topical vancomycin for surgical prophylaxis in non-instrumented pediatric spinal surgeries.
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery
STUDY DESIGN: Retrospective cohort study.OBJECTIVE: To determine if topical vancomycin irrigation reduces the incidence of post-operative surgical site infections following pediatric spinal procedures. Surgical site infections (SSIs) following spinal procedures performed in pediatric patients represent a serious complication. Prophylactic use of topical vancomycin prior to closure has been shown to be effective in reducing incidence of SSIs in adult spinal procedures. Non-instrumented cases make up the majority of spinal procedures in pediatric patients, and the efficacy of prophylactic topical vancomycin in these procedures has not previously been reported.METHODS: This retrospective study reviewed all non-instrumented spinal procedures performed over a period from 05/2014-12/2016 for topical vancomycin use, surgical site infections, and clinical variables associated with SSI. Topical vancomycin was utilized as infection prophylaxis, and applied as a liquid solution within the wound prior to closure.RESULTS: Ninety-five consecutive, non-instrumented, pediatric spinal surgeries were completed between 01/2015 and 12/2016, of which the last 68 utilized topical vancomycin. There was a 11.1% SSI rate in the non-topical vancomycin cohort versus 0% in the topical vancomycin cohort (P=0.005). The number needed to treat was 9. There were no significant differences in risk factors for SSI between cohorts. There were no complications associated topical vancomycin use.CONCLUSIONS: Routine topical vancomycin administration during closure of non-instrumented spinal procedures can be a safe and effective tool for reducing SSIs in the pediatric neurosurgical population.
View details for DOI 10.1007/s00381-018-3881-z
View details for PubMedID 29955942
- In Reply: Neurosurgical Randomized Controlled Trials-Distance Traveled. Neurosurgery 2018
Safety of Dynamic MRI of the Cervical Spine in Children Performed Without Neurosurgical Supervision.
OBJECT: The need for neurosurgical supervision as well as the general safety and utility of dynamic MRI of the cervical spine in children remains controversial. We present the largest descriptive cohort study of cervical flexion-extension MRIs in a pediatric population to help elucidate the safety and utility of this technique.METHODS: All cervical spine MRIs performed at Lucile Packard Children's Hospital at Stanford from 2009-2015 were retrospectively reviewed. Sixty-six dynamic cervical MRIs performed in 45 children and two young adults were identified for further study.RESULTS: Forty-three scans were imaged under general anesthesia. All imaging was performed by the neuroradiology team with no direct supervision by the neurosurgery team. There were no adverse events. Dynamic MRI detected significant instability that was not clearly seen on dynamic radiographs (5 patients) as well as cord compression not seen on static MR scans (9 patients). One patient with asymptomatic instability found on flexion-extension radiographs had no cord compression with movement on MRI and was managed conservatively. Two neonates with significant congenital malformations of the cervical spine were cleared for OR positioning for cardiac procedures based on flexion-extension MR imaging.CONCLUSIONS: Dynamic MRI represents a safe and useful tool for evaluating the cervical spine and cervicomedullary junction in a variety of pediatric patient populations and can be performed safely without direct neurosurgical supervision. Additionally, we describe for the first time the use of flexion-extension MRI to clear neonates with severe congenital cervical spine abnormalities for complex operative positioning and ICU care.
View details for DOI 10.1016/j.wneu.2018.05.210
View details for PubMedID 29883828
White matter abnormalities in mild traumatic brain injury with and without post-traumatic stress disorder: a subject-specific diffusion tensor imaging study
BRAIN IMAGING AND BEHAVIOR
2018; 12 (3): 870–81
Mild traumatic brain injuries (mTBIs) are often associated with posttraumatic stress disorder (PTSD). In cases of chronic mTBI, accurate diagnosis can be challenging due to the overlapping symptoms this condition shares with PTSD. Furthermore, mTBIs are heterogeneous and not easily observed using conventional neuroimaging tools, despite the fact that diffuse axonal injuries are the most common injury. Diffusion tensor imaging (DTI) is sensitive to diffuse axonal injuries and is thus more likely to detect mTBIs, especially when analyses account for the inter-individual variability of these injuries. Using a subject-specific approach, we compared fractional anisotropy (FA) abnormalities between groups with a history of mTBI (n = 35), comorbid mTBI and PTSD (mTBI + PTSD; n = 22), and healthy controls (n = 37). We compared all three groups on the number of abnormal FA clusters derived from subject-specific injury profiles (i.e., individual z-score maps) along a common white matter skeleton. The mTBI + PTSD group evinced a greater number of abnormally low FA clusters relative to both the healthy controls and the mTBI group without PTSD (p < .05). Across the groups with a history of mTBI, increased numbers of abnormally low FA clusters were significantly associated with PTSD symptom severity, depression, post-concussion symptoms, and reduced information processing speed (p < .05). These findings highlight the utility of subject-specific microstructural analyses when searching for mTBI-related brain abnormalities, particularly in patients with PTSD. This study also suggests that patients with a history of mTBI and comorbid PTSD, relative to those without PTSD, are at increased risk of FA abnormalities.
View details for DOI 10.1007/s11682-017-9744-5
View details for Web of Science ID 000434491400023
View details for PubMedID 28676987
View details for PubMedCentralID PMC5756136
RE-MATCH PROTOCOL: PHASE I STUDY OF AUTOLOGOUS TUMOR SPECIFIC LYMPHOCYTE TRANSFER (ALT) plus DC VACCINE (DCV) DURING RECOVERY FROM MYELOABLATIVE CHEMOTHERAPY (MAC) AND AUTOLOGOUS STEM CELL RESCUE (HDC plus ASCR) OR NON-MYELOABLATIVE CHEMOTHERAPY (NMAC) IN PATIENTS WITH RECURRENT CENTRAL PNETS (R-PNET)
OXFORD UNIV PRESS INC. 2018: 104
View details for Web of Science ID 000438339000345
ASL PERFUSION IMAGING OF THE FRONTAL LOBES PREDICTS THE OCCURRENCE AND RESOLUTION OF POSTERIOR FOSSA SYNDROME
OXFORD UNIV PRESS INC. 2018: 170
View details for Web of Science ID 000438339000645
A Combination of Ontogeny and CNS Environment Establishes Microglial Identity.
Microglia, the brain's resident macrophages, are dynamic CNS custodians with surprising origins in the extra-embryonic yolk sac. The consequences of their distinct ontogeny are unknown but critical to understanding and treating brain diseases. We created a brain macrophage transplantation system to disentangle how environment and ontogeny specify microglial identity. We find that donor cells extensively engraft in the CNS of microglia-deficient mice, and even after exposure to a cell culture environment, microglia fully regain their identity when returned to the CNS. Though transplanted macrophages from multiple tissues can express microglial genes in the brain, only those of yolk-sac origin fully attain microglial identity. Transplanted macrophages of inappropriate origin, including primary human cells in a humanized host, express disease-associated genes and specific ontogeny markers. Through brain macrophage transplantation, we discover new principles of microglial identity that have broad applications to the study of disease and development of myeloid cell therapies.
View details for DOI 10.1016/j.neuron.2018.05.014
View details for PubMedID 29861285
Minimally invasive approaches to craniosynostosis.
Journal of neurosurgical sciences
Craniosynostosis (CS) is defined as the premature fusion of one or more calvarial sutures. This carries several consequences, including abnormal/asymmetric cranial vault development, increased intracranial pressure, compromised neurocognitive development, and craniofacial deformity. Definitive management is surgical with the goal of protecting cerebral development by re-establishing normal cranial vault expansion and correcting cosmetic deformity. In today's practice, CS surgery has advanced radically from simple craniectomies to major cranial vault reconstructive (CVR) procedures. More recently there has been considerable interest in endoscopic assisted surgery (EAS). Theoretical benefits include decreased operative time, morbidity, blood loss, postoperative pain, cost and faster recovery times. In this focused review, we summarize the current body of literature reporting clinical outcomes in EAS and review the data comparing EAS and CVR.
View details for DOI 10.23736/S0390-5616.18.04483-1
View details for PubMedID 29790726
Improved operative efficiency using a real-time MRI-guided stereotactic platform for laser amygdalohippocampotomy
JOURNAL OF NEUROSURGERY
2018; 128 (4): 1165–72
OBJECTIVE MR-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive method for thermal destruction of benign or malignant tissue that has been used for selective amygdalohippocampal ablation for the treatment of temporal lobe epilepsy. The authors report their initial experience adopting a real-time MRI-guided stereotactic platform that allows for completion of the entire procedure in the MRI suite. METHODS Between October 2014 and May 2016, 17 patients with mesial temporal sclerosis were selected by a multidisciplinary epilepsy board to undergo a selective amygdalohippocampal ablation for temporal lobe epilepsy using MRgLITT. The first 9 patients underwent standard laser ablation in 2 phases (operating room [OR] and MRI suite), whereas the next 8 patients underwent laser ablation entirely in the MRI suite with the ClearPoint platform. A checklist specific to the real-time MRI-guided laser amydalohippocampal ablation was developed and used for each case. For both cohorts, clinical and operative information, including average case times and accuracy data, was collected and analyzed. RESULTS There was a learning curve associated with using this real-time MRI-guided system. However, operative times decreased in a linear fashion, as did total anesthesia time. In fact, the total mean patient procedure time was less in the MRI cohort (362.8 ± 86.6 minutes) than in the OR cohort (456.9 ± 80.7 minutes). The mean anesthesia time was significantly shorter in the MRI cohort (327.2 ± 79.9 minutes) than in the OR cohort (435.8 ± 78.4 minutes, p = 0.02). CONCLUSIONS The real-time MRI platform for MRgLITT can be adopted in an expedient manner. Completion of MRgLITT entirely in the MRI suite may lead to significant advantages in procedural times.
View details for DOI 10.3171/2017.1.JNS162046
View details for Web of Science ID 000429045500258
View details for PubMedID 28665249
Temporal Delays Along the Neurosurgical Care Continuum for Traumatic Brain Injury Patients at a Tertiary Care Hospital in Kampala, Uganda.
BACKGROUND: Significant care continuum delays between acute traumatic brain injury (TBI) and definitive surgery are associated with poor outcomes. Use of the "3 delays" model to evaluate TBI outcomes in low- and middle-income countries has not been performed.OBJECTIVE: To describe the care continuum, using the 3 delays framework, and its association with TBI patient outcomes in Kampala, Uganda.METHODS: Prospective data were collected for 563 TBI patients presenting to a tertiary hospital in Kampala from 1 June to 30 November 2016. Four time intervals were constructed along 5 time points: injury, hospital arrival, neurosurgical evaluation, computed tomography (CT) results, and definitive surgery. Time interval differences among mild, moderate, and severe TBI and their association with mortality were analyzed.RESULTS: Significant care continuum differences were observed for interval 3 (neurosurgical evaluation to CT result) and 4 (CT result to surgery) between severe TBI patients (7 h for interval 3 and 24 h for interval 4) and mild TBI patients (19 h for interval 3 and 96 h for interval 4). These postarrival delays were associated with mortality for mild (P=.05) and moderate TBI (P=.03) patients. Significant hospital arrival delays for moderate TBI patients were associated with mortality (P=.04).CONCLUSION: Delays for mild and moderate TBI patients were associated with mortality, suggesting that quality improvement interventions could target current triage practices. Future research should aim to understand the contributors to delays along the care continuum, opportunities for more effective resource allocation, and the need to improve prehospital logistical referral systems.
View details for DOI 10.1093/neuros/nyy004
View details for PubMedID 29490070
- Occipital Dermal Sinus Tract JOURNAL OF PEDIATRICS 2018; 193: 276
Multi-site harmonization of diffusion MRI data in a registration framework
BRAIN IMAGING AND BEHAVIOR
2018; 12 (1): 284–95
Diffusion MRI (dMRI) data acquired on different scanners varies significantly in its content throughout the brain even if the acquisition parameters are nearly identical. Thus, proper harmonization of such data sets is necessary to increase the sample size and thereby the statistical power of neuroimaging studies. In this paper, we present a novel approach to harmonize dMRI data (the raw signal, instead of dMRI derived measures such as fractional anisotropy) using rotation invariant spherical harmonic (RISH) features embedded within a multi-modal image registration framework. All dMRI data sets from all sites are registered to a common template and voxel-wise differences in RISH features between sites at a group level are used to harmonize the signal in a subject-specific manner. We validate our method on diffusion data acquired from seven different sites (two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across these sites before and after data harmonization. Validation was also done on a group oftest subjects, which were not used to "learn" the harmonization parameters. We also show results using TBSS before and after harmonization for independent validation of the proposed methodology. Using synthetic data, we show that any abnormality in diffusion measures due to disease is preserved during the harmonization process. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences in the signal can be removed using the proposed method in a model independent manner.
View details for DOI 10.1007/s11682-016-9670-y
View details for Web of Science ID 000425307500025
View details for PubMedID 28176263
First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800.
Journal of neuro-oncology
Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection.Fluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue.The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 ± 0.5) compared to non-CE tumors (1.2 ± 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence.This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.
View details for DOI 10.1007/s11060-018-2854-0
View details for PubMedID 29623552
Life After the Neurosurgical Ward in SubSaharan Africa: Neurosurgical Treatment and Outpatient Outcomes in Uganda.
In the past decade, neurosurgery in Uganda experienced increasing surgical volume and a new residency training program. While research has examined surgical capacity, minimal data exists on the patient population treated by neurosurgery and their eventual outcomes in sub-Saharan Africa.Patients admitted to Mulago National Referral Hospital neurosurgical ward over two years (2014 and 2015) were documented in a prospective database. 1167 were discharged with documented phone numbers, thus eligible for follow-up. Phone surveys were developed and conducted in the participant's language to assess mortality, neurological outcomes, and follow-up healthcare.During the study period, 2032 patients were admitted to the neurosurgical ward, 80% for traumatic brain injury. 7.8% received surgical intervention. The in-hospital mortality rate was 18%. 870 patients were reached for phone follow-up, a 75% response rate. 30-day and 1-year mortality was 4% and 8%, respectively. Almost half of patients had not had subsequent healthcare after the initial encounter. Most patients had GOS-E scores consistent with good recovery and mild disability - trauma patients faring best and tumor patients faring worst. 85% felt they returned to baseline work performance, and 76% of guardians felt that children returned to baseline school performance.The neurosurgical service provided healthcare to a large proportion of non-operative patients. Phone surveys captured data on patients where nearly half would be lost to subsequent healthcare. While mortality during initial hospitalization was high, over 90% of those discharged survived at 1 year follow up, and the vast majority returned to work and school.
View details for DOI 10.1016/j.wneu.2018.01.204
View details for PubMedID 29427813
High-resolution 3D volumetric contrast-enhanced MR angiography with a blood pool agent (ferumoxytol) for diagnostic evaluation of pediatric brain arteriovenous malformations.
Journal of neurosurgery. Pediatrics
OBJECTIVE Patients with brain arteriovenous malformations (AVMs) often require repeat imaging with MRI or MR angiography (MRA), CT angiography (CTA), and digital subtraction angiography (DSA). The ideal imaging modality provides excellent vascular visualization without incurring added risks, such as radiation exposure. The purpose of this study is to evaluate the performance of ferumoxytol-enhanced MRA using a high-resolution 3D volumetric sequence (fe-SPGR) for visualizing and grading pediatric brain AVMs in comparison with CTA and DSA, which is the current imaging gold standard. METHODS In this retrospective cohort study, 21 patients with AVMs evaluated by fe-SPGR, CTA, and DSA between April 2014 and August 2017 were included. Two experienced raters graded AVMs using Spetzler-Martin criteria on all imaging studies. Lesion conspicuity (LC) and diagnostic confidence (DC) were assessed using a 5-point Likert scale, and interrater agreement was determined. The Kruskal-Wallis test was performed to assess the raters' grades and scores of LC and DC, with subsequent post hoc pairwise comparisons to assess for statistically significant differences between pairs of groups at p < 0.05. RESULTS Assigned Spetzler-Martin grades for AVMs on DSA, fe-SPGR, and CTA were not significantly different (p = 0.991). LC and DC scores were higher with fe-SPGR than with CTA (p < 0.05). A significant difference in LC scores was found between CTA and fe-SPGR (p < 0.001) and CTA and DSA (p < 0.001) but not between fe-SPGR and DSA (p = 0.146). A significant difference in DC scores was found among DSA, fe-SPGR, and CTA (p < 0.001) and between all pairs of the groups (p < 0.05). Interrater agreement was good to very good for all image groups (κ = 0.77-1.0, p < 0.001). CONCLUSIONS Fe-SPGR performed robustly in the diagnostic evaluation of brain AVMs, with improved visual depiction of AVMs compared with CTA and comparable Spetzler-Martin grading relative to CTA and DSA.
View details for DOI 10.3171/2018.3.PEDS17723
View details for PubMedID 29882734
- Long-term outcomes of primarily metastatic juvenile pilocytic astrocytoma in children JOURNAL OF NEUROSURGERY-PEDIATRICS 2018; 21 (1): 49–53
- Fractal structure in the volumetric contrast enhancement of malignant gliomas as a marker of oxidative metabolic pathway gene expression TRANSLATIONAL CANCER RESEARCH 2017; 6 (6): 1275-+
Regulatory T cell subsets in patients with medulloblastoma at diagnosis and during standard irradiation and chemotherapy (PBTC N-11)
CANCER IMMUNOLOGY IMMUNOTHERAPY
2017; 66 (12): 1589–95
We evaluated circulating levels of immunosuppressive regulatory T cells (Tregs) and other lymphocyte subsets in patients with newly diagnosed medulloblastoma (MBL) undergoing surgery compared to a control cohort of patients undergo craniectomy for correction of Chiari malformation (CM) and further determined the impact of standard irradiation and chemotherapy on this cell population.Eligibility criteria for this biologic study included age 4-21 years, patients with CM undergoing craniectomy (as non-malignant surgical controls) and receiving dexamethasone for prevention of post-operative nausea, and those with newly diagnosed posterior fossa tumors (PFT) undergoing surgical resection and receiving dexamethasone as an anti-edema measure. Patients with confirmed MBL were also followed for longitudinal blood collection and analysis during radiotherapy and chemotherapy.A total of 54 subjects were enrolled on the study [22-CM, 18-MBL, and 14-PFT]. Absolute number and percentage Tregs (defined as CD4+CD25+FoxP3+CD127low/-) at baseline were decreased in MBL and PFT compared to CM [p = 0.0016 and 0.001, respectively). Patients with MBL and PFT had significantly reduced overall CD4+ T cell count (p = 0.0014 and 0.0054, respectively) compared to those with CM. Radiation and chemotherapy treatment in patients with MBL reduced overall lymphocyte counts; however, within the CD4+ T cell compartment, Tregs increased during treatment but gradually declined post therapy.Our results demonstrate that patients with MBL and PFT exhibit overall reduced CD4+ T cell counts at diagnosis but not an elevated proportion of Tregs. Standard treatment exacerbates lymphopenia in those with MBL while enriching for immunosuppressive Tregs over time.
View details for DOI 10.1007/s00262-017-2051-6
View details for Web of Science ID 000414762600007
View details for PubMedID 28825123
View details for PubMedCentralID PMC5677543
Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial
CRITICAL CARE MEDICINE
2017; 45 (11): 1907–14
A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study.Randomized prospective clinical trial.Ten ICUs in the United States.One hundred nineteen severe traumatic brain injury patients.Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended.A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy.Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.
View details for DOI 10.1097/CCM.0000000000002619
View details for Web of Science ID 000417107000052
View details for PubMedID 29028696
View details for PubMedCentralID PMC5679063
A prospective neurosurgical registry evaluating the clinical care of traumatic brain injury patients presenting to Mulago National Referral Hospital in Uganda
2017; 12 (10): e0182285
Traumatic Brain Injury (TBI) is disproportionally concentrated in low- and middle-income countries (LMICs), with the odds of dying from TBI in Uganda more than 4 times higher than in high income countries (HICs). The objectives of this study are to describe the processes of care and determine risk factors predictive of poor outcomes for TBI patients presenting to Mulago National Referral Hospital (MNRH), Kampala, Uganda.We used a prospective neurosurgical registry based on Research Electronic Data Capture (REDCap) to systematically collect variables spanning 8 categories. Univariate and multivariate analysis were conducted to determine significant predictors of mortality.563 TBI patients were enrolled from 1 June- 30 November 2016. 102 patients (18%) received surgery, 29 patients (5.1%) intended for surgery failed to receive it, and 251 patients (45%) received non-operative management. Overall mortality was 9.6%, which ranged from 4.7% for mild and moderate TBI to 55% for severe TBI patients with GCS 3-5. Within each TBI severity category, mortality differed by management pathway. Variables predictive of mortality were TBI severity, more than one intracranial bleed, failure to receive surgery, high dependency unit admission, ventilator support outside of surgery, and hospital arrival delayed by more than 4 hours.The overall mortality rate of 9.6% in Uganda for TBI is high, and likely underestimates the true TBI mortality. Furthermore, the wide-ranging mortality (3-82%), high ICU fatality, and negative impact of care delays suggest shortcomings with the current triaging practices. Lack of surgical intervention when needed was highly predictive of mortality in TBI patients. Further research into the determinants of surgical interventions, quality of step-up care, and prolonged care delays are needed to better understand the complex interplay of variables that affect patient outcome. These insights guide the development of future interventions and resource allocation to improve patient outcomes.
View details for DOI 10.1371/journal.pone.0182285
View details for Web of Science ID 000414088900001
View details for PubMedID 29088217
View details for PubMedCentralID PMC5663334
Diffusion Tensor Imaging in an Infant Undergoing Functional Hemispherectomy: A Surgical Aid.
2017; 9 (9): e1697
Hemispherectomy is a highly effective treatment option for children with severe, unilateral, medically refractory epilepsy. Many patients undergoing hemispherectomy are younger patients with dysmorphic brains, making accomplishing a complete disconnectionchallenging due to anatomic distortion, even with the aid of intraoperative navigation. Diffusion tensor imaging (DTI) has been proposed as a valuable imaging adjunct perioperatively to help guide surgeons intraoperatively, as well as for post-surgical evaluation and confirmation of complete hemispheric disconnection.We present a case of an infant with Otoharra syndrome and hemimegencephaly who underwent a functional hemispherectomy for treatment of severe, refractory seizures. We demonstrate how DTI was utilized both pre-, intra-, and postoperatively to help plan, guide, and confirm surgical disconnection. The application of exquisite DTI for this child led to her being seizure-free, which is a life-changing event with long-lasting benefits and will become even more critical as we now perform these disconnection procedures with a more minimally invasive approach.
View details for DOI 10.7759/cureus.1697
View details for PubMedID 29167751
- R-SCAN: Imaging for Pediatric Simple Febrile Seizures. Journal of the American College of Radiology 2017
- Modeling and Optimization of Airbag Helmets for Preventing Head Injuries in Bicycling ANNALS OF BIOMEDICAL ENGINEERING 2017; 45 (4): 1148-1160
Disrupting the CD47-SIRP alpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors
SCIENCE TRANSLATIONAL MEDICINE
2017; 9 (381)
Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.
View details for DOI 10.1126/scitranslmed.aaf2968
View details for Web of Science ID 000396307600001
View details for PubMedID 28298418
Perioperative outcomes for pediatric neurosurgical procedures: analysis of the National Surgical Quality Improvement Program-Pediatrics
JOURNAL OF NEUROSURGERY-PEDIATRICS
2017; 19 (3): 361-371
OBJECTIVE Existing studies have shown a high overall rate of adverse events (AEs) following pediatric neurosurgical procedures. However, little is known regarding the morbidity of specific procedures or the association with risk factors to help guide quality improvement (QI) initiatives. The goal of this study was to describe the 30-day mortality and AE rates for pediatric neurosurgical procedures by using the American College of Surgeons (ACS) National Surgical Quality Improvement Program-Pediatrics (NSQIP-Peds) database platform. METHODS Data on 9996 pediatric neurosurgical patients were acquired from the 2012-2014 NSQIP-Peds participant user file. Neurosurgical cases were analyzed by the NSQIP-Peds targeted procedure categories, including craniotomy/craniectomy, defect repair, laminectomy, shunts, and implants. The primary outcome measure was 30-day mortality, with secondary outcomes including individual AEs, composite morbidity (all AEs excluding mortality and unplanned reoperation), surgical-site infection, and unplanned reoperation. Univariate analysis was performed between individual AEs and patient characteristics using Fischer's exact test. Associations between individual AEs and continuous variables (duration from admission to operation, work relative value unit, and operation time) were examined using the Student t-test. Patient characteristics and continuous variables associated with any AE by univariate analysis were used to develop category-specific multivariable models through backward stepwise logistic regression. RESULTS The authors analyzed 3383 craniotomy/craniectomy, 242 defect repair, 1811 laminectomy, and 4560 shunt and implant cases and found a composite overall morbidity of 30.2%, 38.8%, 10.2%, and 10.7%, respectively. Unplanned reoperation rates were highest for defect repair (29.8%). The mortality rate ranged from 0.1% to 1.2%. Preoperative ventilator dependence was a significant predictor of any AE for all procedure groups, whereas admission from outside hospital transfer was a significant predictor of any AE for all procedure groups except craniotomy/craniectomy. CONCLUSIONS This analysis of NSQIP-Peds, a large risk-adjusted national data set, confirms low perioperative mortality but high morbidity for pediatric neurosurgical procedures. These data provide a baseline understanding of current expected clinical outcomes for pediatric neurosurgical procedures, identify the need for collecting neurosurgery-specific risk factors and complications, and should support targeted QI programs and clinical management interventions to improve care of children.
View details for DOI 10.3171/2016.10.PEDS16414
View details for Web of Science ID 000394925800014
View details for PubMedID 28059679
The clinical and financial impact of a pediatric surgical neuro-oncology clinical trial
JOURNAL OF NEURO-ONCOLOGY
2017; 132 (1): 83-87
Pediatric surgical trials are rare and the impact of such trials on the institutions in which they are conducted is unknown. The purpose of this study was to analyze the clinical and financial impact of The Re-MATCH trial, a Phase I clinical trial requiring the biopsy or resection of recurrent medulloblastoma or PNET for enrollment. Inpatient financial and clinical volume information was collected during the 3 years of trial enrollment and the years preceding and following it. The primary endpoints were the difference in direct contribution margin (DCM), or net gain, of study and non-study patients and the difference in surgical volume during the study and non-study periods. The trial enrolled 18 patients; 15 had surgery at the sponsor institution and three had surgery at their home institution, then transferred tumor material to the sponsor institution. There were no differences between the two groups for potentially confounding variables such as neurosurgical procedure work relative value units (P = 0.13) or insurance provider (P = 0.26). There was no difference between the inpatient DCM per case for the institution for non-study patients (mean ± SD, $9039 ± $28,549) and study patients ($14,332 ± $20,231) (P = 0.4819). During the non-study period, there were a mean of 2.78 ± 1.65 pediatric brain tumor resections per month compared to 3.34 ± 1.66 cases per month during the study period, a 17% increase. When the 15 study patients were excluded, there were 2.97 ± 1.64 cases per month, a 7% increase. However, this increase in total case volume including study and non-study patients was not significant (P = 0.121). Phase I investigator-initiated surgically-based clinical trials may increase institutional surgical volume without imposing a financial burden. Finances are unlikely to be a barrier for researchers negotiating for resources to conduct such trials.
View details for DOI 10.1007/s11060-016-2338-z
View details for Web of Science ID 000398052800010
Brain Perfusion and Diffusion Abnormalities in Children Treated for Posterior Fossa Brain Tumors.
journal of pediatrics
To compare cerebral perfusion and diffusion in survivors of childhood posterior fossa brain tumor with neurologically normal controls and correlate differences with cognitive dysfunction.We analyzed retrospectively arterial spin-labeled cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) in 21 patients with medulloblastoma (MB), 18 patients with pilocytic astrocytoma (PA), and 64 neurologically normal children. We generated ANCOVA models to evaluate treatment effects on the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, and cerebral white matter at time points an average of 5.7 years after original diagnosis. A retrospective review of patient charts identified 12 patients with neurocognitive data and in whom the relationship between IQ and magnetic resonance imaging variables was assessed for each brain structure.Patients with MB (all treated with surgery, chemotherapy, and radiation) had significantly lower global CBF relative to controls (10%-23% lower, varying by anatomic region, all adjusted P < .05), whereas patients with PA (all treated with surgery alone) had normal CBF. ADC was decreased specifically in the hippocampus and amygdala of patients with MB and within the amygdala of patients with PA but otherwise remained normal after therapy. In the patients with tumor previously evaluated for IQ, regional ADC, but not CBF, correlated with IQ (R(2) = 0.33-0.75).The treatment for MB, but not PA, was associated with globally reduced CBF. Treatment in both tumor types was associated with diffusion abnormalities of the mesial temporal lobe structures. Despite significant perfusion abnormalities in patients with MB, diffusion, but not perfusion, correlated with cognitive outcomes.
View details for DOI 10.1016/j.jpeds.2017.01.019
View details for PubMedID 28187964
- R-SCAN: Imaging for Pediatric Minor Head Trauma. Journal of the American College of Radiology 2017; 14 (2): 294-297
Neurosurgical Randomized Controlled Trials-Distance Travelled.
The evidence base for many neurosurgical procedures has been limited. We performed a comprehensive and systematic analysis of study design, quality of reporting, and trial results of neurosurgical randomized controlled trials (RCTs).To systematically assess the design and quality characteristics of neurosurgical RCTs.From January 1961 to June 2016, RCTs with >5 patients assessing any 1 neurosurgical procedure against another procedure, nonsurgical treatment, or no treatment were retrieved from MEDLINE, Scopus, and Cochrane Library.The median sample size in the 401 eligible RCTs was 73 patients with a mean patient age of 49.6. Only 111 trials (27.1%) described allocation concealment, 140 (34.6%) provided power calculations, and 117 (28.9%) were adequately powered. Significant efficacy or trend for efficacy was claimed in 226 reports (56.4%), no difference between the procedures was found in 166 trials (41.4%), and significant harm was reported in 9 trials (2.2%). Trials with a larger sample size were more likely to report randomization mode, specify allocation concealment, and power calculations (all P < .001). Government funding was associated with better specification of power calculations ( P = .008) and of allocation concealment ( P = .026), while industry funding was associated with reporting significant efficacy ( P = .02). Reporting of funding, specification of randomization mode and primary outcomes, and mention of power calculations improved significantly (all, P < .05) over time.Several aspects of the design and reporting of RCTs on neurosurgical procedures have improved over time. Better powered and accurately reported trials are needed in neurosurgery to deliver evidence-based care and achieve optimal outcomes.
View details for DOI 10.1093/neuros/nyx319
View details for PubMedID 28645203
Diagnostic Utility of Intraoperative Neurophysiological Monitoring for Intramedullary Spinal Cord Tumors: Systematic Review and Meta-Analysis.
Clinical spine surgery
Systematic review and meta-analysis.The aim of this study was to systematically evaluate the diagnostic utility of intraoperative neurophysiological monitoring (IONM) for detecting postoperative injury in resection of intramedullary spinal cord tumors (IMSCT).Surgical management of IMSCT can involve key neurological and vascular structures. IONM aims to assess the functional integrity of susceptible elements in real time. The diagnostic value of IONM for ISMCT has not been systematically evaluated.We performed a systematic review of the PubMed and MEDLINE databases for studies investigating the use of IONM for IMSCT and conducted a meta-analysis of diagnostic capability.Our search produced 257 citations. After application of exclusion criteria, 21 studies remained, 10 American Academy of Neurology grade III and 11 American Academy of Neurology grade IV. We found that a strong pooled mean sensitivity of 90% [95% confidence interval (CI), 84-94] and a weaker pooled mean specificity of 82% (95% CI, 70-90) for motor-evoked potential (MEP) recording changes. Somatosensory-evoked potential (SSEP) recording changes yielded pooled sensitivity of 85% (95% CI, 75-91) and pooled specificity of 72% (95% CI, 57-83). The pooled diagnostic odds ratio for MEP was 55.7 (95% CI, 26.3-119.1) and 14.3 (95% CI, 5.47-37.3) for SSEP. Bivariate analysis yielded summary receiver operative characteristic curves with area under the curve of 91.8% for MEPs and 86.3% for SSEPs.MEPs and SSEPs appear to be more sensitive than specific for detection of postoperative injury. Patients with perioperative neurological deficits are 56 times more likely to have had changes in MEPs during the procedure. We observed considerable variability in alarm criteria and interventions in response to IONM changes, indicating the need for prospective studies capable of defining standardized alarm criteria and responses.
View details for DOI 10.1097/BSD.0000000000000558
View details for PubMedID 28650882
Magnetic Resonance-Guided Laser-Induced Thermal Therapy for Recurrent Brain Metastases in the Motor Strip After Stereotactic Radiosurgery.
2016; 8 (12)
The authors report a challenging case of a brain metastasis located in the motor cortex, which was not responsive to radiosurgery. Use of a novel technique, magnetic resonance-guided laser-induced thermotherapy (MRgLITT), resulted in the complete obliteration of the lesion without adverse effects or evidence of tumor recurrence at follow-up. This case illustrates that MRgLITT may provide a viable alternative for patients with brain metastases refractory to radiosurgery or in deep locations, where both stereotactic radiosurgery (SRS) and surgical resection may be ineffective.
View details for DOI 10.7759/cureus.919
View details for PubMedID 28083463
View details for PubMedCentralID PMC5218883
Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2016; 113 (48): 13857-13862
Glioblastoma multiforme (GBM) is one of the most intractable of human cancers, principally because of the highly infiltrative nature of these neoplasms. Tracking and eradicating infiltrating GBM cells and tumor microsatellites is of utmost importance for the treatment of this devastating disease, yet effective strategies remain elusive. Here we report polymeric nanoparticle-engineered human adipose-derived stem cells (hADSCs) overexpressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as drug-delivery vehicles for targeting and eradicating GBM cells in vivo. Our results showed that polymeric nanoparticle-mediated transfection led to robust up-regulation of TRAIL in hADSCs, and that TRAIL-expressing hADSCs induced tumor-specific apoptosis. When transplanted in a mouse intracranial xenograft model of patient-derived glioblastoma cells, hADSCs exhibited long-range directional migration and infiltration toward GBM tumor. Importantly, TRAIL-overexpressing hADSCs inhibited GBM growth, extended survival, and reduced the occurrence of microsatellites. Repetitive injection of TRAIL-overexpressing hADSCs significantly prolonged animal survival compared with single injection of these cells. Taken together, our data suggest that nanoparticle-engineered TRAIL-expressing hADSCs exhibit the therapeutically relevant behavior of "seek-and-destroy" tumortropic migration and could be a promising therapeutic approach to improve the treatment outcomes of patients with malignant brain tumors.
View details for DOI 10.1073/pnas.1615396113
View details for Web of Science ID 000388835700085
View details for PubMedID 27849590
View details for PubMedCentralID PMC5137687
Diagnosis and treatment of pediatric frontotemporal pits: report of 2 cases
JOURNAL OF NEUROSURGERY-PEDIATRICS
2016; 18 (4): 471-474
In contrast to more common nasal and cervical lesions, the frontotemporal pit is a rarely encountered lesion that is often associated with a dermoid and may track intracranially. Due to delays in diagnosis, the propensity to spread intracranially, and the risk of infection, awareness of these lesions and appropriate diagnosis and management are important. The authors present 2 cases of frontotemporal pits from a single institution. Epidemiology, presentation, and management recommendations are discussed.
View details for DOI 10.3171/2016.5.PEDS1687
View details for Web of Science ID 000383938500015
View details for PubMedID 27391653
Modeling and Optimization of Airbag Helmets for Preventing Head Injuries in Bicycling.
Annals of biomedical engineering
Bicycling is the leading cause of sports-related traumatic brain injury. Most of the current bike helmets are made of expanded polystyrene (EPS) foam and ultimately designed to prevent blunt trauma, e.g., skull fracture. However, these helmets have limited effectiveness in preventing brain injuries. With the availability of high-rate micro-electrical-mechanical systems sensors and high energy density batteries, a new class of helmets, i.e., expandable helmets, can sense an impending collision and expand to protect the head. By allowing softer liner medium and larger helmet sizes, this novel approach in helmet design provides the opportunity to achieve much lower acceleration levels during collision and may reduce the risk of brain injury. In this study, we first develop theoretical frameworks to investigate impact dynamics of current EPS helmets and airbag helmets-as a form of expandable helmet design. We compared our theoretical models with anthropomorphic test dummy drop test experiments. Peak accelerations obtained from these experiments with airbag helmets achieve up to an 8-fold reduction in the risk of concussion compared to standard EPS helmets. Furthermore, we construct an optimization framework for airbag helmets to minimize concussion and severe head injury risks at different impact velocities, while avoiding excessive deformation and bottoming-out. An optimized airbag helmet with 0.12 m thickness at 72 ± 8 kPa reduces the head injury criterion (HIC) value to 190 ± 25 at 6.2 m/s head impact velocity compared to a HIC of 1300 with a standard EPS helmet. Based on a correlation with previously reported HIC values in the literature, this airbag helmet design substantially reduces the risks of severe head injury up to 9 m/s.
View details for PubMedID 27679447
Integrin-Targeting Knottin Peptide-Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation.
Angewandte Chemie (International ed. in English)
2016; 55 (34): 9894-9897
Antibody-drug conjugates (ADCs) offer increased efficacy and reduced toxicity compared to systemic chemotherapy. Less attention has been paid to peptide-drug delivery, which has the potential for increased tumor penetration and facile synthesis. We report a knottin peptide-drug conjugate (KDC) and demonstrate that it can selectively deliver gemcitabine to malignant cells expressing tumor-associated integrins. This KDC binds to tumor cells with low-nanomolar affinity, is internalized by an integrin-mediated process, releases its payload intracellularly, and is a highly potent inhibitor of brain, breast, ovarian, and pancreatic cancer cell lines. Notably, these features enable this KDC to bypass a gemcitabine-resistance mechanism found in pancreatic cancer cells. This work expands the therapeutic relevance of knottin peptides to include targeted drug delivery, and further motivates efforts to expand the drug-conjugate toolkit to include non-antibody protein scaffolds.
View details for DOI 10.1002/anie.201603488
View details for PubMedID 27304709
Management of moyamoya syndrome in patients with Noonan syndrome
JOURNAL OF CLINICAL NEUROSCIENCE
2016; 28: 107-111
A few isolated reports have described an association between Noonan syndrome and cerebrovascular abnormalities, including moyamoya syndrome. These reports have been limited to pediatric patients presenting with recurrent transient ischemic attacks (TIA) or headaches. Management has primarily been pharmacologic, with only one prior report of surgical revascularization to our knowledge. We report four cases of Noonan syndrome patients presenting with headaches and/or sensorimotor strokes in childhood that caused unilateral sensorimotor impairment. Cerebral angiography and MRI revealed bilateral moyamoya syndrome. All patients underwent successful bilateral extracranial-to-intracranial revascularization. The first patient was a 10-year-old girl who presented following a hemorrhagic stroke and recovered well after indirect bypass. The second patient was an adult with a history of childhood stroke whose symptoms progressed in adulthood. She underwent a direct bypass and improved, but continued to experience TIA at her 4 year follow-up. The third patient was a 7-year-old girl with headaches and a new onset TIA who failed pharmacological therapy and subsequently underwent bilateral indirect bypass. The fourth patient was a 24-year-old woman with worsening headaches and an occluded left middle cerebral artery from unilateral moyamoya syndrome. A left sided direct bypass was completed given delayed MRI perfusion with poor augmentation. To our knowledge these are the first reported surgical cases of combined Noonan and moyamoya syndrome. These cases highlight the need to recognize moyamoya syndrome in patients with Noonan syndrome. Early surgical revascularization should be pursued in order to prevent symptom progression.
View details for DOI 10.1016/j.jocn.2015.11.017
View details for Web of Science ID 000376714500021
View details for PubMedID 26778511
Epilepsy: A Disruptive Force in History.
2016; 90: 685-690
Since it was first described in a Mesopotamian text in 2000 bc, countless individuals have offered their perspectives on epilepsy's cause, treatment, and even deeper spiritual significance. However, despite the attention the disease has received through the millennia, it has only been within the past half-century that truly effective treatment options have been available. As a result, for the vast majority of recorded history, individuals with epilepsy have not only had to deal with the uncertainty of their next epileptic seizure but also the concomitant stigma and ostracization. Interestingly, these individuals have included several prominent historical figures, including Julius Caesar, Vladimir Lenin, and Fyodor Dostoyevsky. The fact that epilepsy has appeared in the lives of influential historical people means that the disease has played some role in affecting the progress of human civilization. Epilepsy has cut short the lives of key political leaders, affected the output of talented cultural icons, and, especially within the past half century, influenced the collective understanding of neuroscience and the human nervous system. In this article, the authors review how epilepsy throughout history has manifested itself in the lives of prominent figures and how the disease has helped shape the course of humanity's political, cultural, and scientific evolution.
View details for DOI 10.1016/j.wneu.2015.11.060
View details for PubMedID 26709155
Radiation-induced brain injury: low-hanging fruit for neuroregeneration
2016; 40 (5)
Brain radiation is a fundamental tool in neurooncology to improve local tumor control, but it leads to profound and progressive impairments in cognitive function. Increased attention to quality of life in neurooncology has accelerated efforts to understand and ameliorate radiation-induced cognitive sequelae. Such progress has coincided with a new understanding of the role of CNS progenitor cell populations in normal cognition and in their potential utility for the treatment of neurological diseases. The irradiated brain exhibits a host of biochemical and cellular derangements, including loss of endogenous neurogenesis, demyelination, and ablation of endogenous oligodendrocyte progenitor cells. These changes, in combination with a state of chronic neuroinflammation, underlie impairments in memory, attention, executive function, and acquisition of motor and language skills. Animal models of radiation-induced brain injury have demonstrated a robust capacity of both neural stem cells and oligodendrocyte progenitor cells to restore cognitive function after brain irradiation, likely through a combination of cell replacement and trophic effects. Oligodendrocyte progenitor cells exhibit a remarkable capacity to migrate, integrate, and functionally remyelinate damaged white matter tracts in a variety of preclinical models. The authors here critically address the opportunities and challenges in translating regenerative cell therapies from rodents to humans. Although valiant attempts to translate neuroprotective therapies in recent decades have almost uniformly failed, the authors make the case that harnessing human radiation-induced brain injury as a scientific tool represents a unique opportunity to both successfully translate a neuroregenerative therapy and to acquire tools to facilitate future restorative therapies for human traumatic and degenerative diseases of the central nervous system.
View details for DOI 10.3171/2016.2.FOCUS161
View details for Web of Science ID 000375119300002
View details for PubMedID 27132524
Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury
2016; 41 (5): 1191-1198
We report findings from a 12-week randomized double-blinded placebo-controlled trial of methylphenidate or galantamine to treat emotional and cognitive complaints in individuals (n=32) with a history of PTSD, TBI, or both conditions. In this small pilot study, methylphenidate treatment was associated with clinically meaningful and statistically significant improvement compared with placebo on the primary outcome, a measure of cognitive complaints (Ruff Neurobehavioral Inventory-Postmorbid Cognitive Scale), as well as on the secondary outcomes reflecting post-concussive (Rivermead Post Concussive Symptom Questionnaire) and post-traumatic stress symptoms (Posttraumatic Stress Disorder Checklist). Treatment was well tolerated. These results suggest the need for a larger RCT to replicate and confirm these findings. Design considerations for such a trial should include the need for multiple sites to facilitate adequate recruitment and extension of the treatment and follow-up periods.
View details for DOI 10.1038/npp.2015.282
View details for Web of Science ID 000371801200002
View details for PubMedID 26361060
Sports-related brain injuries: connecting pathology to diagnosis
2016; 40 (4)
Brain injuries are becoming increasingly common in athletes and represent an important diagnostic challenge. Early detection and management of brain injuries in sports are of utmost importance in preventing chronic neurological and psychiatric decline. These types of injuries incurred during sports are referred to as mild traumatic brain injuries, which represent a heterogeneous spectrum of disease. The most dramatic manifestation of chronic mild traumatic brain injuries is termed chronic traumatic encephalopathy, which is associated with profound neuropsychiatric deficits. Because chronic traumatic encephalopathy can only be diagnosed by postmortem examination, new diagnostic methodologies are needed for early detection and amelioration of disease burden. This review examines the pathology driving changes in athletes participating in high-impact sports and how this understanding can lead to innovations in neuroimaging and biomarker discovery.
View details for DOI 10.3171/2016.1.FOCUS15607
View details for Web of Science ID 000373476500004
View details for PubMedID 27032917
- New tools for studying microglia in the mouse and human CNS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2016; 113 (12): E1738-E1746
New tools for studying microglia in the mouse and human CNS.
Proceedings of the National Academy of Sciences of the United States of America
2016; 113 (12): E1738-46
The specific function of microglia, the tissue resident macrophages of the brain and spinal cord, has been difficult to ascertain because of a lack of tools to distinguish microglia from other immune cells, thereby limiting specific immunostaining, purification, and manipulation. Because of their unique developmental origins and predicted functions, the distinction of microglia from other myeloid cells is critically important for understanding brain development and disease; better tools would greatly facilitate studies of microglia function in the developing, adult, and injured CNS. Here, we identify transmembrane protein 119 (Tmem119), a cell-surface protein of unknown function, as a highly expressed microglia-specific marker in both mouse and human. We developed monoclonal antibodies to its intracellular and extracellular domains that enable the immunostaining of microglia in histological sections in healthy and diseased brains, as well as isolation of pure nonactivated microglia by FACS. Using our antibodies, we provide, to our knowledge, the first RNAseq profiles of highly pure mouse microglia during development and after an immune challenge. We used these to demonstrate that mouse microglia mature by the second postnatal week and to predict novel microglial functions. Together, we anticipate these resources will be valuable for the future study and understanding of microglia in health and disease.
View details for DOI 10.1073/pnas.1525528113
View details for PubMedID 26884166
View details for PubMedCentralID PMC4812770
Junior Seau: An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury
Few neurologic diseases have captured the nation's attention more completely than chronic traumatic encephalopathy (CTE), which has been discovered in the autopsies of professional athletes, most notably professional football players. The tragic case of Junior Seau, a Hall of Fame, National Football League linebacker, has been the most high-profile confirmed case of CTE. Here we describe Seau's case, which concludes an autopsy conducted at the National Institutes of Health that confirmed the diagnosis.Since 1990, Junior Seau had a highly distinguished 20-year career playing for the National Football League as a linebacker, from which he sustained multiple concussions. He committed suicide on May 2, 2012, at age 43, after which an autopsy confirmed a diagnosis of CTE. His clinical history was significant for a series of behavioral disturbances. Seau's history and neuropathologic findings were used to better understand the pathophysiology, diagnosis, and possible risk factors for CTE.This high-profile case reflects an increasing awareness of CTE as a long-term consequence of multiple traumatic brain injuries. The previously unforeseen neurologic risks of American football have begun to cast doubt on the safety of the sport.
View details for DOI 10.1016/j.wneu.2015.10.032
View details for Web of Science ID 000369625300104
View details for PubMedID 26493714
Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse
2016; 89 (1): 37-53
The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain.
View details for DOI 10.1016/j.neuron.2015.11.013
View details for Web of Science ID 000373564300006
View details for PubMedID 26687838
View details for PubMedCentralID PMC4707064
Pediatric Central Nervous System Tumors in Nepal: Retrospective Analysis and Literature Review of Low- and Middle-Income Countries
2015; 84 (6): 1832-1837
Central nervous system (CNS) tumors are the most common cause of cancer-related death in children. Little is known about the demographics and treatment of pediatric brain tumors in low- and middle-income countries (LMICs).We performed a retrospective chart review of all pediatric patients who presented to the neurosurgical service at Tribhuvan University Teaching Hospital in Kathmandu, Nepal from 2009-2014 and collected information on patients <18 years old who received a diagnosis of a CNS tumor. We analyzed age, gender, clinical presentation, extent of surgical resection, histopathology, and length of hospital stay. We also conducted a literature review using specific terminology to capture studies of pediatric neuro-oncologic epidemiology conducted in LMICs. Study location, length of study, sample size, study type, and occurrence of 4 common pediatric brain tumors were extracted.We identified 39 cases of pediatric CNS tumors, with 62.5% observed in male children. We found that male children (median = 13 years) presented later than female children (median = 8 years). The most frequently observed pediatric brain tumor type was ependymoma (17.5%), followed by astrocytoma (15%) and medulloblastoma (15%). Surgical resection was performed for 80% of cases, and gross total resection reported in 62.9% of all surgeries. More than half (54.1%) of patients had symptoms for more than 28 days before seeking treatment. Symptomatic hydrocephalus was noted in 57.1% of children who presented with CNS tumors. The literature review yielded studies from 18 countries. Study length ranged from 2-20 years, and sample sizes varied from 35-1948. Overall, we found more pronounced variation in the relative frequencies of the most common pediatric brain tumors, compared with high-income countries.We present the first operative series of childhood CNS tumors in Nepal. Children often had delayed diagnosis and treatment of a tumor, despite symptoms. More comprehensive data are required to develop improved treatment and management algorithms in the context of a given country's demographics and medical capabilities for childhood CNS tumors.
View details for DOI 10.1016/j.wneu.2015.07.074
View details for Web of Science ID 000366286300060
View details for PubMedID 26283488
- Repeated autologous umbilical cord blood infusions are feasible and had no acute safety issues in young babies with congenital hydrocephalus PEDIATRIC RESEARCH 2015; 78 (6): 712-716
Gorlin syndrome and desmoplastic medulloblastoma: Report of 3 cases with unfavorable clinical course and novel mutations
PEDIATRIC BLOOD & CANCER
2015; 62 (10): 1855-1858
We present three cases of genetically confirmed Gorlin syndrome with desmoplastic medulloblastoma (DMB) in whom tumor recurred despite standard therapy. One patient was found to have a novel germline missense PTCH1 mutation. Molecular analysis of recurrent tumor using fluorescent in situ hybridization (FISH) revealed PTEN and/ or PTCH1 loss in 2 patients. Whole exome sequencing (WES) of tumor in one patient revealed loss of heterozygosity of PTCH1 and a mutation of GNAS gene in its non-coding 3' -untranslated region (UTR) with corresponding decreased protein expression. While one patient died despite high-dose chemotherapy (HDC) plus stem cell rescue (ASCR) and palliative radiotherapy, two patients are currently alive for 18+ and 120+ months respectively following retrieval therapy that did not include irradiation. Infants with DMB and GS should be treated aggressively with chemotherapy at diagnosis to prevent relapse but radiotherapy should be avoided. The use of molecular prognostic markers for DMB should be routinely used to identify the subset of tumors that might have an aggressive course. Pediatr Blood Cancer 2015;62:1855-1858. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/pbc.25560
View details for Web of Science ID 000360228000027
View details for PubMedID 25940061
Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma.
Journal of neuro-oncology
2015; 125 (1): 65-74
Generation of patient-derived, autologous dendritic cells (DCs) is a critical component of cancer immunotherapy with ex vivo-generated, tumor antigen-loaded DCs. An important factor in the ability to generate DCs is the potential impact of prior therapies on DC phenotype and function. We investigated the ability to generate DCs using cells harvested from pediatric patients with medulloblastoma for potential evaluation of DC-RNA based vaccination approach in this patient population. Cells harvested from medulloblastoma patient leukapheresis following induction chemotherapy and granulocyte colony stimulating factor mobilization were cryopreserved prior to use in DC generation. DCs were generated from the adherent CD14+ monocytes using standard procedures and analyzed for cell recovery, phenotype and function. To summarize, 4 out of 5 patients (80 %) had sufficient monocyte recovery to permit DC generation, and we were able to generate DCs from 3 out of these 4 patient samples (75 %). Overall, we successfully generated DCs that met phenotypic requisites for DC-based cancer therapy from 3 out of 5 (60 %) patient samples and met both phenotypic and functional requisites from 2 out of 5 (40 %) patient samples. This study highlights the potential to generate functional DCs for further clinical treatments from refractory patients that have been heavily pretreated with myelosuppressive chemotherapy. Here we demonstrate the utility of evaluating the effect of the currently employed standard-of-care therapies on the ex vivo generation of DCs for DC-based clinical studies in cancer patients.
View details for DOI 10.1007/s11060-015-1890-2
View details for PubMedID 26311248
View details for PubMedCentralID PMC4592836
Evolution of cranioplasty techniques in neurosurgery: historical review, pediatric considerations, and current trends.
Journal of neurosurgery
2015; 123 (4): 1098-1107
Cranial bone repair is one of the oldest neurosurgical practices. Reconstructing the natural contours of the skull has challenged the ingenuity of surgeons from antiquity to the present day. Given the continuous improvement of neurosurgical and emergency care over the past century, more patients survive such head injuries, thus necessitating more than ever before a simple, safe, and durable means of correcting skull defects. In response, numerous techniques and materials have been devised as the art of cranioplasty has progressed. Although the goals of cranioplasty remain the same, the evolution of techniques and diversity of materials used serves as testimony to the complexity of this task. This paper highlights the evolution of these materials and techniques, with a particular focus on the implications for managing pediatric calvarial repair and emerging trends within the field.
View details for DOI 10.3171/2014.11.JNS14622
View details for PubMedID 25699411
- Preface to Clinical Neurosurgery Volume 62, Proceedings of the Congress of Neurological Surgeons 2014 Annual Meeting. Neurosurgery 2015; 62: N1-?
Six Degree-of-Freedom Measurements of Human Mild Traumatic Brain Injury
ANNALS OF BIOMEDICAL ENGINEERING
2015; 43 (8): 1918-1934
This preliminary study investigated whether direct measurement of head rotation improves prediction of mild traumatic brain injury (mTBI). Although many studies have implicated rotation as a primary cause of mTBI, regulatory safety standards use 3 degree-of-freedom (3DOF) translation-only kinematic criteria to predict injury. Direct 6DOF measurements of human head rotation (3DOF) and translation (3DOF) have not been previously available to examine whether additional DOFs improve injury prediction. We measured head impacts in American football, boxing, and mixed martial arts using 6DOF instrumented mouthguards, and predicted clinician-diagnosed injury using 12 existing kinematic criteria and 6 existing brain finite element (FE) criteria. Among 513 measured impacts were the first two 6DOF measurements of clinically diagnosed mTBI. For this dataset, 6DOF criteria were the most predictive of injury, more than 3DOF translation-only and 3DOF rotation-only criteria. Peak principal strain in the corpus callosum, a 6DOF FE criteria, was the strongest predictor, followed by two criteria that included rotation measurements, peak rotational acceleration magnitude and Head Impact Power (HIP). These results suggest head rotation measurements may improve injury prediction. However, more 6DOF data is needed to confirm this evaluation of existing injury criteria, and to develop new criteria that considers directional sensitivity to injury.
View details for DOI 10.1007/s10439-014-1212-4
View details for Web of Science ID 000358249800018
View details for PubMedCentralID PMC4478276
Therapeutic strategies to improve drug delivery across the blood-brain barrier.
2015; 38 (3): E9-?
Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB's physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it.
View details for DOI 10.3171/2014.12.FOCUS14758
View details for PubMedID 25727231
View details for PubMedCentralID PMC4493051
- Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurgical focus 2015; 38 (3): E9-?
Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: An in vitro study
2015; 56 (3): 439-449
Drug toxicity is a hurdle to drug development and to clinical translation of basic research. Antiepileptic drugs such as carbamazepine (CBZ) and selective serotonin reuptake inhibitors such as sertraline (SRT) are commonly co-prescribed to patients with epilepsy and comorbid depression. Because SRT may interfere with cytochrome P450 (CYP) enzyme activity and CYPs have been implicated in the conversion of CBZ to reactive cytotoxic metabolites, we investigated in vitro models to determine whether SRT affects the neurotoxic potential of CBZ and the mechanisms involved.Human fetal brain-derived dopaminergic neurons, human brain microvascular endothelial cells (HBMECs), and embryonic kidney (HEK) cells were used to evaluate cytotoxicity of CBZ and SRT individually and in combination. Nitrite and glutathione (GSH) levels were measured with drug exposure. To validate the role of CYP3A4 in causing neurotoxicity, drug metabolism was compared to cell death in HEK CYP3A4 overexpressed and cells pretreated with the CYP3A4 inhibitor ketoconazole.In all cellular systems tested, exposure to CBZ (127 μm) or SRT (5 μm) alone caused negligible cytotoxicity. By contrast CBZ, tested at a much lower concentration (17 μm) in combination with SRT (5 μm), produced prominent cytotoxicity within 15 min exposure. In neurons and HBMECs, cytotoxicity was associated with increased nitrite levels, suggesting involvement of free radicals as a pathogenetic mechanism. Pretreatment of HBMECs with reduced GSH or with the GSH precursor N-acetyl-l-cysteine prevented cytotoxic response. In HEK cells, the cytotoxic response to the CBZ + SRT combination correlated with the rate of CBZ biotransformation and production of 2-hydroxy CBZ, further suggesting a causative role of reactive metabolites. In the same system, cytotoxicity was potentiated by overexpression of CYP3A4, and prevented by CYP3A4 inhibitor.These results demonstrate an unexpected neurotoxic interaction between CBZ and SRT, apparently related to increased CYP3A4-mediated production of reactive CBZ metabolites. The potential clinical implications of these findings are discussed.
View details for DOI 10.1111/epi.12923
View details for Web of Science ID 000351240300016
View details for PubMedID 25656284
- Joint eQTL assessment of whole blood and dura mater tissue from individuals with Chiari type I malformation BMC GENOMICS 2015; 16
- Is there a role for decompressive craniectomy in children after stroke? World neurosurgery 2015; 83 (1): 44-45
- Preface to clinical neurosurgery volume 61, proceedings of the congress of neurological surgeons 2013 annual meeting. Neurosurgery 2014; 61: N1-?
- Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics BMC MEDICAL GENOMICS 2014; 7
Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition
2014; 25 (3): 393-405
Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
View details for DOI 10.1016/j.ccr.2014.02.004
View details for Web of Science ID 000333233400015
View details for PubMedID 24651015
Reorganization and stability for motor and language areas using cortical stimulation: case example and review of the literature.
2013; 3 (4): 1597-1614
The cerebral organization of language in epilepsy patients has been studied with invasive procedures such as Wada testing and electrical cortical stimulation mapping and more recently with noninvasive neuroimaging techniques, such as functional MRI. In the setting of a chronic seizure disorder, clinical variables have been shown to contribute to cerebral language reorganization underscoring the need for language lateralization and localization procedures. We present a 14-year-old pediatric patient with a refractory epilepsy disorder who underwent two neurosurgical resections of a left frontal epileptic focus separated by a year. He was mapped extraoperatively through a subdural grid using cortical stimulation to preserve motor and language functions. The clinical history and extensive workup prior to surgery is discussed as well as the opportunity to compare the cortical maps for language, motor, and sensory function before each resection. Reorganization in cortical tongue sensory areas was seen concomitant with a new zone of ictal and interictal activity in the previous tongue sensory area. Detailed neuropsychological data is presented before and after any surgical intervention to hypothesize about the extent of reorganization between epochs. We conclude that intrahemispheric cortical plasticity does occur following frontal lobe resective surgery in a teenager with medically refractory seizures.
View details for DOI 10.3390/brainsci3041597
View details for PubMedID 24961623