Clinical Focus


  • Brain Tumors
  • Surgical epilepsy
  • Neuroendoscopy
  • Arnold-Chiari Malformation
  • Minimally invasive craniosynostosis
  • Moya-moya disease
  • Pediatric Neurological Surgery

Academic Appointments


Administrative Appointments


  • 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)

Professional Education


  • Fellowship:University of Washington Neurosurgery Fellowship Program (2002) WA
  • Residency:University of Washington Neurosurgery Fellowship Program (2001) WA
  • Internship:University of Washington Dept of Surgery (1995) WA
  • Medical Education:Stanford University School of Medicine Registrar (1994) CA
  • Board Certification: Pediatric Neurological Surgery, American Board of Pediatric Neurological Surgery (2008)
  • Board Certification: Neurological Surgery, American Board of Neurological Surgery (2005)
  • Bachelor of Sciences, Duke University, Neurosciences (1989)

Community and International Work


  • Stanford Neurosurgery in Uganda, Mulago Hospital

    Topic

    Pediatric Neurosurgery/Endoscopy

    Partnering Organization(s)

    Duke University

    Populations Served

    Uganda

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Current Research and Scholarly Interests


Dr. Grant directs a Blood-brain Barrier Translational Laboratory focusing on enhancing drug delivery to brain tumors in children.

Clinical Trials


  • In Vivo Characterization of Macrophages in Pediatric Patients With Malignant Brain Tumors Using Ferumoxytol-enhanced MRI Recruiting

    This pilot early phase I trial studies how well ferumoxytol-enhanced magnetic resonance imaging (MRI) correlates with inflammatory (macrophage) responses in pediatric patients with malignant brain tumors. If there is good correlation, ferumoxytol-enhanced MRI can serve as a noninvasive imaging biomarker of inflammation.

    View full details

  • Interventions for Convergence Insufficiency in Concussed Children Not Recruiting

    The ICONICC Study is a randomized controlled clinical trial designed to compare the proportion of successful treatment outcomes between children assigned to standard concussion care only, standard concussion care plus simple convergence procedures, or standard concussion care plus office-based vergence/accommodative therapy in children aged 11 to 17 years with symptomatic post-concussion syndrome. Children with post-concussion syndrome (4-12 weeks post-concussion injury) and symptomatic CI will be randomized to a 12-week treatment program of either standard concussion care (SC), SC plus simple convergence procedures (SC+), or SC plus office-based vergence/accommodative therapy SC+OBVAT (1:1:1 ratio). The study will also compare the effect of treatment on clinical measures of both accommodation and vergence, symptom level/burden, health-related quality of life, clinical measures of saccadic eye movement, and objective eye movement measurements of disparity vergence, saccadic function, and accommodative function. The attainment of objective eye movement measures provides an opportunity to understand the underlying neurophysiology of the vergence and accommodative systems. Objective eye movement recordings are powerful because of the rich foundation from primate single-cell recordings that show a direct correlation with vergence and accommodative parameters in the supraoculomotor area of midbrain2, 3 and the oculomotor vermis of the cerebellum.4, 5 Thus, a combined approach of acquiring both clinical vision function measures and objective eye movement recordings in children with PCS-CI may lead to better characterization of the oculomotor phenotype with subsequent improved and personalized therapeutic interventions.

    Stanford is currently not accepting patients for this trial.

    View full details

2019-20 Courses


Stanford Advisees


All Publications


  • Anatomic and Thermometric Analysis of Cranial Nerve Palsy after Laser Amygdalohippocampotomy for Mesial Temporal Lobe Epilepsy. Operative neurosurgery (Hagerstown, Md.) Huang, Y., Leung, S. A., Parker, J. J., Ho, A. L., Wintermark, M., Patel, S. H., Pauly, K. B., Kakusa, B. W., Beres, S. J., Henderson, J. M., Grant, G. A., Halpern, C. H. 2019

    Abstract

    BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive therapy for treating medication-resistant mesial temporal lobe epilepsy. Cranial nerve (CN) palsy has been reported as a procedural complication, but the mechanism of this complication is not understood.OBJECTIVE: To identify the cause of postoperative CN palsy after LITT.METHODS: Four medial temporal lobe epilepsy patients with CN palsy after LITT were identified for comparison with 22 consecutive patients with no palsy. We evaluated individual variation in the distance between CN III and the uncus, and CN IV and the parahippocampal gyrus using preoperative T1- and T2-weighted magnetic resonance (MR) images. Intraoperative MR thermometry was used to estimate temperature changes.RESULTS: CN III (n=2) and CN IV palsies (n=2) were reported. On preoperative imaging, the majority of identified CN III (54%) and CN IV (43%) were located within 1 to 2 mm of the uncus and parahippocampal gyrus tissue border, respectively. Affected CN III and CN IV were more likely to be found<1 mm of the tissue border (PCNIII=.03, PCNIV<.01; chi-squared test). Retrospective assessment of thermal profile during ablation showed higher temperature rise along the mesial temporal lobe tissue border in affected CNs than unaffected CNs after controlling for distance (12.9°C vs 5.8°C; P=.03; 2-sample t-test).CONCLUSION: CN palsy after LITT likely results from direct heating of the respective CN running at extreme proximity to the mesial temporal lobe. Low-temperature thresholds set at the border of the mesial temporal lobe in patients whose CNs are at close proximity may reduce this risk.

    View details for DOI 10.1093/ons/opz279

    View details for PubMedID 31555820

  • Molecular correlates of cerebellar mutism syndrome in medulloblastoma. Neuro-oncology Jabarkheel, R., Amayiri, N., Yecies, D., Huang, Y., Toescu, S., Nobre, L., Mabbott, D. J., Sudhakar, S. V., Malik, P., Laughlin, S., Swaidan, M., Al Hussaini, M., Musharbash, A., Chacko, G., Mathew, L. G., Fisher, P. G., Hargrave, D., Bartels, U., Tabori, U., Pfister, S. M., Aquilina, K., Taylor, M. D., Grant, G. A., Bouffet, E., Mankad, K., Yeom, K. W., Ramaswamy, V. 2019

    Abstract

    BACKGROUND: Cerebellar Mutism Syndrome (CMS) is a common complication following resection of posterior fossa tumors, most commonly after surgery for medulloblastoma. Medulloblastoma subgroups have historically been treated as a single entity when assessing CMS risk; however, recent studies highlighting their clinical heterogeneity suggest the need for subgroup-specific analysis. Here, we examine a large international multicenter cohort of molecularly characterized medulloblastoma patients to assess predictors of CMS.METHODS: We assembled a cohort of 370 molecularly characterized medulloblastoma subjects with available neuroimaging from five sites globally including Great Ormond Street Hospital, Christian Medical College and Hospital, Hospital for Sick Children, King Hussein Cancer Center, and Lucile Packard Children's Hospital. Age at diagnosis, sex, tumour volume, and CMS development were assessed in addition to molecular subgroup.RESULTS: Overall, 23.8% of patients developed CMS. CMS patients were younger (mean difference -2.05 years ± 0.50, P=0.0218) and had larger tumours (mean difference 10.25 cm3 ± 4.60, P=0.0010) that were more often midline (OR=5.72, P<0.0001). In a multivariable analysis adjusting for age, sex, midline location, and tumour volume, WNT (Wingless) (adjusted OR=4.91, p=0.0063), Group 3 (adjusted OR=5.56, p=0.0022) and Group 4 (adjusted OR=8.57 p=9.1x10-5) tumours were found to be independently associated with higher risk of CMS compared with SHH (Sonic Hedgehog) tumours.CONCLUSIONS: Medulloblastoma subgroup is a very strong predictor of CMS development, independent of tumour volume and midline location. These findings have significant implications for management of both the tumour and CMS.

    View details for DOI 10.1093/neuonc/noz158

    View details for PubMedID 31504816

  • Radiological and clinical predictors of scoliosis in patients with Chiari malformation type I and spinal cord syrinx from the Park-Reeves Syringomyelia Research Consortium. Journal of neurosurgery. Pediatrics Strahle, J. M., Taiwo, R., Averill, C., Torner, J., Shannon, C. N., Bonfield, C. M., Tuite, G. F., Bethel-Anderson, T., Rutlin, J., Brockmeyer, D. L., Wellons, J. C., Leonard, J. R., Mangano, F. T., Johnston, J. M., Shah, M. N., Iskandar, B. J., Tyler-Kabara, E. C., Daniels, D. J., Jackson, E. M., Grant, G. A., Couture, D. E., Adelson, P. D., Alden, T. D., Aldana, P. R., Anderson, R. C., Selden, N. R., Baird, L. C., Bierbrauer, K., Chern, J. J., Whitehead, W. E., Ellenbogen, R. G., Fuchs, H. E., Guillaume, D. J., Hankinson, T. C., Iantosca, M. R., Oakes, W. J., Keating, R. F., Khan, N. R., Muhlbauer, M. S., McComb, J. G., Menezes, A. H., Ragheb, J., Smith, J. L., Maher, C. O., Greene, S., Kelly, M., O'Neill, B. R., Krieger, M. D., Tamber, M., Durham, S. R., Olavarria, G., Stone, S. S., Kaufman, B. A., Heuer, G. G., Bauer, D. F., Albert, G., Greenfield, J. P., Wait, S. D., Van Poppel, M. D., Eskandari, R., Mapstone, T., Shimony, J. S., Dacey, R. G., Smyth, M. D., Park, T. S., Limbrick, D. D. 2019: 1–8

    Abstract

    OBJECTIVE: Scoliosis is frequently a presenting sign of Chiari malformation type I (CM-I) with syrinx. The authors' goal was to define scoliosis in this population and describe how radiological characteristics of CM-I and syrinx relate to the presence and severity of scoliosis.METHODS: A large multicenter retrospective and prospective registry of pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for clinical and radiological characteristics of CM-I, syrinx, and scoliosis (coronal curve ≥ 10°).RESULTS: Based on available imaging of patients with CM-I and syrinx, 260 of 825 patients (31%) had a clear diagnosis of scoliosis based on radiographs or coronal MRI. Forty-nine patients (5.9%) did not have scoliosis, and in 516 (63%) patients, a clear determination of the presence or absence of scoliosis could not be made. Comparison of patients with and those without a definite scoliosis diagnosis indicated that scoliosis was associated with wider syrinxes (8.7 vs 6.3 mm, OR 1.25, p < 0.001), longer syrinxes (10.3 vs 6.2 levels, OR 1.18, p < 0.001), syrinxes with their rostral extent located in the cervical spine (94% vs 80%, OR 3.91, p = 0.001), and holocord syrinxes (50% vs 16%, OR 5.61, p < 0.001). Multivariable regression analysis revealed syrinx length and the presence of holocord syrinx to be independent predictors of scoliosis in this patient cohort. Scoliosis was not associated with sex, age at CM-I diagnosis, tonsil position, pB-C2 distance (measured perpendicular distance from the ventral dura to a line drawn from the basion to the posterior-inferior aspect of C2), clivoaxial angle, or frontal-occipital horn ratio. Average curve magnitude was 29.9°, and 37.7% of patients had a left thoracic curve. Older age at CM-I or syrinx diagnosis (p < 0.0001) was associated with greater curve magnitude whereas there was no association between syrinx dimensions and curve magnitude.CONCLUSIONS: Syrinx characteristics, but not tonsil position, were related to the presence of scoliosis in patients with CM-I, and there was an independent association of syrinx length and holocord syrinx with scoliosis. Further study is needed to evaluate the nature of the relationship between syrinx and scoliosis in patients with CM-I.

    View details for DOI 10.3171/2019.5.PEDS18527

    View details for PubMedID 31419800

  • Posterior fossa syndrome and increased mean diffusivity in the olivary bodies. Journal of neurosurgery. Pediatrics Yecies, D., Jabarkheel, R., Han, M., Kim, Y., Bruckert, L., Shpanskaya, K., Perez, A., Edwards, M. S., Grant, G. A., Yeom, K. W. 2019: 1–6

    Abstract

    OBJECTIVE: Posterior fossa syndrome (PFS) is a common postoperative complication following resection of posterior fossa tumors in children. It typically presents 1 to 2 days after surgery with mutism, ataxia, emotional lability, and other behavioral symptoms. Recent structural MRI studies have found an association between PFS and hypertrophic olivary degeneration, which is detectable as T2 hyperintensity in the inferior olivary nuclei (IONs) months after surgery. In this study, the authors investigated whether immediate postoperative diffusion tensor imaging (DTI) of the ION can serve as an early imaging marker of PFS.METHODS: The authors retrospectively reviewed pediatric brain tumor patients treated at their institution, Lucile Packard Children's Hospital at Stanford, from 2004 to 2016. They compared the immediate postoperative DTI studies obtained in 6 medulloblastoma patients who developed PFS to those of 6 age-matched controls.RESULTS: Patients with PFS had statistically significant increased mean diffusivity (MD) in the left ION (1085.17 ± 215.51 vs 860.17 ± 102.64, p = 0.044) and variably increased MD in the right ION (923.17 ± 119.2 vs 873.67 ± 60.16, p = 0.385) compared with age-matched controls. Patients with PFS had downward trending fractional anisotropy (FA) in both the left (0.28 ± 0.06 vs 0.23 ± 0.03, p = 0.085) and right (0.29 ± 0.06 vs 0.25 ± 0.02, p = 0.164) IONs compared with age-matched controls, although neither of these values reached statistical significance.CONCLUSIONS: Increased MD in the ION is associated with development of PFS. ION MD changes may represent an early imaging marker of PFS.

    View details for DOI 10.3171/2019.5.PEDS1964

    View details for PubMedID 31349230

  • Speckle modulation enables high-resolution wide-field human brain tumor margin detection and in vivo murine neuroimaging. Scientific reports Yecies, D., Liba, O., SoRelle, E. D., Dutta, R., Yuan, E., Vogel, H., Grant, G. A., de la Zerda, A. 2019; 9 (1): 10388

    Abstract

    Current in vivo neuroimaging techniques provide limited field of view or spatial resolution and often require exogenous contrast. These limitations prohibit detailed structural imaging across wide fields of view and hinder intraoperative tumor margin detection. Here we present a novel neuroimaging technique, speckle-modulating optical coherence tomography (SM-OCT), which allows us to image the brains of live mice and ex vivo human samples with unprecedented resolution and wide field of view using only endogenous contrast. The increased visibility provided by speckle elimination reveals white matter fascicles and cortical layer architecture in brains of live mice. To our knowledge, the data reported herein represents the highest resolution imaging of murine white matter structure achieved in vivo across a wide field of view of several millimeters. When applied to an orthotopic murine glioblastoma xenograft model, SM-OCT readily identifies brain tumor margins with resolution of approximately 10 mum. SM-OCT of ex vivo human temporal lobe tissue reveals fine structures including cortical layers and myelinated axons. Finally, when applied to an ex vivo sample of a low-grade glioma resection margin, SM-OCT is able to resolve the brain tumor margin. Based on these findings, SM-OCT represents a novel approach for intraoperative tumor margin detection and in vivo neuroimaging.

    View details for DOI 10.1038/s41598-019-45902-9

    View details for PubMedID 31316099

  • Factors Associated with Timeliness of Surgical Repair among Infants with Myelomeningocele: California Perinatal Quality Care Collaborative, 2006 to 2011. American journal of perinatology Kancherla, V., Ma, C., Grant, G., Lee, H. C., Shaw, G. M., Hintz, S. R., Carmichael, S. L. 2019

    Abstract

    OBJECTIVE: To examine factors associated with timely (0-2 days after birth) myelomeningocele surgical repair.STUDY DESIGN: We examined 2006 to 2011 births from the California Perinatal Quality Care Collaborative, linking to hospital discharge and vital records. Selected maternal, infant, and delivery hospital characteristics were evaluated to understand disparities in timely repair. Poisson regression was used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs).RESULTS: Overall, 399 of the 450 (89%) infants had a timely repair and approximately 80% of them were delivered in level III/IV hospitals. Infants with hydrocephalus were significantly less likely to have a delayed myelomeningocele repair compared with those without (aRR=0.22; 95% CI=0.13, 0.39); infants whose medical care was paid by Medi-Cal or other nonprivate insurance were 2.2 times more likely to have a delayed repair compared with those covered by a private insurance (aRR=2.23; 95% CI=1.17, 4.27). Low birth weight was a significant predictor for delayed repair (aRR=2.06; 95% CI=1.10, 3.83).CONCLUSION: There was a significant disparity in myelomenigocele repair based on medical care payer. Families and hospitals should work together for timely repair in hospitals having specialized multidisciplinary teams. Findings from the study can be used to follow best clinical practices for myelomeningocele repair.

    View details for DOI 10.1055/s-0039-1693127

    View details for PubMedID 31307103

  • Spatiotemporal Tracking of Brain-Tumor-Associated Myeloid Cells in Vivo through Optical Coherence Tomography with Plasmonic Labeling and Speckle Modulation ACS NANO SoRelle, E., Yecies, D., Liba, O., Bennett, F., Graef, C., Dutta, R., Mitra, S., Joubert, L., Cheshier, S., Grant, G. A., de la Zerda, A. 2019; 13 (7): 7985–95

    Abstract

    By their nature, tumors pose a set of profound challenges to the immune system with respect to cellular recognition and response coordination. Recent research indicates that leukocyte subpopulations, especially tumor-associated macrophages (TAMs), can exert substantial influence on the efficacy of various cancer immunotherapy treatment strategies. To better study and understand the roles of TAMs in determining immunotherapeutic outcomes, significant technical challenges associated with dynamically monitoring single cells of interest in relevant live animal models of solid tumors must be overcome. However, imaging techniques with the requisite combination of spatiotemporal resolution, cell-specific contrast, and sufficient signal-to-noise at increasing depths in tissue are exceedingly limited. Here we describe a method to enable high-resolution, wide-field, longitudinal imaging of TAMs based on speckle-modulating optical coherence tomography (SM-OCT) and spectral scattering from an optimized contrast agent. The approach's improvements to OCT detection sensitivity and noise reduction enabled high-resolution OCT-based observation of individual cells of a specific host lineage in live animals. We found that large gold nanorods (LGNRs) that exhibit a narrow-band, enhanced scattering cross-section can selectively label TAMs and activate microglia in an in vivo orthotopic murine model of glioblastoma multiforme. We demonstrated near real-time tracking of the migration of cells within these myeloid subpopulations. The intrinsic spatiotemporal resolution, imaging depth, and contrast sensitivity reported herein may facilitate detailed studies of the fundamental behaviors of TAMs and other leukocytes at the single-cell level in vivo, including intratumoral distribution heterogeneity and roles in modulating cancer proliferation.

    View details for DOI 10.1021/acsnano.9b02656

    View details for Web of Science ID 000477786400063

    View details for PubMedID 31259527

  • Early Diffusion Magnetic Resonance Imaging Changes in Normal-Appearing Brain in Pediatric Moyamoya Disease. Neurosurgery Quon, J. L., Kim, L. H., MacEachern, S. J., Maleki, M., Steinberg, G. K., Madhugiri, V., Edwards, M. S., Grant, G. A., Yeom, K. W., Forkert, N. D. 2019

    Abstract

    BACKGROUND: Moyamoya disease often leads to ischemic strokes visible on diffusion-weighted imaging (DWI) and T2-weighted magnetic resonance imaging (MRI) with subsequent cognitive impairment. In adults with moyamoya, apparent diffusion coefficient (ADC) is correlated with regions of steal phenomenon and executive dysfunction prior to white matter changes.OBJECTIVE: To investigate quantitative global diffusion changes in pediatric moyamoya patients prior to explicit structural ischemic damage.METHODS: We retrospectively reviewed children (<20 yr old) with moyamoya disease and syndrome who underwent bypass surgery at our institution. We identified 29 children with normal structural preoperative MRI and without findings of cortical infarction or chronic white matter ischemic changes. DWI datasets were used to calculate ADC maps for each subject as well as for 60 age-matched healthy controls. Using an atlas-based approach, the cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, and brainstem were segmented in each DWI dataset and used to calculate regional volumes and ADC values.RESULTS: Multivariate analysis of covariance using the regional ADC and volume values as dependent variables and age and gender as covariates revealed a significant difference between the groups (P<.001). Post hoc analysis demonstrated significantly elevated ADC values for children with moyamoya in the cerebral cortex, white matter, caudate, putamen, and nucleus accumbens. No significant volume differences were found.CONCLUSION: Prior to having bypass surgery, and in the absence of imaging evidence of ischemic stroke, children with moyamoya exhibit cerebral diffusion changes. These findings could reflect microstructural changes stemming from exhaustion of cerebrovascular reserve.

    View details for DOI 10.1093/neuros/nyz230

    View details for PubMedID 31245817

  • Longitudinal Changes in Hippocampal Subfield Volume Associated with Collegiate Football JOURNAL OF NEUROTRAUMA Parivash, S. N., Goubran, M., Mills, B. D., Rezaii, P., Thaler, C., Wolman, D., Bian, W., Mitchell, L. A., Boldt, B., Douglas, D., Wilson, E. W., Choi, J., Xie, L., Yushkevich, P. A., DiGiacomo, P., Wongsripuemtet, J., Parekh, M., Fiehler, J., Do, H., Lopez, J., Rosenberg, J., Camarillo, D., Grant, G., Wintermark, M., Zeineh, M. 2019
  • Central Nervous System Tumors in Uganda: Outcomes of Surgical Treatment and Complications Assessed Through Telephone Survey. World neurosurgery Kakusa, B. W., Xu, L. W., Vaca, S. D., Nalwanga, J., Kiryabwire, J., Ssenyonjo, H., Mukasa, J., Muhumuza, M., Haglund, M. M., Grant, G. A. 2019

    Abstract

    BACKGROUND: Uganda has one of the largest unmet neurosurgical needs in the world, but has seen major improvements in neurosurgery-largely centered at Mulago National Referral Hospital (MNRH). This study implements the first long-term follow-up and outcomes analysis of central nervous system tumor patients in Uganda.METHODS: Inpatient data were collected using a prospective database of patients presenting to the MNRH neurosurgical ward between 2014 and 2015. Follow-up health care status was assessed in the patient's language using phone surveys. Analysis was performed to identify which factors were associated with patient outcomes.RESULTS: The MNRH neurosurgical ward saw 112 patients with central nervous system tumors (adult N= 87, female: 70%, median age: 37 years). Meningiomas (21%) comprised the most common tumor diagnosis. In-hospital mortality (18%), 30-day mortality (22%), and 1-year mortality (35%) were high. Thirty percent of patients underwent tumor resection in-patient and had greater median overall survival (66.5 months vs. 5.1 months for nonsurgical patients, P= 0.025). For those with known pathologic diagnoses, patients with glioblastomas had decreased median overall survival (0.83 months vs. 59 months for meningiomas, P= 0.02). Phone interviews yielded an 85%response rate. Of the survivors at the time of follow-up, 55% reported a subjective return to normalcy, and 75% received follow-up care for their tumor with most returning to MNRH.CONCLUSIONS: We show evidence for improved overall survival with surgical care at MNRH. In addition, phone interviews as a method of measuring health outcomes provided an effective means of follow-up, showing that most patients do seek follow-up care.

    View details for DOI 10.1016/j.wneu.2019.06.060

    View details for PubMedID 31303566

  • Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary NEUROSURGERY Kochanek, P. M., Tasker, R. C., Carney, N., Totten, A. M., Adelson, P., Selden, N. R., Davis-O'Reilly, C., Hart, E. L., Bell, M. J., Bratton, S. L., Grant, G. A., Kissoon, N., Reuter-Rice, K. E., Vavilala, M. S., Wainwright, M. S. 2019; 84 (6): 1169–78
  • Lateral impacts correlate with falx cerebri displacement and corpus callosum trauma in sports-related concussions BIOMECHANICS AND MODELING IN MECHANOBIOLOGY Hernandez, F., Giordano, C., Goubran, M., Parivash, S., Grant, G., Zeineh, M., Camarillo, D. 2019; 18 (3): 631–49
  • Stability of Blood Biomarkers of Traumatic Brain Injury JOURNAL OF NEUROTRAUMA Rezaii, P., Grant, G., Zeineh, M., Richardson, K., Coburn, M., Bet, A., Weber, A., Jiang, B., Li, Y., Ubungen, K., Routh, G., Wheatcroft, A., Paulino, A., Hayes, R., Steinberg, G., Wintermark, M. 2019: 1–10
  • Mimicking brain tumor-vasculature microanatomical architecture via co-culture of brain tumor and endothelial cells in 3D hydrogels BIOMATERIALS Wang, C., Li, J., Sinha, S., Peterson, A., Grant, G. A., Yang, F. 2019; 202: 35–44
  • Stability of Blood Biomarkers of Traumatic Brain Injury. Journal of neurotrauma Rezaii, P., Grant, G., Zeineh, M., Richardson, K. J., Coburn, M. L., Bet, A. M., Weber, A., Jiang, B., Li, Y., Ubungen, K., Routh, G., Wheatcroft, A. M., Paulino, A., Hayes, R. L., Steinberg, G. K., Wintermark, M. 2019

    Abstract

    Blood biomarker tests were recently approved for clinical diagnosis of traumatic brain injury (TBI), yet there are still fundamental questions which need attention. One such question is the stability of putative biomarkers in blood over the course of several days after injury if the sample is unable to be processed into serum or plasma and stored at low temperatures. Blood may not be able to be stored at ultra-low temperatures in austere combat or sports environments. In this prospective study of 20 adult patients with positive head computed tomography imaging findings, the stability of three biomarkers (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1], and S100B) in whole blood and in serum stored at 4-5°C was evaluated over the course of 72 hours after blood collection. The amount of time whole blood and serum were refrigerated had no significant effect on GFAP concentration in plasma obtained from whole blood and in serum (p=0.6256 and p=0.3687, respectively), UCH-L1 concentration in plasma obtained from whole blood and in serum (p=0.0611 and p=0.5189, respectively), and S100B concentration in serum (p=0.4663). Concentration levels of GFAP, UCH-L1, and S100B in blood collected from patients with TBI were found to be stable at 4-5°C for at least 3 days after blood draw. This study suggests that the levels of the three diagnostic markers above are still valid for diagnostic TBI tests if the sample is stored in 4-5°C refrigerated conditions.

    View details for PubMedID 30968744

  • Arterial spin-labeling cerebral perfusion changes after revascularization surgery in pediatric moyamoya disease and syndrome JOURNAL OF NEUROSURGERY-PEDIATRICS Quon, J. L., Kim, L. H., Lober, R. M., Maleki, M., Steinberg, G. K., Yeom, K. W. 2019; 23 (4): 486–92
  • Lateral impacts correlate with falx cerebri displacement and corpus callosum trauma in sports-related concussions. Biomechanics and modeling in mechanobiology Hernandez, F., Giordano, C., Goubran, M., Parivash, S., Grant, G., Zeineh, M., Camarillo, D. 2019

    Abstract

    Corpus callosum trauma has long been implicated in mild traumatic brain injury (mTBI), yet the mechanism by which forces penetrate this structure is unknown. We investigated the hypothesis that coronal and horizontal rotations produce motion of the falx cerebri that damages the corpus callosum. We analyzed previously published head kinematics of 115 sports impacts (2 diagnosed mTBI) measured with instrumented mouthguards and used finite element (FE) simulations to correlate falx displacement with corpus callosum deformation. Peak coronal accelerations were larger in impacts with mTBI (8592rad/s2avg.) than those without (1412rad/s2avg.). From FE simulations, coronal acceleration was strongly correlated with deep lateral motion of the falx center (r=0.85), while horizontal acceleration was correlated with deep lateral motion of the falx periphery (r>0.78). Larger lateral displacement at the falx center and periphery was correlated with higher tract-oriented strains in the corpus callosum body (r=0.91) and genu/splenium (r>0.72), respectively. The relationship between the corpus callosum and falx was unique: removing the falx from the FE model halved peak strains in the corpus callosum from 35% to 17%. Consistent with model results, we found indications of corpus callosum trauma in diffusion tensor imaging of the mTBI athletes. For a measured alteration of consciousness, depressed fractional anisotropy and increased mean diffusivity indicated possible damage to the mid-posterior corpus callosum. Our results suggest that the corpus callosum may be sensitive to coronal and horizontal rotations because they drive lateral motion of a relatively stiff membrane, the falx, in the direction of commissural fibers below.

    View details for PubMedID 30859404

  • Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary. Neurosurgery Kochanek, P. M., Tasker, R. C., Carney, N., Totten, A. M., Adelson, P. D., Selden, N. R., Davis-O'Reilly, C., Hart, E. L., Bell, M. J., Bratton, S. L., Grant, G. A., Kissoon, N., Reuter-Rice, K. E., Vavilala, M. S., Wainwright, M. S. 2019

    Abstract

    The purpose of this work is to identify and synthesize research produced since the second edition of these Guidelines was published and incorporate new results into revised evidence-based recommendations for the treatment of severe traumatic brain injury in pediatric patients. This document provides an overview of our process, lists the new research added, and includes the revised recommendations. Recommendations are only provided when there is supporting evidence. This update includes 22 recommendations, 9 are new or revised from previous editions. New recommendations on neuroimaging, hyperosmolar therapy, analgesics and sedatives, seizure prophylaxis, temperature control/hypothermia, and nutrition are provided. None are level I, 3 are level II, and 19 are level III. The Clinical Investigators responsible for these Guidelines also created a companion algorithm that supplements the recommendations with expert consensus where evidence is not available and organizes possible interventions into first and second tier utilization. The complete guideline document and supplemental appendices are available electronically (https://doi.org/10.1097/PCC.0000000000001735). The online documents contain summaries and evaluations of all the studies considered, including those from prior editions, and more detailed information on our methodology. New level II and level III evidence-based recommendations and an algorithm provide additional guidance for the development of local protocols to treat pediatric patients with severe traumatic brain injury. Our intention is to identify and institute a sustainable process to update these Guidelines as new evidence becomes available.

    View details for PubMedID 30822776

  • Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Kochanek, P. M., Tasker, R. C., Carney, N., Totten, A. M., Adelson, P. D., Selden, N. R., Davis-O'Reilly, C., Hart, E. L., Bell, M. J., Bratton, S. L., Grant, G. A., Kissoon, N., Reuter-Rice, K. E., Vavilala, M. S., Wainwright, M. S. 2019; 20 (3S Suppl 1): S1–S82

    View details for PubMedID 30829890

  • Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines PEDIATRIC CRITICAL CARE MEDICINE Kochanek, P. M., Tasker, R. C., Carney, N., Totten, A. M., Adelson, P., Selden, N. R., Davis-O'Reilly, C., Hart, E. L., Bell, M. J., Bratton, S. L., Grant, G. A., Kissoon, N., Reuter-Rice, K. E., Vavilala, M. S., Wainwright, M. S. 2019; 20 (3): S1–S82
  • Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Kochanek, P. M., Tasker, R. C., Carney, N., Totten, A. M., Adelson, P. D., Selden, N. R., Davis-O'Reilly, C., Hart, E. L., Bell, M. J., Bratton, S. L., Grant, G. A., Kissoon, N., Reuter-Rice, K. E., Vavilala, M. S., Wainwright, M. S. 2019; 20 (3): 280–89

    Abstract

    OBJECTIVES: The purpose of this work is to identify and synthesize research produced since the second edition of these Guidelines was published and incorporate new results into revised evidence-based recommendations for the treatment of severe traumatic brain injury in pediatric patients.METHODS AND MAIN RESULTS: This document provides an overview of our process, lists the new research added, and includes the revised recommendations. Recommendations are only provided when there is supporting evidence. This update includes 22 recommendations, nine are new or revised from previous editions. New recommendations on neuroimaging, hyperosmolar therapy, analgesics and sedatives, seizure prophylaxis, temperature control/hypothermia, and nutrition are provided. None are level I, three are level II, and 19 are level III. The Clinical Investigators responsible for these Guidelines also created a companion algorithm that supplements the recommendations with expert consensus where evidence is not available and organizes possible interventions into first and second tier utilization. The purpose of publishing the algorithm as a separate document is to provide guidance for clinicians while maintaining a clear distinction between what is evidence based and what is consensus based. This approach allows, and is intended to encourage, continued creativity in treatment and research where evidence is lacking. Additionally, it allows for the use of the evidence-based recommendations as the foundation for other pathways, protocols, or algorithms specific to different organizations or environments. The complete guideline document and supplemental appendices are available electronically from this journal. These documents contain summaries and evaluations of all the studies considered, including those from prior editions, and more detailed information on our methodology.CONCLUSIONS: New level II and level III evidence-based recommendations and an algorithm provide additional guidance for the development of local protocols to treat pediatric patients with severe traumatic brain injury. Our intention is to identify and institute a sustainable process to update these Guidelines as new evidence becomes available.

    View details for PubMedID 30830016

  • Management of Pediatric Severe Traumatic Brain Injury: 2019 Consensus and Guidelines-Based Algorithm for First and Second Tier Therapies. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Kochanek, P. M., Tasker, R. C., Bell, M. J., Adelson, P. D., Carney, N., Vavilala, M. S., Selden, N. R., Bratton, S. L., Grant, G. A., Kissoon, N., Reuter-Rice, K. E., Wainwright, M. S. 2019; 20 (3): 269–79

    Abstract

    OBJECTIVES: To produce a treatment algorithm for the ICU management of infants, children, and adolescents with severe traumatic brain injury.DATA SOURCES: Studies included in the 2019 Guidelines for the Management of Pediatric Severe Traumatic Brain Injury (Glasgow Coma Scale score ≤ 8), consensus when evidence was insufficient to formulate a fully evidence-based approach, and selected protocols from included studies.DATA SYNTHESIS: Baseline care germane to all pediatric patients with severe traumatic brain injury along with two tiers of therapy were formulated. An approach to emergent management of the crisis scenario of cerebral herniation was also included. The first tier of therapy focuses on three therapeutic targets, namely preventing and/or treating intracranial hypertension, optimizing cerebral perfusion pressure, and optimizing partial pressure of brain tissue oxygen (when monitored). The second tier of therapy focuses on decompressive craniectomy surgery, barbiturate infusion, late application of hypothermia, induced hyperventilation, and hyperosmolar therapies.CONCLUSIONS: This article provides an algorithm of clinical practice for the bedside practitioner based on the available evidence, treatment protocols described in the articles included in the 2019 guidelines, and consensus that reflects a logical approach to mitigate intracranial hypertension, optimize cerebral perfusion, and improve outcomes in the setting of pediatric severe traumatic brain injury.

    View details for PubMedID 30830015

  • Mimicking brain tumor-vasculature microanatomical architecture via co-culture of brain tumor and endothelial cells in 3D hydrogels. Biomaterials Wang, C., Li, J., Sinha, S., Peterson, A., Grant, G. A., Yang, F. 2019; 202: 35–44

    Abstract

    Glioblastoma (GBM) is an aggressive malignant brain tumor with median survival of 12 months and 5-year survival rate less than 5%. GBM is highly vascularized, and the interactions between tumor and endothelial cells play an important role in driving tumor growth. To study tumor-endothelial interactions, the gold standard co-culture model is transwell culture, which fails to recapitulate the biochemical or physical cues found in tumor niche. Recently, we reported the development of poly(ethylene-glycol)-based hydrogels as 3D niche that supported GBM proliferation and invasion. To further mimic the microanatomical architecture of tumor-endothelial interactions in vivo, here we developed a hydrogel-based co-culture model that mimics the spatial organization of tumor and endothelial cells. To increase the physiological relevance, patient-derived GBM cells and mouse brain endothelial cells were used as model cell types. Using hydrolytically-degradable alginate fibers as porogens, endothelial cells were deployed and patterned into vessel-like structures in 3D hydrogels with high cell viability and retention of endothelial phenotype. Co-culture led to a significant increase in GBM cell proliferation and decrease in endothelial cell expression of cell adhesion proteins. In summary, we have developed a novel 3D co-culture model that mimics the in vivo spatial organization of brain tumor and endothelial cells. Such model may provide a valuable tool for future mechanistic studies to elucidate the effects of tumor-endothelial interactions on tumor progression in a more physiologically-relevant manner.

    View details for PubMedID 30836243

  • Commentary: Limited Dorsal Myeloschisis: Reconsideration of its Embryological Origin. Neurosurgery Quon, J. L., Grant, G. A. 2019

    View details for DOI 10.1093/neuros/nyz011

    View details for PubMedID 30715453

  • Microglia are effector cells of CD47-SIRPalpha antiphagocytic axis disruption against glioblastoma. Proceedings of the National Academy of Sciences of the United States of America Hutter, G., Theruvath, J., Graef, C. M., Zhang, M., Schoen, M. K., Manz, E. M., Bennett, M. L., Olson, A., Azad, T. D., Sinha, R., Chan, C., Assad Kahn, S., Gholamin, S., Wilson, C., Grant, G., He, J., Weissman, I. L., Mitra, S. S., Cheshier, S. H. 2019

    Abstract

    Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRPalpha-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages (Ccr2 RFP) and microglia (Cx3cr1 GFP). We show that even in the absence of phagocytizing macrophages (Ccr2 RFP/RFP), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications.

    View details for PubMedID 30602457

  • Longitudinal changes in hippocampal subfield volume associated with collegiate football. Journal of neurotrauma Parivash, S. N., Goubran, M., Mills, B. D., Rezaii, P., Thaler, C., Wolman, D., Bian, W., Mitchell, L. A., Boldt, B., Douglas, D., Wilson, E., Choi, J., Xie, L., Yushkevich, P., Digiacomo, P., Wongsripuemtet, J., Parekh, M., Fiehler, J., Do, H., Lopez, J., Rosenerg, J., Camarillo, D. B., Grant, G., Wintermark, M., Zeineh, M. 2019

    Abstract

    Collegiate football athletes are subject to repeated head impacts that may cause brain injury. The hippocampus is composed of several distinct subfields with possible differential susceptibility to injury. The purpose of this study is to determine whether there are longitudinal changes in hippocampal subfield volume in collegiate football. A prospective cohort study was conducted over a 5-year period tracking 63 football and 34 volleyball male collegiate athletes. Athletes underwent high-resolution structural magnetic resonance imaging, and automated segmentation provided hippocampal subfield volumes. At baseline, football athletes demonstrated a smaller subiculum volume than volleyball athletes (-67.77 mm3, P=.012). A regression analysis performed within football athletes similarly demonstrated a smaller subiculum volume among those at increased concussion risk based on athlete position (P=.001). For the longitudinal analysis, a linear mixed-effects model assessed the interaction between sport and time, revealing a significant decrease in CA1 volume in football athletes without an in-study concussion compared to volleyball athletes (volume difference per year=-35.22 mm3, P=.005). This decrease in CA1 volume over time was significant when football athletes were examined in isolation from volleyball athletes (P=.011). Thus, this prospective longitudinal study showed a decrease in CA1 volume over time in football athletes, in addition to baseline differences that were identified in the downstream subiculum. Hippocampal changes may have important implications for high-contact sports.

    View details for PubMedID 31044639

  • Brain abscess caused by Trueperella bernardiae in a child. Surgical neurology international Pan, J., Ho, A. L., Pendharkar, A. V., Sussman, E. S., Casazza, M., Cheshier, S. H., Grant, G. A. 2019; 10: 35

    Abstract

    Background: Recurrent intracranial abscesses secondary to refractory otitis media present a challenge which demands multidisciplinary collaboration.Case Description: We present the first known case of pediatric brain abscess caused by a polymicrobial infection of Trueperella bernardiae, Actinomyces europaeus, and mixed anaerobic species resulting from acute-on-chronic suppurative left otitis media. This patient required two separate stereotactic abscess drainages and a complex course of antibiotics for successful management.Conclusion: Surgery is essential in the management of cerebral abscess both in agent identification and therapeutic drainage. Management of abscesses secondary to unusual and polymicrobial organisms often requires consultation from other medical and surgical specialties.

    View details for DOI 10.4103/sni.sni_376_17

    View details for PubMedID 31528373

  • Targeted genomic CRISPR-Cas9 screen identifies MAP4K4 as essential for glioblastoma invasion. Scientific reports Prolo, L. M., Li, A., Owen, S. F., Parker, J. J., Foshay, K., Nitta, R. T., Morgens, D. W., Bolin, S., Wilson, C. M., Vega L, J. C., Luo, E. J., Nwagbo, G., Waziri, A., Li, G., Reimer, R. J., Bassik, M. C., Grant, G. A. 2019; 9 (1): 14020

    Abstract

    Among high-grade brain tumors, glioblastoma is particularly difficult to treat, in part due to its highly infiltrative nature which contributes to the malignant phenotype and high mortality in patients. In order to better understand the signaling pathways underlying glioblastoma invasion, we performed the first large-scale CRISPR-Cas9 loss of function screen specifically designed to identify genes that facilitate cell invasion. We tested 4,574 genes predicted to be involved in trafficking and motility. Using a transwell invasion assay, we discovered 33 genes essential for invasion. Of the 11 genes we selected for secondary testing using a wound healing assay, 6 demonstrated a significant decrease in migration. The strongest regulator of invasion was mitogen-activated protein kinase 4 (MAP4K4). Targeting of MAP4K4 with single guide RNAs or a MAP4K4 inhibitor reduced migration and invasion in vitro. This effect was consistent across three additional patient derived glioblastoma cell lines. Analysis of epithelial-mesenchymal transition markers in U138 cells with lack or inhibition of MAP4K4 demonstrated protein expression consistent with a non-invasive state. Importantly, MAP4K4 inhibition limited migration in a subset of human glioma organotypic slice cultures. Our results identify MAP4K4 as a novel potential therapeutic target to limit glioblastoma invasion.

    View details for DOI 10.1038/s41598-019-50160-w

    View details for PubMedID 31570734

  • Temporal Delays Along the Neurosurgical Care Continuum for Traumatic Brain Injury Patients at a Tertiary Care Hospital in Kampala, Uganda NEUROSURGERY Vaca, S. D., Kuo, B. J., Vissoci, J., Staton, C. A., Xu, L. W., Muhumuza, M., Ssenyonjo, H., Mukasa, J., Kiryabwire, J., Rice, H. E., Grant, G. A., Haglund, M. M. 2019; 84 (1): 95–102
  • Transnasal endoscopic approach for pediatric skull base lesions: a case series. Journal of neurosurgery. Pediatrics Quon, J. L., Kim, L. H., Hwang, P. H., Patel, Z. M., Grant, G. A., Cheshier, S. H., Edwards, M. S. 2019: 1–12

    Abstract

    Transnasal endoscopic transsphenoidal approaches constitute an essential technique for the resection of skull base tumors in adults. However, in the pediatric population, sellar and suprasellar lesions have historically been treated by craniotomy. Transnasal endoscopic approaches are less invasive and thus may be preferable to craniotomy, especially in children. In this case series, the authors present their institutional experience with transnasal endoscopic transsphenoidal approaches for pediatric skull base tumors.The authors retrospectively reviewed pediatric patients (age ≤ 18 years) who had undergone transnasal endoscopic transsphenoidal approaches for either biopsy or resection of sellar or suprasellar lesions between 2007 and 2016. All operations were performed jointly by a team of pediatric neurosurgeons and skull base otolaryngologists, except for 8 cases performed by one neurosurgeon.The series included 42 patients between 4 and 18 years old (average 12.5 years) who underwent 51 operations. Headache (45%), visual symptoms (69%), and symptoms related to hormonal abnormalities (71%) were the predominant presenting symptoms. Improvement in preoperative symptoms was seen in 92% of cases. Most patients had craniopharyngiomas (n = 16), followed by pituitary adenomas (n = 12), Rathke cleft cysts (n = 4), germinomas (n = 4), chordomas (n = 2), and other lesion subtypes (n = 4). Lesions ranged from 0.3 to 6.2 cm (median 2.5 cm) in their greatest dimension. Gross-total resection was primarily performed (63% of cases), with 5 subsequent recurrences. Nasoseptal flaps were used in 47% of cases, fat grafts in 37%, and lumbar drains in 47%. CSF space was entered intraoperatively in 15 cases, and postoperative CSF was observed only in lesions with suprasellar extension. There were 8 cases of new hormonal deficits and 3 cases of new cranial nerve deficits. Length of hospital stay ranged from 1 to 61 days (median 5 days). Patients were clinically followed up for a median of 46 months (range 1-120 months), accompanied by a median radiological follow-up period of 45 months (range 3.8-120 months). Most patients (76%) were offered adjuvant therapy.In this single-institution report of the transnasal endoscopic transsphenoidal approach, the authors demonstrated that this technique is generally safe and effective for different types of pediatric skull base lesions. Favorable effects of surgery were sustained during a follow-up period of 4 years. Further refinement in technology will allow for more widespread use in the pediatric population.

    View details for DOI 10.3171/2019.4.PEDS18693

    View details for PubMedID 31200365

  • Topical Vancomycin for Surgical Prophylaxis in Pediatric Craniofacial Surgeries. The Journal of craniofacial surgery Mohole, J., Ho, A. L., Cannon, J. G., Pendharkar, A. V., Sussman, E. S., Hong, D. S., Cheshier, S. H., Grant, G. A. 2019

    Abstract

    Topical vancomycin has been demonstrated to be safe and effective for reducing surgical site infections (SSIs) following spine surgery in both adults and children, however, there are no studies of its efficacy in reducing SSIs in craniofacial surgery. The SSIs are one of the most common complications following craniofacial surgery. The complexity of craniofacial procedures, use of grafts and implants, long operative durations and larger surgical wounds all contribute to the heightened risk of SSIs in pediatric craniofacial cases. A retrospective review of all open and endoscopic pediatric craniofacial procedures performed between May 2014 and December 2017 at a single children's hospital was conducted to examine SSI rates between patients receiving topical vancomycin and a historical control group. The treatment group received topical vancomycin irrigation before wound closure. An ad-hoc cost analysis was performed to determine the cost-savings associated with topical vancomycin use. A total of 132 craniofacial procedures were performed during the study period, with 50 cases in the control group and 82 cases in the vancomycin group. Overall, SSI rate was 3.03%. Use of topical vancomycin irrigation led to a significant reduction in SSIs (4/50 SSI or 8.0% in control group vs 0/82 or 0% in vancomycin group, P = 0.04). No adverse events were observed with topical vancomycin use. The potential cost-savings associated with the use of topical vancomycin as SSI prophylaxis in this study was $102,152. Addition of topical vancomycin irrigation as routine surgical infection prophylaxis can be an effective and low-cost method for reducing SSI in pediatric craniofacial surgery.

    View details for DOI 10.1097/SCS.0000000000005708

    View details for PubMedID 31261326

  • Stereotactic laser ablation for completion corpus callosotomy. Journal of neurosurgery. Pediatrics Huang, Y., Yecies, D., Bruckert, L., Parker, J. J., Ho, A. L., Kim, L. H., Fornoff, L., Wintermark, M., Porter, B., Yeom, K. W., Halpern, C. H., Grant, G. A. 2019: 1–9

    Abstract

    Completion corpus callosotomy can offer further remission from disabling seizures when a prior partial corpus callosotomy has failed and residual callosal tissue is identified on imaging. Traditional microsurgical approaches to section residual fibers carry risks associated with multiple craniotomies and the proximity to the medially oriented motor cortices. Laser interstitial thermal therapy (LITT) represents a minimally invasive approach for the ablation of residual fibers following a prior partial corpus callosotomy. Here, the authors report clinical outcomes of 6 patients undergoing LITT for completion corpus callosotomy and characterize the radiological effects of ablation.A retrospective clinical review was performed on a series of 6 patients who underwent LITT completion corpus callosotomy for medically intractable epilepsy at Stanford University Medical Center and Lucile Packard Children's Hospital at Stanford between January 2015 and January 2018. Detailed structural and diffusion-weighted MR images were obtained prior to and at multiple time points after LITT. In 4 patients who underwent diffusion tensor imaging (DTI), streamline tractography was used to reconstruct and evaluate tract projections crossing the anterior (genu and rostrum) and posterior (splenium) parts of the corpus callosum. Multiple diffusion parameters were evaluated at baseline and at each follow-up.Three pediatric (age 8-18 years) and 3 adult patients (age 30-40 years) who underwent completion corpus callosotomy by LITT were identified. Mean length of follow-up postoperatively was 21.2 (range 12-34) months. Two patients had residual splenium, rostrum, and genu of the corpus callosum, while 4 patients had residual splenium only. Postoperative complications included asymptomatic extension of ablation into the left thalamus and transient disconnection syndrome. Ablation of the targeted area was confirmed on immediate postoperative diffusion-weighted MRI in all patients. Engel class I-II outcomes were achieved in 3 adult patients, whereas all 3 pediatric patients had Engel class III-IV outcomes. Tractography in 2 adult and 2 pediatric patients revealed time-dependent reduction of fractional anisotropy after LITT.LITT is a safe, minimally invasive approach for completion corpus callosotomy. Engel outcomes for completion corpus callosotomy by LITT were similar to reported outcomes of open completion callosotomy, with seizure reduction primarily observed in adult patients. Serial DTI can be used to assess the presence of tract projections over time but does not classify treatment responders or nonresponders.

    View details for DOI 10.3171/2019.5.PEDS19117

    View details for PubMedID 31374542

  • Ferumoxytol-enhanced MRI for surveillance of pediatric cerebral arteriovenous malformations. Journal of neurosurgery. Pediatrics Huang, Y., Singer, T. G., Iv, M., Lanzman, B., Nair, S., Stadler, J. A., Wang, J., Edwards, M. S., Grant, G. A., Cheshier, S. H., Yeom, K. W. 2019: 1–8

    Abstract

    Children with intracranial arteriovenous malformations (AVMs) undergo digital DSA for lesion surveillance following their initial diagnosis. However, DSA carries risks of radiation exposure, particularly for the growing pediatric brain and over lifetime. The authors evaluated whether MRI enhanced with a blood pool ferumoxytol (Fe) contrast agent (Fe-MRI) can be used for surveillance of residual or recurrent AVMs.A retrospective cohort was assembled of children with an established AVM diagnosis who underwent surveillance by both DSA and 3-T Fe-MRI from 2014 to 2016. Two neuroradiologists blinded to the DSA results independently assessed Fe-enhanced T1-weighted spoiled gradient recalled acquisition in steady state (Fe-SPGR) scans and, if available, arterial spin labeling (ASL) perfusion scans for residual or recurrent AVMs. Diagnostic confidence was examined using a Likert scale. Sensitivity, specificity, and intermodality reliability were determined using DSA studies as the gold standard. Radiation exposure related to DSA was calculated as total dose area product (TDAP) and effective dose.Fifteen patients were included in this study (mean age 10 years, range 3-15 years). The mean time between the first surveillance DSA and Fe-MRI studies was 17 days (SD 47). Intermodality agreement was excellent between Fe-SPGR and DSA (κ = 1.00) but poor between ASL and DSA (κ = 0.53; 95% CI 0.18-0.89). The sensitivity and specificity for detecting residual AVMs using Fe-SPGR were 100% and 100%, and using ASL they were 72% and 100%, respectively. Radiologists reported overall high diagnostic confidence using Fe-SPGR. On average, patients received two surveillance DSA studies over the study period, which on average equated to a TDAP of 117.2 Gy×cm2 (95% CI 77.2-157.4 Gy×cm2) and an effective dose of 7.8 mSv (95% CI 4.4-8.8 mSv).Fe-MRI performed similarly to DSA for the surveillance of residual AVMs. Future multicenter studies could further investigate the efficacy of Fe-MRI as a noninvasive alternative to DSA for monitoring AVMs in children.

    View details for DOI 10.3171/2019.5.PEDS1957

    View details for PubMedID 31323627

  • Commentary: Optimizing Postoperative Surveillance of Pediatric Low-Grade Glioma Using Tumor Behavior Patterns. Neurosurgery Quon, J. L., Grant, G. A. 2019

    View details for DOI 10.1093/neuros/nyz112

    View details for PubMedID 30997497

  • Arterial spin labeling perfusion changes of the frontal lobes in children with posterior fossa syndrome. Journal of neurosurgery. Pediatrics Yecies, D., Shpanskaya, K., Jabarkheel, R., Maleki, M., Bruckert, L., Cheshier, S. H., Hong, D., Edwards, M. S., Grant, G. A., Yeom, K. W. 2019: 1–7

    Abstract

    Posterior fossa syndrome (PFS) is a common complication following the resection of posterior fossa tumors in children. The pathophysiology of PFS remains incompletely elucidated; however, the wide-ranging symptoms of PFS suggest the possibility of widespread cortical dysfunction. In this study, the authors utilized arterial spin labeling (ASL), an MR perfusion modality that provides quantitative measurements of cerebral blood flow without the use of intravenous contrast, to assess cortical blood flow in patients with PFS.A database of medulloblastoma treated at the authors' institution from 2004 to 2016 was retrospectively reviewed, and 14 patients with PFS were identified. Immediate postoperative ASL for patients with PFS and medulloblastoma patients who did not develop PFS were compared. Additionally, in patients with PFS, ASL following the return of speech was compared with immediate postoperative ASL.On immediate postoperative ASL, patients who subsequently developed PFS had statistically significant decreases in right frontal lobe perfusion and a trend toward decreased perfusion in the left frontal lobe compared with controls. Patients with PFS had statistically significant increases in bilateral frontal lobe perfusion after the resolution of symptoms compared with their immediate postoperative imaging findings.ASL perfusion imaging identifies decreased frontal lobe blood flow as a strong physiological correlate of PFS that is consistent with the symptomatology of PFS. This is the first study to demonstrate that decreases in frontal lobe perfusion are present in the immediate postoperative period and resolve with the resolution of symptoms, suggesting a physiological explanation for the transient symptoms of PFS.

    View details for DOI 10.3171/2019.5.PEDS18452

    View details for PubMedID 31374541

  • Associations between neuropsychiatric and health status outcomes in individuals with probable mTBI. Psychiatry research Bomyea, J., Flashman, L. A., Zafonte, R., Andaluz, N., Coimbra, R., George, M. S., Grant, G. A., Marx, C. E., McAllister, T. W., Shutter, L., Lang, A. J., Stein, M. B. 2018; 272: 531–39

    Abstract

    Mild traumatic brain injury (mTBI) is a common occurrence, and may impact distal outcomes in a subgroup of individuals. Improved characterization of health outcomes and identification of factors associated with poor outcomes is needed to better understand the impact of mTBI, particularly in those with co-occurring posttraumatic stress disorder (PTSD). Participants in a data repository of the Injury and Traumatic Stress (INTRuST) Clinical Consortium (n = 625) completed functional disability [FD] and health-related quality of life [HRQOL] questionnaires, and a subset completed a neuropsychological assessment. FD and HRQOL were compared among participants with probable mTBI (mTBI), probable mTBI with PTSD (mTBI/PTSD), and health comparison participants (HC). Associations between symptoms, neuropsychological performance, and health outcomes were examined in those with probable mTBI with and without PTSD (n = 316). Individuals in the mTBI/PTSD group endorsed poorer health outcomes than those in the mTBI group, who endorsed poorer outcomes than those in the HC group. Individuals in either mTBI group performed worse than those in the HC on verbal learning and memory and psychomotor speed. Health outcomes were correlated with mental health and postconcussive symptoms, as well as neuropsychological variables. mTBI may adversely impact self-reported health, with the greatest effect observed in individuals with co-occurring mTBI/PTSD.

    View details for PubMedID 30616120

  • Virtual Surgical Planning Decreases Operative Time for Isolated Single Suture and Multi-suture Craniosynostosis Repair PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN Andrew, T. W., Baylan, J., Mittermiller, P. A., Cheng, H., Johns, D. N., Edwards, M. B., Cheshier, S. H., Grant, G. A., Lorenz, H. 2018; 6 (12): e2038

    Abstract

    Cranial vault reconstruction is a complex procedure due to the need for precise 3-dimensional outcomes. Traditionally, the process involves manual bending of calvarial bone and plates. With the advent of virtual surgical planning (VSP), this procedure can be streamlined. Despite the advantages documented in the literature, there have been no case-control studies comparing VSP to traditional open cranial vault reconstruction.Data were retrospectively collected on patients who underwent craniosynostosis repair during a 7-year period. Information was collected on patient demographics, intraoperative and postoperative factors, and intraoperative surgical time. High-resolution computed tomography scans were used for preoperative planning with engineers when designing osteotomies, bone flaps, and final positioning guides.A total of 66 patients underwent open craniosynostosis reconstruction between 2010 and 2017. There were 35 control (non-VSP) and 28 VSP cases. No difference in age, gender ratios, or number of prior operations was found. Blood loss was similar between the 2 groups. The VSP group had more screws and an increased length of postoperative hospital stay. The length of the operation was shorter in the VSP group for single suture and for multiple suture operations. Operative time decreased as the attending surgeon increased familiarity with the technique.VSP is a valuable tool for craniosynostosis repair. We found VSP decreases surgical time and allows for improved preoperative planning. Although there have been studies on VSP, this is the first large case-control study to be performed on its use in cranial vault remodeling.

    View details for PubMedID 30656118

  • Development of best practices to minimize wound complications after complex tethered spinal cord surgery: a modified Delphi study JOURNAL OF NEUROSURGERY-PEDIATRICS Alexiades, N. G., Ahn, E. S., Blount, J. P., Brockmeyer, D. L., Browd, S. R., Grant, G. A., Heuer, G. G., Hankinson, T. C., Iskandar, B. J., Jea, A., Krieger, M. D., Leonard, J. R., Limbrick, D. D., Maher, C. O., Proctor, M. R., Sandberg, D., Wellons, J. C., Shao, B., Feldstein, N. A., Anderson, R. E. 2018; 22 (6): 701–9

    Abstract

    OBJECTIVEComplications after complex tethered spinal cord (cTSC) surgery include infections and cerebrospinal fluid (CSF) leaks. With little empirical evidence to guide management, there is variability in the interventions undertaken to limit complications. Expert-based best practices may improve the care of patients undergoing cTSC surgery. Here, authors conducted a study to identify consensus-driven best practices.METHODSThe Delphi method was employed to identify consensual best practices. A literature review regarding cTSC surgery together with a survey of current practices was distributed to 17 board-certified pediatric neurosurgeons. Thirty statements were then formulated and distributed to the group. Results of the second survey were discussed during an in-person meeting leading to further consensus, which was defined as ≥ 80% agreement on a 4-point Likert scale (strongly agree, agree, disagree, strongly disagree).RESULTSSeventeen consensus-driven best practices were identified, with all participants willing to incorporate them into their practice. There were four preoperative interventions: (1, 2) asymptomatic AND symptomatic patients should be referred to urology preoperatively, (3, 4) routine preoperative urine cultures are not necessary for asymptomatic AND symptomatic patients. There were nine intraoperative interventions: (5) patients should receive perioperative cefazolin or an equivalent alternative in the event of allergy, (6) chlorhexidine-based skin preparation is the preferred regimen, (7) saline irrigation should be used intermittently throughout the case, (8) antibiotic-containing irrigation should be used following dural closure, (9) a nonlocking running suture technique should be used for dural closure, (10) dural graft overlay should be used when unable to obtain primary dural closure, (11) an expansile dural graft should be incorporated in cases of lipomyelomeningocele in which primary dural closure does not permit free flow of CSF, (12) paraxial muscles should be closed as a layer separate from the fascia, (13) routine placement of postoperative drains is not necessary. There were three postoperative interventions: (14) postoperative antibiotics are an option and, if given, should be discontinued within 24 hours; (15) patients should remain flat for at least 24 hours postoperatively; (16) routine use of abdominal binders or other compressive devices postoperatively is not necessary. One intervention was prioritized for additional study: (17) further study of additional gram-negative perioperative coverage is needed.CONCLUSIONSA modified Delphi technique was used to develop consensus-driven best practices for decreasing wound complications after cTSC surgery. Further study is required to determine if implementation of these practices will lead to reduced complications. Discussion through the course of this study resulted in the initiation of a multicenter study of gram-negative surgical site infections in cTSC surgery.

    View details for PubMedID 30215584

  • Long-term Supratentorial Radiological Effects of Surgery and Local Radiation in Children with Infratentorial Ependymoma. World neurosurgery Yecies, D., Azad, T. D., Esparza, R., Quon, J., Forkert, N., MacEachern, S. J., Bruckert, L., Maleki, M., Edwards, M., Grant, G., Yeom, K. 2018

    Abstract

    OBJECT: Current standard of care for children with infratentorial ependymoma includes maximal safe resection and local radiation of 54-59gy. High-dose local radiation has been associated with declines in multiple cognitive domains. The anatomic and physiologic correlates of this cognitive decline remain undefined and there have been no radiographic studies on the long-term effects of this treatment paradigm.METHODS: A comprehensive database of pediatric brain tumor patients treated at Stanford Children's from 2004-2016 was queried. Seven patients with posterior fossa ependymoma were identified who were treated with surgery and local radiation alone, who had no evidence of recurrent disease, and had imaging suitable for analysis. Diffusion-weighted MRI (DWI) datasets were used to calculate apparent diffusion coefficient (ADC) maps for each subject, while arterial spin labeling (ASL) datasets were used to calculated maps of cerebral blood flow (CBF). DWI and ASL datasets of 52 age-matched healthy children were a analyzed in the same fashion to enable group comparisons.RESULTS: Several statistically significant differences were detected between the two groups. CBF was lower in the caudate and pallidum and higher in the nucleus accumbens in the ependymoma cohort compared to controls. ADC was increased in the thalamus and trended towards decreased in the amygdala.CONCLUSIONS: Surgery and local radiation for posterior fossa ependymoma are associated with supratentorial ADC and CBF alterations, which may represent an anatomic and physiologic correlate to the previously published decline in neurocognitive outcomes in this population.

    View details for PubMedID 30448581

  • Laser interstitial thermal therapy (LITT): Seizure outcomes for refractory mesial temporal lobe epilepsy. Epilepsy & behavior : E&B Le, S., Ho, A. L., Fisher, R. S., Miller, K. J., Henderson, J. M., Grant, G. A., Meador, K. J., Halpern, C. H. 2018; 89: 37–41

    Abstract

    BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive alternative with less cognitive risks compared with traditional surgery for focal drug-resistant epilepsy.OBJECTIVE: We describe seizure outcomes and complications after LITT in our cohort with intractable mesial temporal lobe epilepsy (MTLE).MATERIAL AND METHODS: We prospectively tracked Stanford's MTLE cases treated with LITT from October 2014 to October 2017. Primary endpoints were seizure outcomes by (1) Engel classification and (2) reduction in baseline seizure frequency. Secondary outcomes were postablation complications.RESULTS: A total of 30 patients underwent selective amygdalohippocampotomy via LITT. Mesial temporal sclerosis (MTS) was present in 23/30 (77%) patients. Median follow-up was 18 ± 12 months (range: 6-44 months). Almost all 28/29 (97%) patients had >50% reduction, and 22/29 (76%) patients had >90% reduction in seizure frequency. Engel Class I outcome was achieved in 18/29 (62%) patients; with complete seizure freedom in 9/29 (31%) patients (Engel Class IA). Three (10%) patients have had only focal aware seizures (Engel Class 1B). Seizures only occurred with medication withdrawal in 6/29 (21%) patients (Engel Class ID). Class II was achieved by 6/29 (21%) and Class III by 5/29 (17%) patients. Complications included perioperative seizures in 10/29 (34%) and nonseizure complaints in 6/29 (21%) patients. Three (10%) patients had neurological deficits including one permanent superior quadrantanopsia, one transient trochlear, and one transient oculomotor nerve palsy.CONCLUSIONS: Overall, Engel Class I outcome was achieved in 62% of patients with MTLE, and 97% of patients achieved >50% seizure frequency reduction. Complications were largely temporary, though there was one persistent visual field deficit. Laser ablation is well-tolerated and offers marked seizure reduction for the majority of patients.

    View details for DOI 10.1016/j.yebeh.2018.09.040

    View details for PubMedID 30384097

  • Common Conditions Requiring Long-Term Anticoagulation in Neurosurgical Patients. Neurosurgery clinics of North America Perez, A. J., Grant, G. A. 2018; 29 (4): 529–35

    Abstract

    Long-term anticoagulant therapy prevents thrombosis. Management of neurosurgical patients with conditions such as atrial fibrillation, mechanical heart valves, and other prothrombotic states necessitates application of a strategy to mitigate hemorrhagic complications of anticoagulation. Development of direct oral anticoagulants, which include the direct thrombin and factor X inhibitors, yields new considerations to be had, in particular, the introduction of reversal agents. This article reviews the more common chronic clinical entities that require the use of prolonged anticoagulant therapy with special consideration for neurosurgical patients. It also includes a discussion of established treatment strategies across available treatment options.

    View details for PubMedID 30223965

  • Neural tube defects in Uganda: follow-up outcomes from a national referral hospital. Neurosurgical focus Xu, L. W., Vaca, S. D., He, J. Q., Nalwanga, J., Muhumuza, C., Kiryabwire, J., Ssenyonjo, H., Mukasa, J., Muhumuza, M., Grant, G. 2018; 45 (4): E9

    Abstract

    OBJECTIVE: Children with neural tube defects (NTDs) require timely surgical intervention coupled with long-term management by multiple highly trained specialty healthcare teams. In resource-limited settings, outcomes are greatly affected by the lack of coordinated care. The purpose of this study was to characterize outcomes of spina bifida patients treated at Mulago National Referral Hospital (MNRH) through follow-up phone surveys.METHODS: All children presenting to MNRH with NTDs between January 1, 2014, and August 31, 2015, were eligible for this study. For those with a documented telephone number, follow-up phone surveys were conducted with the children's caregivers to assess mortality, morbidity, follow-up healthcare, and access to medical resources.RESULTS: Of the 201 patients, the vast majority (n = 185, 92%) were diagnosed with myelomeningocele. The median age at presentation was 6 days, the median length of stay was 20 days, and the median time to surgery was 10 days. Half of the patients had documented surgeries, with 5% receiving multiple procedures (n = 102, 51%): 80 defect closures (40%), 32 ventriculoperitoneal shunts (15%), and 1 endoscopic third ventriculostomy (0.5%). Phone surveys were completed for 53 patients with a median time to follow-up of 1.5 years. There were no statistically significant differences in demographics between the surveyed and nonrespondent groups. The 1-year mortality rate was 34% (n = 18). At the time of survey, 91% of the survivors (n = 30) have received healthcare since their initial discharge from MNRH, with 67% (n = 22) returning to MNRH. Hydrocephalus was diagnosed in 29 patients (88%). Caregivers reported physical deficits in 39% of patients (n = 13), clubfoot in 18% (n = 6), and bowel or bladder incontinence in 12% (n = 4). The surgical complication rate was 2.5%. Glasgow Outcome Scale-Extended pediatric revision scores were correlated with upper good recovery in 58% (n = 19) of patients, lower good recovery in 30% (n = 10), and moderate disability in 12% of patients (n = 4). Only 5 patients (15%) reported access to home health resources postdischarge.CONCLUSIONS: This study is the first to characterize the outcomes of children with NTDs that were treated at Uganda's national referral hospital. There is a great need for improved access to and coordination of care in antenatal, perioperative, and long-term settings to improve morbidity and mortality.

    View details for PubMedID 30269577

  • Complications following pediatric cranioplasty after decompressive craniectomy: a multicenter retrospective study JOURNAL OF NEUROSURGERY-PEDIATRICS Rocque, B. G., Agee, B. S., Thompson, E. M., Piedra, M., Baird, L. C., Selden, N. R., Greene, S., Deibert, C. P., Hankinson, T. C., Lew, S. M., Iskandar, B. J., Bragg, T. M., Frim, D., Grant, G., Gupta, N., Auguste, K. I., Nikas, D. C., Vassilyadi, M., Muh, C. R., Wetjen, N. M., Lam, S. K. 2018; 22 (3): 225–32

    Abstract

    OBJECTIVE In children, the repair of skull defects arising from decompressive craniectomy presents a unique set of challenges. Single-center studies have identified different risk factors for the common complications of cranioplasty resorption and infection. The goal of the present study was to determine the risk factors for bone resorption and infection after pediatric cranioplasty. METHODS The authors conducted a multicenter retrospective case study that included all patients who underwent cranioplasty to correct a skull defect arising from a decompressive craniectomy at 13 centers between 2000 and 2011 and were less than 19 years old at the time of cranioplasty. Prior systematic review of the literature along with expert opinion guided the selection of variables to be collected. These included: indication for craniectomy; history of abusive head trauma; method of bone storage; method of bone fixation; use of drains; size of bone graft; presence of other implants, including ventriculoperitoneal (VP) shunt; presence of fluid collections; age at craniectomy; and time between craniectomy and cranioplasty. RESULTS A total of 359 patients met the inclusion criteria. The patients' mean age was 8.4 years, and 51.5% were female. Thirty-eight cases (10.5%) were complicated by infection. In multivariate analysis, presence of a cranial implant (primarily VP shunt) (OR 2.41, 95% CI 1.17-4.98), presence of gastrostomy (OR 2.44, 95% CI 1.03-5.79), and ventilator dependence (OR 8.45, 95% CI 1.10-65.08) were significant risk factors for cranioplasty infection. No other variable was associated with infection. Of the 240 patients who underwent a cranioplasty with bone graft, 21.7% showed bone resorption significant enough to warrant repeat surgical intervention. The most important predictor of cranioplasty bone resorption was age at the time of cranioplasty. For every month of increased age the risk of bone flap resorption decreased by 1% (OR 0.99, 95% CI 0.98-0.99, p < 0.001). Other risk factors for resorption in multivariate models were the use of external ventricular drains and lumbar shunts. CONCLUSIONS This is the largest study of pediatric cranioplasty outcomes performed to date. Analysis included variables found to be significant in previous retrospective reports. Presence of a cranial implant such as VP shunt is the most significant risk factor for cranioplasty infection, whereas younger age at cranioplasty is the dominant risk factor for bone resorption.

    View details for PubMedID 29882736

  • COMMENT NEUROSURGERY Mahaney, K. B., Grant, G. A. 2018; 83 (3): 487
  • Stereoelectroencephalography in children: a review. Neurosurgical focus Ho, A. L., Feng, A. Y., Kim, L. H., Pendharkar, A. V., Sussman, E. S., Halpern, C. H., Grant, G. A. 2018; 45 (3): E7

    Abstract

    Stereoelectroencephalography (SEEG) is an intracranial diagnostic measure that has grown in popularity in the United States as outcomes data have demonstrated its benefits and safety. The main uses of SEEG include 1) exploration of deep cortical/sulcal structures; 2) bilateral recordings; and 3) 3D mapping of epileptogenic zones. While SEEG has gradually been accepted for treatment in adults, there is less consensus on its utility in children. In this literature review, the authors seek to describe the current state of SEEG with a focus on the more recent technology-enabled surgical techniques and demonstrate its efficacy in the pediatric epilepsy population.

    View details for PubMedID 30173607

  • Robot-guided pediatric stereoelectroencephalography: single-institution experience. Journal of neurosurgery. Pediatrics Ho, A. L., Muftuoglu, Y., Pendharkar, A. V., Sussman, E. S., Porter, B. E., Halpern, C. H., Grant, G. A. 2018: 1–8

    Abstract

    OBJECTIVE Stereoelectroencephalography (SEEG) has increased in popularity for localization of epileptogenic zones in drug-resistant epilepsy because safety, accuracy, and efficacy have been well established in both adult and pediatric populations. Development of robot-guidance technology has greatly enhanced the efficiency of this procedure, without sacrificing safety or precision. To date there have been very limited reports of the use of this new technology in children. The authors present their initial experience using the ROSA platform for robot-guided SEEG in a pediatric population. METHODS Between February 2016 and October 2017, 20 consecutive patients underwent robot-guided SEEG with the ROSA robotic guidance platform as part of ongoing seizure localization and workup for medically refractory epilepsy of several different etiologies. Medical and surgical history, imaging and trajectory plans, as well as operative records were analyzed retrospectively for surgical accuracy, efficiency, safety, and epilepsy outcomes. RESULTS A total of 222 leads were placed in 20 patients, with an average of 11.1 leads per patient. The mean total case time (± SD) was 297.95 (± 52.96) minutes and the mean operating time per lead was 10.98 minutes/lead, with improvements in total (33.36 minutes/lead vs 21.76 minutes/lead) and operative (13.84 minutes/lead vs 7.06 minutes/lead) case times/lead over the course of the study. The mean radial error was 1.75 (± 0.94 mm). Clinically useful data were obtained from SEEG in 95% of cases, and epilepsy surgery was indicated and performed in 95% of patients. In patients who underwent definitive epilepsy surgery with at least a 3-month follow-up, 50% achieved an Engel class I result (seizure freedom). There were no postoperative complications associated with SEEG placement and monitoring. CONCLUSIONS In this study, the authors demonstrate that rapid adoption of robot-guided SEEG is possible even at a SEEG-naive institution, with minimal learning curve. Use of robot guidance for SEEG can lead to significantly decreased operating times while maintaining safety, the overall goals of identification of epileptogenic zones, and improved epilepsy outcomes.

    View details for PubMedID 30117789

  • Rapid-sequence brain magnetic resonance imaging for Chiari I abnormality JOURNAL OF NEUROSURGERY-PEDIATRICS Pan, J., Quon, J. L., Johnson, E., Lanzman, B., Chukus, A., Ho, A. L., Edwards, M. B., Grant, G. A., Yeom, K. W. 2018; 22 (2): 158–64

    Abstract

    OBJECTIVE Fast magnetic resonance imaging (fsMRI) sequences are single-shot spin echo images with fast acquisition times that have replaced CT scans for many conditions. Introduced as a means of evaluating children with hydrocephalus and macrocephaly, these sequences reduce the need for anesthesia and can be more cost-effective, especially for children who require multiple surveillance scans. However, the role of fsMRI has yet to be investigated in evaluating the posterior fossa in patients with Chiari I abnormality (CM-I). The goal of this study was to examine the diagnostic performance of fsMRI in evaluating the cerebellar tonsils in comparison to conventional MRI. METHODS The authors performed a retrospective analysis of 18 pediatric patients with a confirmed diagnosis of CM-I based on gold-standard conventional brain MRI and 30 controls without CM-I who had presented with various neurosurgical conditions. The CM-I patients were included if fsMRI studies had been obtained within 1 year of conventional MRI with no surgical intervention between the studies. Two neuroradiologists reviewed the studies in a blinded fashion to determine the diagnostic performance of fsMRI in detecting CM-I. For the CM-I cohort, the fsMRI and T2-weighted MRI exams were randomized, and the blinded reviewers performed tonsillar measurements on both scans. RESULTS The mean age of the CM-I cohort was 7.39 years, and 50% of these subjects were male. The mean time interval between fsMRI and conventional T2-weighted MRI was 97.8 days. Forty-four percent of the subjects had undergone imaging after posterior fossa decompression. The sensitivity and specificity of fsMRI in detecting CM-I was 100% (95% CI 71.51%-100%) and 92.11% (95% CI 78.62%-98.34%), respectively. If only preoperative patients are considered, both sensitivity and specificity increase to 100%. The authors also performed a cost analysis and determined that fsMRI was significantly cost-effective compared to T2-weighted MRI or CT. CONCLUSIONS Despite known limitations, fsMRI may serve as a useful diagnostic and surveillance tool for CM-I. It is more cost-effective than full conventional brain MRI and decreases the need for sedation in young children.

    View details for PubMedID 29749883

  • 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 Cannon, J. G., Ho, A. L., Mohole, J., Pendharkar, A. V., Sussman, E. S., Cheshier, S. H., Grant, G. A. 2018

    Abstract

    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 PubMedID 29955942

  • In Reply: Neurosurgical Randomized Controlled Trials-Distance Traveled. Neurosurgery Azad, T. D., Grant, G. A. 2018

    View details for PubMedID 29931353

  • Safety of Dynamic MRI of the Cervical Spine in Children Performed Without Neurosurgical Supervision. World neurosurgery Yecies, D., Fogel, N., Edwards, M., Grant, G., Yeom, K. W., Cheshier, S. 2018

    Abstract

    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 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 Lepage, C., de Pierrefeu, A., Koerte, I. K., Coleman, M. J., Pasternak, O., Grant, G., Marx, C. E., Morey, R. A., Flashman, L. A., George, M. S., McAllister, T. W., Andaluz, N., Shutter, L., Coimbra, R., Zafonte, R. D., Stein, M. B., Shenton, M. E., Bouix, S. 2018; 12 (3): 870–81

    Abstract

    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 PubMedID 28676987

    View details for PubMedCentralID PMC5756136

  • Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy ANNALS OF NEUROLOGY Winawer, M. R., Griffin, N. G., Samanamud, J., Baugh, E. H., Rathakrishnan, D., Ramalingam, S., Zagzag, D., Schevon, C. A., Dugan, P., Hegde, M., Sheth, S. A., McKhann, G. M., Doyle, W. K., Grant, G. A., Porter, B. E., Mikati, M. A., Muh, C. R., Malone, C. D., Bergin, A. R., Peters, J. M., McBrian, D. K., Pack, A. M., Akman, C. I., LaCoursiere, C. M., Keever, K. M., Madsen, J. R., Yang, E., Lidov, H. W., Shain, C., Allen, A. S., Canoll, P. D., Crino, P. B., Poduri, A. H., Heinzen, E. L. 2018; 83 (6): 1133–46

    Abstract

    Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD.We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD.We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen.We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

    View details for DOI 10.1002/ana.25243

    View details for Web of Science ID 000439994300008

    View details for PubMedID 29679388

  • ASL PERFUSION IMAGING OF THE FRONTAL LOBES PREDICTS THE OCCURRENCE AND RESOLUTION OF POSTERIOR FOSSA SYNDROME Yecies, D., Shpanskaya, K., Grant, G., Cheshier, S., Hong, D., Edwards, M., Yeom, K. OXFORD UNIV PRESS INC. 2018: 170
  • A Combination of Ontogeny and CNS Environment Establishes Microglial Identity. Neuron Bennett, F. C., Bennett, M. L., Yaqoob, F., Mulinyawe, S. B., Grant, G. A., Hayden Gephart, M., Plowey, E. D., Barres, B. A. 2018

    Abstract

    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 PubMedID 29861285

  • Minimally invasive approaches to craniosynostosis. Journal of neurosurgical sciences Pendharkar, A. V., Shahin, M. N., Cavallo, C., Zhao, X., Ho, A. L., Sussman, E. S., Grant, G. A. 2018

    Abstract

    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 PubMedID 29790726

  • Improved operative efficiency using a real-time MRI-guided stereotactic platform for laser amygdalohippocampotomy JOURNAL OF NEUROSURGERY Ho, A. L., Sussman, E. S., Pendharkar, A. V., Le, S., Mantovani, A., Keebaugh, A. C., Drover, D. R., Grant, G. A., Wintermark, M., Halpern, C. H. 2018; 128 (4): 1165–72

    Abstract

    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 PubMedID 28665249

  • Temporal Delays Along the Neurosurgical Care Continuum for Traumatic Brain Injury Patients at a Tertiary Care Hospital in Kampala, Uganda. Neurosurgery Vaca, S. D., Kuo, B. J., Nickenig Vissoci, J. R., Staton, C. A., Xu, L. W., Muhumuza, M., Ssenyonjo, H., Mukasa, J., Kiryabwire, J., Rice, H. E., Grant, G. A., Haglund, M. M. 2018

    Abstract

    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 PubMedID 29490070

  • Multi-site harmonization of diffusion MRI data in a registration framework BRAIN IMAGING AND BEHAVIOR Mirzaalian, H., Ning, L., Savadjiev, P., Pasternak, O., Bouix, S., Michailovich, O., Karmacharya, S., Grant, G., Marx, C. E., Morey, R. A., Flashman, L. A., George, M. S., McAllister, T. W., Andaluz, N., Shutter, L., Coimbra, R., Zafonte, R. D., Coleman, M. J., Kubicki, M., Westin, C., Stein, M. B., Shenton, M. E., Rathi, Y. 2018; 12 (1): 284–95

    Abstract

    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 PubMedID 28176263

  • Occipital Dermal Sinus Tract JOURNAL OF PEDIATRICS Prolo, L. M., Grant, G. A. 2018; 193: 276

    View details for PubMedID 29174077

  • A novel mesial temporal stereotactic coordinate system. Journal of neurosurgery Miller, K. J., Halpern, C. H., Sedrak, M. F., Duncan, J. A., Grant, G. A. 2018: 1–9

    Abstract

    OBJECTIVE Stereotactic laser ablation and neurostimulator placement represent an evolution in staged surgical intervention for epilepsy. As this practice evolves, optimal targeting will require standardized outcome measures that compare electrode lead or laser source with postprocedural changes in seizure frequency. The authors propose and present a novel stereotactic coordinate system based on mesial temporal anatomical landmarks to facilitate the planning and delineation of outcomes based on extent of ablation or region of stimulation within mesial temporal structures. METHODS The body of the hippocampus contains a natural axis, approximated by the interface of cornu ammonis area 4 and the dentate gyrus. The uncal recess of the lateral ventricle acts as a landmark to characterize the anterior-posterior extent of this axis. Several volumetric rotations are quantified for alignment with the mesial temporal coordinate system. First, the brain volume is rotated to align with standard anterior commissure-posterior commissure (AC-PC) space. Then, it is rotated through the axial and sagittal angles that the hippocampal axis makes with the AC-PC line. RESULTS Using this coordinate system, customized MATLAB software was developed to allow for intuitive standardization of targeting and interpretation. The angle between the AC-PC line and the hippocampal axis was found to be approximately 20°-30° when viewed sagittally and approximately 5°-10° when viewed axially. Implanted electrodes can then be identified from CT in this space, and laser tip position and burn geometry can be calculated based on the intraoperative and postoperative MRI. CONCLUSIONS With the advent of stereotactic surgery for mesial temporal targets, a mesial temporal stereotactic system is introduced that may facilitate operative planning, improve surgical outcomes, and standardize outcome assessment.

    View details for PubMedID 29372873

  • Life After the Neurosurgical Ward in SubSaharan Africa: Neurosurgical Treatment and Outpatient Outcomes in Uganda. World neurosurgery Xu, L. W., Vaca, S. D., Nalwanga, J., Muhumuza, C., Vail, D., Lerman, B. J., Kiryabwire Surg, J., Ssenyonjo, H., Mukasa, J., Muhumuza, M., Haglund, M. M., Grant, G. 2018

    Abstract

    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 PubMedID 29427813

  • Surgical outcomes of pediatric spinal cord astrocytomas: systematic review and meta-analysis. Journal of neurosurgery. Pediatrics Azad, T. D., Pendharkar, A. V., Pan, J., Huang, Y., Li, A., Esparza, R., Mehta, S., Connolly, I. D., Veeravagu, A., Campen, C. J., Cheshier, S. H., Edwards, M. S., Fisher, P. G., Grant, G. A. 2018: 1–7

    Abstract

    OBJECTIVE Pediatric spinal astrocytomas are rare spinal lesions that pose unique management challenges. Therapeutic options include gross-total resection (GTR), subtotal resection (STR), and adjuvant chemotherapy or radiation therapy. With no randomized controlled trials, the optimal management approach for children with spinal astrocytomas remains unclear. The aim of this study was to conduct a systematic review and meta-analysis on pediatric spinal astrocytomas. METHODS The authors performed a systematic review of the PubMed/MEDLINE electronic database to investigate the impact of histological grade and extent of resection on overall survival among patients with spinal cord astrocytomas. They retained publications in which the majority of reported cases included astrocytoma histology. RESULTS Twenty-nine previously published studies met the eligibility criteria, totaling 578 patients with spinal cord astrocytomas. The spinal level of intramedullary spinal cord tumors was predominantly cervical (53.8%), followed by thoracic (40.8%). Overall, resection was more common than biopsy, and GTR was slightly more commonly achieved than STR (39.7% vs 37.0%). The reported rates of GTR and STR rose markedly from 1984 to 2015. Patients with high-grade astrocytomas had markedly worse 5-year overall survival than patients with low-grade tumors. Patients receiving GTR may have better 5-year overall survival than those receiving STR. CONCLUSIONS The authors describe trends in the management of pediatric spinal cord astrocytomas and suggest a benefit of GTR over STR for 5-year overall survival.

    View details for PubMedID 30028275

  • Long-term outcomes of primarily metastatic juvenile pilocytic astrocytoma in children. Journal of neurosurgery. Pediatrics Yecies, D., Fisher, P. G., Cheshier, S., Edwards, M., Grant, G. 2018; 21 (1): 49–53

    Abstract

    OBJECTIVE Primarily metastatic juvenile pilocytic astrocytoma (JPA) is rare, likely representing 2%-3% of all cases of JPA. Due to the rarity of primarily metastatic JPA, there is currently no standard treatment paradigm and the long-term outcomes are not fully known. The goal of this case series was to add to the current understanding of this disease process. METHODS The authors searched a comprehensive database of pediatric patients with brain and spinal cord tumors treated at Lucile Packard Children's Hospital from 1997 to 2016 and identified 5 patients with primarily metastatic JPA. A retrospective chart review was performed and details of the patients' treatment and clinical course were recorded for further analysis. RESULTS For the 5 patients with primarily metastatic JPA, the mean follow-up period was 12.3 years. All patients in our series had biopsies or subtotal resections and upfront treatment. Three patients were treated with chemotherapy alone, one was treated with chemotherapy and radiotherapy, and one was treated with radiotherapy alone. Four patients had stable disease after initial treatment, and one patient had multiple episodes of progressive disease but underwent successful salvage therapy and has had stable disease for 19 years. One patient died of an intracerebral hemorrhage 10 years following initial radiation treatment believed to be secondary to radiation vasculopathy. CONCLUSIONS Evaluation of the entire neuraxis should be performed in all instances of initial JPA diagnosis to properly assess for primarily metastatic disease. Many patients with primarily metastatic JPA will have stable disease after upfront treatment, although the higher rate of stable disease found in this series relative to other reports is likely secondary to the small sample size.

    View details for PubMedID 29125440

  • Long-term follow-up of pediatric head trauma patients treated at Mulago National Referral Hospital in Uganda. Journal of neurosurgery. Pediatrics 2018: 1–8

    Abstract

    OBJECTIVEThere is a paucity of literature on long-term neurosurgical outcomes in sub-Saharan Africa, and as neurosurgical services expand in each country, it would be beneficial to understand the impact of these services on the national population. Since follow-up can be inconsistent, the authors here used the novel method of telephone surveys to conduct the first-ever long-term follow-up in Uganda to elucidate the outcomes of pediatric head trauma patients treated at the national referral hospital.METHODSA prospectively maintained database of pediatric head trauma patients treated at the Mulago National Referral Hospital (MNRH) between 2014 and 2015 included 232 patients eligible for this study. Quality of life was assessed through phone surveys conducted by a Ugandan collaborator on site who performed all interviews with the guardian listed at the time of hospital admission, using each participant's language.RESULTSPhone interviews were completed for 142 patients, resulting in a 61% response rate. Including inpatient deaths, the mortality rate was 10%. Almost half of the patients (48%) did not return to MNRH postdischarge, and 37% received no subsequent healthcare at all. Including inpatient deaths, the average Extended Glasgow Outcome Scale-Pediatric Revision (GOSE-Peds) scores for patients with severe, moderate, and mild head trauma were 5.68 ± 2.85, 4.79 ± 2.38, and 3.12 ± 2.08, respectively, at 1 year postinjury and 5.56 ± 2.58, 4.00 ± 2.45, and 2.21 ± 1.49, respectively, at 2 years postinjury.CONCLUSIONSThis first-ever long-term follow-up of pediatric head trauma patients in Uganda confirmed the feasibility of a novel phone follow-up method for patients throughout Uganda. The results at 2 years showed poor long-term recovery in patients who suffered moderate or severe head trauma but good recovery in patients who suffered mild head trauma. However, there was greater overall disability than that in comparable head trauma studies in the US. The current study lays the groundwork for phone follow-up in low- and middle-income countries as a viable way to obtain outcome data.

    View details for PubMedID 30485178

  • Intraoperative Imaging Modalities and the Potential Role of Speckle Modulating Optical Coherence Tomography. Neurosurgery Yecies, D., Liba, O., Zerda, A., Grant, G. A. 2018; 65 (CN_suppl_1): 74–77

    View details for PubMedID 31076788

  • Quality of Care and Outcomes in Pediatric Neurosurgery: Incorporating Evidence-Based Practice QUALITY AND SAFETY IN NEUROSURGERY Quon, J. L., Grant, G. A., Guillaume, D. J., Hunt, M. A. 2018: 237–50
  • Topical vancomycin surgical prophylaxis in pediatric open craniotomies: an institutional experience. Journal of neurosurgery. Pediatrics Ho, A. L., Cannon, J. G., Mohole, J., Pendharkar, A. V., Sussman, E. S., Li, G., Edwards, M. S., Cheshier, S. H., Grant, G. A. 2018: 1–6

    Abstract

    OBJECTIVE Topical antimicrobial compounds are safe and can reduce cost and complications associated with surgical site infections (SSIs). Topical vancomycin has been an effective tool for reducing SSIs following routine neurosurgical procedures in the spine and following adult craniotomies. However, widespread adoption within the pediatric neurosurgical community has not yet occurred, and there are no studies to report on the safety and efficacy of this intervention. The authors present the first institution-wide study of topical vancomycin following open craniotomy in the pediatric population. METHODS In this retrospective study the authors reviewed all open craniotomies performed over a period from 05/2014 to 12/2016 for topical vancomycin use, SSIs, and clinical variables associated with SSI. Topical vancomycin was utilized as an infection prophylaxis and was applied as a liquid solution following replacement of a bone flap or after dural closure when no bone flap was reapplied. RESULTS Overall, 466 consecutive open craniotomies were completed between 05/2014 and 12/2016, of which 43% utilized topical vancomycin. There was a 1.5% SSI rate in the nontopical cohort versus 0% in the topical vancomycin cohort (p = 0.045). The number needed to treat was 66. There were no significant differences in risk factors for SSI between cohorts. There were no complications associated with topical vancomycin use. CONCLUSIONS Routine topical vancomycin administration during closure of open craniotomies can be a safe and effective tool for reducing SSIs in the pediatric neurosurgical population.

    View details for PubMedID 30141749

  • 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 Iv, M., Choudhri, O., Dodd, R. L., Vasanawala, S. S., Alley, M. T., Moseley, M., Holdsworth, S. J., Grant, G., Cheshier, S., Yeom, K. W. 2018: 1–10

    Abstract

    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 PubMedID 29882734

  • Long-term outcomes of primarily metastatic juvenile pilocytic astrocytoma in children JOURNAL OF NEUROSURGERY-PEDIATRICS Yecies, D., Fisher, P., Cheshier, S., Edwards, M., Grant, G. 2018; 21 (1): 49–53
  • First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800. Journal of neuro-oncology Miller, S. E., Tummers, W. S., Teraphongphom, N., van den Berg, N. S., Hasan, A., Ertsey, R. D., Nagpal, S., Recht, L. D., Plowey, E. D., Vogel, H., Harsh, G. R., Grant, G. A., Li, G. H., Rosenthal, E. L. 2018

    Abstract

    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 PubMedID 29623552

  • Fractal structure in the volumetric contrast enhancement of malignant gliomas as a marker of oxidative metabolic pathway gene expression TRANSLATIONAL CANCER RESEARCH Miller, K. J., Berendsen, S., Seute, T., Yeom, K., Gephardt, M. H., Grant, G. A., Robe, P. A. 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 Gururangan, S., Reap, E., Schmittling, R., Kocak, M., Reynolds, R., Grant, G., Onar-Thomas, A., Baxter, P., Pollack, I. F., Phillips, P., Boyett, J., Fouladi, M., Mitchell, D. 2017; 66 (12): 1589–95

    Abstract

    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 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 Okonkwo, D. O., Shutter, L. A., Moore, C., Temkin, N. R., Puccio, A. M., Madden, C. J., Andaluz, N., Chesnut, R. M., Bullock, M., Grant, G. A., McGregor, J., Weaver, M., Jallo, J., LeRoux, P. D., Moberg, D., Barber, J., Lazaridis, C., Diaz-Arrastia, R. R. 2017; 45 (11): 1907–14

    Abstract

    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 PLOS ONE Kuo, B. J., Vaca, S. D., Vissoci, J., Staton, C. A., Xu, L., Muhumuza, M., Ssenyonjo, H., Mukasa, J., Kiryabwire, J., Nanjula, L., Muhumuza, C., Rice, H. E., Grant, G. A., Haglund, M. M. 2017; 12 (10): e0182285

    Abstract

    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 PubMedID 29088217

  • Diffusion Tensor Imaging in an Infant Undergoing Functional Hemispherectomy: A Surgical Aid. Cureus Ho, A. L., Pendharkar, A. V., Sussman, E. S., Casazza, M., Grant, G. A. 2017; 9 (9): e1697

    Abstract

    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 PubMedID 29167751

  • Prolonged Blood-Brain Barrier Disruption Following Laser Interstitial Ablation in Epilepsy: A Case Series with a Case Report of Postablation Optic Neuritis WORLD NEUROSURGERY Morris, S., Rollo, M., Rollo, P., Johnson, J., Grant, G. A., Friedman, E., Kalamangalam, G., Tandon, N. 2017; 104: 467–75

    Abstract

    Laser interstitial thermal therapy has become increasingly popular for targeting epileptic foci in a minimally invasive fashion. Despite its use in >1000 patients, the long-term effects of photothermal injury on brain physiology remain poorly understood.We prospectively followed clinical and radiographic courses of 13 patients undergoing laser ablation for focal epilepsy by the senior author (N.T.). Only patients with nonenhancing lesions and patients who had a delayed postoperative magnetic resonance imaging (MRI) scan with gadolinium administration approximately 6 months after ablation were considered. Volumetric estimates of the amount of enhancement immediately after ablation and on the delayed MRI scan were made.Median interval between surgery and delayed postoperative MRI scan was 6 months (range, 5-8 months). In 12 of 13 cases, persistent enhancement was seen, consistent with prolonged blood-brain barrier dysfunction. Enhancement, when present, was 9%-67% (mean 30%). There was no correlation between the time from surgery and the relative percentage of postoperative enhancement on MRI. The blood-brain barrier remained compromised to gadolinium contrast for up to 8 months after thermal therapy. There were no adverse events from surgical intervention; however, 1 patient developed delayed optic neuritis.Prolonged incompetence of the blood-brain barrier produced by thermal ablation may provide a path for delivery of macromolecules into perilesional tissue, which could be exploited for therapeutic benefit, but rarely it may result in autoimmune central nervous system inflammatory conditions.

    View details for PubMedID 28502693

  • R-SCAN: Imaging for Pediatric Simple Febrile Seizures. Journal of the American College of Radiology Lee, S., Fisher, P., Grant, G. A., Porter, B., Dannenberg, B., Wintermark, M. 2017

    View details for DOI 10.1016/j.jacr.2017.04.007

    View details for PubMedID 28551342

  • Modeling and Optimization of Airbag Helmets for Preventing Head Injuries in Bicycling ANNALS OF BIOMEDICAL ENGINEERING Kurt, M., Laksari, K., Kuo, C., Grant, G. A., Camarillo, D. B. 2017; 45 (4): 1148-1160

    Abstract

    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 DOI 10.1007/s10439-016-1732-1

    View details for Web of Science ID 000398737100026

  • 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 Gholamin, S., Mitra, S. S., Feroze, A. H., Liu, J., Kahn, S. A., Zhang, M., Esparza, R., Richard, C., Ramaswamy, V., Remke, M., Volkmer, A. K., Willingham, S., Ponnuswami, A., McCarty, A., Lovelace, P., Storm, T. A., Schubert, S., Hutter, G., Narayanan, C., Chu, P., Raabe, E. H., Harsh, G., Taylor, M. D., Monje, M., Cho, Y., Majeti, R., Volkmer, J. P., Fisher, P. G., Grant, G., Steinberg, G. K., Vogel, H., Edwards, M., Weissman, I. L., Cheshier, S. H. 2017; 9 (381)

    Abstract

    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 PubMedID 28298418

  • Perioperative outcomes for pediatric neurosurgical procedures: analysis of the National Surgical Quality Improvement Program-Pediatrics JOURNAL OF NEUROSURGERY-PEDIATRICS Kuo, B. J., Vissoci, J. R., Egger, J. R., Smith, E. R., Grant, G. A., Haglund, M. M., Rice, H. E. 2017; 19 (3): 361-371

    Abstract

    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 Thompson, E. M., Gururangan, S., Grant, G., Mitchell, D., Sampson, J. H. 2017; 132 (1): 83-87

    Abstract

    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 Li, M. D., Forkert, N. D., Kundu, P., Ambler, C., Lober, R. M., Burns, T. C., Barnes, P. D., Gibbs, I. C., Grant, G. A., Fisher, P. G., Cheshier, S. H., Campen, C. J., Monje, M., Yeom, K. W. 2017

    Abstract

    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 Lee, S., Grant, G. A., Fisher, P. G., Imler, D., Padrez, R., Avery, C., Sharp, A. L., Wintermark, M. 2017; 14 (2): 294-297

    View details for DOI 10.1016/j.jacr.2016.10.006

    View details for PubMedID 28017272

  • Neurosurgical Randomized Controlled Trials-Distance Travelled. Neurosurgery Azad, T. D., Veeravagu, A., Mittal, V., Esparza, R., Johnson, E., Ioannidis, J. P., Grant, G. A. 2017

    Abstract

    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 PubMedID 28645203

  • Near-Fatal Gastrointestinal Hemorrhage in a Child with Medulloblastoma on High Dose Dexamethasone. Cureus Yecies, D., Tawfik, D., Damman, J., Thorson, C., Hong, D. S., Grant, G. A., Bensen, R., Damian, M. 2017; 9 (7): e1442

    Abstract

    A four-year-old female was admitted to a university-based children's hospital with a newly-diagnosed posterior fossa tumor. She was started on famotidine and high-dose dexamethasone and underwent gross total resection of a medulloblastoma. She was continued on dexamethasone and famotidine. She exhibited postoperative posterior fossa syndrome and was started on enteral feeds via the nasoduodenal tube. She had small gastrointestinal bleeds on postoperative days eight, 11, and 18, and was found to have a well-circumscribed posterior duodenal ulcer. On postoperative day 19, she suffered a massive life-threatening gastrointestinal bleed requiring aggressive resuscitation with blood products. She required an emergent laparotomy due to ongoing blood loss and she was found to have posterior duodenal wall erosion into her gastroduodenal artery. She recovered and subsequently began delayed chemotherapy. This case demonstrates a rare and life-threatening complication of high-dose dexamethasone therapy in the setting of posterior fossa pathology despite stress ulcer prophylaxis. We present a historical perspective with the review of the association between duodenal and intracranial pathology and the usage of high-dose dexamethasone in such cases.

    View details for PubMedID 28924528

  • Molecular Analyses Reveal Inflammatory Mediators in the Solid Component and Cyst Fluid of Human Adamantinomatous Craniopharyngioma. Journal of neuropathology and experimental neurology Donson, A. M., Apps, J., Griesinger, A. M., Amani, V., Witt, D. A., Anderson, R. C., Niazi, T. N., Grant, G., Souweidane, M., Johnston, J. M., Jackson, E. M., Kleinschmidt-DeMasters, B. K., Handler, M. H., Tan, A. C., Gore, L., Virasami, A., Gonzalez-Meljem, J. M., Jacques, T. S., Martinez-Barbera, J. P., Foreman, N. K., Hankinson, T. C. 2017; 76 (9): 779–88

    Abstract

    Pediatric adamantinomatous craniopharyngioma (ACP) is a highly solid and cystic tumor, often causing substantial damage to critical neuroendocrine structures such as the hypothalamus, pituitary gland, and optic apparatus. Paracrine signaling mechanisms driving tumor behavior have been hypothesized, with IL-6R overexpression identified as a potential therapeutic target. To identify potential novel therapies, we characterized inflammatory and immunomodulatory factors in ACP cyst fluid and solid tumor components. Cytometric bead analysis revealed a highly pro-inflammatory cytokine pattern in fluid from ACP compared to fluids from another cystic pediatric brain tumor, pilocytic astrocytoma. Cytokines and chemokines with particularly elevated concentrations in ACPs were IL-6, CXCL1 (GRO), CXCL8 (IL-8) and the immunosuppressive cytokine IL-10. These data were concordant with solid tumor compartment transcriptomic data from a larger cohort of ACPs, other pediatric brain tumors and normal brain. The majority of receptors for these cytokines and chemokines were also over-expressed in ACPs. In addition to IL-10, the established immunosuppressive factor IDO-1 was overexpressed by ACPs at the mRNA and protein levels. These data indicate that ACP cyst fluids and solid tumor components are characterized by an inflammatory cytokine and chemokine expression pattern. Further study regarding selective cytokine blockade may inform novel therapeutic interventions.

    View details for PubMedID 28859336

    View details for PubMedCentralID PMC6005018

  • Somatic uniparental disomy of Chromosome 16p in hemimegalencephaly. Cold Spring Harbor molecular case studies Griffin, N. G., Cronin, K. D., Walley, N. M., Hulette, C. M., Grant, G. A., Mikati, M. A., LaBreche, H. G., Rehder, C. W., Allen, A. S., Crino, P. B., Heinzen, E. L. 2017; 3 (5)

    Abstract

    Hemimegalencephaly (HME) is a heterogeneous cortical malformation characterized by enlargement of one cerebral hemisphere. Somatic variants in mammalian target of rapamycin (mTOR) regulatory genes have been implicated in some HME cases; however, ∼70% have no identified genetic etiology. Here, we screened two HME patients to identify disease-causing somatic variants. DNA from leukocytes, buccal swabs, and surgically resected brain tissue from two HME patients were screened for somatic variants using genome-wide genotyping arrays or sequencing of the protein-coding regions of the genome. Functional studies were performed to evaluate the molecular consequences of candidate disease-causing variants. Both HME patients evaluated were found to have likely disease-causing variants in DNA extracted from brain tissue but not in buccal swab or leukocyte DNA, consistent with a somatic mutational mechanism. In the first case, a previously identified disease-causing somatic single nucleotide in MTOR was identified. In the second case, we detected an overrepresentation of the alleles inherited from the mother on Chromosome 16 in brain tissue DNA only, indicative of somatic uniparental disomy (UPD) of the p-arm of Chromosome 16. Using methylation analyses, an imprinted locus on 16p spanning ZNF597 was identified, which results in increased expression of ZNF597 mRNA and protein in the brain tissue of the second case. Enhanced mTOR signaling was observed in tissue specimens from both patients. We speculate that overexpression of maternally expressed ZNF597 led to aberrant hemispheric development in the patient with somatic UPD of Chromosome 16p possibly through modulation of mTOR signaling.

    View details for PubMedID 28864461

    View details for PubMedCentralID PMC5593155

  • Diagnostic Utility of Intraoperative Neurophysiological Monitoring for Intramedullary Spinal Cord Tumors: Systematic Review and Meta-Analysis. Clinical spine surgery Azad, T. D., Pendharkar, A. V., Nguyen, V., Pan, J., Connolly, I. D., Veeravagu, A., Popat, R., Ratliff, J. K., Grant, G. A. 2017

    Abstract

    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 PubMedID 28650882

  • Magnetic Resonance-Guided Laser-Induced Thermal Therapy for Recurrent Brain Metastases in the Motor Strip After Stereotactic Radiosurgery. Cureus Iyer, A., Halpern, C. H., Grant, G. A., Deb, S., Li, G. H. 2016; 8 (12)

    Abstract

    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

  • 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 Jiang, X., Fitch, S., Wang, C., Wilson, C., Li, J., Grant, G. A., Yang, F. 2016; 113 (48): 13857-13862

    Abstract

    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

  • The clinical and financial impact of a pediatric surgical neuro-oncology clinical trial. Journal of neuro-oncology Thompson, E. M., Gururangan, S., Grant, G., Mitchell, D., Sampson, J. H. 2016: -?

    Abstract

    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 PubMedID 27864705

  • Diagnosis and treatment of pediatric frontotemporal pits: report of 2 cases JOURNAL OF NEUROSURGERY-PEDIATRICS Bliss, M., Grant, G., Tittler, E., Loven, T., Yeom, K. W., Sidell, D. 2016; 18 (4): 471-474

    Abstract

    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 Kurt, M., Laksari, K., Kuo, C., Grant, G. A., Camarillo, D. B. 2016: -?

    Abstract

    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) Cox, N., Kintzing, J. R., Smith, M., Grant, G. A., Cochran, J. R. 2016; 55 (34): 9894-9897

    Abstract

    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 Gupta, M., Choudhri, O. A., Feroze, A. H., Do, H. M., Grant, G. A., Steinberg, G. K. 2016; 28: 107-111

    Abstract

    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

  • Rasmussen encephalitis tissue transfer program EPILEPSIA Kruse, C. A., Pardo, C. A., Hartman, A. L., Jallo, G., Vining, E. G., Voros, J., Gaillard, W. D., Liu, J., Oluigbo, C., Malone, S., Bleasel, A. F., Dexter, M., Micati, A., Velasco, T. R., Machado, H. R., Martino, A. M., Huang, A., Wheatley, B. M., Grant, G. A., Granata, T., Freri, E., Garbelli, R., Koh, S., Nordli, D. R., Campos, A. R., O'Neill, B., Handler, M. H., Chapman, K. E., Wilfong, A. A., Curry, D. J., Yaun, A., Madsen, J. R., Smyth, M. D., Mercer, D., Bingaman, W., Harvey, A. S., Leventer, R. J., Lockhart, P. J., Gillies, G., Pope, K., Giller, C. A., Park, Y. D., Rojiani, A. M., Sharma, S. J., Jenkins, P., Tung, S., Huynh, M. N., Chirwa, T. W., Cepeda, C., Levine, M. S., Chang, J. W., Owens, G. C., Vinters, H. V., Mathern, G. W. 2016; 57 (6): 1004–6

    View details for PubMedID 27286752

  • Epilepsy: A Disruptive Force in History. World neurosurgery Ali, R., Connolly, I. D., Feroze, A. H., Awad, A. J., Choudhri, O. A., Grant, G. A. 2016; 90: 685-690

    Abstract

    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 NEUROSURGICAL FOCUS Burns, T. C., Awad, A. J., Li, M. D., Grant, G. A. 2016; 40 (5)

    Abstract

    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 NEUROPSYCHOPHARMACOLOGY McAllister, T. W., Zafonte, R., Jain, S., Flashman, L. A., George, M. S., Grant, G. A., He, F., Lohr, J. B., Andaluz, N., Summerall, L., Paulus, M. P., Raman, R., Stein, M. B. 2016; 41 (5): 1191-1198

    Abstract

    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

    View details for PubMedCentralID PMC4793116

  • Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis LANCET ONCOLOGY Thompson, E. M., Hielscher, T., Bouffet, E., Remke, M., Luu, B., Gururangan, S., McLendon, R. E., Bigner, D. D., Lipp, E. S., Perreault, S., Cho, Y., Grant, G., Kim, S., Lee, J. Y., Rao, A. A., Giannini, C., Li, K. K., Ng, H., Yao, Y., Kumabe, T., Tominaga, T., Grajkowska, W. A., Perek-Polnik, M., Low, D. C., Seow, W. T., Chang, K. T., Mora, J., Pollack, I. F., Hamilton, R. L., Leary, S., Moore, A. S., Ingram, W. J., Hallahan, A. R., Jouvet, A., Fevre-Montange, M., Vasiljevic, A., Faure-Conter, C., Shofuda, T., Kagawa, N., Hashimoto, N., Jabado, N., Weil, A. G., Gayden, T., Wataya, T., Shalaby, T., Grotzer, M., Zitterbart, K., Sterba, J., Kren, L., Hortobagyi, T., Klekner, A., Laszlo, B., Pocza, T., Hauser, P., Schueller, U., Jung, S., Jang, W., French, P. J., Kros, J. M., van Veelen, M. C., Massimi, L., Leonard, J. R., Rubin, J. B., Vibhakar, R., Chambless, L. B., Cooper, M. K., Thompson, R. C., Faria, C. C., Carvalho, A., Nunes, S., Pimentel, J., Fan, X., Muraszko, K. M., Lopez-Aguilar, E., Lyden, D., Garzia, L., Shih, D. J., Kijima, N., Schneider, C., Adamski, J., Northcott, P. A., Kool, M., Jones, D. T., Chan, J. A., Nikolic, A., Garre, M. L., Van Meir, E. G., Osuka, S., Olson, J. J., Jahangiri, A., Castro, B. A., Gupta, N., Weiss, W. A., Moxon-Emre, I., Mabbott, D. J., Lassaletta, A., Hawkins, C. E., Tabori, U., Drake, J., Kulkarni, A., Dirks, P., Rutka, J. T., Korshunov, A., fister, S. M., Packer, R. J., Ramaswamy, V., Taylor, M. D. 2016; 17 (4): 484-495

    Abstract

    Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner.We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival.We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084).The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection.Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

    View details for DOI 10.1016/S1470-2045(15)00581-1

    View details for PubMedID 26976201

  • Sports-related brain injuries: connecting pathology to diagnosis NEUROSURGICAL FOCUS Pan, J., Connolly, I. D., Dangelmajer, S., Kintzing, J., Ho, A. L., Grant, G. 2016; 40 (4)

    Abstract

    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 Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., Weissman, I. L., Chang, E. F., Li, G., Grant, G. A., Gephart, M. G., Barres, B. A. 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 Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., Weissman, I. L., Chang, E. F., Li, G., Grant, G. A., Hayden Gephart, M. G., Barres, B. A. 2016; 113 (12): E1738-46

    Abstract

    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

  • Six Degree-of-Freedom Measurements of Human Mild Traumatic Brain Injury (vol 43, pg 1918, 2015) ANNALS OF BIOMEDICAL ENGINEERING Hernandez, F., Wu, L. C., Yip, M. C., Laksari, K., Hoffman, A. R., Lopez, J. R., Grant, G. A., Kleiven, S., Camarillo, D. B. 2016; 44 (3): 828–29

    View details for PubMedID 26518413

  • Junior Seau: An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury WORLD NEUROSURGERY Azad, T. D., Li, A., Pendharkar, A. V., Veeravagu, A., Grant, G. A. 2016; 86

    Abstract

    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 NEURON Zhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Steinberg, G. K., Edwards, M. S., Li, G., Duncan, J. A., Cheshier, S. H., Shuer, L. M., Chang, E. F., Grant, G. A., Gephart, M. G., Barres, B. A. 2016; 89 (1): 37-53

    Abstract

    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 PubMedID 26687838

  • Assessment of obstetric brachial plexus injury with preoperative ultrasound. Muscle & nerve Smith, E. C., Xixis, K. I., Grant, G. A., Grant, S. A. 2016; 53 (6): 946–50

    Abstract

    Tools used in the assessment of obstetric brachial plexus injuries (OBPIs) have traditionally included electrodiagnostic studies, computerized tomography with myelography, and MRI. However, the utility of ultrasound (US) in infants for such assessment has not been extensively examined.This retrospective case series reports the preoperative brachial plexus US findings in 8 patients with OBPI and compares US with intraoperative findings. When available, the preoperative US was compared with the preoperative MRI.US revealed abnormalities in all 8 patients. Although MRI detected abnormalities in the majority of patients, US provided accurate information regarding severity and anatomic location of injury in some patients.US is a relatively inexpensive, noninvasive, painless diagnostic modality that can be used to assess OBPI. This case series suggests that US is a valuable adjunct to current diagnostic modalities. Muscle Nerve 53: 946-950, 2016.

    View details for PubMedID 26565729

  • Pediatric Central Nervous System Tumors in Nepal: Retrospective Analysis and Literature Review of Low- and Middle-Income Countries WORLD NEUROSURGERY Azad, T. D., Shrestha, R. K., Vaca, S., Niyaf, A., Pradhananga, A., Sedain, G., Sharma, M. R., Shilpakar, S. K., Grant, G. A. 2015; 84 (6): 1832-1837

    Abstract

    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 Sun, J. M., Grant, G. A., McLaughlin, C., Allison, J., Fitzgerald, A., Waters-Pick, B., Kurtzberg, J. 2015; 78 (6): 712-716

    Abstract

    Babies with congenital hydrocephalus often experience developmental disabilities due to brain injury associated with prolonged increased pressure on the developing brain parenchyma. Umbilical cord blood (CB) infusion has favorable effects in animal models of brain hypoxia and stroke and is being investigated in clinical trials of brain injury in both children and adults. We sought to establish the safety and feasibility of repeated intravenous infusions of autologous CB in young babies with congenital hydrocephalus.Infants with severe congenital hydrocephalus and an available qualified autologous CB unit traveled to Duke for evaluation and CB infusion. When possible, the CB unit was utilized for multiple infusions. Patient and CB data were obtained at the time of infusion and analyzed retrospectively.From October 2006 to August 2014, 76 patients with congenital hydrocephalus received 143 autologous CB infusions. Most babies received repeated doses, for a total of two (n = 45), three (n = 18), or four (n = 4) infusions. There were no infusion-related adverse events. As expected, all babies experienced developmental delays.Cryopreserved CB products may be effectively manipulated to provide multiple CB doses. Repeated intravenous infusion of autologous CB is safe and feasible in young babies with congenital hydrocephalus.

    View details for DOI 10.1038/pr.2015.161

    View details for Web of Science ID 000367114900017

    View details for PubMedID 26331765

  • Gorlin syndrome and desmoplastic medulloblastoma: Report of 3 cases with unfavorable clinical course and novel mutations PEDIATRIC BLOOD & CANCER Gururangan, S., Robinson, G., Ellison, D. W., Wu, G., He, X., Lu, Q. R., McLendon, R., Grant, G., Driscoll, T., Neuberg, R. 2015; 62 (10): 1855-1858

    Abstract

    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 Nair, S. K., Driscoll, T., Boczkowski, D., Schmittling, R., Reynolds, R., Johnson, L. A., Grant, G., Fuchs, H., Bigner, D. D., Sampson, J. H., Gururangan, S., Mitchell, D. A. 2015; 125 (1): 65-74

    Abstract

    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

  • Evolution of cranioplasty techniques in neurosurgery: historical review, pediatric considerations, and current trends. Journal of neurosurgery Feroze, A. H., Walmsley, G. G., Choudhri, O., Lorenz, H. P., Grant, G. A., Edwards, M. S. 2015; 123 (4): 1098-1107

    Abstract

    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 Grant, G. A., Tomei, K. L., Hankinson, T. C., Muh, C. R., Dumont, A. S., Cheshier, S. H., Upadhyaya, C., Choudhri, O. 2015; 62: N1-?

    View details for DOI 10.1227/NEU.0000000000000822

    View details for PubMedID 26182050

  • Six Degree-of-Freedom Measurements of Human Mild Traumatic Brain Injury ANNALS OF BIOMEDICAL ENGINEERING Hernandez, F., Wu, L. C., Yip, M. C., Laksari, K., Hoffman, A. R., Lopez, J. R., Grant, G. A., Kleiven, S., Camarillo, D. B. 2015; 43 (8): 1918-1934

    Abstract

    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. Neurosurgical focus Azad, T. D., Pan, J., Connolly, I. D., Remington, A., Wilson, C. M., Grant, G. A. 2015; 38 (3): E9-?

    Abstract

    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 Azad, T. D., Pan, J., Connolly, I. D., Remington, A., Wilson, C. M., Grant, G. A. 2015; 38 (3): E9-?

    View details for DOI 10.3171/2014.12.FOCUS14758

    View details for PubMedID 25727231

  • Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: An in vitro study EPILEPSIA Ghosh, C., Hossain, M., Spriggs, A., Ghosh, A., Grant, G. A., Marchi, N., Perucca, E., Janigro, D. 2015; 56 (3): 439-449

    Abstract

    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 Lock, E. F., Soldano, K. L., Garrett, M. E., Cope, H., Markunas, C. A., Fuchs, H., Grant, G., Dunson, D. B., Gregory, S. G., Ashley-Koch, A. E. 2015; 16
  • Is there a role for decompressive craniectomy in children after stroke? World neurosurgery Grant, G. A. 2015; 83 (1): 44-45

    View details for DOI 10.1016/j.wneu.2013.08.049

    View details for PubMedID 24012655

  • Six Degree-of-Freedom Measurements of Human Mild Traumatic Brain Injury. Annals of biomedical engineering Hernandez, F., Wu, L. C., Yip, M. C., Laksari, K., Hoffman, A. R., Lopez, J. R., Grant, G. A., Kleiven, S., Camarillo, D. B. 2015; 43 (8): 1918–34

    Abstract

    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 PubMedID 25533767

  • Joint eQTL assessment of whole blood and dura mater tissue from individuals with Chiari type I malformation. BMC genomics Lock, E. F., Soldano, K. L., Garrett, M. E., Cope, H., Markunas, C. A., Fuchs, H., Grant, G., Dunson, D. B., Gregory, S. G., Ashley-Koch, A. E. 2015; 16: 11

    Abstract

    Expression quantitative trait loci (eQTL) play an important role in the regulation of gene expression. Gene expression levels and eQTLs are expected to vary from tissue to tissue, and therefore multi-tissue analyses are necessary to fully understand complex genetic conditions in humans. Dura mater tissue likely interacts with cranial bone growth and thus may play a role in the etiology of Chiari Type I Malformation (CMI) and related conditions, but it is often inaccessible and its gene expression has not been well studied. A genetic basis to CMI has been established; however, the specific genetic risk factors are not well characterized.We present an assessment of eQTLs for whole blood and dura mater tissue from individuals with CMI. A joint-tissue analysis identified 239 eQTLs in either dura or blood, with 79% of these eQTLs shared by both tissues. Several identified eQTLs were novel and these implicate genes involved in bone development (IPO8, XYLT1, and PRKAR1A), and ribosomal pathways related to marrow and bone dysfunction, as potential candidates in the development of CMI.Despite strong overall heterogeneity in expression levels between blood and dura, the majority of cis-eQTLs are shared by both tissues. The power to detect shared eQTLs was improved by using an integrative statistical approach. The identified tissue-specific and shared eQTLs provide new insight into the genetic basis for CMI and related conditions.

    View details for PubMedID 25609184

    View details for PubMedCentralID PMC4342828

  • Responsive stimulation of motor cortex for medically and surgically refractive epilepsy. Seizure Miller, K. J., Burns, T. C., Grant, G. A., Halpern, C. H. 2015; 33: 38–40

    View details for PubMedID 26556676

  • Preface to clinical neurosurgery volume 61, proceedings of the congress of neurological surgeons 2013 annual meeting. Neurosurgery Grant, G. A., Hankinson, T., Muh, C., Dumont, A., Cheshier, S. 2014; 61: N1-?

    View details for DOI 10.1227/NEU.0000000000000442

    View details for PubMedID 25032656

  • Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics BMC MEDICAL GENOMICS Markunas, C. A., Lock, E., Soldano, K., Cope, H., Ding, C. C., Enterline, D. S., Grant, G., Fuchs, H., Ashley-Koch, A. E., Gregory, S. G. 2014; 7
  • Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition CANCER CELL Kool, M., Jones, D. T., Jaeger, N., Northcott, P. A., Pugh, T. J., Hovestadt, V., Piro, R. M., Esparza, L. A., Markant, S. L., Remke, M., Milde, T., Bourdeaut, F., Ryzhova, M., Sturm, D., Pfaff, E., Stark, S., Hutter, S., Seker-Cin, H., Johann, P., Bender, S., Schmidt, C., Rausch, T., Shih, D., Reimand, J., Sieber, L., Wittmann, A., Linke, L., Witt, H., Weber, U. D., Zapatka, M., Koenig, R., Beroukhim, R., Bergthold, G., Van Sluis, P., Volckmann, R., Koster, J., Versteeg, R., Schmidt, S., Wolf, S., Lawerenz, C., Bartholomae, C. C., von Kalle, C., Unterberg, A., Herold-Mende, C., Hofer, S., Kulozik, A. E., von Deimling, A., Scheurlen, W., Felsberg, J., Reifenberger, G., Hasselblatt, M., Crawford, J. R., Grant, G. A., Jabado, N., Perry, A., Cowdrey, C., Croul, S., Zadeh, G., Korbel, J. O., Doz, F., Delattre, O., Bader, G. D., McCabe, M. G., Collins, V. P., Kieran, M. W., Cho, Y., Pomeroy, S. L., Witt, O., Brors, B., Taylor, M. D., Schueller, U., Korshunov, A., Eils, R., Wechsler-Reya, R. J., Lichter, P., Pfister, S. M. 2014; 25 (3): 393-405

    Abstract

    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 PubMedID 24651015

  • A Bioengineered Peptide that Localizes to and Illuminates Medulloblastoma: A New Tool with Potential for Fluorescence-Guided Surgical Resection. Cureus Ackerman, S. E., Wilson, C. M., Kahn, S. A., Kintzing, J. R., Jindal, D. A., Cheshier, S. H., Grant, G. A., Cochran, J. R. 2014; 6 (9)

    Abstract

    Tumors of the central nervous system are challenging to treat due to the limited effectiveness and associated toxicities of chemotherapy and radiation therapy. For tumors that can be removed surgically, extent of malignant tissue resection has been shown to correlate with disease progression, recurrence, and survival. Thus, improved technologies for real-time brain tumor imaging are critically needed as tools for guided surgical resection. We previously engineered a novel peptide that binds with high affinity and unique specificity to αVβ3, αVβ5, and α5β1 integrins, which are present on tumor cells, and the vasculature of many cancers, including brain tumors. In the current study, we conjugated this engineered peptide to a near infrared fluorescent dye (Alexa Fluor 680), and used the resulting molecular probe for non-invasive whole body imaging of patient-derived medulloblastoma xenograft tumors implanted in the cerebellum of mice. The engineered peptide exhibited robust targeting and illumination of intracranial medulloblastoma following both intravenous and intraperitoneal injection routes. In contrast, a variant of the engineered peptide containing a scrambled integrin-binding sequence did not localize to brain tumors, demonstrating that tumor-targeting is driven by specific integrin interactions. Ex vivo imaging was used to confirm the presence of tumor and molecular probe localization to the cerebellar region. These results warrant further clinical development of the engineered peptide as a tool for image-guided resection of central nervous system tumors.

    View details for PubMedID 28729960

  • Reorganization and stability for motor and language areas using cortical stimulation: case example and review of the literature. Brain sciences Serafini, S., Komisarow, J. M., Gallentine, W., Mikati, M. A., Bonner, M. J., Kranz, P. G., Haglund, M. M., Grant, G. 2013; 3 (4): 1597-1614

    Abstract

    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

    View details for PubMedCentralID PMC4061887