John Y. K. Lee, John T. Pierce, Jayesh P. Thawani, Ryan Zeh, Shuming Nie, Maria Martinez-Lage and Sunil Singhal
Meningiomas are the most common primary tumor of the central nervous system. Complete resection can be curative, but intraoperative identification of dural tails and tumor remnants poses a clinical challenge. Given data from preclinical studies and previous clinical trials, the authors propose a novel method of localizing tumor tissue and identifying residual disease at the margins via preoperative systemic injection of a near-infrared (NIR) fluorescent contrast dye. This technique, what the authors call “second-window indocyanine green” (ICG), relies on the visualization of ICG approximately 24 hours after intravenous injection.
Eighteen patients were prospectively identified and received 5 mg/kg of second-window ICG the day prior to surgery. An NIR camera was used to localize the tumor prior to resection and to inspect the margins following standard resection. The signal to background ratio (SBR) of the tumor to the normal brain parenchyma was measured in triplicate. Gross tumor and margin specimens were qualitatively reported with respect to fluorescence. Neuropathological diagnosis served as the reference gold standard to calculate the sensitivity and specificity of the imaging technique.
Eighteen patients harbored 15 WHO Grade I and 3 WHO Grade II meningiomas. Near-infrared visualization during surgery ranged from 18 to 28 hours (mean 23 hours) following second-window ICG infusion. Fourteen of the 18 tumors demonstrated a markedly elevated SBR of 5.6 ± 1.7 as compared with adjacent brain parenchyma. Four of the 18 patients showed an inverse pattern of NIR signal, that is, stronger in the adjacent normal brain than in the tumor (SBR 0.31 ± 0.1). The best predictor of inversion was time from injection, as the patients who were imaged earlier were more likely to demonstrate an appropriate SBR. The second-window ICG technique demonstrated a sensitivity of 96.4%, specificity of 38.9%, positive predictive value of 71.1%, and a negative predictive value of 87.5% for tumor.
Systemic injection of NIR second-window ICG the day before surgery can be used to visualize meningiomas intraoperatively. Intraoperative NIR imaging provides higher sensitivity in identifying meningiomas than the unassisted eye. In this study, 14 of the 18 patients with meningioma demonstrated a strong SBR compared with adjacent brain. In the future, reducing the time interval from dye injection to intraoperative imaging may improve fluorescence at the margins, though this approach requires further investigation.
Clinical trial registration no.: NCT02280954 (clincialtrials.gov).
Ryan P. Morton, Renee M. Reynolds, Rohan Ramakrishna, Michael R. Levitt, Richard A. Hopper, Amy Lee and Samuel R. Browd
In this study, the authors describe their experience with a low-dose head CT protocol for a preselected neurosurgical population at a dedicated pediatric hospital (Seattle Children's Hospital), the largest number of patients with this protocol reported to date.
All low-dose head CT scans between October 2011 and November 2012 were reviewed. Two different low-dose radiation dosages were used, at one-half or one-quarter the dose of a standard head CT scan, based on patient characteristics agreed upon by the neurosurgery and radiology departments. Patient information was also recorded, including diagnosis and indication for CT scan.
Six hundred twenty-four low-dose head CT procedures were performed within the 12-month study period. Although indications for the CT scans varied, the most common reason was to evaluate the ventricles and catheter placement in hydrocephalic patients with shunts (70%), followed by postoperative craniosynostosis imaging (12%). These scans provided adequate diagnostic imaging, and no patient required a follow-up full-dose CT scan as a result of poor image quality on a low-dose CT scan. Overall physician comfort and satisfaction with interpretation of the images was high. An additional 2150 full-dose head CT scans were performed during the same 12-month time period, making the total number of CT scans 2774. This value compares to 3730 full-dose head CT scans obtained during the year prior to the study when low-dose CT and rapid-sequence MRI was not a reliable option at Seattle Children's Hospital. Thus, over a 1-year period, 22% of the total CT scans were able to be converted to low-dose scans, and full-dose CT scans were able to be reduced by 42%.
The implementation of a low-dose head CT protocol substantially reduced the amount of ionizing radiation exposure in a preselected population of pediatric neurosurgical patients. Image quality and diagnostic utility were not significantly compromised.
Ryan P. Lee, Kimberly A. Foster, Jock C. Lillard, Paul Klimo Jr., David W. Ellison, Brent Orr and Frederick A. Boop
Thalamopeduncular tumors are a group of pediatric low-grade gliomas that arise at the interface of the thalamus and brainstem peduncle. They typically occur within the first 2 decades of life, presenting with progressive spastic hemiparesis. Treatment strategies, including surgical intervention, have varied significantly. The authors present their experience in the treatment of 13 children, ages 2–15 years, with non-neurofibromatosis–related pilocytic astrocytomas located in the thalamopeduncular region.
Between 2003 and 2016, 13 children presenting with progressive spastic hemiparesis due to a pilocytic astrocytoma at the interface of the thalamus and cerebral peduncles were identified. Medical records were reviewed retrospectively for clinical, radiological, pathological, and surgical data. Formalin-fixed, paraffin-embedded tissue was obtained for 12 cases and tested for KIAA1549-BRAF fusion and BRAF V600E point mutation.
On preoperative diffusion tensor imaging tractography (performed in 12 patients), the ipsilateral corticospinal tract was displaced laterally in 1 case (8.3%), medially in 1 case (8.3%), anterolaterally in 10 cases (83%), and posteriorly in no cases. Ten patients underwent resection via a transtemporal, transchoroidal approach, which was chosen to avoid further damage to motor function in cases of tumors that caused anterolateral or medial corticospinal tract displacement. With this approach, complications included hemianopia, oculomotor palsy, and tremor at a rate of 50%. Among the 12 patients with obtainable follow-up (mean 50.9 months), none received adjuvant therapy, and only 2 (17%) experienced recurrence or progression. KIAA1549-BRAF fusions were present in 10 cases (83%), while BRAF V600E was absent (0%). The 2 fusion-negative tumors had clinical features atypical for the series, including multi-focality and infiltration.
Transcortical, transchoroidal resection of thalamopeduncular tumors through the middle temporal gyrus allows for a high rate of gross-total resection and cure. Diffuse tensor tractography is a critical component of the preoperative planning process to determine the location of white matter tracts in proximity. Molecular status may correlate with clinical features, and the presence of BRAF lesions offers an additional target for future novel therapeutics.
Alexander G. Weil, John Ragheb, Toba N. Niazi and Sanjiv Bhatia
Brandon P. Lucke-Wold, Ryan C. Turner, Aric F. Logsdon, Linda Nguyen, Julian E. Bailes, John M. Lee, Matthew J. Robson, Bennet I. Omalu, Jason D. Huber and Charles L. Rosen
Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration.
The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors’ clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler.
The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase–3β. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p < 0.05), improved cognition (t = 6.532, p < 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p < 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy.
Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.
Marlon G. Saria, Courtney Corle, Jethro Hu, Jeremy D. Rudnick, Surasak Phuphanich, Maciej M. Mrugala, Laura K. Crew, Daniela A. Bota, Beverly Dan Fu, Ryan Y. Kim, Tiffany Brown, Homira Feely, Joanne Brechlin, Bradley D. Brown, Jan Drappatz, Patrick Y. Wen, Clark C. Chen, Bob Carter, Jong Woo Lee and Santosh Kesari
The object of this study was to determine the tolerability and activity of lacosamide in patients with brain tumors.
The authors reviewed the medical records at 5 US academic medical centers with tertiary brain tumor programs, seeking all patients in whom a primary brain tumor had been diagnosed and who were taking lacosamide.
The authors identified 70 patients with primary brain tumors and reviewed seizure frequency and toxicities. The majority of the patients had gliomas (96%). Fifty-five (78%) had partial seizures only, and 12 (17%) had generalized seizures. Most of the patients (74%) were started on lacosamide because of recurrent seizures. Forty-six patients (66%) reported a decrease in seizure frequency, and 21 patients (30%) reported stable seizures. Most of the patients (54 [77%]) placed on lacosamide did not report any toxicities.
This retrospective analysis demonstrated that lacosamide was both well tolerated and active as an add-on antiepileptic drug (AED) in patients with brain tumors. Lacosamide's novel mechanism of action will allow for concurrent use with other AEDs, as documented by its activity across many different types of AEDs used in this patient population. Larger prospective studies are warranted.
Ryan P. Lee, Raymond Xu, Pooja Dave, Sonia Ajmera, Jock C. Lillard, David Wallace, Austin Broussard, Mustafa Motiwala, Sebastian Norrdahl, Carissa Howie, Oluwatomi Akinduro, Garrett T. Venable, Nickalus R. Khan, Douglas R. Taylor, Brandy N. Vaughn and Paul Klimo Jr.
There has been an increasing interest in the quantitative analysis of publishing within the field of neurosurgery at the individual, group, and institutional levels. The authors present an updated analysis of accredited pediatric neurosurgery training programs.
All 28 Accreditation Council for Pediatric Neurosurgery Fellowship programs were contacted for the names of pediatric neurosurgeons who were present each year from 2011 through 2015. Faculty names were queried in Scopus for publications and citations during this time period. The 5-year institutional Hirsch index [ih(5)-index] and revised 5-year institutional h-index [ir(5)-index] were calculated to rank programs. Each publication was reviewed to determine authorship value, tier of research, clinical versus basic science research, subject matter, and whether it was pediatrics-specific. A unique 3-tier article classification system was introduced to stratify clinical articles by quality and complexity, with tier 3 being the lowest tier of publication (e.g., case reports) and tier 1 being the highest (e.g., randomized controlled trials).
Among 2060 unique publications, 1378 (67%) were pediatrics-specific. The pediatrics-specific articles had a mean of 15.2 citations per publication (median 6), whereas the non–pediatrics-specific articles had a mean of 23.0 citations per publication (median 8; p < 0.0001). For the 46% of papers that had a pediatric neurosurgeon as first or last author, the mean number of citations per publication was 12.1 (median 5.0) compared with 22.5 (median 8.0) for those in which a pediatric neurosurgeon was a middle author (p < 0.0001). Seventy-nine percent of articles were clinical research and 21% were basic science or translational research; however, basic science and translational articles had a mean of 36.9 citations per publication (median 15) compared with 12.6 for clinical publications (median 5.0; p < 0.0001). Among clinical articles, tier 1 papers had a mean of 15.0 citations per publication (median 8.0), tier 2 papers had a mean of 18.7 (median 8.0), and tier 3 papers had a mean of 7.8 (median 3.0). Neuro-oncology papers received the highest number of citations per publication (mean 25.7). The most common journal was the Journal of Neurosurgery: Pediatrics (20%). MD/PhD faculty members had significantly more citations per publication than MD faculty members (mean 26.7 vs 14.0; p < 0.0001) and also a higher number of publications per author (mean 38.6 vs 20.8). The median ih(5)- and ir(5)-indices per program were 14 (range 5–48) and 10 (range 5.6–37.2), respectively. The mean ir(5)/ih(5)-index ratio was 0.8. The top 5 fellowship programs (in descending order) as ranked by the ih(5)-index corrected for number of faculty members were The Hospital for Sick Children, Toronto; Children’s Hospital of Pittsburgh; University of California, San Francisco Benioff Children’s Hospital; Seattle Children’s Hospital; and St. Louis Children’s Hospital.
About two-thirds of publications authored by pediatric neurosurgeons are pediatrics-specific, although non–pediatrics-specific articles averaged more citations. Most of the articles authored by pediatric neurosurgeons are clinical, with basic and translational articles averaging more citations. Neurosurgeons with PhD degrees averaged more total publications and more citations per publication. In all, this is the most advanced and informative analysis of publication productivity in pediatric neurosurgery to date.
Sonia Ajmera, Ryan P. Lee, Andrew Schultz, David S. Hersh, Jacob Lepard, Raymond Xu, Hassan Saad, Olutomi Akinduro, Melissa Justo, Brittany D. Fraser, Mustafa Motiwala, Pooja Dave, Brian Jimenez, David A. Wallace, Olufemi Osikoya, Sebastian Norrdahl, Jennings H. Dooley, Nickalus R. Khan, Brandy N. Vaughn, Cormac O. Maher and Paul Klimo Jr.
The objective of this study was to analyze the publication output of postgraduate pediatric neurosurgery fellows for a 10-year period as well as identify 25 individual highly productive pediatric neurosurgeons. The correlation between academic productivity and the site of fellowship training was studied.
Programs certified by the Accreditation Council for Pediatric Neurosurgery Fellowships that had 5 or more graduating fellows from 2006 to 2015 were included for analysis. Fellows were queried using Scopus for publications during those 10 years with citation data through 2017. Pearson correlation coefficients were calculated, comparing program rankings of faculty against fellows using the revised Hirsch index (r-index; primary) and Hirsch index (h-index; secondary). A list of 25 highly accomplished individual academicians and their fellowship training locations was compiled.
Sixteen programs qualified with 152 fellows from 2006 to 2015; 136 of these surgeons published a total of 2009 articles with 23,735 citations. Most publications were pediatric-specific (66.7%) clinical articles (93.1%), with middle authorship (55%). Co-investigators were more likely from residency than fellowship. There was a clustering of the top 7 programs each having total publications of around 120 or greater, publications per fellow greater than 12, more than 1200 citations, and adjusted ir10 (revised 10-year institutional h-index) and ih10 (10-year institutional h-index) values of approximately 2 or higher. Correlating faculty and fellowship program rankings yielded correlation coefficients ranging from 0.53 to 0.80. Fifteen individuals (60%) in the top 25 (by r5 index) list completed their fellowship at 1 of these 7 institutions.
Approximately 90% of fellowship-trained pediatric neurosurgeons have 1 or more publications, but the spectrum of output is broad. There is a strong correlation between where surgeons complete their fellowships and postgraduate publications.