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2.  Intra and Interrater Reliability of the Pediatric AVM Compactness Score 
Introduction
– Cerebral arteriovenous malformations (AVM) have a higher post-resection recurrence rate in children than in adults. Our previous study demonstrated that a diffuse AVM (low compactness score) predicts post-resection recurrence. The aims of this study were to evaluate the intra and interrater reliability of our AVM compactness score.
Methods
– Angiograms of 24 subjects assigned a preoperative compactness score (scale of 1 to 3, 1=most diffuse, 3= most compact) in our previous study were re-rated by the same pediatric neuroradiologist 9 months later. A pediatric neurosurgeon, pediatric neuroradiology fellow, and interventional radiologist blinded to each other’s ratings, the original ratings, and AVM recurrence also rated each AVM’s compactness. Intra and interrater reliability were calculated using the kappa (κ) statistic.
Results
– Of the 24 AVMs, scores by the original neuroradiologist were a score of 1 in 6 subjects, 2 in 16 subjects, and 3 in 2 subjects. Intrarater reliability was 1.0. κ among the four raters was 0.69 [95% confidence interval (CI) 0.44–0.89], which indicates substantial reliability. The interrater reliability between the neuroradiologist and neuroradiology fellow was moderate (κ=0.59, 95%CI 0.20–0.89) and was substantial between the neuroradiologist and neurosurgeon (κ=0.74, 95%CI 0.41–1.0). The neuroradiologist and interventional radiologist had perfect agreement (κ=1.0).
Conclusions
– Intra and interrater reliability of AVM compactness scoring were excellent and substantial, respectively. These results demonstrate that the AVM compactness score is reproducible. However, the neuroradiologist and interventional radiologist had perfect agreement, which indicates that the compactness score is most accurately applied by those with extensive angiography experience.
doi:10.3171/2013.2.PEDS12465
PMCID: PMC3644017  PMID: 23495808
arteriovenous malformation; AVM; surgery; angiogram; recurrence; pediatric; compactness; reliability
3.  Leaving tissue associated with infrequent intracranial EEG seizure onsets is compatible with post-operative seizure freedom 
Journal of pediatric epilepsy  2012;1(4):211-219.
Identify seizure onset electrodes that need to be resected for seizure freedom in children undergoing intracranial electroencephalography recording for treatment of medically refractory epilepsy. All children undergoing intracranial electroencephalography subdural grid electrode placement at the Children’s Hospital of Philadelphia from 2002-2008 were asked to enroll. We utilized intraoperative pictures to determine the location of the electrodes and define the resection cavity. A total of 15 patients had surgical fields that allowed for complete identification of the electrodes over the area of resection. Eight of 15 patients were seizure free after a follow up of 1.7 to 8 yr. Only one seizure-free patient had complete resection of all seizure onset associated tissue. Seizure free patients had resection of 64.1% of the seizure onset electrode associated tissue, compared to 35.2% in the not seizure free patients (p=0.05). Resection of tissue associated with infrequent seizure onsets did not appear to be important for seizure freedom. Resecting ≥ 90% of the electrodes from the predominant seizure contacts predicted post-operative seizure freedom (p=0.007). The best predictor of seizure freedom was resecting ≥ 90% of tissue involved in majority of a patient’s seizures. Resection of tissue under infrequent seizure onset electrodes was not necessary for seizure freedom.
doi:10.3233/PEP-12033
PMCID: PMC3930198  PMID: 24563805
Epilepsy; epilepsy surgery; cortical dysplasia; neocortical epilepsy; intracranial electroencephalography
4.  Surgical treatment of a clival-C2 atypical teratoid/rhabdoid tumor 
The authors present the case of en bloc resection of a clival-C2 atypical teratoid/rhabdoid tumor. These aggressive lesions of early childhood generally occur in the cerebellum or cerebral hemispheres. This 7-year-old boy presented with pain on turning his head and was found to have a clival-C2 mass. A metastatic workup was negative for disseminated disease. A transoral biopsy procedure revealed an atypical teratoid/rhabdoid tumor on histological examination. The tumor was resected via a transoral approach, and the patient’s spine was stabilized with posterior instrumented fusion from the occiput to C-5. Postoperatively, the patient underwent 16 months of chemotherapy along with 6 weeks of overlapping radiation therapy. Twenty-seven months after the initial surgery he presented with leg pain and was found to have a solitary metastatic lesion at the conus medullaris. There was no local recurrence at the clivus. The conus tumor was resected and found to be consistent with the primary tumor. Several months later the patient presented with disseminated intrathecal disease and ultimately died 42 months after the initial resection.
doi:10.3171/2009.8.PEDS08421
PMCID: PMC2840717  PMID: 20043739
medulloblastoma; transoral approach; clivus; atypical teratoid/rhabdoid tumor
5.  Cranial Irradiation Increases Risk of Stroke in Pediatric Brain Tumor Survivors 
Background and Purpose
To determine the incidence of neurovascular events as late complications in pediatric brain tumor patients and to evaluate radiation as a risk factor.
Methods
Patients were ascertained using the tumor database of a pediatric tertiary care center. Included patients had a primary brain tumor, age birth to 21 years, initial treatment 1/1/93-12/31/02, and at least two visits with Neuro-Oncology. Radiation exposure included: whole brain, whole brain plus a focal boost, or focal brain. The primary outcome was stroke or transient ischemic attack (TIA).
Results
Of 431 subjects, 14 had 19 events of stroke or TIA over a median follow-up of 6.3 years. The incidence rate was 548/100,000 person-years. Overall, 61.5% of subjects received radiation, including 13/14 subjects with events. Median time from first radiation to first event was 4.9 years. The stroke/TIA hazard ratio for any brain irradiation was 8.0 (95% CI:1.05-62, p=0.045); for Circle of Willis (COW) radiation was 9.0 (95% CI:1.2-70, p=0.035); and for focal non-COW radiation was 3.4 (95% CI:0.21-55, p=0.38).
Conclusions
The incidence of neurovascular events in this population is 100-fold higher than in the general pediatric population and cranial irradiation is an important risk factor. By defining the incidence of this late effect, physicians are better able to counsel parents regarding treatment, monitor patients at risk, and target a population for primary stroke prevention in future studies.
doi:10.1161/STROKEAHA.112.661561
PMCID: PMC3492057  PMID: 22968468
childhood brain tumors; stroke; treatment-related stroke
6.  Surgical Treatment of Brain Tumors in Infants Less than 6 months of Age and Literature Review 
World neurosurgery  2011;78(1-2):137-144.
Object
Brain tumors are rare in infants under 6-months of age. These tumors can be challenging to treat surgically. We analyzed a modern series of patients treated by a multidisciplinary team at a tertiary care center and performed a literature review of this unique population.
Methods
Retrospective clinical data was collected for patients surgically treated for intracranial mass lesions at The Children’s Hospital of Philadelphia from 1998 to 2007. Dermoid cysts and other skull-based lesions were excluded from the analysis.
Results
Sixteen patients under 6-months of age underwent surgery for primary intracranial mass lesions. The median age of the patients at surgery was 5.2 months (range 1.4 to 6 months of age). Children most often presented with a bulging fontanelle, hydrocephalus, or macrocephaly (7 patients). Vomiting was seen in 5 patients, cranial nerve palsies in 1 patient, and seizures in 3 patients.
All patients had tumor resections and post-operatively were monitored in the intensive care unit. The final pathology consisted of atypical teratoid/rhabdoid tumor (3 cases), primitive neuroectodermal tumor/medulloblastoma (3 cases), choroid plexus papilloma (2 cases), astrocytoma (2 cases), ganglioglioma (2 cases), desmoplastic infantile ganglioglioma (2), glioblastoma multiforme (1), and choroid plexus carcinoma (1).
Two intra-operative deaths occurred. Of the surviving 14, a gross total resection was achieved in 4. Adjuvant therapy was determined by a multidisciplinary team composed of neuro-oncology, neurosurgery, and radiation oncology. Seven patients were treated with chemotherapy, 1 patient had proton beam therapy. Five-year overall survival was 45%. The eight surviving patients had neurological sequelae, and developmental outcome was variable.
Conclusions
Brain tumors are uncommon in children under 6-months of age. Patients present with a variety of tumor pathologies. Children who survive have neurological sequelae. More studies are necessary to understand the impact that different treatment options, tumor pathology, and tumor location have on neurological outcome.
doi:10.1016/j.wneu.2011.09.012
PMCID: PMC3292637  PMID: 22120270
brain tumor; surgery; neonates; congenital
7.  Follow-up Imaging to Detect Recurrence of Surgically Treated Pediatric Arteriovenous Malformations 
Introduction
The true post-operative arteriovenous malformation (AVM) recurrence incidence in the pediatric population remains largely unreported. Some literature suggests that delayed imaging six months to one year after a negative post-operative angiogram should be obtained. The aim of this study was to describe the timing of AVM recurrences after resection and the modalities on which the recurrences were detected.
Methods
This study was a retrospective cohort of all pediatric patients treated surgically for AVM resection by a single neurosurgeon from 2005 to 2010. Patients were followed radiographically after resection with magnetic resonance angiography (MRA) or cerebral angiography, when possible, at various time points. A visual scale of initial AVM nidus compactness was used and correlated with probability of recurrence after surgery.
Results
A total of 28 patients (13 female, 15 male) underwent an AVM resection. Eighteen patients (64.3%) received an intra-operative angiogram. In four cases, the intra-operative angiogram revealed residual AVM and the AVMs were re-resected immediately. Recurrent AVMs were found in 4 children (14.3%) at 50, 51, 56, and 60 weeks from the initial resection. Recurrence risk was 0.08 per person-year. No patient with a normal angiogram at 1 year developed a recurrence on either a 5-year angiogram or an angiogram at 18 years of age. All patients with recurrence had a compactness score of 1 (diffuse AVM). Lower compactness score was associated with recurrence, p=0.0003.
Conclusions
All recurrences in our cohort occurred less than 15 months from the initial resection. We recommend intraoperative angiography to help ensure complete resection at the time of the surgery. Follow-up vascular imaging is crucial for detecting recurrent AVMs, and conventional angiogram is preferred since MRA can miss smaller AVMs. One year follow-up imaging detected these recurrences and no one who had a negative angiogram at 1 year had a late recurrence. However, not all the subjects have been followed for 5 years or to age 18, so longer follow is required for these patients. Lower compactness score predicted recurrent AVM in this cohort.
doi:10.3171/2012.1.PEDS11453
PMCID: PMC3484378  PMID: 22546027
arteriovenous malformation; AVM; surgery; angiogram; recurrence; pediatric; compactness
8.  Early Progenitor Cell Marker Expression Distinguishes Type II from Type I Focal Cortical Dysplasias 
Type I and type II focal cortical dysplasias (FCDs) exhibit distinct histopathological features that suggest different pathogenic mechanisms. Type I FCDs are characterized by mild laminar disorganization and hypertrophic neurons whereas type II FCDs exhibit dramatic laminar disorganization and cytomegalic cells (balloon cells). Both FCD types are associated with intractable epilepsy; therefore, identifying cellular or molecular differences between these lesion types that explains the histological differences could provide new diagnostic and therapeutic insights. Type II FCDs express nestin, a neuroglial progenitor protein that is modulated in vitro by the stem cell proteins c-Myc, SOX2, and Oct-4 following activation of mammalian target of rapamycin complex 1 (mTORC1). Since mTORC1 activation has been demonstrated in type II FCDs, we hypothesized that c-Myc, SOX2, and Oct-4 expression would distinguish type II from type I FCDs. In addition, we assayed the expression of progenitor cell proteins FOXG1, KLF4, Nanog, and SOX3. Differential expression of 7 stem cell proteins and aberrant phosphorylation of 2 mTORC1 substrates, S6 and S6 kinase 1 proteins, clearly distinguished type II from type I FCDs (n = 10 each). Our results demonstrate new potential pathogenic pathways in type II FCDs and suggest biomarkers for diagnostic pathology in resected epilepsy specimens.
doi:10.1097/NEN.0b013e3181eac1f5
PMCID: PMC3474261  PMID: 20613634
Cortical dysplasia; Epilepsy; mTOR; STRADa; Tuberous sclerosis
9.  Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas 
Neuro-Oncology  2010;12(7):621-630.
In the present study, DNA from 27 grade I and grade II pediatric gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, dysembryoplastic neuroepithelial tumor, and pleomorphic xanthoastrocytoma was analyzed using the Illumina 610K Beadchip SNP-based oligonucleotide array. Several consistent abnormalities, including gain of chromosome 7 and loss of 9p21 were observed. Based on our previous studies, in which we demonstrated BRAF mutations in 3 gangliogliomas, 31 tumors were screened for activating mutations in exons 11 and 15 of the BRAF oncogene or a KIAA1549-BRAF fusion product. There were no cases with a KIAA1549-BRAF fusion. A BRAF V600E mutation was detected in 14 of 31 tumors, which was not correlated with any consistent pattern of aberrations detected by the SNP array analysis. Tumors were also screened for mutations in codon 132 in exon 4 of IDH1, exons 2 and 3 of KRAS, and exons 2–9 of TP53. No mutations in KRAS or TP53 were identified in any of the samples, and there was only 1 IDH1 R132H mutation detected among the sample set. BRAF mutations constitute a major genetic alteration in this histologic group of pediatric brain tumors and may serve as a molecular target for biologically based inhibitors.
doi:10.1093/neuonc/noq007
PMCID: PMC2940652  PMID: 20156809
BRAF; desmoplastic infantile ganglioglioma; dysembryoplastic neuroepithelial tumor; ganglioglioma; pleomorphic xanthoastrocytoma; SNP array
10.  The genetic landscape of the childhood cancer medulloblastoma 
Science (New York, N.Y.)  2010;331(6016):435-439.
Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high density microarrays and sequenced all known protein-coding genes and miRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, 5 to 10-fold fewer than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.
doi:10.1126/science.1198056
PMCID: PMC3110744  PMID: 21163964
11.  Interictal EEG spikes identify the region of seizure onset in some, but not all pediatric epilepsy patients 
Epilepsia  2009;51(4):592-601.
Purpose
The role of sharps and spikes, interictal epileptiform discharges (IEDs), in guiding epilepsy surgery in children remains controversial, particularly with intracranial EEG (IEEG). While ictal recording is the mainstay of localizing epileptic networks for surgical resection, current practice dictates removing regions generating frequent IEDs if they are near the ictal onset zone. Indeed, past studies suggest an inconsistent relationship between IED and seizure onset location, though these studies were based upon relatively short EEG epochs.
Methods
We employ a previously validated, computerized spike detector, to measure and localize IED activity over prolonged, representative segments of IEEG recorded from 19 children with intractable, mostly extra temporal lobe epilepsy. Approximately 8 hours of IEEG, randomly selected thirty-minute segments of continuous interictal IEEG per patient were analyzed over all intracranial electrode contacts.
Results
When spike frequency was averaged over the 16-time segments, electrodes with the highest mean spike frequency were found to be within the seizure onset region in 11 of 19 patients. There was significant variability between individual 30-minute segments in these patients, indicating that large statistical samples of interictal activity were required for improved localization. Low voltage fast EEG at seizure onset was the only clinical factor predicting IED localization to the seizure onset region.
Conclusions
Our data suggest that automated IED detection over multiple representative samples of IEEG may be of utility in planning epilepsy surgery for children with intractable epilepsy. Further research is required to better determine which patients may benefit from this technique a priori.
doi:10.1111/j.1528-1167.2009.02306.x
PMCID: PMC2907216  PMID: 19780794
Spike density; intracranial EEG; Seizure onset; Pediatric Epilepsy
12.  Predictors of outcome in childhood intracerebral hemorrhage: a prospective consecutive cohort study 
Background and Purpose
To describe features of children with intracerebral hemorrhage (ICH) and to determine predictors of short-term outcome in a single-center prospective cohort study.
Methods
Single-center prospective consecutive cohort study of spontaneous ICH in children age 1-18 years from January 2006 to June 2008. Exclusion criteria were inciting trauma; intracranial tumor; isolated epidural, subdural, intraventricular, or subarachnoid hemorrhage; hemorrhagic transformation of ischemic stroke; and cerebral sinovenous thrombosis. Hospitalization records were abstracted. Follow-up assessments included outcome scores using the Pediatric Stroke Outcome Measure (PSOM) and King's Outcome Scale for Childhood Head Injury (KOSCHI). ICH volumes and total brain volumes (TBV) were measured by manual tracing.
Results
Twenty-two patients, median age of 10.3 years (range 4.2-16.6 years), had presenting symptoms of headache in 77%, focal deficits 50%, altered mental status 50%, and seizures 41%. Vascular malformations caused hemorrhage in 91%. Surgical treatment (hematoma evacuation, lesion embolization or excision) was performed during acute hospitalization in 50%. One patient died acutely. At median follow-up of 3.5 months (range 0.3-7.5 months), 71% of survivors had neurological deficits; 55% had clinically significant disability. Outcome based on PSOM and KOSCHI scores was worse in patients with ICH volume >2% of TBV (p=0.023) and altered mental status at presentation (p = 0.005).
Conclusions
Spontaneous childhood ICH was due mostly to vascular malformations. Acute surgical intervention was commonly performed. Although death was rare, 71% of survivors had persisting neurological deficits. Larger ICH volume and altered mental status predicted clinically significant disability.
doi:10.1161/STROKEAHA.109.568071
PMCID: PMC2821039  PMID: 20019325
intracerebral hemorrhage; outcome; childhood; vascular malformation
13.  Duplication of 7q34 in Pediatric Low-Grade Astrocytomas Detected by High-Density Single-Nucleotide Polymorphism-Based Genotype Arrays Results in a Novel BRAF Fusion Gene 
In the present study, DNA from 28 pediatric low-grade astrocytomas was analyzed using Illumina HumanHap550K single-nucleotide polymorphism oligonucleotide arrays. A novel duplication in chromosome band 7q34 was identified in 17 of 22 juvenile pilocytic astrocytomas and three of six fibrillary astrocytomas. The 7q34 duplication spans 2.6 Mb of genomic sequence and contains approximately 20 genes, including two candidate tumor genes, HIPK2 and BRAF. There were no abnormalities in HIPK2, and analysis of two mutation hot-spots in BRAF revealed a V600E mutation in only one tumor without the duplication. Fluorescence in situ hybridization confirmed the 7q34 copy number change and was suggestive of a tandem duplication. Reverse transcription polymerase chain reaction-based sequencing revealed a fusion product between KIAA1549 and BRAF. The predicted fusion product includes the BRAF kinase domain and lacks the auto-inhibitory N-terminus. Western blot analysis revealed phosphorylated mitogen-activated protein kinase (MAPK) protein in tumors with the duplication, consistent with BRAF-induced activation of the pathway. Further studies are required to determine the role of this fusion gene in downstream MAPK signaling and its role in development of pediatric low-grade astrocytomas.
doi:10.1111/j.1750-3639.2008.00225.x
PMCID: PMC2850204  PMID: 19016743
astrocytoma; BRAF; glioma; HIPK2; SNP array; 7q34
14.  Treatment of osteoblastoma at C7: a multidisciplinary approach. A case report and review of the literature 
European Spine Journal  2008;18(Suppl 2):196-200.
Osteoblastoma is a rare benign bone tumor that presents with back pain and occurs in the spine approximately 40% of the time. The time from onset of symptoms to diagnosis is typically several months because it is a rare entity and radiographic studies are often negative early in the course of the disease. These highly vascular and locally aggressive tumors require complete and precise resection. The patient presented is a 15-year-old boy with a 14-month history of right-sided neck and shoulder pain. Computerized tomography and magnetic resonance imaging demonstrated a lesion in the posterior elements of C7 which extended through the pedicle and into the body. Preoperative angiography confirmed a hypervascular lesion which was successfully embolized. He subsequently underwent piecemeal tumor resection and instrumented fusion. Immediate postoperative imaging demonstrated complete resection. At 18 months follow up the patient has maintained resolution of preoperative symptoms and demonstrates evidence of solid fusion on CT. This multidisciplinary approach markedly decreased blood loss and improved visualization to help achieve complete surgical resection and resolution of clinical symptoms.
doi:10.1007/s00586-008-0806-7
PMCID: PMC2899567  PMID: 18839223
Osteoblastoma; Embolization; Spinal fusion; Spinal tumor; CT; Bone scan
15.  Treatment of pediatric atlantoaxial instability with traditional and modified Goel–Harms fusion constructs 
European Spine Journal  2009;18(6):884-892.
There are several treatment options for rigid fixation at C1–C2 including Brooks and Gallie type wired fusions and C1–2 transarticular screws. The use of a Goel–Harms type fusion, a construct with C1 lateral mass screws and C2 pedicle screws, has not been extensively described in pediatric patients. Here, we describe its relatively safe and effective use for treating pediatric patients by retrospective chart review of patients treated by the senior author for atlantoaxial instability with a Goel–Harms-type constructs during a 3-year period (2005–2007). Six patients were treated using Goel–Harms-type constructs. Five patients were treated utilizing a construct containing C1 lateral mass screws and C2 pedicle screws; one patient was treated using construct containing C1 lateral mass screws and C2 trans-laminar screws. The patients ranged in age from 7 to 17 years old (mean 12.7). All patients had findings of an os odontoideum on CT scans and three of the six patients had T2 hyperintensity on MRI. Three of the six patients presented with transient neurologic deficits: quadraplegia in two patients and paresthesias in two patients. In each patient C1 lateral mass and C2 screws were placed and the subluxation was reduced to attain an anatomical alignment. No bone grafts were harvested from the iliac crest or rib. Local morsalized bone and sub-occipital skull graft was used. All patients tolerated the procedure well and were discharged home on post-operative day 3–4. The patients wore a hard cervical collar and no halo-vests were needed. All patients had solid fusion constructs and normal alignment on post-operative imaging studies performed on average 14 months post-operatively (range: 7–29). The results demonstrated that Goel–Harms fusions are a relatively safe and effective method of treating pediatric patients with atlantoaxial instability and are not dependent on vertebral anatomy or an intact ring of C1. Follow-up visits and studies in this limited series of patients demonstrated solid fusion constructs and anatomical alignment in all patients treated.
doi:10.1007/s00586-009-0969-x
PMCID: PMC2899651  PMID: 19357876
Atlantoaxial instability; Os odontoideum; Goel–Harms fusion; Pediatrics; Cervical spine

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