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Increasing evidence indicates that fetal metabolic stress may result in a variety of post-natal perturbations during brain development. The goal of the study was to determine the duration of hypoxia/ischemia that would elicit a demonstrable regional depression of metabolism in the fetal brain and further to examine several end-points to determine if the metabolic stress affects the developing brain. The uterine artery and uterine branch of the ovarian artery were occluded with aneurysm clamps for a period of 45 min, the clips removed and the metabolites in five regions of the perinatal brain were measured at 0, 2 and 6 h of reflow. Regional P-creatine, ATP and glucose levels were significantly depleted at the end of the 45 min occlusion. The levels of glycogen and glutamate at the end of the occlusion indicated a decreasing trend which was not significant. The concentration of citrate remained essentially unchanged at the end of the occlusion. To ensure that the insult was not lethal to the tissue, the recovery of the metabolites was examined at 2 and 6 h of reflow and generally the concentrations of the high-energy phosphates and glucose were normal or near-normal by 6 h of reperfusion in the five regions of the brain examined. The changes in the metabolites indicate that 45 min of hypoxia/ischemia is an appropriate model for studying neonatal development after fetal metabolic stress.

Tuberous sclerosis complex is a genetic disorder characterized by the development of hamartomas in multiple organs including the brain, skin, eye, kidney, and heart. Neurological features include seizures and mental retardation. Cortical tubers and subependymal nodules are the characteristic intracranial lesions of tuberous sclerosis. Subependymal giant cell astrocytomas, typically located adjacent to the foramen of Monro, can enlarge and cause symptomatic ventricular obstruction. The authors describe the case of a 3-year-old boy with a history of tuberous sclerosis and retinal lesions who presented with an enlarging enhancing pineal region mass. Via an infratentorial supracerebellar approach, the mass was removed using both the operative microscope and a rigid neuroendoscope. Pathological examination showed a giant cell astrocytoma. To the authors' knowledge, this is the first reported case of tuberous sclerosis associated with a giant cell astrocytoma of the pineal region. Diagnostic considerations are discussed.

Summary: Purpose: Many children with refractory epilepsy can achieve better seizure control with surgical therapy. An abnormality on magnetic resonance imaging (MRI), along with corroborating localization by other modalities, markedly increases chances of successful surgical outcome. We studied the impact of high-resolution MRI on the surgical outcome of intractable epilepsy. Methods: High-resolution MRI using four-coil phased surface array was obtained as part of the comprehensive presurgical protocol for children with focal onset intractable seizures evaluated by our epilepsy center during the first half of 2002. Results: Thirteen consecutive children, ages 5 to 18 years, entered this prospective study. For four patients with a lesion on a recent MRI examination with a standard head coil, management did not change with high-resolution MRI. Standard MRI in the other nine patients did not identify a lesion. However, high-resolution MRI with the phased-array surface coil found previously undiagnosed focal abnormalities in five of nine patients. These abnormalities included hippocampal dysplasia, hippocampal atrophy, and dual pathology with frontal cortical dysplasia. In four of nine patients, no identifiable lesion was identified on the high-resolution MRI. All patients underwent invasive monitoring. In three of five patients, newly diagnosed lesions correlated with EEG abnormalities, and resection was performed. Conclusions: In our center, high-resolution MRI identified lesions not detected by standard MRI in more than half the children (56%). Technical advances such as four-coil phased surface array MRI can help identify and better delineate lesions, improving the diagnosis of patients who are candidates for surgical treatment of refractory epilepsy.

While progesterone has been well studied in experimental models of adult traumatic brain injury (TBI), it has not been evaluated in pediatric models. The study of promising interventions in pediatric TBI is important because children have the highest public health burden of such injuries. Therapies that are beneficial in adults may not necessarily be effective in the pediatric population. The purpose of this study was to evaluate whether progesterone treatment improves outcomes in an experimental model of pediatric TBI.The authors determined whether progesterone administered after controlled cortical impact (CCI) improves functional and histopathological outcomes in 4-week-old mice. Both male and female mice (58 mice total) were included in this study, as the majority of prior studies have used only male and/or reproductively senescent females. Mice were randomized to treatment with progesterone or vehicle and to CCI injury or sham injury. Motor (wire grip test) and memory (Morris water maze) testing were performed to determine the effect of progesterone on TBI. Lesion volume was also assessed.Compared with their vehicle-treated counterparts, the progesterone-treated CCI-injured male mice had improved motor performance (p0.001). In contrast, progesterone-treated CCI-injured female mice had a worse performance than their vehicle-treated counterparts (p = 0.001). Progesterone treatment had no effect on spatial memory performance or lesion volume in injured male or female mice.These data suggest a sex-specific effect of progesterone treatment after CCI in adolescent mice and could inform clinical trials in children.

Encephalopathy of prematurity (EoP) encompasses the central nervous system (CNS) abnormalities associated with injury from preterm birth. Although rapid progress is being made, limited understanding exists of how cellular and molecular CNS injury from early birth manifests as the myriad of neurological deficits in children who are born preterm. More importantly, this lack of direct insight into the pathogenesis of these deficits hinders both our ability to diagnose those infants who are at risk in real time and could potentially benefit from treatment and our ability to develop more effective interventions. Current barriers to clarifying the pathophysiology, developmental trajectory, injury timing, and evolution include preclinical animal models that only partially recapitulate the molecular, cellular, histological, and functional abnormalities observed in the mature CNS following EoP. Inflammation from hypoxic-ischemic and/or infectious injury induced in utero in lower mammals, or actual prenatal delivery of more phylogenetically advanced mammals, are likely to be the most clinically relevant EOP models, facilitating translation to benefit infants. Injury timing, type, severity, and pathophysiology need to be optimized to address the specific hypothesis being tested. Functional assays of the mature animal following perinatal injury to mimic EoP should ideally test for the array of neurological deficits commonly observed in preterm infants, including gait, seizure threshold and cognitive and behavioral abnormalities. Here, we review the merits of various preclinical models, identify gaps in knowledge that warrant further study and consider challenges that animal researchers may face in embarking on these studies. While no one model system is perfect, insights relevant to the clinical problem can be gained with interpretation of experimental results within the context of inherent limitations of the chosen model system. Collectively, optimal use of multiple models will address a major challenge facing the field today - to identify the type and severity of CNS injury these vulnerable infants suffer in a safe and timely manner, such that emerging neurointerventions can be tailored to specifically address individual reparative needs.

Background: Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month. Methods: Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/ or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction. Results: Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/ neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001). Conclusions: Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.

Preterm birth impacts brain development and leads to chronic deficits including cognitive delay, behavioral problems, and epilepsy. Premature loss of the subplate, a transient subcortical layer that guides development of the cerebral cortex and axonal refinement, has been implicated in these neurological disorders. Subplate neurons influence postnatal upregulation of the potassium chloride co-transporter KCC2 and maturation of γ-amino-butyric acid A receptor (GABAAR) subunits. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) in Sprague-Dawley rats that mimic brain injury from extreme prematurity in humans would cause premature subplate loss and affect cortical layer IV development. Further, we predicted that the neuroprotective agent erythropoietin (EPO) could attenuate the injury. Prenatal TSHI induced subplate neuronal loss via apoptosis. TSHI impaired cortical layer IV postnatal upregulation of KCC2 and GABAAR subunits, and postnatal EPO treatment mitigated the loss (n ≥ 8). To specifically address how subplate loss affects cortical development, we used in vitro mechanical subplate ablation in slice cultures (n ≥ 3) and found EPO treatment attenuates KCC2 loss. Together, these results show that subplate loss contributes to impaired cerebral development, and EPO treatment diminishes the damage. Limitation of premature subplate loss and the resultant impaired cortical development may minimize cerebral deficits suffered by extremely preterm infants.

Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

The prognosis for recovery from brachial plexus injury sustained at or before birth is generally favorable. However, roughly 10% of these infants remain profoundly weak and later exhibit functional disability in the affected arm. Early identification of these at-risk infants would be helpful in selecting patients for surgical management. In our prospective study, 80 infants with brachial plexus injury were examined on a monthly basis. Complete recovery occurred in 53 (66%); in 9 (11%), mild weakness persisted. In each child, recovery to antigravity strength in the biceps, triceps, and deltoid was noted by 6 months of age. Moderate arm weakness persisted in 7 children (9%); none had antigravity strength in the deltoid at age 6 months. Eleven children (14%) had severe permanent weakness (mean follow-up: 4.4 years). At age 6 months, these individuals exhibited at best 2/5 strength proximally and typically 0-1/5 strength in the wrist and finger extensors. Our results demonstrate that detailed strength testing up to 6 months of age predicts not only complete recovery of neonatal brachial plexus injury but also those children destined for long-term severe disability. (J Child Neurol 2001;16:488-492).

Objective Gliomas may result from transformation of glial precursor cells. In the developing rat central nervous system (CNS), a paracrine pathway involving the cytokines growth-related oncogene (GRO1) and platelet-derived growth factor (PDGF) A chain closely regulates oligodendrocyte precursor cell number. The purpose of the present study was to analyze whether abnormal expression and activity of the GRO1-PDGF pathway is present in human gliomas. Methods Tumor specimens were studied to compare the messenger ribonucleic acid with the protein expression of components of the GRO1-PDGF pathway. Neutralizing antibodies were used in vitro to analyze whether the pathway contributed to tumor cell proliferation. Results Immunohistochemistry demonstrated that all components of the GRO1-PDGF pathway (GRO1 protein, its receptor CXCR2, PDGF A chain, and its receptor PDGFalphaR) were expressed by tumor cells in 6 (86%) of 7 of oligodendrogliomas as well as by 0 of 4 diffuse astrocytomas (World Health Organization Grades II and III) and 2 (18%) of 11 glioblastomas. Analysis by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay showed CXCR2 messenger ribonucleic acid and GRO1 protein expression were present in oligodendrogliomas. Functional analyses with neutralizing antibodies limited bromodeoxyuridine incorporation in vitro by oligodendroglioma tumor cells, demonstrating a requirement for the GRO1-PDGF pathway in the proliferation of these cells. Conclusion The GRO1-PDGF pathway was primarily expressed and functional in oligodendrogliomas. The tightly controlled paracrine pathway that regulates oligodendrocyte precursor proliferation in the developing rodent CNS was constitutively active in most oligodendrogliomas in the present study. The presence of this aberrantly functioning oncogenic pathway in a subset of primary CNS tumors opens new avenues to glioma treatment that are based directly on the biology of the proliferative glial cell type, a novel strategy for primary CNS tumor therapy.

The dysmyelinating mutantjimpy(jp) arises from a point mutation in the mouse gene encoding proteolipid protein and is characterized by severe dysmyelination attributable to oligodendrocyte death. This mutant was used to investigate the regulation of oligodendrocyte progenitor proliferation in the postnatal spinal cord. At postnatal day 18,jpspinal cord contained a three- to eightfold greater number of proliferating oligodendrocyte progenitor cells than didwild-type(wt) spinal cord. Increased proliferation injpspinal cord was accompanied by a twofold increase in the number of progenitor cells. Semiquantitative reverse transcriptase-PCR revealed no change in the level of mRNA encoding the platelet-derived growth factor A, transforming growth factor-β, or insulin-like growth factor-I, all of which have been implicated as regulators of proliferation and differentiation of oligodendrocyte progenitor cells. There was, however, a 17-fold increase in the level of mRNA encoding the chemokine GRO-1 and a 5- to 6-fold increase in GRO-1 protein in thejpspinal cord. Double immunofluorescence labeling revealed elevated levels of GRO-1 in reactive astrocytes injpspinal cord white matter.In vitrostudies indicated that extracts fromjpspinal cord stimulated oligodendrocyte progenitor proliferation. Furthermore, removal of GRO-1 fromjpextracts by immunoprecipitation reduced the proliferation of progenitor cells to a level similar to that achieved bywtextracts. These findings suggest a novel mechanism by which proliferation of oligodendrocyte progenitor cells is regulated in the postnatal spinal cord in response to insult.

Chemokines, (chemotactic cytokines) are a family of regulatory molecules involved in modulating inflammatory responses. Here we demonstrate that the chemokine growth-regulated oncogene-alpha (GRO-alpha) is a potent promoter of oligodendrocyte precursor proliferation. The proliferative response of immature spinal cord oligodendrocyte precursors to their major mitogen, platelet derived growth factor (PDGF), is dramatically enhanced by GRO-alpha present in spinal cord conditioned medium. One source of GRO-alpha is a subset of spinal cord astrocytes. Cultures of astrocytes contain GRO-alpha mRNA and protein and secrete biologically active concentrations of GRO-alpha. In postnatal spinal cord white matter the location of GRO-alpha-immunoreactive cells is developmentally regulated: GRO-alpha+ cells first appear in ventral and later in dorsal spinal cord white matter. These results suggest that localized proliferation of oligodendrocytes is mediated by synergy between PDGF and GRO-alpha.

The authors describe a technique for the initial management of patients with pineal region neoplams and symptomatic hydrocephalus. Endoscopic third ventriculostomy and, if possible, tumor biopsy are performed through a single precoronal burr hole. When indicated, formal tumor resection can be performed nonemergently, without the need for ventricular drainage or shunting.

Brain injury from preterm birth causes white matter injury (WMI), and it leads to chronic neurological deficits including cerebral palsy, epilepsy, cognitive, and behavioral delay. Immature O4+ oligodendrocytes are particularly vulnerable to WMI. Understanding how the developing brain recovers after injury is essential to finding more effective therapeutic strategies. Erythropoietin (EPO) promotes neuronal recovery after injury; however, its role in enhancing oligodendroglial lineage recovery is unclear. Previously, we found that recombinant EPO (rEPO) treatment enhances myelin basic protein (MBP) expression and functional recovery in adult rats after prenatal transient systemic hypoxia-ischemia (TSHI). We hypothesized that after injury, rEPO would enhance oligodendroglial lineage cell genesis, survival, maturation, and myelination.In vitro assays were used to define how rEPO contributes to specific stages of oligodendrocyte development and recovery after TSHI.After prenatal TSHI injury, rEPO promotes genesis of oligodendrocyte progenitors from oligodendrospheres, survival of oligodendrocyte precursor cells (OPCs) and O4+ immature oligodendrocytes, O4+ cell process extension, and MBP expression. rEPO did not alter OPC proliferation.Together, these studies demonstrate that EPO signaling promotes critical stages of oligodendroglial lineage development and recovery after prenatal TSHI injury. EPO treatment may be beneficial to preterm and other infant patient populations with developmental brain injury hallmarked by WMI.

Hydrocephalus remains a major public health problem. Conventional treatment has relied on extracranial shunting of CSF to another systemic site, but this approach is associated with a high rate of complications. Endoscopic third ventriculostomy (ETV) is a novel treatment for select forms of hydrocephalus that can eliminate the need for implantation of a lifelong ventricular shunt system. However, the indications for ETV are contested and its long-term effectiveness is not well established.The authors selected 100 consecutive patients who underwent ETV for hydrocephalus beginning in 1994. Patients were enrolled and treated at a single institution by a single surgeon. The primary outcome was success of ETV, with success defined as no need for subsequent surgery for hydrocephalus.Ninety-five patients satisfied the inclusion criteria. The mean follow-up period was 5.1 years (median 4.7 years) with follow-up data available for as long as 17 years. Patients commonly presented with headache (85%), ataxia (34%), emesis (29%), and changes in vision (27%). The success rate for ETV was 75%. Twenty-one patients (22%) in the series had malfunctioning shunts preoperatively and 13 (62%) were successfully treated with ETV. Preoperative inferior bowing of the third ventricle floor on MRI was significantly associated with ETV success (p0.05).Endoscopic third ventriculostomy is an effective and durable treatment for select patients with hydrocephalus. When successful, the procedure eliminates the lifelong complications associated with implanted ventricular shunts.

Open neural tube defects (NTDs) result from failure of the embryonic process of neural tube closure. This chapter discusses pathophysiology and preventative strategies within each of these recognized subgroups: folate, chromosomal, single gene defects, genetic syndromes, diabetes and obesity, medications and smoking, hyperthermia, amniotic bands, twinning, genes and environment. The greatest success story in NTD prevention is folate supplementation. Through individual supplementation and population-based strategies such as food fortification there has been between a 20% and 70% reduction in NTDs reported across all countries actively supplementing. Diabetes and obesity are potentially modifiable risk factors for NTDs; however, despite general health campaigns regarding the health risks of obesity it remains an ever increasing problem amongst reproductive aged women. Medication and smoking exposures are amenable to prevention with health education advice and further research into safer medication use in pregnancy.

This volume of Neurosurgical Focus covers an array of topics useful to many specialists who care for patients with neural tube defects and related abnormalities. These patients have specific needs at each stage of the lifespan. Today, many individuals with significant developmental abnormalities of the spinal cord are leading full lives. For example, it is important for obstetricians and anesthesiologists to be cognizant of the underlying abnormalities associated with a lipomyelomeningocele or myelomeningocele to optimally care for a woman with one of these lesions during the delivery of her child. These lesions are exceedingly interesting from a developmental perspective, and a better understanding of the pathophysiology will continue to improve our management. The paper by Kalani et al. focuses primarily on the pathophysiology of intradural spinal teratomas. Dr. Vogel and associates describe recent advances in our understanding of how primary cilia contribute to the pathogenesis of neural tube defects and hydrocephalus. Dr. Sarris and colleagues provide a useful review of the pathology, treatment, and outcomes of lipomyelomeningoceles. A review of the management of urologic dysfunction in patients with neural tube defects by Amarante and colleagues will be useful to providers from a wide range of specialties. Maintaining optimal urologic health is a challenge throughout life. Finally, Dr. Cox and colleagues describe an unusual presentation of bilateral paramedian cutaneous dermal sinus tracts that caused multiple episodes of infection prior to definitive neurosurgical treatment. (http://thejns.org/doi/abs/10.3171/2012.8.FOCUS12285)

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4 alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappa B signalling in Group 4, suggest future avenues for rational, targeted therapy.

The history of surgical treatment for hemispheric epilepsy is rich with colorful twists and turns. The authors trace the evolution of the surgical treatment of hemispheric epilepsy from radical anatomic resections to current less invasive disconnection procedures. Anatomic hemispherectomy (AH) was first described by Dandy in 1928 as a treatment for gliomas. The first report of this technique to control seizures was by McKenzie in 1938. AH gained wide popularity but began to fall out of favor after the description of superficial cerebral hemosiderosis in 1966. To reduce the morbidity and mortality associated with AH, Rasmussen introduced functional hemispherectomy in 1974. The technique of hemispherotomy was introduced in the 1990 s to minimize the extent of brain removal while maximizing the white matter disconnections. Thus, surgery for hemispheric epilepsy has undergone dramatic transformation since the technique was first introduced. Less invasive techniques have been developed to reduce surgical morbidity. Although optimal seizure control is best achieved with radical AH, the newer less invasive disconnection techniques appear to achieve near-comparable postoperative seizure control with a significantly lower rate of complications.

Background: Callosotomy is a surgical option for treatment of a small number of patients with intractable seizures who are not candidates for surgical resection. The procedure is done conventionally with the aid of a microscope. In this article, we describe a new technique of endoscopic callosotomy through a parasagittal burr hole in a cadaveric model. Methods: We utilized this technique with a single frontal burr hole. Callosotomies were performed on 4 silicon-injected cadaver heads in our minimally invasive neurosurgical laboratory. Results: We were able to successfully perform total callosotomies in all cadaveric specimens without injury to the adjacent neurovascular structures. The advantages of our technique over microsurgery are the minimally invasive nature of the exposure and the improved visualization of the vascular structures near the rostrum and genu of the corpus callosum. A potential disadvantage we anticipate is the difficulty controlling bleeding in the event of vascular injury. Conclusion: We believe that this minimally invasive approach could have potential clinical applications.

Objective The microsurgical anatomy of the temporal region has been well described. However, there is a paucity of information about the transventricular endoscopic anatomy of the mesial temporal lobe, and little is known about endoscopic approaches to this region. In this report, we describe the technique of endoscopic amygdalohippocampectomy (AH). The endoscopic anatomy of the mesial temporal region both before and after AH is shown. Methods We used 4 silicon-injected cadaver heads for the study in our minimally invasive neurosurgery laboratory. The lateral ventricle was accessed through an occipital burr hole. Results Predissection transventricular endoscopic anatomy of this region showed the choroid plexus, hippocampus, amygdala, choroid fissure, and collateral eminence. The hippocampus, parahippocampal gyrus, and amygdala were removed endoscopically, keeping the pia on the inferior surface of the mesial temporal region intact. Postdissection anatomy of the mesial temporal region showed a clear view of the brainstem, posterior cerebral vessels, choroidal vessels, and tentorium. Conclusions We studied the transventricular endoscopic anatomy of the mesial temporal region and described a technique for safe endoscopic AH. The advantages and potential risks of endoscopic AH are discussed, along with suggestions for minimizing complications. We believe that knowledge of the endoscopic anatomy of the mesial temporal lobe will be useful for endoscopic AH and the removal of other lesions in this region.

Nonaccidental head trauma (NAHT) is a major cause of death in infants. During the current economic recession, the authors noticed an anecdotal increase in infants with NAHT without an increase in the overall number of infants admitted with traumatic injuries. An analysis was performed to determine whether there was an association between economic recession and NAHT.With Institutional Review Board approval, the trauma database was searched for NAHT in infants 0-2 years old during nonrecession (December 2001 to November 2007) and recession (December 2007 to June 2010) periods. Incidence is reported as infants with NAHT per month summarized over time periods. Continuous variables were compared using Mann-Whitney U-tests, and proportions were compared using the Fisher exact test.Six hundred thirty-nine infant traumas were observed during the study time period. From the nonrecession to the recession period, there was an 8.2% reduction in all traumas (458 in 72 months [6.4 /month] vs 181 in 31 months [5.8/month]) and a 3.5% reduction in accidental head traumas (142 in 72 months [2.0/month] vs 59 in 31 months [1.9/month]). Nonaccidental head trauma accounted for 14.6% of all traumas (93/639). The median patient age was 4.0 months and 52% were boys. There were no significant differences in the representative counties of referral or demographics between nonrecession and recession populations (all p0.05). The monthly incidence rates of NAHT doubled from nonrecession to recession periods (50 in 72 months [0.7/month] vs 43 in 31 months [1.4/month]; p = 0.01). During this recession, at least 1 NAHT was reported in 68% of the months compared with 44% of the months during the nonrecession period (p = 0.03). The severity of NAHTs also increased, with a greater proportion of deaths (11.6% vs 4%, respectively; p = 0.16) and severe brain injury (Glasgow Coma Scale score ≤ 8: 19.5% vs 4%, respectively; p = 0.06) during the recession.In the context of an overall reduction in head trauma, the significant increase in the incidence of NAHT appears coincident with economic recession. Although the cause is likely multifactorial, a full analysis of the basis of this increase is beyond the scope of this study. This study highlights the need to protect vulnerable infants during challenging economic times.

An infant sustained a significant depressed skull fracture from a fall. Before the planned surgical repair of the fracture could be carried out, the child sustained a second fall that led to the complete resolution of the depressed fracture. Mechanisms to explain this unusual phenomenon are discussed.

Surgery for medically intractable epilepsy secondary to unihemispheric pathology has evolved from more aggressive hemispherectomy to less aggressive variations of hemispherotomy. The authors propose a novel minimally invasive endoscopic hemispherotomy that should give results comparable to conventional open craniotomy and microsurgery.Endoscopic transventricular hemispherotomy was performed in 5 silicon-injected cadaveric heads in the authors' minimally invasive neurosurgery laboratory. The lateral ventricle was accessed endoscopically through a frontal and occipital bur hole. White matter disconnections were performed to unroof the temporal horn and to disconnect the frontobasal region, corpus callosum, and fornix.Using an endoscopic transventricular approach, all white matter disconnections were successfully performed in all 5 cadavers.The authors have demonstrated the feasibility of endoscopic transventricular hemispherotomy in a cadaveric model. The technique is simple and could be useful in a subgroup of patients with parenchymal volume loss and ventriculomegaly.

The aim of epilepsy surgery in children is not only to control seizures but also to curtail future adverse neurological sequelae and improve quality of life. If presurgical evaluation demonstrates discordant or multifocal disease, intracranial surgery may be denied as a viable treatment option. When surgical therapy is offered not just as curative but also as palliative therapy, many children not considered optimal surgical candidates may benefit. From a consecutive series of 57 cases involving children who underwent intracranial epilepsy surgery at Rainbow Babies and Children's Hospital during 2001–2005, the authors present in detail 3 cases involving children who benefited significantly from such an aggressive approach. Marked improvement occurred not only in seizure control, but also in developmental and social functioning.

Object Tapping of a suspected malfunctioning ventriculoperitoneal shunt is usually easy, sometimes informative, but also potentially misleading. The purpose of this study was to determine the effectiveness of a shunt evaluation protocol that does not involve direct shunt tapping except in rare and specific cases. Methods The authors adopted a protocol for shunt evaluation that involves shunt tapping only in selected cases of suspected infection or in patients with noncommunicating hydrocephalus and equivocal computed tomography (CT) findings of shunt infection. They then reviewed the clinical characteristics and surgical findings in 373 consecutive assessments of 155 pediatric patients who were evaluated for shunt malfunction and/or infection by using this protocol between January 2003 and December 2005. Results Mental status change and headache were the symptoms most concordant with shunt malfunction, but no symptom had a predictive value much better than 50%. Follow-up CT scans demonstrated enlarged ventricles in 72 of 126 cases of shunt revision. Among those with obstruction but without remarkable CT changes, 8 patients had evidence of distal obstruction on x-ray “shunt series” consisting of skull, chest, and abdominal radiographs, and 5 had obvious symptoms that rendered further testing unnecessary; 38 cases of obstruction were diagnosed based on elevated opening pressure on lumbar puncture (mean 34.7 cm H2O). A shunt tap was required in only 8 cases (2%). Conclusions The authors have shown that it is possible to evaluate the majority of ventricular shunt malfunctions without tapping the device. Because it is possible to diagnose shunt obstruction correctly by other means, the shunt tap may not be obligatory as a routine test of the device's patency.

Rasmussen syndrome (RS) is a clinical diagnosis characterized by persistent focal seizures in a previously healthy child. Occasionally, the typical features of RS may be followed by another diagnosis. We discuss the course of a 12-year-old girl who presented with RS but was later diagnosed with CNS granulomatous disease and NOD2/CARD15 mutations. Her response to infliximab suggests that it should be included in immune-modulatory therapies used to treat these refractory disorders.

Pediatric cancer patients frequently suffer higher levels of treatment-induced toxicities than adults, limiting the use of potentially curative therapies. For example, brain irradiation contributes to the cure of medulloblastomas in 80% of children yet also causes cell death in healthy neurons, resulting in a permanent and devastating loss of IQ. Likewise, children commonly experience dose-limiting cardiotoxicity from doxorubicin treatment. These treatments are comparatively well tolerated in adults yet the basis for this dramatic contrast in sensitivity is unknown. Both radiation and cytotoxic chemotherapies can induce an apoptotic cell death, prompting us to hypothesize that apoptosis may be regulated in a fundamentally different manner in children versus adults. By testing the functional state of the apoptotic pathway in tissues with BH3 Profiling, we found that healthy brain, heart and kidney tissues from young mice are extremely sensitive to pro-apoptotic signals and are therefore “primed for apoptosis.” In stark contrast, these same tissues are completely insensitive to even saturating amounts of pro-apoptotic signals in adult mice. Apoptosis could be triggered in adult brain, heart or kidney cells only when complemented with exogenous BAX protein suggesting that these tissues lack sufficient levels of BAX or BAK for mitochondrial permeabilization and are thus “incompetent for apoptosis.” Immunoblotting revealed that BAX and BAK protein levels are strongly downregulated in these tissues during postnatal development and become nearly undetectable by adulthood, along with several other components of the apoptotic machinery. Parallel studies with spleen and bone marrow demonstrated high levels of apoptotic priming in young animals which continued into adulthood, highlighting the organ-specific nature of apoptosis regulation. In agreement with these findings, we observed apoptotic cell death in response to radiation damage in the brain, heart and kidneys of early postnatal but not adult mice. Likewise, the extent of doxorubicin-induced damage to cardiac tissue correlated strongly with changes in apoptotic priming and competence. Furthermore, we utilized BAX and/or BAK knockout mice to characterize the pivotal roles of these proteins in regulating apoptotic competence and damage responses in somatic tissues. We extended these findings to humans by BH3 profiling normal brain tissue and confirmed that brain tissue in young children is primed to undergo apoptosis while in adults it is apoptotically incompetent. Finally, we identified the epigenetic mechanisms that modulate apoptotic pathways during postnatal development. Our findings elucidate the molecular mechanisms responsible for the devastating vital organ sensitivity to damage in children and a strategy for its prevention. Citation Format: Kristopher A. Sarosiek, Michael Ziller, Cameron Fraser, Patrick Bhola, Jeremy Ryan, Jing Deng, Brian Jian, Marti Goldenberg, Joseph Madsen, Ruben Carrasco, Shenandoah Robinson, Javid Moslehi, Anthony Letai. Apoptotic priming is regulated by a developmental program and predisposes children to therapy-induced toxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4728. doi:10.1158/1538-7445.AM2015-4728

Perinatal brain injury leads to chronic neurological deficits in children. Damage to the premature brain produces white matter lesions (WMLs), but the impact on cortical development is less well defined. Gamma-aminobutyric acid(GABA)ergic neurons destined for the cerebral cortex migrate through the developing white matter and form the subplate during late gestation. The authors hypothesized that GABAergic neurons are vulnerable to perinatal systemic insults in premature infants, and that damage to these neurons contributes to impaired cortical development.An immunohistochemical analysis involving markers for oligodendrocytes, GABAergic neurons, axons, and apoptosis was performed on a consecutive series of 15 human neonatal telencephalon samples obtained postmortem from infants born at 25 to 32 weeks of gestation. The tissue samples were divided into two groups based on the presence or absence of WMLs by performing routine histological analyses. The expression of GABAergic neurons was compared between the two groups by using age-matched samples. Two-tailed t-tests were used for statistical analyses. Ten infants had WMLs and five did not. Significant losses of oligodendrocytes and axons and markedly increased apoptosis were appreciated in tissue samples from the infants with WMLs. Samples from infants with WMLs also showed significant losses of glutamic acid decarboxylase-67-positive cells and calretinin-positive cells, shorter neuropeptide Y-positive neurite lengths, and losses of cells expressing GABA(A)alpha1, GABA(B)R1, and N-acetylaspartate diethylamide NR1 receptors when these factors were compared with those in samples from infants without WMLs (all p0.02).In addition to oligodendrocyte loss, axonal disruption, and excess apoptosis, a significant loss of telencephalon GABAergic neuron expression was found in neonatal brains with WMLs, compared with neonates' brains without WMLs. The loss of GABAergic subplate neurons in infants with WMLs may contribute to the pathogenesis of neurological deficits in children.

Object The authors describe a series of children with Chiari I malformation who presented with fulminating symptoms of “cerebellar fits” characterized by drop attacks with or without deterioration of consciousness, opisthotonic posturing, and varying degrees of respiratory compromise. Methods A retrospective analysis was undertaken of the medical records of 47 consecutive patients undergoing surgery for symptomatic Chiari I malformations at Rainbow Babies and Children's Hospital. Thirteen (28%) of the 47 patients presented with complaints consistent with cerebellar fits. Before the correct diagnosis was made, nine (69%) of the 13 children had previously undergone evaluation with electroencephalography and/or electrocardicography and Holter monitoring because of suspected cortical epilepsy or cardiogenic syncope. In each of the 13 children magnetic resonance imaging demonstrated pegged cerebellar tonsils herniated below the foramen magnum. A deep indentation or blanched discoloration of the cerebellar tonsils was noted in five (38%) of these 13 patients at the time of surgery. Of patients with symptomatic Chiari I malformations, the mean degree of tonsillar herniation was significantly less for those in whom cerebellar fits occurred than those in whom they were absent (8.8 mm and 13.9 mm, respectively; p = 0.007). In only one of the patients with cerebellar fits was a syrinx present, and this was a small focal lower thoracic collection. Spells resolved after surgery in all patients who presented with cerebellar fits. Conclusions Cerebellar fits may mimic other disorders such as cardiogenic syncope and epileptic seizures. The correct diagnosis may be delayed or the conditions may be misdiagnosed by those who fail to consider Chiari I malformation as a cause of drop attacks, abnormal extensor posturing, and apneic spells in children. The response to decompressive surgery in these patients is gratifying.

Object Cowden disease is a rare autosomal-dominant phacomatosis and cancer syndrome that is associated with Lhermitte–Duclos disease (LDD), also called dysplastic cerebellar gangliocytoma. Methods In this review the authors summarize the additions to the literature during the past 5 years, with emphasis on new case reports and advances in imaging and molecular biology. Adult-onset LDD is now considered pathognomonic for Cowden disease. Approximately 220 cases of LDD have been reported. Magnetic resonance imaging in patients with LDD is often diagnostic, and imaging studies have facilitated accurate diagnosis and contributed to the improved outcome in affected patients. Cowden disease and other rare, related disorders, such as Bannayan-Riley-Ruvalcaba, Proteus, and Proteus-like syndromes, are often caused by mutations of the PTEN gene. Conclusions Because of the high incidence of systemic cancer in patients with Cowden disease, it is important for neurosurgeons to recognize the association between this disease and LDD and to refer affected patients for appropriate cancer screenings and interventions.

Infants born prematurely are prone to chronic neurologic deficits including cerebral palsy, epilepsy, cognitive delay, behavioral problems, and neurosensory impairments. In affected children, imaging and neuropathological findings demonstrate significant damage to white matter. The extent of cortical damage has been less obvious. Advances in the understanding of telencephalon development provide insights into how systemic intrauterine insults affect the developing white matter, subplate, and cortex, and lead to multiple neurologic impairments. In addition to white matter oligodendrocytes and axons, other elements at risk for perinatal brain injury include subplate neurons, GABAergic neurons migrating through white matter and subplate, and afferents of maturing neurotransmitter systems. Common insults including hypoxia–ischemia and infection often affect the developing brain differently than the mature brain, and insults precipitate a cascade of damage to multiple neural lineages. Insights from development can identify potential targets for therapies to repair the damaged neonatal brain before it has matured.

Meningioangiomatosis (MA) is a rare seizure-associated lesion of presumed hamartomatous or developmental origin. It is occasionally combined with a neoplasm, most commonly meningioma (MA-M). In the current study, we examined 24 cases (14 pure MA, 10 MA-M) using immunohistochemistry for merlin, protein 4. 1 B, progesterone receptor (PR), and MIB-1, as well as FISH for NF2 and 4.1B gene dosages. Nine cases of MA-M (90%) had gene deletions (NF2/4.1B), protein losses (merlin/protein 4.1B), and/or PR positivity, with a similar or identical phenotype in both components. No PR positivity or gene deletions were seen in pure MAs, though merlin and/or protein 4.1B were immunonegative in six cases. Our data suggest that in most MA-Ms, the MA component is neoplastic, likely representing an exuberant perivascular pattern of spread from the meningioma, rather than an underlying hamartoma. This pattern of spread may be facilitated by meningiomas that are predominantly leptomeningeal or intracerebral in origin. It remains important to distinguish this pattern from true brain invasion, given the more ominous prognostic significance of the latter. In contrast, most perivascular spindled cells of pure MA are genetically and immunohistochemically similar to non-neoplastic meningothelial cells, consistent with current histogenetic theories.

In infants, a common consequence of systemic perinatal insults is disruption of neonatal brain development. Such insults can cause cerebral palsy, cognitive delay, epilepsy and other chronic neurologic deficits in children. The mechanisms underlying disruption of brain development after perinatal insults are poorly defined. To mimic human systemic insults, a transient prenatal hypoxic–ischemic insult model was developed in rodents. Ischemic animals showed reproducible histological lesions including oligodendrocyte loss, gliosis, and axonal disruption. Ischemic animals displayed persistent postnatal loss of oligodendrocyte lineage cells and cortical neurons, decreased cell proliferation, increased cell death, elevated pro-inflammatory cytokine levels, and impaired motor skills as young adults. Progressive ischemic intervals produced a graded pattern of injury. This systemic rodent prenatal hypoxic–ischemic insult accurately models human perinatal brain injury in several important criteria, including functional association of altered brain development with motor delay, and consequently provides novel insights into the pathogenesis of human perinatal brain insults.

Though a pastime rarely considered rough or dangerous, sledding is not risk-free. The presentation of several serious injuries to Rainbow Babies and Children’s Hospital in Cleveland, Ohio, led us to examine our emergency department and admitting records to determine the incidence of neurological injury among children involved in sledding accidents. We discovered 24 children who had sustained brain or spine injuries as sequelae to sledding mishaps during a 5-year period. The ages ranged from 3 months to 15 years. Injuries included multiple skull fractures, 2 epidural hematomas, 1 subdural hematoma, 1 odontoid fracture and 1 anoxic brain injury. There was 1 death. Twenty-one of 24 patients incurred their injuries by colliding with fixed objects. Both improvised crafts and models intended for sledding were involved in the injuries. Only 3 sleds possessed steering capability. Eight of the 9 children who sustained a serious neurosurgical injury were supervised by an adult. Only 2 children had received instruction before sledding. The lack of awareness of the potential for injury together with the dearth of instruction and lack of control over a vehicle dashing down a hill studded with obstacles can change a carefree pastime into a hazardous activity.

Objective: Ventriculoperitoneal shunts have one of the highest complication rates of all neurosurgical procedures. The purpose of this study was to identify factors associated with malfunction of shunts placed in infants with neonatal hydrocephalus, with the goal of maximizing long-term shunt survival. Methods: We performed a retrospective chart review of 200 consecutive patients less than 1 year old who underwent primary intracranial shunt placement for hydrocephalus by one of two experienced pediatric neurosurgeons at a single institution. A multivariate analysis was conducted to identify variables that were statistically independent predictors of a shunt malfunction or problem. Results: Adequate data were available for 158 patients, with a mean follow-up of 39.8 months (range 6–99 months). Variables tested for independent prediction of shunt revision included the etiology of the hydrocephalus, gestation period, age at shunt placement, surgeon, ventricular catheter entry site and valve opening pressure. Frontal versus occipital catheter entry site was not associated with a different revision rate. The only significant controllable factor associated with shunt malfunction was the valve opening pressure. The revision rate per year of follow-up was 4 times higher for patients with no valve or a low-pressure valve than for patients with a medium- or high-pressure valve. Conclusions: This retrospective review demonstrated that the valve opening pressure is an important component of the shunt complication rate. A prospective multicenter randomized trial is warranted to further evaluate the conclusions of this study.

Introduction: Atypical teratoid/rhabdoid tumors (ATT/RT) of the central nervous system (CNS) are uncommon malignancies of childhood with an aggressive course and a uniformly fatal outcome. Methods: The medical records, radiographic images and pathologic files at the Rainbow Babies and Childrens Hospital over the previous 6 years were retrospectively reviewed. Results: Eight children underwent surgery for CNS ATT/RT at our institution since 1996. There were 6 boys and 2 girls. Median age at presentation was 21 months. Four tumors had multifocal disease at the time of diagnosis. Six patients received multiagent chemotherapy including 3 patients with autologous bone marrow transplantation, and 6 patients received radiation therapy. Median survival was 9 months from the time of diagnosis. Conclusions: In spite of aggressive therapy, the prognosis for ATT/RT remains dismal. The search for effective treatment strategies will require a better understanding of the biology and molecular genetics of this tumor.

Oligodendrocyte precursor proliferation is precisely regulated spatially and temporally during development to allow optimal myelination of the central nervous system (CNS). We propose that a paracrine regulatory pathway involving the chemokine GRO1 and platelet-derived growth factor (PDGF) permit local control of precursor proliferation in the brain. GRO1, PDGF, and their receptors act synergistically to precisely regulate oligodendrocyte precursor proliferation in vitro and in vivo in the rat CNS. The nature of the paracrine regulatory loop with astrocyte and neuronal GRO1 expression in a pattern that is closely correlated with PDGFαR+ oligodendrocyte precursors suggests that the GRO1/PDGF regulatory mechanism provides local control of oligodendrocyte precursor proliferation during development.

Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated during development through the proliferation and differentiation of a distinct progenitor population. Not all oligodendrocyte progenitors generated during development differentiate, however, and large numbers of oligodendrocyte progenitors are present in the adult CNS, particularly in white matter. These “adult progenitors” can be identified through expression of the NG2 proteoglycan. Adult oligodendrocyte progenitors are thought to develop from the original pool of progenitors and in vitro are capable of differentiating into oligodendrocytes. Why these cells fail to differentiate in the intact CNS is currently unclear. Here we show that contact with CNS myelin inhibits the maturation of immature oligodendrocyte progenitors. The inhibition of oligodendrocyte progenitor maturation is a characteristic of CNS myelin that is not shared by several other membrane preparations including adult and neonatal neural membrane fractions, PNS myelin, or liver. This inhibition is concentration dependent, is reversible, and appears not to be mediated by either myelin basic protein or basic fibroblast growth factor. Myelin-induced inhibition of oligodendrocyte progenitor maturation provides a mechanism to explain the generation of a residual pool of immature oligodendrocyte progenitors in the mature CNS.

The timing of oligodendrogenesis depends on the specific location within the central nervous system, suggesting the local environment influences oligodendrocyte precursor proliferation. Spinal cord and optic nerve oligodendrocyte precursors both proliferate in response to platelet-derived growth factor (PDGF). Here we show that neurotrophin-3 (NT-3) enhanced PDGF-induced proliferation of optic nerve oligodendrocyte precursors, and these cells were labeled by an anti-trkC antibody. By contrast, NT-3 did not enhance PDGF-induced proliferation of spinal cord oligodendrocyte precursors, and these cells were not labeled by an anti-trkC antibody. Furthermore, PDGF-induced oligodendrocyte precursor proliferation was greater in spinal cord than in optic nerve cultures. The difference in NT-3 response between spinal cord and optic nerve oligodendrocyte precursors appears cell intrinsic, while the enhanced PDGF-induced proliferation of spinal cord oligodendrocyte precursors appears environmentally regulated. The spinal cord PDGF proliferation-enhancing activity may provide a mechanism to allow temporal and spatial regulation of gliogenesis.

Neural tube defects (NTDs) are a set of disorders that occur from perturbation of normal neural development. They occur in open or closed forms anywhere along the craniospinal axis and often result from a complex interaction between environmental and genetic factors. One burgeoning area of genetics research is the effect of cilia signaling on the developing neural tube and how the disruption of primary cilia leads to the development of NTDs. Recent progress has implicated the hedgehog (Hh), wingless-type integration site family (Wnt), and planar cell polarity (PCP) pathways in primary cilia as involved in normal neural tube patterning. A set of disorders involving cilia function, known as ciliopathies, offers insight into abnormal neural development. In this article, the authors discuss the common ciliopathies, such as Meckel-Gruber and Joubert syndromes, that are associated with NTDs, and review cilia-related signaling cascades responsible for mammalian neural tube development. Understanding the contribution of cilia in the formation of NTDs may provide greater insight into this common set of pediatric neurological disorders.