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Objective To investigate the impact of a video-based educational resource on home exercise compliance among caregivers of children with neonatal brachial plexus palsy (NBPP). Design Retrospective analysis of self-reported caregiver home exercise habits and resultant shoulder range of motion (ROM) and biceps power in patients with NBPP. Setting Home-based exercise program. Participants Adult caregivers of children with NBPP followed up through the Brachial Plexus Program at the University of Michigan (N = 83 surveyed initially, with N=37 completing the final survey). Methods Caregivers completed surveys before and approximately 3, 6, and 12 months (times A, B, and C, respectively) after receiving the "Home Exercise Therapy Program for Brachial Plexus Palsy" digital video disk (DVD). A retrospective analysis of shoulder ROM and biceps power of patients was completed as representative of arm function during the study. Main Outcome Measurements Surveys assessed home exercise compliance, resources used to guide exercises, and caregiver confidence in the correctness of exercises being performed. Functional outcomes analyzed include biceps strength and shoulder active and passive ROM. Results Home exercise compliance increased from 74% initially to 96% at time A ( P P P = .016). Use of the DVD to guide home exercise decreased from 69% at time A to 57% at time B and C ( P = .026). After receiving the DVD, exercise frequency and caregiver confidence increased. Although some measures of shoulder active ROM and biceps power improved during the course of the study, there was no consistent statistically significant relationship between increased caregiver confidence and functional outcomes. No causal relationship exists between DVD content and functional status at this time. Conclusions As the first formal evaluation of a video-based resource guiding exercise therapy for children with NBPP, we suggest that this population may be receptive to alternative media and may benefit from dynamic modeling of home exercises.

We investigate the incidence of torticollis associated with neonatal brachial plexus palsy, whether the severity of brachial plexus palsy affects outcomes and the rate of recovery. We performed a retrospective review of 128 consecutive neonatal brachial plexus palsy patients evaluated at the University of Michigan from 2005-2009. Patients were followed for at least 3 months, with regular physical examinations and imaging. Forty-three percent presented concurrently with torticollis. Significant differences were evident in mean age at first brachial plexus examination, suggesting that patients with concurrent torticollis present earlier for clinical examination. Recovery from torticollis was evident in 62% of patients by 23 ± 12 weeks with conservative management. No statistically significant differences were evident between torticollis and nontorticollis groups after reviewing their severity of neonatal brachial plexus palsy (Narakas score), recovery from neonatal brachial plexus palsy (biceps function at 6 months), need for nerve repair or reconstructive procedures, or infant, maternal, or other factors associated with labor. Results suggest that although torticollis occurs with increased frequency in children with brachial plexus palsy, its presence is not related to severity and does not affect the probability of recovery from brachial plexus palsy. Conservative management for torticollis yields reasonable recovery.

Congenital malformations encompass a diverse group of disorders present at birth as result of genetic abnormalities, infection, errors of morphogenesis, or abnormalities in the intrauterine environment. Congenital disorders affecting the brain and spinal cord are often diagnosed before delivery with the use of prenatal ultrasonography and maternal serum screening. Over the past several decades there have been major advances in the understanding and management of these conditions. This article focuses on the most common spinal congenital malformations.

Object Extracorporeal membrane oxygenation (ECMO) is a potentially life-saving treatment for patients in refractory cardiorespiratory failure. Neurological complications that result from ECMO treatment are known to significantly impact patient survival and quality of life. The purpose of this study was to review the incidence of neurological complications of ECMO in the pediatric population and the role of neurosurgery in the treatment of these patients. Methods Data were obtained from the national Extracorporeal Life Support Organization (ELSO) Registry for the years 1990 to 2009. The neurological complications recorded by the registry include CNS hemorrhage, CNS infarction, and seizure. The ECMO Registry at the authors' institution was then searched, and 3 pediatric patients who had undergone craniotomy during ECMO treatment were identified. Results Children in the ELSO Registry who were treated with ECMO survived to hospital discharge in 65% of cases. Intracranial hemorrhage occurred in 7.4% of the ECMO-treated patients, with 36% of those surviving to hospital discharge. Hemorrhage was more likely in patients younger than 30 days old and in those requiring ECMO for cardiac indications. Cerebral infarction occurred in 5.7% of all ECMO-treated patients. Clinically diagnosed seizures occurred in 8.4% of all ECMO-treated patients. The ECMO Registry at the authors' institution revealed that 1898 patients were treated there. Intracranial hemorrhage was diagnosed in 81 patients (5.8%), and 3 of these patients were treated with craniotomy. Two of the patients were alive with minimal neurological impairment and normal school performance at 10 and 16 years of follow-up. Conclusions Intracranial hemorrhage is a serious complication of ECMO treatment. While the surgical risk is substantial, there may be a role for surgical evacuation of hemorrhage in well-selected patients.

The stem cell factor/kit tyrosine kinase receptor pathway is related to tumor growth and progression in several cancers including Ewing sarcoma, a peripheral PNET (pPNET). Identifying additional groups of tumors that may use the pathway is important as they might be responsive to imatinib mesylate treatment. MB and central PNET (cPNET) are embryonal tumors of the CNS that share similar undifferentiated morphology with Ewing sarcomas and display aggressive clinical behavior. cPNET outcome is significantly lower than MB outcome, even for localized tumors treated with high-risk MB therapy. The elucidation of signaling pathways involved in MB and cPNET pathogenesis, and the discovery of new therapeutic targets is necessary to improve the treatment of these neoplasms. We analyzed KIT expression in 2 MB, one pPNET, one cPNET and 2 rhabdomyosarcoma (RMS) cell lines. Also, in 13 tumor samples (12 MB and one cPNET), we found KIT overexpression in the most aggressive cell lines (metastatic MB and pPNET). Hypermethylation of KIT was clear in the RMS non-expressing cell lines. Among MB tumors, we could see variable levels of KIT expression; a subset of them (25%) might be related in its growth pattern to KIT up-regulation. No methylated KIT was detected in the tumors expressing the lowest levels of KIT. Our results point to methylation as an epigenetic regulatory mechanism for KIT inhibition only in the KIT non-expressing RMS cell lines, and neither in the rest of the cell lines nor in the tumor samples.

The authors report an unusual case of bilateral large petrous apex cephaloceles in a 14-year-old boy with a history of recurrent meningitis. Although these lesions are rare and usually asymptomatic, surgical correction is recommended if they are associated with a persistent CSF leak. In this patient, the extensive bilateral cranial defects were not adequately treated by an intracranial approach alone. Repair of a defect in the posterior pharyngeal wall, the site of a prior tonsillectomy, ultimately resulted in repair of the CSF fistula.

In cases of temporal horn entrapment caused by primary malignant central nervous system tumors, the goal is to restore physiological flow of cerebrospinal fluid (CSF) while preventing the spread of malignant tumor cells to distant sites. This goal is usually accomplished by placement of a traditional ventriculoperitoneal, ventriculopleural, or ventriculoatrial shunt. In this study, the authors describe a novel treatment approach using placement of a frontal-to-temporal horn shunt as an alternative to distal CSF diversion. Stereotactic surgery was used for placement of frontal-to-temporal horn shunts in 3 patients who presented with focal compressive symptoms caused by temporal horn dilation. Serial imaging studies confirmed temporal horn decompression with symptom resolution after a maximum of 20 months of follow-up (minimum 2 months in 1 patient who died of tumor progression). The authors believe this simple technique may be considered for use in all patients with neurological symptoms resulting from temporal horn dilation caused by malignant central nervous system neoplasms in which seeding of distant sites by CSF diversion is a concern.

OBJECT Awake craniotomy is currently a useful surgical approach to help identify and preserve functional areas during cortical and subcortical tumor resections. Methodologies have evolved over time to maximize patient safety and minimize morbidity using this technique. The goal of this study is to analyze a single surgeon's experience and the evolving methodology of awake language and sensorimotor mapping for glioma surgery. METHODS The authors retrospectively studied patients undergoing awake brain tumor surgery between 1986 and 2014. Operations for the initial 248 patients (1986–1997) were completed at the University of Washington, and the subsequent surgeries in 611 patients (1997–2014) were completed at the University of California, San Francisco. Perioperative risk factors and complications were assessed using the latter 611 cases. RESULTS The median patient age was 42 years (range 13–84 years). Sixty percent of patients had Karnofsky Performance Status (KPS) scores of 90–100, and 40% had KPS scores less than 80. Fifty-five percent of patients underwent surgery for high-grade gliomas, 42% for low-grade gliomas, 1% for metastatic lesions, and 2% for other lesions (cortical dysplasia, encephalitis, necrosis, abscess, and hemangioma). The majority of patients were in American Society of Anesthesiologists (ASA) Class 1 or 2 (mild systemic disease); however, patients with severe systemic disease were not excluded from awake brain tumor surgery and represented 15% of study participants. Laryngeal mask airway was used in 8 patients (1%) and was most commonly used for large vascular tumors with more than 2 cm of mass effect. The most common sedation regimen was propofol plus remifentanil (54%); however, 42% of patients required an adjustment to the initial sedation regimen before skin incision due to patient intolerance. Mannitol was used in 54% of cases. Twelve percent of patients were active smokers at the time of surgery, which did not impact completion of the intraoperative mapping procedure. Stimulation-induced seizures occurred in 3% of patients and were rapidly terminated with ice-cold Ringer's solution. Preoperative seizure history and tumor location were associated with an increased incidence of stimulation-induced seizures. Mapping was aborted in 3 cases (0.5%) due to intraoperative seizures (2 cases) and patient emotional intolerance (1 case). The overall perioperative complication rate was 10%. CONCLUSIONS Based on the current best practice described here and developed from multiple regimens used over a 27-year period, it is concluded that awake brain tumor surgery can be safely performed with extremely low complication and failure rates regardless of ASA classification; body mass index; smoking status; psychiatric or emotional history; seizure frequency and duration; and tumor site, size, and pathology.

Approximately 19,000 gliomas are diagnosed in the United States each year, most ultimately leading to death.1 Resection improves outcome, especially for patients with low-grade gliomas.2,3 These tumors commonly involve eloquent areas, and the risk of injuring eloquent brain regions limits the extent of resection in many patients. The challenge is greatest for tumors near the perisylvian language network due to the wide variability in functional anatomy of language sites and changes in functional anatomy induced by the gliomas.

Non-malignant brain tumors occur at an incidence of 17.9 per 100,000 people in the United States. Low-grade gliomas and benign meningiomas are the most common non-malignant brain tumors in adults. Low-grade gliomas are slow-growing tumors originating from supporting glial cells, while meningiomas grow attached to dural surfaces outside of the brain. Prior radiation exposure is the only known modifiable risk factor. Treatment is focused on decreasing tumor burden, controlling seizures, and decreasing the rate of malignant transformation while preserving neurological function. This is particularly important because patients with non-malignant brain tumors can live for decades with this diagnosis. Surgical resection plays a critical role. Maximal safe resection using techniques such as neuronavigation, functional MRI, diffusion tensor imaging, and direct stimulation mapping allow for preservation of neurological function while reducing tumor burden. Subsequent radiotherapy can improve progression-free survival, particularly for recurrent tumors or residual disease. Targeted chemotherapeutic agents against specific pathways necessary for tumor growth are currently being investigated.

Symptomatic cerebral edema from diabetic ketoacidosis occurs infrequently but carries a high rate of mortality and morbidity owing to complications from intracranial hypertension. Treatment options are limited but include hyperosmolar therapy with mannitol or hypertonic saline, tracheal intubation for airway protection, and hyperventilation via mechanical ventilation. We describe here the successful use of an intracranial pressure/cerebral perfusion pressure-targeted management strategy through ventriculostomy catheter placement with intracranial pressure monitoring and cerebrospinal fluid drainage, hyperosmolar therapy with hypertonic saline, and controlled hyperventilation to treat life-threatening complications of cerebral edema in a pediatric patient with severe diabetic ketoacidosis.

Cervical total disc replacementwasdeveloped to treat symptomsassociatedwithdiscdegenerationwhilepreservingphysiological motion. Several clinical trials have compared its use with traditional anterior cervical discectomy and fusion for both single-level and multilevel disease.1,2 Ament et al3 analyzed data from a published multicenter randomizedclinical trial by Davis et al4 that demonstrated the clinical superiority of the Mobi-C cervical artificial disc vs anterior discectomy and fusion for 2-level contiguous degenerative disc disease and proposed that 2-level total cervical disc replacement is a cost-effective intervention. This is a potentially significant conclusion. As health care costs continue to increase, there is growing scrutiny ofmedical and surgical treatments offered topatients that, despite efficacy,maybecostprohibitive.Using thequality-adjusted lifeyear scale, the authors showed that 2-level cervical total disc replacement is a cost-effective treatment modality.3 However, several limitationsneed tobeconsidered.First, datawere derived from a multicenter randomized clinical study with strict inclusionandexclusion criteria.As such, the resultsmay not be generalizable to the general populationof patientswho are candidates for anterior cervical surgery. In addition, although thedecisionanalyticmodelingused in thestudyseems reasonable, assumptions that may not be valid were used for the analysis. Even so, the results of this study provide compelling evidence that cervical total disc replacement is a costeffective option for 2-level symptomatic cervical spondylitic disease.

Optimal treatment for recurrent high-grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients. In this analysis, we reviewed the literature to examine the role of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence.

Vascular endothelial growth factor (VEGF) is the major proangiogenic factor in many solid tumors. Vascular endothelial growth factor receptor (VEGFR) is expressed in abundance in pediatric patients with medulloblastoma and is associated with tumor metastasis, poor prognosis, and proliferation. Gadolinium enhancement on MRI has been suggested to have prognostic significance for some tumors. The association of VEGF/VEGFR and Gd enhancement in medulloblastoma has never been closely examined. The authors therefore sought to evaluate whether Gd-enhancing medulloblastomas have higher levels of VEGFR and CD31. Outcomes and survival in patients with enhancing and nonenhancing tumors were also compared.A retrospective analysis of patients with enhancing, nonenhancing, and partially enhancing medulloblastomas was performed. Primary end points included risk stratification, extent of resection, and perioperative complications. A cohort of 3 enhancing and 3 nonenhancing tumors was selected for VEGFR and CD31 analysis as well as microvessel density measurements.Fifty-eight patients were analyzed, and 20.7% of the medulloblastomas in these patients were nonenhancing. Enhancing medulloblastomas exhibited strong VEGFR1/2 and CD31 expression relative to nonenhancing tumors. There was no significant difference in perioperative complications or patient survival between the 2 groups.These results suggest that in patients with medulloblastoma the presence of enhancement on MRI may correlate with increased vascularity and angiogenesis, but does not correlate with worse patient prognosis in the short or long term.

Cerebrospinal fluid (CSF) leak is an uncommon but well-documented occurrence after blunt head trauma, typically manifesting as otorrhea or rhinorrhea. Blunt cranio-orbital trauma also may cause CSF leak into the orbit, manifesting as orbitocele, blepharocele, chemosis, or tearing ("oculorrhea"). We report a patient who developed oculorrhea after blunt head trauma, and neuroimaging disclosed comminuted fractures of the left frontal, greater sphenoid wing, nasal, and maxillary bones. Because he also displayed chemosis and markedly reduced ocular ductions and periocular pain, carotid-cavernous fistula was suspected but appropriate vascular imaging was negative. Aspiration of subconjunctival fluid was positive for beta-2 transferrin, a specific marker for CSF. Chemosis lessened and the oculorrhea ceased spontaneously within 6 days of the trauma. This manifestation of CSF leak must not be overlooked because of the threat of meningitis.

Central nervous system tumors are a major cause of morbidity and mortality in the United States. Outside of brain metastasis, low- and high-grade gliomas are the most common intrinsic brain tumors. Low-grade gliomas have a 5- and 10-year survival rate of 97 % and 91 %, respectively, when extent of resection is greater than 90 %. High-grade gliomas are extremely aggressive with the vast majority of patients experiencing recurrence and a median survival of 1 to 3 years. Survival of patients with both low- and high-grade gliomas is enhanced with maximal tumor resection. The pursuit of more aggressive extent of resection must be balanced with preservation of functional pathways. Several innovations in neurosurgical oncology have expanded our understanding of individualized patient neuroanatomy, physiology, and function. Emerging imaging technologies as well as intraoperative techniques have expanded our ability to resect maximal amounts of tumor while preserving essential function. Stimulation mapping of language and motor pathways is well-established for the safe resection of intrinsic brain lesions. Additional techniques including neuro-navigation, fluorescence-guided microsurgery using 5-aminolevulinic acid, intraoperative magnetic resonance imaging, and high-frequency ultrasonography can all be used to improve extent of resection in glioma patients.

When resecting gliomas, extra-axial tumors, or their overlying cortex, cortical veins may become suspended over the resection cavity and ultimately prolapse and kink into the cavity, promoting venous thrombosis. To prevent this, we describe a technique to secure a Gelfoam scaffold beneath the cortical vein at the edge of the resection cavity to prevent kinking and possible thrombosis from taking place after tumor removal. Depending on the diameter of the resection cavity, this can be done at 1 or both edges of the resection cavity to prevent prolapse of the vein into the cavity. In our experience with this technique, during the past 10 years, there have been no cases of venous thrombosis after tumor removal on postoperative imaging or clinical examination.

Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Every year ~22,000 patients are diagnosed with GBM in the US, and less than 5% survive 5 years post-diagnosis. Thus, novel therapeutic approaches are urgently needed to improve the outcome in these patients. Immunotherapy has the potential of stimulating the immune system to eliminate GBM cells that might have spread throughout the brain. Here we will discuss the latest advances in preclinical immunotherapy for glioma, which involve the local delivery of pro-inflammatory cytokines, such as Flt3L, Type I IFNs, IL-2, IL-4, and IL-12 using gene therapy vectors and neural stem cells, or the blockade of immune-suppressive mediators such as TGF-beta, FasL and phosphorylated STAT3. Novel immunotherapeutic approaches have also been assessed in clinical trials implemented in GBM patients. These involve the systemic or local adoptive transfer of autologous immune cells activated ex vivo back into the patient, and the administration of dendritic cell vaccines loaded with tumor peptides or cells, which induce active immunity against GBM. Preclinical and clinical findings so far indicate that immunotherapy improves anti-tumor immunity in preclinical GBM models and patients, which makes it a valuable adjuvant in the treatment of GBM. Fil: Wilson, Thomas J.. University of Michigan; Estados Unidos Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Assi, Hikmat. University of Michigan; Estados Unidos Fil: Moreno Ayala, Mariela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Mineharu,Yohei. University of Michigan; Estados Unidos Fil: Hervey-Jumper, Shawn L.. University of Michigan; Estados Unidos Fil: Lowenstein, Pedro R.. University of Michigan; Estados Unidos Fil: Castro, Maria Graciela. University of Michigan; Estados Unidos

Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults; it carries a dismal prognosis despite improvements in standard of care. We developed a combined gene therapy strategy using (1) herpes simplex type 1-thymidine kinase in conjunction with the cytotoxic prodrug ganciclovir to kill actively proliferating tumor cells and (2) doxycycline (DOX)-inducible Fms-like tyrosine kinase 3 ligand (Flt3L), an immune stimulatory molecule that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we examined the efficacy and safety of this approach (Muhammad et al., 2010, 2012). In the present article, we investigated the efficacy and safety of the "off-label" use of the antibiotic DOX to turn on the high-capacity adenoviral vector (HC-Ad) encoding therapeutic Flt3L expression. DOX-inducible Flt3L expression in male Lewis rats was assessed using DOX doses of 30.8 mg/kg/day (low-DOX) or 46.2 mg/kg/day (high-DOX), which are allometrically equivalent (Voisin et al., 1990) to the human doses that are recommended for the treatment of infections: 200 or 300 mg/day. Naïve rats were intracranially injected with 1×10(9) viral particles of HC-Ad-TetOn-Flt3L, and expression of the therapeutic transgene, that is, Flt3L, was assessed using immunohistochemistry in brain sections after 2 weeks of DOX administration via oral gavage. The results show robust expression of Flt3L in the rat brain parenchyma in areas near the injection site in both the low-DOX and the high-DOX groups, suggesting that Flt3L will be expressed in human glioma patients at a DOX dose of 200 or 300 mg/day. These doses have been approved by the U.S. Food and Drug Administration to treat infections in humans and would thus be considered safe for an off-label use to treat GBM patients undergoing HC-Ad-mediated gene therapy in a phase I clinical trial.

Neuropathic pain is rare in children, and few reports provide adequate guidelines for treatment. The authors describe the successful treatment of tardy neuropathic pain via macrovascular decompression in a 15-year-old boy who presented with progressive pain 11 years following trauma to the upper extremity that had required surgical repair of the brachial artery. Examination revealed mild chronic median and ulnar motor neuropathy as well as recent progressive lancinating pain and a Tinel sign at the prior scar. A soft tissue mass in the neurovascular bundle at the site of previous injury was noted on MRI. Surgical exploration demonstrated an altered anatomical relationship of the previously repaired brachial artery and the median nerve, resulting in pulsatile compression of the median nerve by the brachial artery. Neurolysis and decompression of the median nerve with physical separation from the brachial artery resulted in immediate pain relief. This is the first report of macrovascular decompression of a major peripheral nerve with complete symptom resolution. Noninvasive imaging together with a thorough history and physical examination can support identification of this potential etiology of peripheral neuralgic pain. Recognition and treatment of this uncommon problem may yield improved outcomes for children with neuropathic pain.

Using an illustrative case of a presumed pontine unidentified bright object (UBO) with spontaneous lesion regression over 2 years, we review the importance of including UBOs in the differential diagnosis of children with confirmed or possible neurofibromatosis type 1 (NF1) who present with diffuse pontine enlargement and T2-weighted changes on MRI. Asymptomatic children with presumed NF1 and diffuse pontine lesions should not be treated with radiation and should not be biopsied. Prior reports of good prognosis associated with pontine glioma in patients with NF1 may have been unrecognized UBOs in some cases.

ANGI-16. IN VIVO AND IN VITRO STUDIES SHOW THAT BRAIN DERIVED ENDOTHELIAL CELLS STIMULATE MIGRATION OF HUMAN, MOUSE AND RAT GLIOMA CELLS Viveka Nand Yadav1,2, Gregory J. Baker1,2, Daniel A. Orringer1, Jason A. Heth1, Shawn Hervey-Jumper1, Oren Sagher1, Maria G. Castro1,2, and Pedro R. Lowenstein1,2; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA Glioblastoma multiforme (GBM) is the most lethal of human brain tumors. Glioma cells invade the brain by active migration along blood vessels, white matter tracts, interstitially, or surrounding the meninges. Molecular determinants of glioma migration patterns, i.e., those that attract glioma cells to blood vessels remain partially understood. We observed that several mouse and human glioma cells migrate primarily along the blood vasculature. Here, we tested the ability of human and mouse brain-derived endothelial (MBVE) cells to stimulate the migration of human, mouse and rat-derived glioma cell lines in an in vitro migration assay. Among different primary human glioma cell lines, HF2303 and MSP-12 cells showed significant directional migration while MGG8, IN859, IN2045 and U251 cells did not. Further, Gl26-cit, a mouse glioma and CNS1-cit a rat cell line also exhibited significant migration towards MBVE. These results were in line with our in vivo data wherein HF2303, and Gl26-cit, but not MGG8 cells, invaded mainly along blood vessels. Differential migration of various human glioma cell lines in response to MBVE cells in vitro is probably related to their growth patterns in vivo. To decipher the mechanism of GBM cell migration, we tested the role of various chemokines using in vitro migration assays. The migration of Gl26-cit and HF2303 towards MBVE were significantly inhibited by AMD3100, an inhibitor of CXCR4. Lastly,MBVE together with mouse astrocytes promote the in vitro migration of Gl26-cit cells to a greater extent than MBVE alone. In summary, the behavior of glioma cells in vitro is consistent with their migration patterns in vivo and therefore, using in vitro migration models are a good tool to identify molecular mechanisms responsible for glioma cell growth towards blood vessels. The CXCL12-CXCR4 signaling was found to be critical for the migration of both mouse and human glioma cell lines. Neuro-Oncology 17:v41–v44, 2015. doi:10.1093/neuonc/nov207.16 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Congenital malformations encompass a diverse group of disorders that often present at birth, either as the result of genetic abnormalities, infection, errors of morphogenesis, or abnormalities in the intrauterine environment. Congenital disorders affecting the brain are now often diagnosed before delivery with the use of prenatal ultrasonography. Over the past several decades, there have been major advances in the understanding and management of these conditions. This review focuses on the most common cranial congenital malformations, limiting the discussion to the neurosurgically relevant aspects of arachnoid cysts, pineal cysts, Chiari malformations, and encephaloceles.

Extracorporeal membrane oxygenation (ECMO) is a potentially life-saving treatment for patients in refractory cardiorespiratory failure. Neurological complications that result from ECMO treatment are known to significantly impact patient survival and quality of life. The purpose of this study was to review the incidence of neurological complications of ECMO in the pediatric population and the role of neurosurgery in the treatment of these patients.Data were obtained from the national Extracorporeal Life Support Organization (ELSO) Registry for the years 1990 to 2009. The neurological complications recorded by the registry include CNS hemorrhage, CNS infarction, and seizure. The ECMO Registry at the authors' institution was then searched, and 3 pediatric patients who had undergone craniotomy during ECMO treatment were identified.Children in the ELSO Registry who were treated with ECMO survived to hospital discharge in 65% of cases. Intracranial hemorrhage occurred in 7.4% of the ECMO-treated patients, with 36% of those surviving to hospital discharge. Hemorrhage was more likely in patients younger than 30 days old and in those requiring ECMO for cardiac indications. Cerebral infarction occurred in 5.7% of all ECMO-treated patients. Clinically diagnosed seizures occurred in 8.4% of all ECMO-treated patients. The ECMO Registry at the authors' institution revealed that 1898 patients were treated there. Intracranial hemorrhage was diagnosed in 81 patients (5.8%), and 3 of these patients were treated with craniotomy. Two of the patients were alive with minimal neurological impairment and normal school performance at 10 and 16 years of follow-up.Intracranial hemorrhage is a serious complication of ECMO treatment. While the surgical risk is substantial, there may be a role for surgical evacuation of hemorrhage in well-selected patients.

One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment. Cancer Res; 71(18); 6061–72. ©2011 AACR.

Background and importance Langerhans cell histiocytosis (LCH) is an uncommon disease, usually affecting the cranium and peripheral bones. We present a rare case of isolated optic chiasm involvement by LCH to highlight the importance of considering LCH in the differential diagnosis of optic chiasm lesions. Clinical presentation A 71-year-old woman presented with a 6-week history of worsening peripheral vision, headaches, weakness, cold sensitivity, and fatigue. She was found to have dense bitemporal hemianopsia. Magnetic resonance imaging revealed a 2-cm lesion, contrast enhancing on T1 and bright on T2 signal, involving the optic chiasm but not the pituitary gland. Preoperative considerations included optic nerve glioma, choristoma of the stalk, sarcoid, hypothalamic glioma, and Langerhans cell histiocytosis. The patient underwent a right subfrontal craniotomy for biopsy of the lesion. The optic chiasm was grossly enlarged with no tissue external to the chiasm. A midline incision was made in the lamina terminalis, and multiple biopsies were taken of firm fibrous material. Histologically, the tumor was characteristic for LCH and included a mixture of histiocytes with features of Langerhans cells, eosinophils, small lymphocytes, macrophages, neutrophils, and plasma cells. Conclusion LCH is a rare disease, generally affecting bone, skin, lymph nodes, and in more severe cases, visceral organs. LCH involving the optic pathways is a rare condition that should be included in the differential for adults with mass lesions involving the orbit, eye, optic nerve, or chiasm. Future clinical and basic science research is needed to better understand LCH, its molecular origin, and its growth pattern.

Pediatric and inherited neurovascular syndromes have diverse presentations and treatments. Although many of these diseases are uncommon, they must be included in the differential diagnosis for children with strokes or hemorrhages. In neurosurgical practice, familial cavernous malformations, hereditary hemorrhagic telangiectasia (HHT), and moyamoya are the most frequently encountered of these diseases. In this article, we will discuss familial cavernomas and HHT, as well as more unusual entities such as PHACE(S) syndrome, Klippel-Trenaunay syndrome, Wyburn-Mason syndrome, sinus pericranii, radiation-induced vasculopathy, and blue rubber bleb nevus (BRBN) syndrome. Moyamoya disease is covered in several other articles in this volume.

The authors report an unusual case of bilateral large petrous apex cephaloceles in a 14-year-old boy with a history of recurrent meningitis. Although these lesions are rare and usually asymptomatic, surgical correction is recommended if they are associated with a persistent CSF leak. In this patient, the extensive bilateral cranial defects were not adequately treated by an intracranial approach alone. Repair of a defect in the posterior pharyngeal wall, the site of a prior tonsillectomy, ultimately resulted in repair of the CSF fistula.

In cases of temporal horn entrapment caused by primary malignant central nervous system tumors, the goal is to restore physiological flow of cerebrospinal fluid (CSF) while preventing the spread of malignant tumor cells to distant sites. This goal is usually accomplished by placement of a traditional ventriculoperitoneal, ventriculopleural, or ventriculoatrial shunt. In this study, the authors describe a novel treatment approach using placement of a frontal-to-temporal horn shunt as an alternative to distal CSF diversion. Stereotactic surgery was used for placement of frontal-to-temporal horn shunts in 3 patients who presented with focal compressive symptoms caused by temporal horn dilation. Serial imaging studies confirmed temporal horn decompression with symptom resolution after a maximum of 20 months of follow-up (minimum 2 months in 1 patient who died of tumor progression). The authors believe this simple technique may be considered for use in all patients with neurological symptoms resulting from temporal horn dilation caused by malignant central nervous system neoplasms in which seeding of distant sites by CSF diversion is a concern.

OBJECTIVE: Awake craniotomy is the gold standard for the identification and preservation of functional areas. The goal of this study was to analyze a single surgeon's experience and the evolving methodology of awake language and sensorimotor mapping for glioma surgery to maximize perioperative safety. METHODS: We retrospectively studied patients from 1986-2013 undergoing awake brain tumor surgery. Perioperative risk factors and complications were assessed using 611 cases. RESULTS: Median patient age was 42 years (range, 13-84 years). Sixty percent of patients had KPS scores of 90-100, and 40% had KPS scores under 80. Fifty-five percent of patients received surgery for high-grade gliomas, 42% for low-grade gliomas, 1% for metastatic lesions, and 2% for other lesions (cortical dysplasia, encephalitis, necrosis, abscess, hemangioma). The majority of patients were ASA class 1 or 2 (mild systemic disease). Laryngeal mask airway (LMA) was used in 8 patients (1%), and was most commonly used for large vascular tumors with more than 2 cm of mass effect. The most common sedation regimen was propofol plus remifentanil (PR; 54%); however, 42% required an adjustment to the initial sedation regimen before skin incision. Mannitol was used in 54% of cases. Twelve percent of patients were active smokers at the time of surgery, which did not impact intraoperative mapping procedure failure. Stimulation-induced seizures occurred in 3% of patients and were rapidly terminated with ice-cold Ringer's solution. Preoperative seizure history and tumor location were associated with an increased incidence of stimulation-induced seizures. Mapping was aborted in 3 cases (0.5%) due to intraoperative seizures and patient emotional intolerance. The overall perioperative complication rate was 10%. CONCLUSIONS: Awake brain tumor surgery can be safely performed with low complication and failure rates regardless of ASA classification, Mallampati score, body mass index, smoking status, psychiatric history, seizure history, tumor site, or tumor pathology.

An 8-year-old boy with no significant past medical history presented to the emergency department following 2 weeks of progressive headaches, fatigue, and vomiting. On physical examination, the patient had no fever, or focal motor or sensory neurological deficits. Initially diagnosed with an H1N1 viral upper respiratory and gastrointestinal infection, he was discharged home with conservative management. After failure to improve over the next several days, a superimposed bacterial infection was suspected. He was given a course of oral antibiotics, which failed to improve his symptoms. Imaging revealed a large, heterogenously enhancing mass measuring 5.6 × 4.7 × 5.2 cm, which contained partially hemorrhagic material centered within the left thalamus extending into the body of the lateral ventricle (Figures 1a). Gross total resection of the tumor was confirmed by postoperative imaging. Staging revealed no metastases. The patient was discharged home 1 week later. NEUROPATHOLOGICAL FINDINGS

Infantile hemangiomas are tumors commonly seen in children. Few authors have reported infantile hemangiomas affecting the CNS, and there are no prior reports detailing spontaneous resolution of a histologically proven juvenile hemangioma within a dorsal root ganglion. The authors report the case of a newborn boy with a large cutaneous hemangioma in the midline of his back. Spinal MR images were obtained to rule out associated spinal cord tethering, and an intradural spinal lesion was unexpectedly discovered. Biopsy revealed an intradural infantile hemangioma within the dorsal root ganglion, and, based on this diagnosis, no resection was performed. Sixteen months following the biopsy, the cutaneous hemangioma had become involuted and the intradural hemangioma had completely resolved. The behavior of the intradural component in this case follows the natural history of many cutaneous infantile hemangiomas.

The Patient Protection and Affordable Care Act, also known as the House of Representatives Bill HR 3590, was created to improve the quality of patient care and access to health care for American citizens. Provisions of this bill are likely to have both intended and unintended consequences on surgical education. The purpose of this article is to explore the ways in which HR 3590 may affect the educational experience of surgical house officers at teaching hospitals.

Recent data show that endothelial cells function as a stem cell niche to promote CD133-positive cancer stem-like cells (CSLCs) self-renewal in glioblastoma (GBM). However, the molecular mechanism by which endothelial cells function as a stem cell niche is largely unknown. We had demonstrated recently that activation of NOTCH signaling is required for GBM CSLC propagation both in vitro and in vivo. To investigate if the acquisition of NOTCH activation in GBM CSLCs results from adjacent endothelial cells, we first examined the expression of NOTCH ligands JAG/DLL in primary GBM frozen samples. We found that JAG1, JAG2 and DLL4 are expressed mostly in endothelial cells adjacent to NESTIN- and NOTCH receptor-positive cancer cells. Some tumor cells also express JAG1, JAG2, and DLL1, but not DLL4, adjacent to NESTIN- and NOTCH-receptor positive cells in primary GBMs. Furthermore, we found that forced differentiated GBM cells from GBM neurospheres express a higher level of NOTCH ligands and a lower level of stem cell marker CD133, have reduced NOTCH activity, and are less tumorigenic in mice compared to GBM neurospheres. In addition, when we co-cultured GBM neurospheres with human brain microvascular endothelial cells (hBMECs) which express NOTCH ligands JAG/DLL, we found that hBMECs promote GBM neurosphere growth, increase the CD133-positive CSLC population and clonogenicity in vitro, whereas knocking down JAG1 or DLL4 in hBMECs abrogates hBMEC-induced GBM growth both in vitro and in vivo. Finally, we found that knockdown of JAG1 or DLL4 in hBMECs decreases growth of GBM intracranial xenograft in mice through reducing the CD133-positive population. In summary, we have demonstrated that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and surrounding endothelial cells, suggesting that targeting both CSLCs and their niche may provide an effective strategy to deplete GBM CSLCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3297. doi:10.1158/1538-7445.AM2011-3297

Introduction: Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Even with optimal therapy, more than 70% of GBM patients will die within 2 years of diagnosis. MicroRNAs (miR) are important regulators of gene expression through posttranscriptional silencing of target mRNA. MicroRNA roles in cell proliferation, invasion, angiogenesis, and glioma stem cell activity are little known. In this study, we focus on the expression and function of microRNAs in human gliomas. Methods: Using RNA extracted from 15 GBM patient samples and serum collected from 2 glioma patients, miR 338-3p expression, relative to normal brain and control serum, was examined using RT PCR. Regional miR expression within a single tumor was identified. A DNA fragment containing the hsa-miR-338-3p locus was amplified and cloned into a lentiviral vector, then transduced into GBM neurosphere lines. MicroRNA 338-3p and its downstream target, expression was assessed by RT PCR and western blot. GBM neurosphere growth was examined in vitro. Results: Over-expression in miR 338-3p is associated with decreased glioma cell proliferation and neurosphere formation. MicroRNA 338-3p shows decreased expression in the core of malignant gliomas with increased expression at the tumors rim and migrating edge. MiR 338-3p expression induces cleaved caspase 3 expression. MiR 338-3p targets Histone deacetylase 4 (HDAC4). Conclusion: MicroRNA 338-3p inhibits GBM neurosphere growth in vitro through reducing proliferation and inducing apoptosis possibly via targeting of HDAC4. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 134. doi:10.1158/1538-7445.AM2011-134

Recent data shows that endothelial cells function as a stem cell niche to promote CD133-positive cancer stem-like cells (CSLCs) self-renewal in glioblastoma (GBM). However, the mechanism by which endothelial cells function as a stem cell niche is largely unknown. To test if endothelial cells and differentiated tumor cells could function as a niche by providing Notch ligands to CSLCs, first we co-cultured GBM neurospheres with primary human endothelial cells (PHECs) which express Notch ligand Jagged/Delta. We found that PHECs promote GBM neurosphere growth, CD133 expression and clonogenicity in vitro, whereas knocking down Notch ligand expression in PHECs abrogates PHEC-induced GBM growth. We also found that the CD133-negative GBM cells express a higher level of Jagged/Delta and glial differentiation marker GFAP compared with CD133-positive population. When GBM neurospheres were forced to differentiate and grow as mono-layer attached cells, CD133-positive population was reduced, whereas expression of GFAP (glial marker), GalC (oligodendrocyte marker), Tuj1 (neuronal marker) and Notch ligands were induced. Furthermore, treatment of GBM neurospheres with a Jagged peptide increases GBM growth in a dosage dependent fashion. In addition, Notch ligands are highly expressed in the blood vessels of GBM primary tumors and intracranial xenografts in mouse, and CSLCs accumulate around the blood vessels within the tumors. Finally, we found that knocking down Notch ligands in PHECs inhibits GBM xenograft propagation in mice through reducing CD133-positive population. In summary, we show that Notch activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells replicating the classical process of lateral inhibition and by stromal niche signals, suggesting that targeting both CSLCs and their niche may provide a profound strategy to deplete GBM CSLCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4235.