Bevacizumab in the Treatment of Refractory Brain Edema in High-grade Glioma.

We report the case of a 14-year-old boy with a steroid-dependent refractory tumor whose longstanding dexamethasone treatment was successfully discontinued after a course of bevacizumab. The use of bevacizumab despite the absence of clear evidence of radionecrosis allowed a significant decrease in the amount of the brain edema.

Very Long-term Survivorship in Pediatric DIPG: Case Report and Review of the Literature.

Diffuse intrinsic pontine gliomas are lethal tumors with a prognosis generally less than 1 year. Few cases of survivors of 5 years or more have been reported. This case report highlights the journey of a 9.5-year survivor who underwent 3 rounds of focal radiotherapy; she experienced 6 years of progression-free survival following the first round but ultimately succumbed to her disease. An autopsy revealed a favorable IDH1 mutation and the absence of H3K27M. This case reiterates the importance of extensive molecular analyses in diffuse intrinsic pontine gliomas and explores the potential benefit of re-irradiation in patients with positive responses and long periods of remission.

Recurrent primary intracranial sarcoma, DICER1-mutant in a pediatric patient with DICER1 syndrome: the importance of molecular testing.

Pediatric intracranial sarcomas are rare, aggressive tumors with a poor prognosis in general. Here we report the case of a child who was initially diagnosed with a primary intracranial sarcoma, DICER1-mutant; subsequent genetic analyses confirmed a pathogenic germline DICER1 mutation. She received multimodal standard treatments consisting of surgery, radiotherapy and chemotherapy. The tumor recurred 2.5 years later within the surgical cavity. Following the gross tumor resection of this new lesion, the same multimodal standard approach was used. From a molecular perspective, evidence of hyperactivation of the MAPK-kinase pathway with a pathogenic KRAS mutation at both diagnosis and recurrence was present. The patient is currently in remission, 18 months post-end of treatment.

Cerebrospinal fluid external leak after penetrating trauma in a neurologic intact infant patient: a case report.

Cranial cerebrospinal fluid (CSF) leak is an extremely rare complication of blunt head trauma causing skull fractures, especially fractures involving the skull base. We present the case of a 10-month-old male who received glass fragments on the midline and posterior tier of his anterior fontanelle producing a cranial cerebrospinal fluid leak without any skull fracture or symptoms. Neurologic exam was completely normal and a superficial stitch wound repair was performed. He was observed for 24 h, had no antibiotic, and left with a 1-week outpatient neurosurgical follow-up. The patient had no negative outcome. Cerebrospinal fluid leak should be included in the differential diagnosis of a head trauma in a patient with open fontanelles. No similar case was found in literature.

Neuronavigation-Guided Endoscopic Endonasal Drainage of Pediatric Anterior Cranial Base Epidural and Subdural Empyema.

In children, epidural and/or subdural intracranial empyema can complicate frontal sinusitis or pansinusitis. The standard transcranial approach used to treat epidural or subdural empyema has many drawbacks, but these can be avoided with an endoscopic expanded endonasal approach (EEA). To support the feasibility and advantages of this approach, we report the successful drainage through endoscopic EEA of a bifrontal empyema caused by an intracranial extension of pansinusitis. Our case and the ones previously reported in the literature establish well that endoscopic EEA offers several advantages over the standard craniotomy. Hence, EEA should be considered as an alternative to the transcranial approach when surgically draining anterior skull base empyema resulting from pansinusitis in children.

Trametinib for progressive pediatric low-grade gliomas.

INTRODUCTION: Pediatric pilocytic astrocytomas (PAs) are low grade gliomas and the most common brain tumors in children. They often represent a therapeutic challenge when incompletely resected as they can recur and progress despite the use of several lines of chemotherapeutic agents or even radiation therapy. Genetic alterations leading to activation of the mitogen-activated-protein-kinase pathway are a hallmark of this disease and offer an interesting therapeutic alternative through the use of targeted inhibitors. METHODS: Here, we describe six children with sporadic PA who were treated with trametinib, a MEK inhibitor, following progression under conventional therapies. Retrospective chart review was performed. RESULTS: The median age at diagnosis was 2.3 years (y) old [range 11 months (m)-8.5 y old]. KIAA1549-BRAF fusion was identified in five cases, and hotspot FGFR1/NF1/PTPN11 mutations in one. All patients received at least one previous line of chemotherapy (range 1-4). The median time on treatment was 11 m (range 4-20). Overall, we observed two partial responses and three minor responses as best response; three of these patients are still on therapy. Treatment was discontinued in the patient with progressive disease. The most frequent toxicities were minor to moderately severe skin rash and gastro-intestinal symptoms. Two patients had dose reduction due to skin toxicity. Quality of life was excellent with decreased hospital visits and a close to normal life. CONCLUSION: Trametinib appears to be a suitable option for refractory pediatric low-grade glioma and warrants further investigations in case of progression.

Survival in pediatric medulloblastoma: a population-based observational study to improve prognostication.

Medulloblastoma is the most common form of brain malignancy of childhood. The mainstay of epidemiological data regarding childhood medulloblastoma is derived from case series, hence population-based studies are warranted to improve the accuracy of survival estimates. To utilize a big-data approach to update survival estimates in a contemporary cohort of children with medulloblastoma. We performed a population-based retrospective observational cohort study utilizing the Surveillance, Epidemiology, and End Results Program database that captures all children, less than 20 years of age, between 1973 and 2012 in 18 geographical regions representing 28% of the US population. We included all participants with a presumed or histologically diagnosis of medulloblastoma. The main outcome of interest is survivors at 1, 5 and 10 years following diagnosis. A cohort of 1735 children with a median (interquartile range) age at diagnosis of 7 (4-11) years, with a diagnosis of medulloblastoma were identified. The incidence and prevalence of pediatric medulloblastoma has remained stable over the past 4 decades. There is a critical time point at 1990 when the overall survival has drastically improved. In the contemporary cohort (1990 onwards), the percentage of participants alive was 86, 70 and 63% at 1, 5 and 10 years, respectively. Multivariate Cox-Regression model demonstrated Radiation (HR 0.37; 95% CI 0.30-0.46, p < 0.001) and Surgery (HR 0.42; 95% CI 0.30-0.58, p < 0.001) independently predict survival. The probability of mortality from a neurological cause is <5% in patients who are alive 8 years following diagnosis. The SEER cohort analysis demonstrates significant improvements in pediatric medulloblastoma survival. In contrast to previous reports, the majority of patients survive in the modern era, and those alive 8 years following initial diagnosis are likely a long-term survivor. The importance of minimizing treatment-related toxicity is increasingly apparent given the likelihood of long-term survival.

Conservative Management of Large Traumatic Supratentorial Epidural Hematoma in the Pediatric Population.

BACKGROUND/AIMS: Conservative management of traumatic epidural hematomas is being recognized as a safe alternative to surgical treatment in asymptomatic children. There is still debate about the maximal size of epidural hematoma that should be tolerated before deciding for surgery. METHODS: We report - through a retrospective cohort study from a single institution - a series of 16 conservatively managed traumatic epidural hematomas of more than 15 mm thickness. RESULTS: 14 patients (88%) were successfully treated using conservative management. Two patients required surgery. These 2 patients had the only 2 documented high-velocity injury mechanisms. All patients had a Glasgow Outcome Scale of 5/5 on follow-up. CONCLUSION: Conservative management with close observation is a safe alternative even in this population of voluminous hematomas. Injury velocity may be a contributing factor for failure of conservative management in this population.

Hyperosmolar therapy in pediatric traumatic brain injury: a retrospective study.

OBJECTIVES: The objectives of the study are to describe the use of hyperosmolar therapy in pediatric traumatic brain injury (TBI) and examine its effect on intracranial pressure (ICP) and cerebral perfusion pressure (CPP). DESIGN: A retrospective review of patients with severe TBI admitted to the pediatric intensive care unit (PICU) was conducted. Inclusion criteria were ICP monitoring and administration of a hyperosmolar agent (20 % mannitol or 3 % hypertonic saline) within 48 h of PICU admission; for which dose and timing were recorded. For the first two boluses received for increased ICP (>20 mmHg), the impact on ICP and CPP was assessed during the following 4 h, using repeated measures ANOVA. Co-interventions to control ICP (additional hyperosmolar agent, propofol, or barbiturate bolus) and serum sodium were also documented. SETTING: A tertiary care pediatric hospital center. PATIENTS: Children aged 1 month to 18 years, with severe traumatic brain injury (Glasgow Coma Score ≤ 8) and intracranial pressure (ICP) monitor. RESULTS: Sixty-four patients were eligible, of which 16 met inclusion criteria. Average age was 11 years (SD ± 4) and median Glasgow Coma Score was 6 (range 4-7). Seventy percent of boluses were 3 % hypertonic saline, with no identified baseline difference associated with this initial choice. Both mannitol and hypertonic saline were followed by a non-significant decrease in ICP (mannitol, p = 0.055 and hypertonic saline, p = 0.096). There was no significant change in CPP post bolus. A co-intervention occurred in 69 % of patients within the 4 h post hyperosmolar agent, and eight patients received continuous 3 % saline. CONCLUSION: In pediatric TBI with intracranial hypertension, mannitol and 3 % hypertonic saline are commonly used, but dose and therapeutic threshold for use vary without clear indications for one versus another. Controlled trials are warranted, but several barriers were identified, including high exclusion rate, multiple co-interventions, and care variability.

Efficacy and safety of endoscopic third ventriculostomy and choroid plexus cauterization for infantile hydrocephalus: a systematic review and meta-analysis.

PURPOSE: Endoscopic third ventriculostomy/choroid plexus cauterization (ETV/CPC) has gained popularity in its treatment of infantile hydrocephalus over the past decade. In this manuscript, we perform a systematic review and meta-analysis to determine the efficacy and safety of ETV/CPC, and to compare the procedural outcomes between North American and sub-Saharan African cohorts. METHODS: Systematic review was performed using four electronic databases and bibliographies of relevant articles, with no language or date restrictions. Cohort studies of participants undergoing ETV/CPC that reported outcome were included using MOOSE guidelines. The outcome was time to repeat CSF diversion or death. Forest plots were created for pooled mean and its 95 % CI of outcome and morbidity. RESULTS: Of 78 citations, 11 retrospective reviews (with 524 total participants) were eligible. Efficacy was achieved in 63 % participants at follow-up periods between 6 months and 8 years. Adverse events and mortality was reported in 3.7 and 0.4 % of participants, respectively. Publication bias was detected with respect to efficacy and morbidity of the procedure. A large discrepancy in success was identified between ETV/CPC in six studies from sub-Saharan Africa (71 %), compared to three studies from North America (49 %). CONCLUSIONS: The reported success of ETV/CPC for infantile hydrocephalus is higher in sub-Saharan Africa than developed nations. Large long-term prospective multi-center observational studies addressing patient-important outcomes are required to further evaluate the efficacy and safety of this re-emerging procedure.

Derivation and validation of a clinical decision rule to identify young children with skull fracture following isolated head trauma.

BACKGROUND: There is no clear consensus regarding radiologic evaluation of head trauma in young children without traumatic brain injury. We conducted a study to develop and validate a clinical decision rule to identify skull fracture in young children with head trauma and no immediate need for head tomography. METHODS: We performed a prospective cohort study in 3 tertiary care emergency departments in the province of Quebec. Participants were children less than 2 years old who had a head trauma and were not at high risk of clinically important traumatic brain injury (Glasgow Coma Scale score < 15, altered level of consciousness or palpable skull fracture). The primary outcome was skull fracture. For each participant, the treating physician completed a standardized report form after physical examination and before radiologic evaluation. The decision to order skull radiography was at the physician's discretion. The clinical decision rule was derived using recursive partitioning. RESULTS: A total of 811 patients (49 with skull fracture) were recruited during the derivation phase. The 2 predictors identified through recursive partitioning were parietal or occipital swelling or hematoma and age less than 2 months. The rule had a sensitivity of 94% (95% confidence interval [CI] 83%-99%) and a specificity of 86% (95% CI 84%-89%) in the derivation phase. During the validation phase, 856 participants (44 with skull fracture) were recruited. The rule had a sensitivity of 89% and a specificity of 87% during this phase. INTERPRETATION: The clinical decision rule developed in this study identified about 90% of skull fractures among young children with mild head trauma who had no immediate indication for head tomography. Use of the rule would have reduced the number of radiologic evaluations by about 60%.

ICP monitoring in children: why are we not adhering to guidelines?

BACKGROUND: Despite pediatric guidelines, variability exists in the management of severe traumatic brain injury (TBI), as somewhere between 7 and 60% of children undergo intracranial pressure (ICP) monitoring. Reasons for this low adherence to TBI management guidelines remain unclear. The objective of this study was to evaluate the current practices at CHU Sainte-Justine with regards to ICP monitoring in severe TBI and explore the reasons why ICP monitoring is not undertaken. METHODS: A retrospective review was conducted of all patients age 1 month to 18 years, with severe TBI (Glasgow Coma Scale (GCS) ≤8) from 2007 to 2014. Presence of ICP monitoring, head imaging reports, and reasons for lack of monitoring were recorded. RESULTS: Sixty-four patients with severe TBI were admitted. Twenty (31%) patients had invasive ICP monitoring in the first 6 h and 5 in the following 24 h. Improvement of the GCS on arrival to tertiary care center (20%, n = 13) and moribund status (20%, n = 13) were the two main reasons ICP monitoring was not undertaken. Fourteen patients (21%) with reassuring cerebral tomography (Rotterdam scores 1-3) and median GCS 7 (IQR 6-8) were initially followed with clinical surveillance, five of which ended up with an ICP monitor (>6 h). CONCLUSION: Our study confirms that many children with severe TBI do not undergo ICP monitoring, mainly due to rapid improvement or moribund status. A subgroup of patients, with reassuring cerebral CT scan, was not monitored. Further research is necessary to assess if imaging should be considered in ICP indication, as in adult guidelines.

Abnormal movements associated with oropharyngeal dysfunction in a child with Chiari I malformation.

BACKGROUND: Chiari I malformations (CM I) are rare hindbrain herniations. Dysphagia and other oropharyngeal dysfunctions may be associated with CM I, but to our knowledge, no clinical presentation similar to ours has ever been reported. The purpose of this communication is to draw attention to a unique and atypical clinical presentation of a child with CM I. CASE PRESENTATION: A 7-year-old boy was evaluated for a two month history of atypical movements which would occur in the evening, and last for an hour after eating. These stereotypical movements with the head and chest bending forward and to the left side, accompanied by a grimace, were associated with sensation of breath locking without cyanosis. Pain and dysphagia were absent. The neurological examination was normal. The possibility of Sandifer syndrome posturing occurring with gastroesophageal reflux disease was considered but neither pain nor back hyperextension were associated with the atypical movements. Neither proton pump inhibitors (PPI) nor prokinetic agents improved his symptoms. Upper endoscopy and esophageal biopsy did not reveal eosinophilic esophagitis nor reflux esophagitis. Ear, throat and nose (ENT) exam was normal. A severe gastroparesis was demonstrated on milk scan study. Two 24 hour oesophageal pH probe studies pointed out severe gastroesophageal reflux (GER). High resolution manometric evaluation of the oesophagus revealed normal sphincter pressures and relaxations with no dysmotility of the esophageal body. Electroencephalography and polysomnography were normal. A brain magnetic resonance imaging (MRI) was performed and revealed a CM I: cerebellar tonsils extending to 12 mm, with syringomyelia (D4-D5). For a long period of time, the child's abnormal movements were considered to be nothing but tics and the CM I a fortuitous finding. Since the child remained symptomatic despite medical treatment, it was decided to proceed with surgery. One year after the onset of his symptoms, he underwent posterior fossa decompression with upper cervical laminectomy and expansion duroplasty. Postoperative MRI confirmed adequate decompression. His atypical posture and dyspnea completely resolved after surgery and he remains asymptomatic two years later. CONCLUSION: Children may have atypical presentations of CM I. Thus, CM I diagnosis should be considered in unexplained atypical oropharyngeal dysfunctions.

Minimal access to deep intracranial lesions using a serial dilatation technique: case-series and review of brain tubular retractor systems.

Surgical access to deep intracranial lesions causing the least amount of iatrogenic trauma to the surrounding brain tissue remains a challenging task. In this article, we evaluate the use of a set of sequential tubes that dilate and provide retraction of the overlying brain tissue acting as a surgical corridor for deep-seated brain lesions resection. In addition, we conducted a comprehensive review of the literature of previously described techniques using variable brain tubular retractor systems. We discuss the adaptation of a system designed for spinal use to intracranial pathologies and evaluate the outcomes for the patients involved in the study. Moreover, the advantages and limitations of the described technique were presented. Between August 2005 and 2011, a total of 30 patients with deep brain lesions were operated on using an incremental increase of tubing size for brain retraction guided by a frameless navigation device. Of these, seven cases were intraventricular, and 23 were intraparenchymal. Gross total resection was achieved in 70 % of cases, and the remaining had planned subtotal resections due to involvement of an eloquent area. In conclusion, the technique of serial dilatation of the brain tissue can be used in conjunction with a microscope or endoscope to provide satisfactory access to deep intracranial pathologies. It appears to minimize the associated retraction injury to the surrounding tissue by gradually dilating the white fiber tracts. This operative approach may be considered as an effective and safe alternative for brain tumor resections in selected cases, especially deep-seated lesions.

The combination of subdural and depth electrodes for intracranial EEG investigation of suspected insular (perisylvian) epilepsy.

PURPOSE: We present two methods of implantation for the investigation of suspected insular and perisylvian epilepsy that combine depth and subdural electrodes to capitalize on the advantages of each technique. METHODS: Retrospective study of all intracranial EEG studies that included insular electrodes from 2004-2010. Patients were divided according to the implantation scheme. The first method (type 1) consisted of a craniotomy, insertion of insular electrodes after microdissection of the sylvian fissure, orthogonal implantation of mesiotemporal structures with neuronavigation, and coverage of the adjacent lobes with subdural electrodes. The second method (type 2) consisted of magnetic resonance imaging (MRI)-stereotactic frame-guided depth electrode implantation into insula and hippocampus using sagittal axes, and insertion of subdural electrodes through burr holes to cover the adjacent lobes. The combined implantations were developed and performed by one neurosurgeon (AB). KEY FINDINGS: Nineteen patients had an intracranial study that sampled the insula, among other regions. Sixteen patients were implanted using the first method, which allowed a mean of 4, 5, 20, 15, and 42 contacts per patient to be positioned into/over the insular, mesial temporal, neocortical temporal, parietal, and frontal areas, respectively. The second method (three patients) allowed a mean of 8, 7, 16, 6, and 9 contacts per patient to sample the same areas, respectively. The four patients in whom transient neurologic deficits occurred were investigated with use of type 1 implantation. SIGNIFICANCE: Combined depth and subdural electrodes can be used safely to investigate complex insular/perisylvian refractory epilepsy. Choice of implantation scheme should be individualized according to presurgical data and the need for functional localization.

Trauma association of Canada Pediatric Subcommittee National Pediatric Cervical Spine Evaluation Pathway: consensus guidelines.

BACKGROUND: The Institute of Medicine calls for the use of clinical guidelines and practice parameters to promote "best practices" and improve patient outcomes. In 2006, The Trauma Association of Canada Pediatric Committee set out to create an evidence-based, national pediatric cervical spine (c-spine) clearance guideline based on the literature, existing algorithms from each pediatric trauma center and from expert opinion from across Canada. METHODS: A review of the literature took place in September 2006 using the PubMed database. Search criteria were "cervical spine," "c-spine," "clearance," and "trauma." Limits that were applied were "Languages: English," "Humans," "Type of Article: Meta-Analysis, Practice Guidelines, Randomized Control Trial, Review," and "Ages: all child 0-18 years." These search criteria were repeated in December 2007, April 2009, and October 2009. A total of 248 articles were identified. Existing guidelines were identified and their practices examined as models of care. Two draft guidelines were created for discussion: one for the pediatric patient with a reliable clinical examination and the other for the pediatric patient with an unreliable clinical examination. Via email, telephone, and two national videoconferences, the content of the guidelines was reviewed, discussed, and amended. The final article was prepared and circulated for author input until consensus was reached. RESULTS: A consensus was reached on two pathways to evaluate the pediatric cervical spine: a patient with a reliable clinical examination and a patient with an unreliable examination. CONCLUSION: Presented herein are the consensus Trauma Association of Canada, National Pediatric Cervical Spine Evaluation Pathways for the patient with a reliable clinical examination, and the patient with and unreliable clinical examination.

Moyamoya-like vasculopathy and Seckel syndrome: just a coincidence?

INTRODUCTION: Seckel syndrome (SS) and other microcephalic primordial dwarfisms (MPDs) are a group of autosomal recessive disorders characterized by prenatal and postnatal growth retardation, microcephaly, and distinct facial dysmorphic features. There are an increasing number of reports in the literature linking MPDs with cerebrovascular anomalies, including intracranial aneurysms and moyamoya. CASE REPORT: An 18-year-old female patient with SS and mental retardation was referred for spontaneous subarachnoid hemorrhage. At the age of 3 years, she had suffered multifocal ischemic cerebrovascular accidents following an elective urological procedure. Cardiac, hematologic, and serologic workups were negative, and cerebral angiography was recommended but declined by the parents. Brain MRA and cerebral angiography showed bilateral narrowing of extracranial and intracranial internal carotid arteries (ICAs), obliteration of the right supraclinoid ICA without moya-moya collaterals, and multiple bilateral saccular aneurysms on the hypertrophied posterior cerebral arteries. Considering the patient's previous quality of life and the high risks of either endovascular or surgical treatment, all invasive treatments were withheld at the parents' request and only palliative care was offered. CONCLUSION: It appears that patients with MPD are prone to the development of cerebrovascular anomalies. Therefore, imaging of cerebral vessels should be performed when such patients present with cerebral ischemia or stroke.

Stalled developmental programs at the root of pediatric brain tumors.

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.

Ventricular catheter tack-down screw.

The frequent need for revision of ventriculoperitoneal shunts particularly in the pediatric population is a well-known complication of the procedure. A not infrequent etiology demanding revision is the dislodgement of the catheter, particularly, in our experience, with posterior fossa shunts. Suturing the shunt to the periosteum is a common practice amongst pediatric neurosurgeons. We describe a novel technique of fastening the reservoir directly to the skull with the aid of titanium screws providing a more secure attachment and potentially reducing the number of subsequent revisions related to proximal end displacement.