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.

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.

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.

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.

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.

Dissecting spontaneous cerebrospinal fluid collection.

Hydrocephalus is a common condition in the pediatric population known to have many causes and presentation patterns. We report from the analysis of 2 cases the existence of a new complication of pediatric hydrocephalus. Naming this entity "dissecting intraparenchymal cerebrospinal fluid collection", we advance a hypothesis regarding its pathophysiology and discuss its clinical implications and management.

The importance of extent of choroid plexus cauterization in addition to endoscopic third ventriculostomy for infantile hydrocephalus: a retrospective North American observational study using propensity score-adjusted analysis.

OBJECTIVE Combined endoscopic third ventriculostomy (ETC) and choroid plexus cauterization (CPC)-ETV/CPC- is being investigated to increase the rate of shunt independence in infants with hydrocephalus. The degree of CPC necessary to achieve improved rates of shunt independence is currently unknown. METHODS Using data from a single-center, retrospective, observational cohort study involving patients who underwent ETV/CPC for treatment of infantile hydrocephalus, comparative statistical analyses were performed to detect a difference in need for subsequent CSF diversion procedure in patients undergoing partial CPC (describes unilateral CPC or bilateral CPC that only extended from the foramen of Monro [FM] to the atrium on one side) or subtotal CPC (describes CPC extending from the FM to the posterior temporal horn bilaterally) using a rigid neuroendoscope. Propensity scores for extent of CPC were calculated using age and etiology. Propensity scores were used to perform 1) case-matching comparisons and 2) Cox multivariable regression, adjusting for propensity score in the unmatched cohort. Cox multivariable regression adjusting for age and etiology, but not propensity score was also performed as a third statistical technique. RESULTS Eighty-four patients who underwent ETV/CPC had sufficient data to be included in the analysis. Subtotal CPC was performed in 58 patients (69%) and partial CPC in 26 (31%). The ETV/CPC success rates at 6 and 12 months, respectively, were 49% and 41% for patients undergoing subtotal CPC and 35% and 31% for those undergoing partial CPC. Cox multivariate regression in a 48-patient cohort case-matched by propensity score demonstrated no added effect of increased extent of CPC on ETV/CPC survival (HR 0.868, 95% CI 0.422-1.789, p = 0.702). Cox multivariate regression including all patients, with adjustment for propensity score, demonstrated no effect of extent of CPC on ETV/CPC survival (HR 0.845, 95% CI 0.462-1.548, p = 0.586). Cox multivariate regression including all patients, with adjustment for age and etiology, but not propensity score, demonstrated no effect of extent of CPC on ETV/CPC survival (HR 0.908, 95% CI 0.495-1.664, p = 0.755). CONCLUSIONS Using multiple comparative statistical analyses, no difference in need for subsequent CSF diversion procedure was detected between patients in this cohort who underwent partial versus subtotal CPC. Further investigation regarding whether there is truly no difference between partial versus subtotal extent of CPC in larger patient populations and whether further gain in CPC success can be achieved with complete CPC is warranted.

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.

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.

Ondansetron for pediatric concussion; a pilot study for a randomized controlled trial.

OBJECTIVES: Assess the feasibility of a study evaluating one dose of oral ondansetron to decrease post-concussion symptoms at one week and one month following concussion in children aged 8 to 17 years old. METHOD: This was a pilot study for a randomized, triple-blind controlled trial of one dose of either ondansetron or placebo performed in a tertiary care pediatric emergency department. Participants were children aged 8 to 17 years who sustained a concussion in the previous 24 hours and visited a single emergency department. The outcome of interest was an increase from pre-concussion baseline of at least 3 symptoms from the Post-Concussion Symptom Inventory, measured at one week and at one month following concussion. The primary outcome was to determine the proportion of children who completed the assessment at one week following the intervention. Secondary outcome was the proportion of children who completed the assessment at one month following the intervention. All children, care givers, and those assessing the outcomes were blinded to the group assignment. RESULTS: Of the 218 children presenting with a concussion during the study period, we screened 108 and found 36/108 (33%) eligible to participate and 16/108 (14.8%) agreed to participate. All enrolled patients were compliant with the intervention and follow-up. CONCLUSION: In our study population, approximately one-third of the screened concussion patients were eligible to participate and approximately one half of those eligible agreed to participate. Our study found that most enrolled patients preferred electronic follow-up; the noncompliance rate was minimal.

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.

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.

Management of skull fractures in children less than 1 year of age.

BACKGROUND: Management of skull fracture (SF) in pediatric patients varies from observation in the emergency department (ED) to floor admission. Since 2010, a protocol for admitting children with SF specifically to the trauma service was implemented at our institution. The purpose of our study was to review the management of children with SF younger than 1 year of age. METHODS: Retrospective chart review of all patients between 0 and 1year of age seen in our ED for a SF was done from 2010 to 2013. RESULTS: A total of 180 patients with a mean age of 4.5months (1day-12months) were identified. Of these, 131 patients (73%) were admitted. Mean length of stay was 1.6days. Admitted patients had more depressed (21 vs. 8%) and diastatic (43 vs. 14%) fractures. Fifty-seven children had intracranial hemorrhages (32%) but only 8 patients required non-emergent surgery for depressed fractures. Admission to the trauma service increased from none to 76% with phone follow-ups increasing from 12% to 91%. CONCLUSIONS: Instituting a protocol allowed a safer management of patients with SF. Moreover, we argue that asymptomatic infants with isolated SF can be safely discharged home after brief observation in the ED.

Association of postoperative furosemide use with a reduced blood transfusion rate in sagittal craniosynostosis surgery.

OBJECT A major challenge in sagittal craniosynostosis surgery is the high transfusion rate (50%-100%) related to blood loss in small pediatric patients. Several approaches have been proposed to prevent packed red blood cell (PRBC) transfusion, including endoscopic surgery, erythropoietin ortranexamic acid administration, and preoperative hemodilution. The authors hypothesized that a significant proportion of postoperative anemia observed in pediatric patients is actually dilutional. Consequently, since 2005, at CHU Sainte-Justine, furosemide has been administered to correct the volemic status and prevent PRBC transfusion. The purpose of this study was to evaluate the impact of postoperative furosemide administration on PRBC transfusion rates. METHODS This was a retrospective study of 96 consecutive patients with sagittal synostosis who underwent surgery at CHU Sainte-Justine between January 2000 and May 2012. The mean age at surgery was 4.9 ± 1.5 months (range 2.8-8.7 months). Patients who had surgery before 2005 constituted the control group. Those who had surgery in 2005 or 2006 were considered part of an implementation phase because furosemide administration was not routine. Patients who had surgery after 2006 were part of the experimental (or furosemide) group. Transfusion rates among the 3 groups were compared. The impact of furosemide administration on transfusion requirement was also measured while accounting for other variables of interest in a multiple logistic regression model. RESULTS The total transfusion rate was significantly reduced in the furosemide group compared with the control group (31.3% vs 62.5%, respectively; p = 0.009), mirroring the decrease in the postoperative transfusion rate between the groups (18.3% vs 50.0%, respectively; p = 0.003). The postoperative transfusion threshold remained similar throughout the study (mean hemoglobin 56.0 g/dl vs 60.9 g/dl for control and furosemide groups, respectively; p = 0.085). The proportion of nontransfused patients with recorded hemoglobin below 70 g/dl did not differ between the control and furosemide groups (41.7% vs 28.6%, respectively; p = 0.489). Surgical procedure, preoperative hemoglobin level, estimated blood loss, and furosemide administration significantly affected the risk of receiving a postoperative PRBC transfusion. When these variables were analyzed in a multiple logistic regression model, furosemide administration remained strongly associated with a reduced risk of being exposed to a blood transfusion (OR 0.196, p = 0.005). There were no complications related to furosemide administration. CONCLUSIONS A significant part of the postoperative anemia observed in patients who underwent sagittal craniosynostosis surgery was due to hypervolemic hemodilution. Correction of the volemic status with furosemide administration significantly reduces postoperative PRBC transfusion requirements in these patients.

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.