Louis Crevier

Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Minimally invasive approach for the resection of spinal neoplasm.

Study Design. Retrospective Case Series. Objective. To determine if extradural, intradural extramedullary, and intramedullary spinal neoplasms can be safely resected through a minimally invasive corridor. Summary of Background Data. The use of minimally invasive approaches for resection of spinal neoplasms has been described for intradural schwannomas and ependymomas. We demonstrate that this approach can be extended to the resection of a variety of extradural, intradural and intramedullary spinal tumors. Methods. We undertook a retrospective review of all patients presenting with clinical and radiographic evidence of spinal neoplasm that subsequently underwent a minimally invasive approach for resection of the tumor using the METRx MAST QUADRANT Retractor System (Medtronics, Memphis, TN). Primary endpoints analyzed include completeness of resection, postoperative neurologic status, operative time, blood loss, postoperative pain, length of hospital stay, and operative complications. Results. Two cervical, seven thoracic and 13 lumbar neoplasms were identified in 20 patients operated on between September 2005 and May 2009. Mean intraoperative time was 210 minutes, blood loss 428 mL and average length of hospital stay was 3 days. Four patients required postoperative patient-controlled analgesia for pain control and an average of 5.8 doses of narcotic were given per patient. Two patients developed postoperative complications. Fifteen of 22 tumors (68%) were completely resected, with only one patient requiring repeat operation for residual tumor. All but one patient were improved from preoperative status at 6 months. Conclusion. Intramedullary, intradural and extradural spinal neoplasms can be resected through a minimally invasive approach without increased risk for adverse neurologic outcome. This technique may be an appropriate alternative to the open approach for well-circumscribed extramedullary lesions spanning one or two spinal levels. With increasing experience, reduced operative time, blood loss, complications, length of hospital stay, postoperative pain, and spinal instability may be seen.

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.

Interventions provided in the acute phase for mild traumatic brain injury: a systematic review

BackgroundMost patients who sustain mild traumatic brain injury (mTBI) have persistent symptoms at 1 week and 1 month after injury. This systematic review investigated the effectiveness of interventions initiated in acute settings for patients who experience mTBI.MethodsWe performed a systematic review of all randomized clinical trials evaluating any intervention initiated in an acute setting for patients experiencing acute mTBI. All possible outcomes were included. The primary sources of identification were MEDLINE, Embase, PsycINFO, CINAHL, and the Cochrane Central register of Controlled Trials, from 1980 to August 2012. Hand searching of proceedings from five meetings related to mTBI was also performed. Study selection was conducted by two co-authors, and data abstraction was completed by a research assistant specialized in conducting systematic reviews. Study quality was evaluated using Cochrane’s Risk of Bias assessment tool.ResultsFrom a potential 15,156 studies, 1,268 abstracts were evaluated and 120 articles were read completely. Of these, 15 studies fulfilled the inclusion/exclusion criteria. One study evaluated a pharmacological intervention, two evaluated activity restriction, one evaluated head computed tomography scan versus admission, four evaluated information interventions, and seven evaluated different follow-up interventions. Use of different outcome measures limited the possibilities for analysis. However, a meta-analysis of three studies evaluating various follow-up strategies versus routine follow-up or no follow-up failed to show any effect on three outcomes at 6 to 12 months post-trauma. In addition, a meta-analysis of two studies found no effect of an information intervention on headache at 3 months post-injury.ConclusionsThere is a paucity of well-designed clinical studies for patients who sustain mTBI. The large variability in outcomes measured in studies limits comparison between them.

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%.

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.

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.

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.

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.

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.