Autologous bone marrow mononuclear cells to treat severe traumatic brain injury in children.

Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.

Epithelioid neoplasm of the spinal cord in a child with spinal muscular atrophy treated with onasemnogene abeparvovec.

Spinal muscular atrophy is an autosomal recessive disease resulting in motor neuron degeneration and progressive life-limiting motor deficits when untreated. Onasemnogene abeparvovec is an adeno-associated virus serotype 9-based gene therapy that improves survival, motor function, and motor milestone achievement in symptomatic and presymptomatic patients. Although the adeno-associated virus genome is maintained as an episome, theoretical risk of tumorigenicity persists should genomic insertion occur. We present the case of a 16-month-old male with spinal muscular atrophy who was diagnosed with an epithelioid neoplasm of the spinal cord approximately 14 months after receiving onasemnogene abeparvovec. In situ hybridization analysis detected an onasemnogene abeparvovec nucleic acid signal broadly distributed in many but not all tumor cells. Integration site analysis on patient formalin-fixed, paraffin-embedded tumor samples failed to detect high-confidence integration sites of onasemnogene abeparvovec. The finding was considered inconclusive because of limited remaining tissue/DNA input. The improved life expectancy resulting from innovative spinal muscular atrophy therapies, including onasemnogene abeparvovec, has created an opportunity to analyze the long-term adverse events and durability of these therapies as well as identify potential disease associations that were previously unrecognized because of the premature death of these patients.

Pediatric Moyamoya Revascularization Perioperative Care: A Modified Delphi Study.

BACKGROUND: Surgical revascularization decreases the long-term risk of stroke in children with moyamoya arteriopathy but can be associated with an increased risk of stroke during the perioperative period. Evidence-based approaches to optimize perioperative management are limited and practice varies widely. Using a modified Delphi process, we sought to establish expert consensus on key components of the perioperative care of children with moyamoya undergoing indirect revascularization surgery and identify areas of equipoise to define future research priorities. METHODS: Thirty neurologists, neurosurgeons, and intensivists practicing in North America with expertise in the management of pediatric moyamoya were invited to participate in a three-round, modified Delphi process consisting of a 138-item practice patterns survey, anonymous electronic evaluation of 88 consensus statements on a 5-point Likert scale, and a virtual group meeting during which statements were discussed, revised, and reassessed. Consensus was defined as ≥ 80% agreement or disagreement. RESULTS: Thirty-nine statements regarding perioperative pediatric moyamoya care for indirect revascularization surgery reached consensus. Salient areas of consensus included the following: (1) children at a high risk for stroke and those with sickle cell disease should be preadmitted prior to indirect revascularization; (2) intravenous isotonic fluids should be administered in all patients for at least 4 h before and 24 h after surgery; (3) aspirin should not be discontinued in the immediate preoperative and postoperative periods; (4) arterial lines for blood pressure monitoring should be continued for at least 24 h after surgery and until active interventions to achieve blood pressure goals are not needed; (5) postoperative care should include hourly vital signs for at least 24 h, hourly neurologic assessments for at least 12 h, adequate pain control, maintaining normoxia and normothermia, and avoiding hypotension; and (6) intravenous fluid bolus administration should be considered the first-line intervention for new focal neurologic deficits following indirect revascularization surgery. CONCLUSIONS: In the absence of data supporting specific care practices before and after indirect revascularization surgery in children with moyamoya, this Delphi process defined areas of consensus among neurosurgeons, neurologists, and intensivists with moyamoya expertise. Research priorities identified include determining the role of continuous electroencephalography in postoperative moyamoya care, optimal perioperative blood pressure and hemoglobin targets, and the role of supplemental oxygen for treatment of suspected postoperative ischemia.

Cerebral revascularization surgery reduces cerebrovascular events in children with sickle cell disease and moyamoya syndrome: Results of the stroke in sickle cell revascularization surgery retrospective study.

BACKGROUND: Recent studies suggest that cerebral revascularization surgery may be a safe and effective therapy to reduce stroke risk in patients with sickle cell disease and moyamoya syndrome (SCD-MMS). METHODS: We performed a multicenter, retrospective study of children with SCD-MMS treated with conservative management alone (conservative group)-chronic blood transfusion and/or hydroxyurea-versus conservative management plus surgical revascularization (surgery group). We monitored cerebrovascular event (CVE) rates-a composite of strokes and transient ischemic attacks. Multivariable logistic regression was used to compare CVE occurrence and multivariable Poisson regression was used to compare incidence rates between groups. Covariates in multivariable models included age at treatment start, age at moyamoya diagnosis, antiplatelet use, CVE history, and the risk period length. RESULTS: We identified 141 patients with SCD-MMS, 78 (55.3%) in the surgery group and 63 (44.7%) in the conservative group. Compared with the conservative group, preoperatively the surgery group had a younger age at moyamoya diagnosis, worse baseline modified Rankin scale scores, and increased prevalence of CVEs. Despite more severe pretreatment disease, the surgery group had reduced odds of new CVEs after surgery (odds ratio = 0.27, 95% confidence interval [CI] = 0.08-0.94, p = .040). Furthermore, comparing surgery group patients during presurgical versus postsurgical periods, CVEs odds were significantly reduced after surgery (odds ratio = 0.22, 95% CI = 0.08-0.58, p = .002). CONCLUSIONS: When added to conservative management, cerebral revascularization surgery appears to reduce the risk of CVEs in patients with SCD-MMS. A prospective study will be needed to validate these findings.

Using Billing Codes to Create a Pediatric Functional Status e-Score for Children Receiving Inpatient Rehabilitation.

OBJECTIVE: Provide proof-of-concept for development of a Pediatric Functional Status eScore (PFSeS). Demonstrate that expert clinicians rank billing codes as relevant to patient functional status and identify the domains that codes inform in a way that reliably matches analytical modeling. DESIGN: Retrospective chart review, modified Delphi, and nominal group techniques. SETTING: Large, urban, quaternary care children's hospital in the Midwestern United States. PARTICIPANTS: Data from 1955 unique patients and 2029 hospital admissions (2000-2020); 12 expert consultants representing the continuum of rehabilitation care reviewed 2893 codes (procedural, diagnostic, pharmaceutical, durable medical equipment). MAIN OUTCOME MEASURES: Consensus voting to determine whether codes were associated with functional status at discharge and, if so, what domains they informed (self-care, mobility, cognition/ communication). RESULTS: The top 250 and 500 codes identified by statistical modeling were mostly composed of codes selected by the consultant panel (78%-80% of the top 250 and 71%-78% of the top 500). The results provide evidence that clinical experts' selection of functionally meaningful codes corresponds with codes selected by statistical modeling as most strongly associated with WeeFIM domain scores. The top 5 codes most strongly related to functional independence ratings from a domain-specific assessment indicate clinically sensible relationships, further supporting the use of billing data in modeling to create a PFSeS. CONCLUSIONS: Development of a PFSeS that is predicated on billing data would improve researchers' ability to assess the functional status of children who receive inpatient rehabilitation care for a neurologic injury or illness. An expert clinician panel, representing the spectrum of medical and rehabilitative care, indicated that proposed statistical modeling identifies relevant codes mapped to 3 important domains: self-care, mobility, and cognition/communication.

Current evidence for pharmacological management of pediatric concussion: a systematic review.

PURPOSE: Mild traumatic brain injury (mTBI) is a global public health problem and its current management is limited to rest and symptom management. Despite frequent use of drugs for symptom control, there is a lack of consensus on the optimal pharmacological management of post-concussive symptoms. We reviewed the relevant literature to compile the evidence about the pharmaceutical management of pediatric mTBI. METHODS: We performed a systematic review of the literature available in PubMed, Cochrane CENTRAL, and ClinicalTrials.Gov as well as through citation tracing. A modified PICO framework was used for the construction of search strategy and eligibility criteria. Risk of bias was assessed using RoB-2 tool for randomized and ROBINS-I for non-randomized studies. RESULTS: A total of 6260 articles were screened for eligibility. After exclusions, a total of 88 articles received full text review. A total of 15 reports representing 13 studies (5 randomized clinical trials, 1 prospective randomized cohort study, 1 prospective cohort study, and 6 retrospective cohort studies) met the eligibility criteria and were included in the review. We identified 16 pharmacological interventions in a total of 931 pediatric patients with mTBI. Amytriptiline (n = 4), ondansetron (n = 3), melatonin (n = 3), metoclopramide (n = 2), magnesium (n = 2), and topiramate (n = 2) were investigated in multiple studies. All RCTs were relatively of small size (n ≤ 33/group). CONCLUSION: The available evidence supporting pharmacological intervention in pediatric mild traumatic brain injury is scarce. We propose a framework to facilitate future collaborative research efforts to test and validate various pharmacological interventions for acute and persistent post-concussive symptoms in children.

Early Electroencephalographic Features Predicting Cerebral Physiology and Functional Outcomes After Pediatric Traumatic Brain Injury.

BACKGROUND: We investigated whether early electroencephalographic features predicted intracranial pressure (ICP), cerebrovascular pressure reactivity, brain tissue oxygenation, and functional outcomes in patients with pediatric traumatic brain injury (TBI). METHODS: This was a retrospective analysis of a prospective data set of 63 patients with pediatric TBI. Electroencephalographic features were collected in the first 24 h of recording to predict values of ICP, pressure reactivity index (PRx), and brain tissue oxygenation (PbtO2) through the initial 7 days of critical care monitoring, in addition to Glasgow Outcome Scale Extended-Pediatric Revision (GOSE-Peds) scores at 12 months. Electroencephalographic features were averaged over all surface electrodes and included seizures, interictal epileptiform discharges, suppression percentage, complexity, the alpha/delta power ratio, and both absolute asymmetry indices and power in beta (13-20 Hz), alpha (8-13 Hz), theta (4-7 Hz) and delta (0-4 Hz) bands. Demographic data and injury severity scores, such as the Glasgow Coma Scale (GCS) and Pediatric Risk of Mortality III (PRISM III) scores, at presentation were also assessed. Univariate and multiple linear regression with guided stepwise variable selection was used to find combinations of risk factors that best explain variability in ICP, PRx, PbtO2, and GOSE-Peds values, and best fit models were applied to pediatric age strata. We hypothesized that suppression percentage and the alpha/delta power ratio in the first 24 h of recording predict ICP, PRx, PbtO2, and GOSE-Peds values. RESULTS: Best subset model selection identified that increased suppression percentage and PRISM III scores predicted increased ICP (R2 = 79%, Akaike information criterion [AIC] = 332.30, root mean square error [RMSE] = 6.62), with suppression percentages < 5% (slope = - 5687.0, p = 0.0001) and ≥ 45% (slope = 9825.9, p = 0.0000) being predictive of dose of intracranial hypertension. When accounting for age and GCS score, increased suppression percentage predicted increased PRx values, suggestive of inefficient cerebrovascular pressure reactivity (R2 = 53%, AIC = 3.93, RMSE = 0.23), with suppression percentages ≥ 5% (p = 0.0033) and ≥ 45% (p = 0.0027) being predictive of median PRx values ≥ 0.3. Lower GCS scores, the presence of seizures, and increased suppression percentages each were independently associated with higher GOSE-Peds scores (R2 = 52%, AIC = 194.04, RMSE = 1.58), suggestive of unfavorable outcomes, with suppression percentages ≥ 5% (p = 0.0005) and ≥ 45% (p = 0.0000) being predictive of GOSE-Peds scores ≥ 5. At the univariate level, no electroencephalographic or clinical feature was associated with differences in PbtO2 values. CONCLUSIONS: Increased electroencephalographic suppression percentage on the initial day of monitoring may identify patients with pediatric TBI at risk of increased ICP, inefficient cerebrovascular pressure reactivity, and unfavorable outcomes.

Responsive neurostimulation in pediatric patients with drug-resistant epilepsy.

OBJECTIVE: Medically refractory epilepsy remains a therapeutic challenge when resective surgery is not a practical option and indirect neurostimulation efficacy may be limited. In these instances responsive neurostimulation (RNS) has been used in adults, with good outcomes in most patients. However, the utility of RNS in children and young adults has not been systematically explored. In this study, the authors present a single institution's experience with RNS in pediatric patients. METHODS: A single-center retrospective chart review of patients who underwent RNS implantation at Phoenix Children's Hospital during the 4-year period between January 2018 and December 2021 was performed. RESULTS: Following evaluation for epilepsy surgery, 22 patients underwent RNS implantation using different anatomical targets depending on the predetermined epileptic focus/network. In the cohort, 59% of patients were male, the mean age at implantation was 16.4 years (range 6-22 years), and the mean follow-up time was 2.7 years (range 1.0-4.3 years). All patients had a preoperative noninvasive evaluation that included MRI, video-electroencephalography, and resting-state functional MRI. Additionally, 13 patients underwent invasive monitoring with stereo-electroencephalography to help determine RNS targets. All patients had variable positive responses with reduction of seizure frequency and/or intensity. Overall, seizure frequency reduction of > 50% was seen in the majority (86%) of patients. There were two complications: one patient experienced transitory weakness and one generator failed, requiring replacement. A patient died of sudden unexpected death in epilepsy 3 years after implantation despite being seizure free during the previous year. CONCLUSIONS: RNS used in children with medically refractory epilepsy improved seizure control after implantation, with decreases in seizure frequency > 50% from preoperative baseline in the majority of patients. Preliminary findings indicate that functional MRI and stereo-electroencephalography were helpful for RNS targeting and that RNS can be used safely even in young children.

Effect of Implementing the Out-of-Hospital Traumatic Brain Injury Treatment Guidelines: The Excellence in Prehospital Injury Care for Children Study (EPIC4Kids).

STUDY OBJECTIVE: We evaluate the effect of implementing the out-of-hospital pediatric traumatic brain injury guidelines on outcomes in children with major traumatic brain injury. METHODS: The Excellence in Prehospital Injury Care for Children study is the preplanned secondary analysis of the Excellence in Prehospital Injury Care study, a multisystem, intention-to-treat study using a before-after controlled design. This subanalysis included children younger than 18 years who were transported to Level I trauma centers by participating out-of-hospital agencies between January 1, 2007, and June 30, 2015, throughout Arizona. The primary and secondary outcomes were survival to hospital discharge or admission for children with major traumatic brain injury and in 3 subgroups, defined a priori as those with moderate, severe, and critical traumatic brain injury. Outcomes in the preimplementation and postimplementation cohorts were compared with logistic regression, adjusting for risk factors and confounders. RESULTS: There were 2,801 subjects, 2,041 in preimplementation and 760 in postimplementation. The primary analysis (postimplementation versus preimplementation) yielded an adjusted odds ratio of 1.16 (95% confidence interval 0.70 to 1.92) for survival to hospital discharge and 2.41 (95% confidence interval 1.17 to 5.21) for survival to hospital admission. In the severe traumatic brain injury cohort (Regional Severity Score-Head 3 or 4), but not the moderate or critical subgroups, survival to discharge significantly improved after guideline implementation (adjusted odds ratio = 8.42; 95% confidence interval 1.01 to 100+). The improvement in survival to discharge among patients with severe traumatic brain injury who received positive-pressure ventilation did not reach significance (adjusted odds ratio = 9.13; 95% confidence interval 0.79 to 100+). CONCLUSION: Implementation of the pediatric out-of-hospital traumatic brain injury guidelines was not associated with improved survival when the entire spectrum of severity was analyzed as a whole (moderate, severe, and critical). However, both adjusted survival to hospital admission and discharge improved in children with severe traumatic brain injury, indicating a potential severity-based interventional opportunity for guideline effectiveness. These findings support the widespread implementation of the out-of-hospital pediatric traumatic brain injury guidelines.

Assessment of primary outcome measures for a clinical trial of pediatric hemorrhagic injuries.

OBJECTIVE: We evaluated the acceptability of the Pediatric Quality of Life Inventory (PedsQL) and other outcomes as the primary outcomes for a pediatric hemorrhagic trauma trial (TIC-TOC) among clinicians. METHODS: We conducted a mixed-methods study that included an electronic questionnaire followed by teleconference discussions. Participants confirmed or rejected the PedsQL as the primary outcome for the TIC-TOC trial and evaluated and proposed alternative primary outcomes. Responses were compiled and a list of themes and representative quotes was generated. RESULTS: 73 of 91 (80%) participants completed the questionnaire. 61 (84%) participants agreed that the PedsQL is an appropriate primary outcome for children with hemorrhagic brain injuries. 32 (44%) participants agreed that the PedsQL is an acceptable primary outcome for children with hemorrhagic torso injuries, 27 (38%) participants were neutral, and 13 (18%) participants disagreed. Several themes were identified from responses, including that the PedsQL is an important and patient-centered outcome but may be affected by other factors, and that intracranial hemorrhage progression assessed by brain imaging (among patients with brain injuries) or blood product transfusion requirements (among patients with torso injuries) may be more objective outcomes than the PedsQL. CONCLUSIONS: The PedsQL was a well-accepted proposed primary outcome for children with hemorrhagic brain injuries. Traumatic intracranial hemorrhage progression was favored by a subset of clinicians. A plurality of participants also considered the PedsQL an acceptable outcome for children with hemorrhagic torso injuries. Blood product transfusion requirement was favored by fewer participants.

Association of Outcomes with Model-Based Indices of Cerebral Autoregulation After Pediatric Traumatic Brain Injury.

BACKGROUND: We investigated whether model-based indices of cerebral autoregulation (CA) are associated with outcomes after pediatric traumatic brain injury. METHODS: This was a retrospective analysis of a prospective clinical database of 56 pediatric patients with traumatic brain injury undergoing intracranial pressure monitoring. CA indices were calculated, including pressure reactivity index (PRx), wavelet pressure reactivity index (wPRx), pulse amplitude index (PAx), and correlation coefficient between intracranial pressure pulse amplitude and cerebral perfusion pressure (RAC). Each CA index was used to compute optimal cerebral perfusion pressure (CPP). Time of CPP below lower limit of autoregulation (LLA) or above upper limit of autoregulation (ULA) were computed for each index. Demographic, physiologic, and neuroimaging data were collected. Primary outcome was determined using Pediatric Glasgow Outcome Scale Extended (GOSE-Peds) at 12 months, with higher scores being suggestive of unfavorable outcome. Univariate and multiple linear regression with guided stepwise variable selection was used to find combinations of risk factors that can best explain the variability of GOSE-Peds scores, and the best fit model was applied to the age strata. We hypothesized that higher GOSE-Peds scores were associated with higher CA values and more time below LLA or above ULA for each index. RESULTS: At the univariate level, CPP, dose of intracranial hypertension, PRx, PAx, wPRx, RAC, percent time more than ULA derived for PAx, and percent time less than LLA derived for PRx, PAx, wPRx, and RAC were all associated with GOSE-Peds scores. The best subset model selection on all pediatric patients identified that when accounting for CPP, increased dose of intracranial hypertension and percent time less than LLA derived for wPRx were independently associated with higher GOSE-Peds scores. Age stratification of the best fit model identified that in children less than 2 years of age or 8 years of age or more, percent time less than LLA derived for wPRx represented the sole independent predictor of higher GOSE-Peds scores when accounting for CPP and dose of intracranial hypertension. For children 2 years or younger to less than 8 years of age, dose of intracranial hypertension was identified as the sole independent predictor of higher GOSE-Peds scores when accounting for CPP and percent time less than LLA derived for wPRx. CONCLUSIONS: Increased dose of intracranial hypertension, PRx, wPRx, PAx, and RAC values and increased percentage time less than LLA based on PRx, wPRx, PAx, and RAC are associated with higher GOSE-Peds scores, suggestive of unfavorable outcome. Reducing intracranial hypertension and maintaining CPP more than LLA based on wPRx may improve outcomes and warrants prospective investigation.

Cerebrovascular Autoregulation Monitoring in the Management of Adult Severe Traumatic Brain Injury: A Delphi Consensus of Clinicians.

BACKGROUND: Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. AIM: To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. METHODS: A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. RESULTS: Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. CONCLUSION: The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.

Network-targeted approach and postoperative resting-state functional magnetic resonance imaging are associated with seizure outcome.

OBJECTIVE: Postoperative resting-state functional magnetic resonance imaging (MRI) in children with intractable epilepsy has not been quantified in relation to seizure outcome. Therefore, its value as a biomarker for epileptogenic pathology is not well understood. METHODS: In a sample of children with intractable epilepsy who underwent prospective resting-state seizure onset zone (SOZ)-targeted epilepsy surgery, postoperative resting-state functional MRI (rs-fMRI) was performed 6 to 12 months later. Graded normalization of the postoperative resting-state SOZ was compared to seizure outcomes, patient, surgery, and anatomical MRI characteristics. RESULTS: A total of 64 cases were evaluated. Network-targeted surgery, followed by postoperative rs-fMRI normalization was significantly (p < 0.001) correlated with seizure reduction, with a Spearman rank correlation coefficient of 0.83. Of 39 cases with postoperative rs-fMRI SOZ normalization, 38 (97%) became completely seizure free. In contrast, of the 25 cases without complete rs-fMRI SOZ normalization, only 3 (5%) became seizure free. The accuracy of rs-fMRI as a biomarker predicting seizure freedom is 94%, with 96% sensitivity and 93% specificity. INTERPRETATION: Among seizure localization techniques in pediatric epilepsy, network-targeted surgery, followed by postoperative rs-fMRI normalization, has high correlation with seizure freedom. This study shows that rs-fMRI SOZ can be used as a biomarker of the epileptogenic zone, and postoperative rs-fMRI normalization is a biomarker for SOZ quiescence. ANN NEUROL 2019;86:344-356.

Intracranial Electroencephalography in Pediatric Severe Traumatic Brain Injury.

OBJECTIVES: Electroencephalography is used in neurocritical care for detection of seizures and assessment of cortical function. Due to limited resolution from scalp electroencephalography, important abnormalities may not be readily detectable. We aimed to identify whether intracranial electroencephalography allows for improved methods of monitoring cortical function in children with severe traumatic brain injury. DESIGN: This is a retrospective cohort study from a prospectively collected clinical database. We investigated the occurrence rate of epileptiform abnormalities detected on intracranial electroencephalography when compared with scalp electroencephalography. We also investigated the strength of association of quantitative electroencephalographic parameters and cerebral perfusion pressure between both intracranial and scalp electroencephalography. SETTING: This is a single-institution study performed in the Phoenix Children's Hospital PICU. PATIENTS: Eleven children with severe traumatic brain injury requiring invasive neuromonitoring underwent implantation of a six-contact intracranial electrode as well as continuous surface electroencephalography. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Visual detection of epileptiform abnormalities was performed by pediatric epileptologists. Association of intracranial and scalp electroencephalography total power, alpha percentage, and alpha-delta power ratio to cerebral perfusion pressure was performed using univariate dynamic structural equations modeling. Demographic data were assessed by retrospective analysis. Intracranial and scalp electroencephalography was performed in 11 children. Three of 11 children had observed epileptiform abnormalities on intracranial electroencephalography. Two patients had epileptiform abnormalities identified exclusively on intracranial electroencephalography, and one patient had seizures initiating on intracranial electroencephalography before arising on scalp electroencephalography. Identification of epileptiform abnormalities was associated with subsequent identification of stroke or malignant cerebral edema. We observed statistically significant positive associations between intracranial alpha-delta power ratio to cerebral perfusion pressure in nine of 11 patients with increased strength of association on intracranial compared with scalp recordings. CONCLUSIONS: These findings suggest that intracranial electroencephalography may be useful for detection of secondary insult development in children with traumatic brain injury.

Management of Pediatric Severe Traumatic Brain Injury: 2019 Consensus and Guidelines-Based Algorithm for First and Second Tier Therapies.

OBJECTIVES: To produce a treatment algorithm for the ICU management of infants, children, and adolescents with severe traumatic brain injury. DATA SOURCES: Studies included in the 2019 Guidelines for the Management of Pediatric Severe Traumatic Brain Injury (Glasgow Coma Scale score ≤ 8), consensus when evidence was insufficient to formulate a fully evidence-based approach, and selected protocols from included studies. DATA SYNTHESIS: Baseline care germane to all pediatric patients with severe traumatic brain injury along with two tiers of therapy were formulated. An approach to emergent management of the crisis scenario of cerebral herniation was also included. The first tier of therapy focuses on three therapeutic targets, namely preventing and/or treating intracranial hypertension, optimizing cerebral perfusion pressure, and optimizing partial pressure of brain tissue oxygen (when monitored). The second tier of therapy focuses on decompressive craniectomy surgery, barbiturate infusion, late application of hypothermia, induced hyperventilation, and hyperosmolar therapies. CONCLUSIONS: This article provides an algorithm of clinical practice for the bedside practitioner based on the available evidence, treatment protocols described in the articles included in the 2019 guidelines, and consensus that reflects a logical approach to mitigate intracranial hypertension, optimize cerebral perfusion, and improve outcomes in the setting of pediatric severe traumatic brain injury.

Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary.

OBJECTIVES: The purpose of this work is to identify and synthesize research produced since the second edition of these Guidelines was published and incorporate new results into revised evidence-based recommendations for the treatment of severe traumatic brain injury in pediatric patients. METHODS AND MAIN RESULTS: This document provides an overview of our process, lists the new research added, and includes the revised recommendations. Recommendations are only provided when there is supporting evidence. This update includes 22 recommendations, nine are new or revised from previous editions. New recommendations on neuroimaging, hyperosmolar therapy, analgesics and sedatives, seizure prophylaxis, temperature control/hypothermia, and nutrition are provided. None are level I, three are level II, and 19 are level III. The Clinical Investigators responsible for these Guidelines also created a companion algorithm that supplements the recommendations with expert consensus where evidence is not available and organizes possible interventions into first and second tier utilization. The purpose of publishing the algorithm as a separate document is to provide guidance for clinicians while maintaining a clear distinction between what is evidence based and what is consensus based. This approach allows, and is intended to encourage, continued creativity in treatment and research where evidence is lacking. Additionally, it allows for the use of the evidence-based recommendations as the foundation for other pathways, protocols, or algorithms specific to different organizations or environments. The complete guideline document and supplemental appendices are available electronically from this journal. These documents contain summaries and evaluations of all the studies considered, including those from prior editions, and more detailed information on our methodology. CONCLUSIONS: New level II and level III evidence-based recommendations and an algorithm provide additional guidance for the development of local protocols to treat pediatric patients with severe traumatic brain injury. Our intention is to identify and institute a sustainable process to update these Guidelines as new evidence becomes available.

Initiating Nutritional Support Before 72 Hours Is Associated With Favorable Outcome After Severe Traumatic Brain Injury in Children: A Secondary Analysis of a Randomized, Controlled Trial of Therapeutic Hypothermia.

OBJECTIVES: To understand the relationship between the timing of initiation of nutritional support in children with severe traumatic brain injury and outcomes. DESIGN: Secondary analysis of a randomized, controlled trial of therapeutic hypothermia (Pediatric Traumatic Brain Injury Consortium: Hypothermia, also known as "the Cool Kids Trial" (NCT 00222742). SETTINGS: Fifteen clinical sites in the United States, Australia, and New Zealand. SUBJECTS: Inclusion criteria included 1) age less than 18 years, 2) postresuscitation Glasgow Coma Scale less than or equal to 8, 3) Glasgow Coma Scale motor score less than 6, and 4) available to be randomized within 6 hours after injury. Exclusion criteria included normal head CT, Glasgow Coma Scale equals to 3, hypotension for greater than 10 minutes (< fifth percentile for age), uncorrectable coagulopathy, hypoxia (arterial oxygen saturation < 90% for > 30 min), pregnancy, penetrating injury, and unavailability of a parent or guardian to consent at centers without emergency waiver of consent. INTERVENTIONS: Therapeutic hypothermia (32-33°C for 48 hr) followed by slow rewarming for the primary study. For this analysis, the only intervention was the extraction of data regarding nutritional support from the existing database. MEASUREMENTS AND MAIN RESULTS: Timing of initiation of nutritional support was determined and patients stratified into four groups (group 1-no nutritional support over first 7 d; group 2-nutritional support initiated < 48 hr after injury; group 3-nutritional support initiated 48 to < 72 hr after injury; group 4-nutritional support initiated 72-168 hr after injury). Outcomes were also stratified (mortality and Glasgow Outcomes Scale-Extended for Pediatrics; 1-4, 5-7, 8) at 6 and 12 months. Mixed-effects models were performed to define the relationship between nutrition and outcome. Children (n = 90, 77 randomized, 13 run-in) were enrolled (mean Glasgow Coma Scale = 5.8); the mortality rate was 13.3%. 57.8% of subjects received hypothermia Initiation of nutrition before 72 hours was associated with survival (p = 0.01), favorable 6 months Glasgow Outcomes Scale-Extended for Pediatrics (p = 0.03), and favorable 12 months Glasgow Outcomes Scale-Extended for Pediatrics (p = 0.04). Specifically, groups 2 and 3 had favorable outcomes versus group 1. CONCLUSIONS: Initiation of nutritional support before 72 hours after traumatic brain injury was associated with decreased mortality and favorable outcome in this secondary analysis. Although this provides a rationale to initiate nutritional support early after traumatic brain injury, definitive studies that control for important covariates (severity of injury, clinical site, calories delivered, parenteral/enteral routes, and other factors) are needed to provide definitive evidence on the optimization of the timing of nutritional support after severe traumatic brain injury in children.

Presenting Characteristics Associated With Outcome in Children With Severe Traumatic Brain Injury: A Secondary Analysis From a Randomized, Controlled Trial of Therapeutic Hypothermia.

OBJECTIVES: To identify injury patterns and characteristics associated with severe traumatic brain injury course and outcome, within a well-characterized cohort, which may help guide new research and treatment initiatives. DESIGN: A secondary analysis of a phase 3, randomized, controlled trial that compared therapeutic hypothermia versus normothermia following severe traumatic brain injury in children. SETTING: Fifteen sites in the United States, Australia, and New Zealand. PATIENTS: Children (< 18 yr old) with severe traumatic brain injury. MEASUREMENTS AND MAIN RESULTS: Baseline, clinical, and CT characteristics of patients (n = 77) were examined for association with mortality and outcome, as measured by the Glasgow Outcome Scale-Extended Pediatric Revision 3 months after traumatic brain injury. Data are presented as odds ratios with 95% CIs. No demographic, clinical, or CT characteristic was associated with mortality in bivariate analysis. Characteristics associated with worse Glasgow Outcome Scale-Extended Pediatric Revision in bivariate analysis were two fixed pupils (14.17 [3.38-59.37]), abdominal Abbreviated Injury Severity score (2.03 [1.19-3.49]), and subarachnoid hemorrhage (3.36 [1.30-8.70]). Forward stepwise regression demonstrated that Abbreviated Injury Severity spine (3.48 [1.14-10.58]) and midline shift on CT (8.35 [1.05-66.59]) were significantly associated with mortality. Number of fixed pupils (one fixed pupil 3.47 [0.79-15.30]; two fixed pupils 13.61 [2.89-64.07]), hypoxia (5.22 [1.02-26.67]), and subarachnoid hemorrhage (3.01 [1.01-9.01]) were independently associated with worse Glasgow Outcome Scale-Extended Pediatric Revision following forward stepwise regression. CONCLUSIONS: Severe traumatic brain injury is a clinically heterogeneous disease that can be accompanied by a range of neurologic impairment and a variety of injury patterns at presentation. This secondary analysis of prospectively collected data identifies several characteristics associated with outcome among children with severe traumatic brain injury. Future, larger trials are needed to better characterize phenotypes within this population.

Blood-brainbarrier disruption dictates nanoparticle accumulation following experimental brain injury.

Clinically, traumatic brain injury (TBI) results in complex heterogeneous pathology that cannot be recapitulated in single pre-clinical animal model. Therefore, we focused on evaluating utility of nanoparticle (NP)-based therapeutics following three diffuse-TBI models: mildclosed-head injury (mCHI), repetitive-mCHI and midline-fluid percussion injury (FPI). We hypothesized that NP accumulation after diffuse TBI correlates directly with blood-brainbarrier permeability. Mice received PEGylated-NP cocktail (20-500 nm) (intravenously) after single- or repetitive-(1 impact/day, 5 consecutive days) CHI (immediately) and midline-FPI (1 h, 3 h and 6 h). NPs circulated for 1 h before perfusion/brain extraction. NP accumulation was analyzed using fluorescent microscopy in brain regions vulnerable to neuropathology. Minimal/no NP accumulation after mCHI/RmCHI was observed. In contrast, midlineFPI resulted in significant peak accumulation of up to 500 nm NP at 3 h post-injury compared to sham, 1 h, and 6 h groups in the cortex. Therefore, our study provides the groundwork for feasibility of NP-delivery based on NPinjection time and NPsize after mCHI/RmCHI and midline-FPI.

Outcomes of Titanium Mesh Cranioplasty in Pediatric Patients.

PURPOSE: Cranial defects in children have been repaired with various materials ranging from autologous bone to synthetic materials. There is little published literature on the outcomes of titanium mesh cranioplasty (TMC) in calvarial reconstruction in the pediatric population. This study evaluates a pediatric cohort who underwent calvarial defect reconstruction with titanium mesh and assesses the efficacy and outcomes of TMC. METHODS: An Institutional Review Board approved retrospective review of patients ≤18 years of age who underwent cranioplasty from 1999 to 2014 at 2 centers was performed. The cohort undergoing TMC was studied. RESULTS: A total of 159 cranioplasties were performed. Autologous reconstruction included 84 bone flap replacements and 36 split calvarial bone graft reconstructions. Six patients underwent PEEK implant reconstruction. Titanium mesh cranioplasty was performed on 33 patients. Two patients underwent 2 separate cranioplasties. The median age of patients was 6 years (19 months to 18 years). The most common underlying etiologies were congenital syndromes/craniosynostosis (13 patients), and trauma (11). The majority of patients had prior cranial surgeries (85%). Various types of titanium mesh were used with sizes ranging from 2×3 cm to 19×20 cm, with some patients requiring distinct areas of defect reconstruction. Perioperative complications were noted in 2 patients that subsequently improved. Two patients had late soft tissue problems with complications of wound infections requiring resection of a portion of the mesh. Patients were followed an average of 4 years (range 13 days to 6.8 years), with 2 patients lost to follow-up. Overall, all patients with follow-up achieved a cranial contour with good symmetry to the unaffected side, as well as effective protection to the brain. CONCLUSIONS: Titanium mesh cranioplasty is an effective option for correcting pediatric cranial defects when autologous bone availability is limited and soft tissue coverage allows placement of an implant. The interim outcome for these patients is favorable with few complications and no evidence of growth restriction in the authors' series. Follow-up will be ongoing for these patients.