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.

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.

Changes in attentional processing following neurofeedback in patients with persistent post-concussive symptoms: a pilot study.

OBJECTIVE: Persistent post-concussive symptoms (PPCS) often include attention deficits, particularly orienting and executive attention. Research in other clinical populations has demonstrated that neurofeedback therapy (NFT) is effective at improving orienting and executive attention, although its effects on attentional networks in patients with PPCS are unknown. METHOD: In this single-group pilot study, we examined attention-related event-related potentials (ERPs) - N1 and P3 - and cognitive outcomes following Live Z-score training (LZT), a variant of NFT. RESULTS: No changes in early selective attention, as indexed by N1 amplitude, were observed; however, P3 amplitude, which indexes neural resource allocation, increased following LZT and returned to baseline by 3 months. Cognitive performance improved following treatment, which was sustained at 3 months. The magnitude of change in P3 and ANT performance did not differ between orienting or executive attention, suggesting LZT improved general attentional processing efficiency. CONCLUSION: Our results suggest that LZT may positively affect attention globally, but does not target specific attention networks. These pilot data warrant the initiation of a clinical trial evaluating the effectiveness of LZT for treating attention deficits in patients with PPCS.

Posttraumatic seizures in children with severe traumatic brain injury.

PURPOSE: Traumatic brain injury (TBI) remains a leading cause of childhood death and disability worldwide. Seizures are a common complication of TBI and they are particularly common in pediatric populations. The proper management of children sustaining severe TBI is still controversial. Our study aims to share our experience contributing to build evidence for better care. METHODS: Retrospective chart review was performed on individuals ages 0 to <18 who presented to a level 1 trauma center during a 10-year period with the diagnosis of severe TBI. Data analyzed included patient's demographics, event information, clinical and radiological presentation, management, and midterm follow-up. Presence of seizures was tracked through EEG monitoring, staff witnessing, or guardian referral. RESULTS: The incidence of early posttraumatic seizures (EPTS) observed in our population (19 %) exceeds those previously reported. Such findings likely reflect the importance of close monitoring including EEG. An association between the presence of EPTS and the development of late posttraumatic seizures (LPTS) was evidenced (p=0.001; 95 % CI 2.2, 16.5), while this association should not be assumed as a measure of causality, it should be considered for the management of patients presenting EPTS. Non-accidental trauma and young age were identified as independent predictors for the development of seizures. CONCLUSIONS: Seizures are a common complication of severe TBI among children aged 0-3 years. Given the detrimental effects that seizures produce on the injured brain, close observation and appropriate monitoring with EEG are essential for the management of children sustaining severe TBI.

Central Nervous System Metabolism in Autism, Epilepsy and Developmental Delays: A Cerebrospinal Fluid Analysis.

Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without known DD/ASD (n = 34) was analyzed using large-scale targeted mass spectrometry. Eighteen also had epilepsy (EPI). Metabolites significantly related to ASD, DD and EPI were identified by linear models and entered into metabolite-metabolite network pathway analysis. Common disrupted pathways were analyzed for each group of interest. Central metabolites most involved in metabolic pathways were L-cysteine, adenine, and dodecanoic acid for ASD; nicotinamide adenine dinucleotide phosphate, L-aspartic acid, and glycine for EPI; and adenosine triphosphate, L-glutamine, ornithine, L-arginine, L-lysine, citrulline, and L-homoserine for DD. Amino acid and energy metabolism pathways were most disrupted in all disorders, but the source of the disruption was different for each disorder. Disruption in vitamin and one-carbon metabolism was associated with DD and EPI, lipid pathway disruption was associated with EPI and redox metabolism disruption was related to ASD. Two microbiome metabolites were also detected in the CSF: shikimic and cis-cis-muconic acid. Overall, this study provides increased insight into unique metabolic disruptions in distinct but overlapping neurodevelopmental disorders.

Mild Traumatic Brain Injury and Postconcussive Symptom Endorsement: A Parallel Comparison Between Two Nonclinical Cohorts.

INTRODUCTION: The prevalence of mild traumatic brain injury (mTBI) is commonly estimated based on indirect metrics such as emergency department visits and self-reporting tools. The study of postconcussive symptoms faces similar challenges because of their unspecific character and indistinct causality. In this article, we compare two nonclinical, epidemiological studies that addressed these two elements and were performed within a relatively narrow period in the state of Colorado. MATERIALS AND METHODS: De-identified datasets were obtained from a random digit-dialed survey study conducted by the Craig Hospital and a study surveying soldiers returning from deployment by Defense and Veteran Traumatic Brain Injury Center. Information pertinent to participants' demographics, a history of mTBI, and symptom endorsement was extracted and homogenized in order to establish a parallel comparison between the populations of the two studies. RESULTS: From the 1,558 (Warrior Strong, 679; Craig Hospital, 879) records selected for analysis, 43% reported a history of at least one mTBI. The prevalence was significantly higher among individuals from the Defense and Veteran Traumatic Brain Injury Center study independent of gender or race. Repetitive injuries were reported by 15% of the total combined cohort and were more prevalent among males. Symptom endorsement was significantly higher in individuals with a positive history of mTBI, but over 80% of those with a negative history of mTBI endorsed at least one of the symptoms interrogated. Significant differences were observed between the military and the civilian populations in terms of the types and frequencies of the symptoms endorsed. CONCLUSIONS: The prevalence of mTBI and associated symptoms identified in the two study populations is higher than that of previously reported. This suggests that not all individuals sustaining concussion seek medical care and highlights the limitations of using clinical reports to assess such estimates. The lack of appropriate mechanisms to determine symptom presence and causality remains a challenge. However, the differences observed in symptom reporting between cohorts raise questions about the nature of the symptoms, the impact on the quality of life for different individuals, and the effects on military health and force readiness.

Severe Pediatric TBI Management in a Middle-Income Country and a High-Income Country: A Comparative Assessment of Two Centers.

Background: Traumatic brain injury (TBI) is a global public health issue with over 10 million deaths or hospitalizations each year. However, access to specialized care is dependent on institutional resources and public health policy. Phoenix Children's Hospital USA (PCH) and the Neiva University Hospital, Colombia (NUH) compared the management and outcomes of pediatric patients with severe TBI over 5 years to establish differences between outcomes of patients managed in countries of varying resources availability. Methods: We conducted a retrospective review of individuals between 0 and 17 years of age, with a diagnosis of severe TBI and admitted to PCH and NUH between 2010 and 2015. Data collected included Glasgow coma scores, intensive care unit monitoring, and Glasgow outcome scores. Pearson Chi-square, Fisher exact, T-test, or Wilcoxon-rank sum test was used to compare outcomes. Results: One hundred and one subjects met the inclusion criteria. NUH employed intracranial pressure monitoring less frequently than PCH (p = 0.000), but surgical decompression and subdural evacuation were higher at PCH (p = 0.031 and p = 0.003). Mortality rates were similar between the institutions (15% PCH, 17% NUH) as were functional outcomes (52% PCH, 54% NUH). Conclusions: Differences between centers included time to specialized care and utilization of monitoring. No significant differences were evidenced in survival and the overall functional outcomes.

Comparison of autograft versus allograft in the surgical repair of pediatric obstetrical brachial plexus injuries.

OBJECTIVE: The goal of this study was to determine the functional efficacy of acellular processed nerve allograft (ALG) as compared to sural nerve autograft (AUG) harvested at time of surgery for children with obstetrical brachial plexus injury (OBPI). METHODS: A retrospective review of records was performed in patients who underwent surgical repair of OBPI between 2009 and 2015 at Phoenix Children's Hospital. Patients were grouped based on the type of nerve graft used (AUG using the patient's own sural nerve or decellularized processed cadaveric nerve ALG) and compared in terms of motor strength, British Medical Research Council score, functionality (Mallet scale score), surgical time, rate of complications, and need for further intervention. RESULTS: A total of 52 records were identified meeting study criteria. Sural nerve AUG was used in 22 cases and ALG in 30 cases. Changes from pre- to postsurgical assessment of motor strength were significant for all muscle groups measured except for elbow extension for both groups. All Mallet scores increased significantly. No significant differences were observed in motor strength and functional components between groups. Interventions using ALG had shorter operative times than those performed using AUG. No significant difference was observed in terms of need for further intervention. Two patients (9%) in the AUG group developed stitch abscesses at the harvest site, whereas there were no infectious complications reported in the ALG group. CONCLUSIONS: These findings suggest equivalence in terms of muscle strength and functional outcomes between the use of AUG and ALG for patients with OBPI. However, the less invasive character of ALG repair decreases surgical time and risk of complications.

Implementation of a Generalized Vestibular Rehabilitation Approach.

INTRODUCTION: Vestibular dysfunction is common in military populations as the result of traumatic brain injury, blast exposure, and/or repetitive acoustic insult. Vestibular rehabilitation (VR) has been proven to be an effective approach in the treatment of vestibular dysfunction. VR consists of a series of exercises prescribed on the basis of individual patient needs by a vestibular trained physical therapist (PT). A generalized approach to VR in a military setting could help widen the system capacity to take care of patients with vestibular symptoms, shorten waiting times for patients without impacting the burden on PTs. The rehabilitation team at the Warrior Recovery Center on Fort Carson, Colorado, developed a generalized approach in which a series of exercises were administered to individuals with vestibular dysfunction. The implementation of this approach was evaluated for quality improvement purposes and is presented below. MATERIALS AND METHODS: We utilized a combined observational/survey approach to evaluate the patients' tolerance to a variety of exercises provocative of dizziness symptoms, their overall satisfaction with the intervention, the appropriateness of the allocated resources, and the providers' confidence with the treatment and its administration. Research staff members were present as observers in all therapy sessions during the 3-month implementation period and administered surveys to patients and clinical staff at pre-established time points. Descriptive analysis was performed to summarize observations and responses to surveys. Linear regression was utilized to evaluate if a reduction in the number of patient:provider interactions occurred over the course of the implementation period. RESULTS: A total of 25 therapy sessions took place during the implementation period. Each visit lasted an average of 56 minutes with 6 minutes allocated for set up, 45 minutes for intervention and 5 minutes for cleanup. The mean number of patients per session was 3 (Max 6, Min 1) with one staff member running the intervention 56% of the time and two staff members running the intervention 44% of the time. Exercise tolerance was at 99% and the need for one-on-one interactions between providers and patients was easily attained at a 3:1 patient:provider rate. Survey assessment demonstrated 100% patient satisfaction with the program and 100% provider confidence with treatment delivery. CONCLUSION: Generalized Vestibular Rehabilitation Treatment (GVRT) was successfully implemented at the Warrior Recovery Center at Fort Carson, Colorado. The individual exercises used during the interventions were challenging to patients yet well tolerated. Resource allocation was appropriate in terms of personnel, time, and equipment. Both the clinical staff and the patients felt comfortable with the therapy and subjectively found it to be effective. The project provided valuable information to clinical staff, administrators, and the organization.

Semi-Automated Neurofeedback Therapy for Persistent Postconcussive Symptoms in a Military Clinical Setting: A Feasibility Study.

INTRODUCTION: Neurofeedback therapy (NFT) has demonstrated effectiveness for reducing persistent symptoms following traumatic brain injury (TBI); however, its reliance on NFT experts for administration and high number of treatment sessions limits its use in military medicine. Here, we assess the feasibility of live Z-score training (LZT)-a variant of NFT that requires fewer treatment sessions and can be administered by nonexperts-for use in a military clinical setting. MATERIALS AND METHODS: A single group design feasibility study was conducted to assess acceptability, tolerance, treatment satisfaction, and change in symptoms after a 6-week LZT intervention in 38 Service Members (SMs) with persistent symptoms comorbid with or secondary to mild TBI. Acceptance and feasibility were assessed using treatment completion and patients' satisfaction with treatment. To evaluate changes in symptom status, a battery of self-report questionnaires was administered at baseline, posttreatment, and 3-month follow-up to evaluate changes in psychological, neurobehavioral, sleep, pain, and headache symptoms, as well as self-efficacy in symptom management and life satisfaction. RESULTS: Participants tolerated the treatment well and reported a positive experience. Symptom improvement was observed, including depressive, neurobehavioral, and pain-related symptoms, with effects sustained at 3-month follow-up. CONCLUSION: LZT treatment appears to be a feasible, non-pharmacological therapy amenable to SMs. Results from this pilot study promote further investigation of LZT as an intervention for SMs with persistent symptoms following TBI.

Computed tomography grading systems poorly predict the need for intervention after spleen and liver injuries.

Computed tomography (CT) grading systems are often used clinically to forecast the need for interventions after abdominal trauma with solid organ injuries. We compared spleen and liver CT grading methods to determine their utility in predicting the need for operative intervention or angiographic embolization. Abdominal CT scans of 300 patients with spleen injuries, liver injuries, or both were evaluated by five trauma faculty members blinded to clinical outcomes. Studies were graded by American Association for the Surgery of Trauma criteria, a novel splenic injury CT grading system, and a novel liver injury grading system. The sensitivity and specificity of each methodology in predicting the need for intervention were calculated. The kappa statistic was used to determine interrater variability. Twenty-one per cent (39/189) of patients with splenic injuries visible on CT scans required interventions, whereas 14 per cent (21/154) of patients with liver injuries visible on CT required interventions. The overall sensitivity of all grading systems in predicting the need for surgery or angioembolization of the spleen or liver was poor; the specificity seemed to be fairly good. When evaluators were compared, the strength of agreement for the various scoring systems was only moderate. Anatomic CT grading systems are ineffective screening tools for excluding the need for operation or embolization after splenic or hepatic trauma. Although insensitive, CT is a good predictor (highly specific) of the need for intervention if certain definitive abnormalities are identified. Considerable inconsistency exists in interpretation of abdominal CT scans after trauma, even among experienced clinicians.

Hypothermia in hypoxic ischemic encephalopathy: a 5-year experience at Phoenix Children's Hospital Neuro NICU.

We found TH to be safe and effective in improving survival and neurodevelopmental outcomes following HIE in term children. Additionally, the use of a multidisciplinary team involved with these complex patients and the use of advanced monitoring techniques will likely assist in identifying second insults (ie, seizures), leading to more rapidly instituted treatments. Our study, however, had the limitation of including only retrospective data from patients in whom TH was provided. This makes it difficult to identify the specific sources for the improved outcomes and/or the presence of complications.