The Association of Saliva Cytokines and Pediatric Sports-Related Concussion Outcomes.

OBJECTIVES: This study aimed to explore cytokine alterations following pediatric sports-related concussion (SRC) and whether a specific cytokine profile could predict symptom burden and time to return to sports (RTS). SETTING: Sports Medicine Clinic. PARTICIPANTS: Youth ice hockey participants (aged 12-17 years) were recruited prior to the 2013-2016 hockey season. DESIGN: Prospective exploratory cohort study. MAIN MEASURE: Following SRC, saliva samples were collected and a Sport Concussion Assessment Tool version 3 (SCAT3) was administered within 72 hours of injury and analyzed for cytokines. Additive regression of decision stumps was used to model symptom burden and length to RTS based on cytokine and clinical features. RRelieFF feature selection was used to determine the predictive value of each cytokine and clinical feature, as well as to identify the optimal cytokine profile for the symptom burden and RTS. RESULTS: Thirty-six participants provided samples post-SRC (81% male; age 14.4 ± 1.3 years). Of these, 10 features, sex, number of previous concussions, and 8 cytokines, were identified to lead to the best prediction of symptom severity (r = 0.505, P = .002), while 12 cytokines, age, and history of previous concussions predicted the number of symptoms best (r = 0.637, P < .001). The prediction of RTS led to the worst results, requiring 21 cytokines, age, sex, and number of previous concussions as features (r = -0.320, P = .076). CONCLUSIONS: In pediatric ice hockey participants following SRC, there is evidence of saliva cytokine profiles that are associated with increased symptom burden. However, further studies are needed.

Early Supported Discharge for Neurorehabilitation Following Acquired Brain Injury.

Introduction: Early Supported Discharge (ESD) is a clinical flow management service offering interdisciplinary rehabilitation, wherein patients are provided supported in-home rehabilitation treatment; in comparison to conventional hospital-based rehabilitation model of service delivery. There has been little research into the functional outcomes for other types of acquired brain injury (ABI). Methods: In this prospective cohort study, ABI patients presenting at a level I trauma center in Calgary, Canada were placed in either an ESD program or conventional inpatient rehabilitation (IPR) program based on their medical history and presentation. A small number of patients completed both programs (ESD+IPR group). ESD therapies were designed to emulate IPR. Participants completed professionally-rated Mayo-Portland Adaptability Index-4 (MPAI), Quality of Life after Brain Injury (QOLIBRI), Generalized Anxiety Questionnaire-7 (GAD7), Montreal Cognitive Assessment (MoCA), and Patient Health Questionnaire-9 (PHQ9) surveys at 1, 3, and 6 months following initial assessment pre-rehabilitation. Caregivers completed the Zarit Burden Interview (ZBI) at the same time points. The Supervision Rating Scale (SRS) and Disability Rating Scale (DRS) were completed at admission to rehabilitation and all follow-ups. Generalized estimate equations models were used to describe the three groups over time, including age as a covariate. Results: Significant effects of time were reported in the MPAI participant sub-score in the ESD and IPR groups ( χ ( 2 ) 2 = 42.429, p < 0.000; χ ( 2 ) 2 = 9.773, p = 0.008), showing significantly higher scores between 1 and 3 month timepoints for both groups. ZBI scores were significantly lower in the ESD group at 1 month compared to 3 and 6 months ( χ ( 2 ) 2 = 31.252, p < 0.001). The proportion of patients with medical complications during rehabilitation was 25.3% in ESD compared to 74.7% patients in IPR. Conclusions: Improvements in functional outcomes were evident in patients participating in ESD and IPR, with more medical complications reported in the IPR group. Caregiver burden lessened over time in the ESD group but not in the IPR group. Both ESD and ESD+IPR groups can be considered viable alternatives to traditional inpatient rehabilitation. A randomized control trial would be required to properly compare rehabilitation streams. Further investigation into affective and lifestyle elements of ABI recovery would also improve our understanding of targeted neurorehabilitation in this population.

Longitudinal Assessment of Cortical Excitability in Children and Adolescents With Mild Traumatic Brain Injury and Persistent Post-concussive Symptoms.

Introduction: Symptoms following a mild traumatic brain injury (mTBI) usually resolve quickly but may persist past 3 months in up to 15% of children. Mechanisms of mTBI recovery are poorly understood, but may involve alterations in cortical neurophysiology. Transcranial Magnetic Stimulation (TMS) can non-invasively investigate such mechanisms, but the time course of neurophysiological changes in mTBI are unknown. Objective/Hypothesis: To determine the relationship between persistent post-concussive symptoms (PPCS) and altered motor cortex neurophysiology over time. Methods: This was a prospective, longitudinal, controlled cohort study comparing children (8-18 years) with mTBI (symptomatic vs. asymptomatic) groups to controls. Cortical excitability was measured using TMS paradigms at 1 and 2 months post injury. The primary outcome was the cortical silent period (cSP). Secondary outcomes included short interval intracortical inhibition (SICI) and facilitation (SICF), and long-interval cortical inhibition (LICI). Generalized linear mixed model analyses were used to evaluate the effect of group and time on neurophysiological parameters. Results: One hundred seven participants (median age 15.1, 57% female) including 78 (73%) with symptomatic PPCS and 29 with asymptomatic mTBI, were compared to 26 controls. Cortical inhibition (cSP and SICI) was reduced in the symptomatic group compared to asymptomatic group and tended to increase over time. Measures of cortical facilitation (SICF and ICF) were increased in the asymptomatic group and decreased over time. TMS was well tolerated with no serious adverse events. Conclusions: TMS-assessed cortical excitability is altered in children following mild TBI and is dependent on recovery trajectory. Our findings support delayed return to contact sports in children even where clinical symptoms have resolved.

Contralesional Corticomotor Neurophysiology in Hemiparetic Children With Perinatal Stroke.

BACKGROUND: Perinatal stroke causes most hemiparetic cerebral palsy. Ipsilateral connections from nonlesioned hemisphere to affected hand are common. The nonlesioned primary motor cortex (M1) determines function and is a potential therapeutic target but its neurophysiology is poorly understood. OBJECTIVE: We aimed to characterize the neurophysiological properties of the nonlesioned M1 in children with perinatal stroke and their relationship to clinical function. METHODS: Fifty-two participants with hemiparetic cerebral palsy and magnetic resonance imaging-confirmed perinatal stroke and 40 controls aged 8 to 18 years completed the same transcranial magnetic stimulation (TMS) protocol. Single-pulse TMS to nonlesioned M1 determined rest and active motor thresholds (RMT/AMT), motor-evoked potential (MEP) latencies, and stimulus recruitment curves (SRC: 100%-150% RMT). Paired-pulse TMS evaluated short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF). Ipsilateral (IP) participants (ipsilateral MEP ≥0.05 mV in ≥5/20 trials) were compared with contralateral MEP only, nonipsilateral (NI) participants. Assisting Hand and Melbourne assessments quantified clinical function. RESULTS: Twenty-five IP were compared with 13 NI (n = 38, median age 12 years, 66% male). IP had lower motor function. SRC to unaffected hand were comparable between IP and NI while IP had smaller ipsilateral SRC. Ipsilateral MEP latencies were prolonged (23.5 ± 1.8 vs 22.2 ± 1.5 ms contra, P < .001). Contralateral SICI was different between IP (-42%) and NI (-20%). Ipsilateral SICI was reduced (-20%). Contralateral ICF was comparable between groups (+43%) and ipsilaterally (+43%). Measures correlated between contralateral and ipsilateral sides. CONCLUSION: Neurophysiology of nonlesioned M1 and its relationship to motor function is measureable in children with perinatal stroke. Correlation of excitability and intracortical circuitry measures between contralateral and ipsilateral sides suggests common control mechanisms.

Cortical excitability after pediatric mild traumatic brain injury.

INTRODUCTION: Mild traumatic brain injury (mTBI) outcomes are variable, and 10-15% may suffer from prolonged symptoms beyond 3 months that impair the child's return to normal activities. Neurophysiological mechanisms of mTBI are incompletely understood, particularly in children, but alterations in cortical excitability have been proposed to underlie post-concussion syndrome. Improved understanding is required to advance interventions and improve outcomes. OBJECTIVE/HYPOTHESIS: To determine if cortical excitability is altered in children with mTBI, and its association with clinical symptoms. METHODS: This was a cross-sectional controlled cohort study. School-aged children (8-18 years) with mTBI were compared to healthy controls. Cortical excitability was measured using multiple TMS paradigms in children with (symptomatic) and without (recovered) persistent symptoms one-month post-injury. Primary outcome was the cortical silent period (cSP), a potential neurophysiological biomarker of GABAergic inhibition. Secondary outcomes included additional TMS neurophysiology, safety and tolerability. Associations between neurophysiology parameters and clinical symptoms were evaluated. RESULTS: Fifty-three children with mTBI (55% male; mean age 14.1 SD: 2.4 years; 35 symptomatic and 27 asymptomatic participants) and 28 controls (46% male; mean age 14.3 SD: 3.1 years) were enrolled. cSP duration was similar between groups (F (2, 73) = 0.55, p = 0.582). Log10 long interval intracortical inhibition (LICI) was reduced in symptomatic participants compared to healthy controls (F (2, 59) = 3.83, p = 0.027). Procedures were well tolerated with no serious adverse events. CONCLUSIONS: TMS measures of cortical excitability are altered at one month in children with mTBI. Long interval cortical inhibition is decreased in children who remain symptomatic at one month post-injury.

Occipital Nerve Blocks for Pediatric Posttraumatic Headache: A Case Series.

Posttraumatic headache is one of the most common and disabling symptoms after traumatic brain injury. However, evidence for treating posttraumatic headache is sparse, especially in the pediatric literature. This retrospective chart review evaluated the use of occipital nerve blocks in adolescents treated for posttraumatic headache following mild traumatic brain injury, presenting to the Complex Concussion and Traumatic Brain Injury clinic. Fifteen patients (mean age 15.47; range: 13-17) received occipital nerve block for posttraumatic headache. Follow-up was obtained in 14 patients at 5.57 (standard deviation = 3.52) months postinjury. The headache burden was high, with all except one having headaches 15 or more days per month (median 30, range 10-30). Sixty-four percent reported long-term response to the occipital nerve blocks, with associated improved quality of life and decreased postconcussion symptom scores (P < .05). One patient reported transient allopecia. Occipital nerve blocks are well tolerated and can be helpful in posttraumatic headache.

A double-blind, placebo-controlled intervention trial of 3 and 10 mg sublingual melatonin for post-concussion syndrome in youths (PLAYGAME): study protocol for a randomized controlled trial.

BACKGROUND: By the age of sixteen, one in five children will sustain a mild traumatic brain injury also known as concussion. Our research found that one in seven school children with mild traumatic brain injury suffer post-concussion syndrome symptoms for three months or longer. Post-concussion syndrome is associated with significant disability in the child and his/her family and yet there are no evidence-based medical treatments available. Melatonin has several potential mechanisms of action that could be useful following mild traumatic brain injury, including neuroprotective effects. The aim of this study is to determine if treatment with melatonin improves post-concussion syndrome in youths following mild traumatic brain injury. Our hypothesis is that treatment of post-concussion syndrome following mild traumatic brain injury with 3 or 10 mg of sublingual melatonin for 28 days will result in a decrease in post-concussion syndrome symptoms compared with placebo. METHODS/DESIGN: Ninety-nine youths with mild traumatic brain injury, aged between 13 and 18 years, who are symptomatic at 30 days post-injury will be recruited. This study will be conducted as a randomized, double blind, placebo-controlled superiority trial of melatonin. Three parallel treatment groups will be examined with a 1:1:1 allocation: sublingual melatonin 3 mg, sublingual melatonin 10 mg, and sublingual placebo. Participants will receive treatment for 28 days. The primary outcome is a change on the Post-Concussion Symptom Inventory (Parent and Youth). The secondary outcomes will include neurobehavioral function, health-related quality of life and sleep. Neurophysiological and structural markers of change, using magnetic resonance imaging techniques and transcranial magnetic stimulation, will also be investigated. DISCUSSION: Melatonin is a safe and well-tolerated agent that has many biological properties that may be useful following a traumatic brain injury. This study will determine whether it is a useful treatment for children with post-concussion syndrome. Recruitment commenced on 4 December 2014. TRIAL REGISTRATION: This trial was registered on 6 June 2013 at ClinicalTrials.gov. REGISTRATION NUMBER: NCT01874847.