Utility of Early Magnetic Resonance Imaging to Enhance Outcome Prediction in Critically Ill Children with Severe Traumatic Brain Injury.

BACKGROUND: Many children with severe traumatic brain injury (TBI) receive magnetic resonance imaging (MRI) during hospitalization. There are insufficient data on how different patterns of injury on early MRI inform outcomes. METHODS: Children (3-17 years) admitted in 2010-2021 for severe TBI (Glasgow Coma Scale [GCS] score < 9) were identified using our site's trauma registry. We used multivariable modeling to determine whether the hemorrhagic diffuse axonal injury (DAI) grade and the number of regions with restricted diffusion (subcortical white matter, corpus callosum, deep gray matter, and brainstem) on MRI obtained within 7 days of injury were independently associated with time to follow commands and with Functional Independence Measure for Children (WeeFIM) scores at the time of discharge from inpatient rehabilitation. We controlled for the clinical variables age, preadmission cardiopulmonary resuscitation, pupil reactivity, motor GCS score, and fever (> 38 °C) in the first 12 h. RESULTS: Of 260 patients, 136 (52%) underwent MRI within 7 days of injury at a median of 3 days (interquartile range [IQR] 2-4). Patients with early MRI were a median age of 11 years (IQR 7-14), 8 (6%) patients received cardiopulmonary resuscitation, 19 (14%) patients had bilateral unreactive pupils, the median motor GCS score was 1 (IQR 1-4), and 82 (60%) patients had fever. Grade 3 DAI was present in 46 (34%) patients, and restricted diffusion was noted in the corpus callosum in 75 (55%) patients, deep gray matter in 29 (21%) patients, subcortical white matter in 23 (17%) patients, and the brainstem in 20 (15%) patients. After controlling for clinical variables, an increased number of regions with restricted diffusion, but not hemorrhagic DAI grade, was independently associated with longer time to follow commands (hazard ratio 0.68, 95% confidence interval 0.53-0.89) and worse WeeFIM scores (estimate ß - 4.67, 95% confidence interval - 8.33 to - 1.01). CONCLUSIONS: Regional restricted diffusion on early MRI is independently associated with short-term outcomes in children with severe TBI. Multicenter cohort studies are needed to validate these findings and elucidate the association of early MRI features with long-term outcomes in children with severe TBI.

Efficacy of IV Valproic Acid and Oral Valproic Acid Tapers for the Treatment of Pediatric Headaches in the Emergency Department.

Background and Objectives: Pediatric headaches, including migraine, are a common reason for emergency department (ED) presentation. IV valproic acid (VPA) followed by oral VPA tapers are often used to abort pediatric headache and reduce recurrence, though limited data exist regarding this approach. This study evaluated the effectiveness of IV VPA and oral VPA tapers for the treatment of acute pediatric headaches in the ED in preventing return encounters. Methods: This is a retrospective cohort study of patients aged 5-21 years presenting to a tertiary-care pediatric ED from 2010 to 2016 who received IV VPA for headache or migraine. Primary outcomes were ED disposition, percent pain reduction (initial vs 2-hour patient-reported pain score [10-point scale]), and return for acute headache treatment within 1 month. Results: A total of 486 ED encounters were included with a median patient age of 15 years; most of them were females (76%, 369/486). Of available pain scores within 2 hours of IV VPA administration, 41% (173/425) had ≥50% pain reduction. Fifty-two percent (254/486) were discharged without additional treatment, 14% (69/486) were discharged after additional treatment, and 33% (163/486) were admitted to the hospital. Initial pain score, number of preceding home treatments, and number of preceding ED treatments were not associated with ED disposition. Oral VPA tapers were prescribed in 39% (94/253) of encounters when the patient was discharged after IV VPA. Oral VPA tapers produced a transient decrease in recurrence at 72 hours, which was no longer present at 1 week nor 1 month. There was no difference in the time to recurrence or total number of return visits within 1 month. Discussion: IV VPA was efficacious in treating pediatric headaches evaluated in the ED, with nearly two-thirds of patients discharged home after administration. Oral VPA tapers did not reduce total headache recurrence nor time to recurrence. Given the limited benefit of oral VPA tapers, this practice should be re-examined. Classification of Evidence: This study provides Class IV evidence that for children with headache seen in the ED, IV VPA reduces head pain and Class III evidence that following this with an oral VPA taper is of no benefit.

Development and Evaluation of a Child Neurology Resident Curriculum for Communication Around Serious Illness.

Background: Communication around serious illness is a core competency for all residencies. One-fifth of neurology residencies have no curriculum. Published curricula use didactics or role-play to assess confidence performing this skill without evaluation in clinical settings. The SPIKES mnemonic (Setting, Perception, Invitation, Knowledge, Empathy, Strategy/Summary) outlines 6 evidence-based steps for communication around serious illness. It is unknown whether child neurology residents can incorporate SPIKES into communication around serious illness in clinical settings. Objective: To develop and evaluate a curriculum on communication around serious illness using SPIKES for child neurology residents that shows long-term skill retention in clinical settings at a single institution. Methods: In 2019, we created a pre-post survey and skills checklist based on SPIKES, with 20 total including 10 core skills. Faculty observed residents' (n = 7) communication with families and completed both preintervention and postintervention checklists for comparison. Residents underwent training in SPIKES during a 2-hour session using didactic and coached role-play. Results: All (n = 7) residents completed preintervention surveys, 4 of 6 completed postintervention. All (n = 6) participated in the training session. Following the training, 75% of residents reported improved confidence in use of SPIKES, though 50% were still unsure about appropriately responding to emotions. There was improvement in all SPIKES skills, with significant improvement in 6 of 20 skills up to 1 year following training. Conclusion: This is the first evaluation of the implementation of a communication around serious illness curriculum for child neurology residents. We identified improved comfort with SPIKES after training. Successful acquisition and utilization of this framework in our program suggests it could be incorporated into any residency program.

The State of Inpatient Child Neurology: A Survey of North American Academic Programs.

BACKGROUND AND OBJECTIVES: Inpatient child neurology programs provide essential services for children. We sought to understand the current structure and challenges of inpatient pediatric neurologic care delivery in academic programs in North America. METHODS: We identified a single child neurologist from 39 of the first 40 programs on the 2019-2020 US News and World Report ranking and 3 large Canadian programs to be invited to participate in an inpatient focused survey. In October 2020, these 42 child neurologists were invited to complete an anonymous on-line survey including 37 questions about the structure, workload, and challenges of their inpatient program. Data was analyzed descriptively. RESULTS: We received responses from 30/42 (71%) invited child neurologists from unique programs. The majority (25/30, 83%) were Child Neurology Program Directors, Inpatient Directors, and/or Division Chiefs. Two-thirds (20/30, 67%) reported a total of 2-4 inpatient services. Two-thirds (20/30, 67%) reported a primary neurology admitting service. Nearly two-thirds (19/30, 63%) reported a separate ICU service, and about one-third (11/30, 37%) reported a separate stroke/vascular service. Half of respondents (15/30, 50%) reported some attendings whose primary clinical effort is in the inpatient setting. Over half (17/30, 57%) reported having trainees interested in inpatient-focused careers. About half (16/30, 53%) reported a full-time equivalent metric for inpatient time, and under half (13/30, 43%) reported use of critical-care billing. Most respondents (26/30, 87%) endorsed that inpatient attendings frequently complete documentation/sign notes outside of normal daytime hours. During night call, attendings commonly spend 30 minutes-2 hours on patient care-related phone calls between 5pm-10pm (24/30, 80%) and receive 1-3 patient care-related phone calls after 10pm (21/30, 70%). Faculty burnout was the biggest inpatient-specific challenge before the COVID-19 pandemic (25/30, 83%), and concern about faculty well-being during the COVID-19 pandemic was reported in nearly all respondents (28/30, 93%). DISCUSSION: Academic child neurology programs in North America implement varied models for inpatient care delivery and face common challenges. The information presented in this study serves to stimulate discussion, help optimize operations, and encourage novel approaches to accomplish work and advance careers in academic inpatient child neurology.

Neuroimaging for Pediatric Non-First-Time Seizures in the Emergency Department.

Background and Objectives: Neuroimaging is often part of the workup for a pediatric patient presenting with a seizure to an emergency department (ED). We aim to evaluate when neuroimaging in the ED for children with a non-first-time seizure, or nonindex seizure (NIS), is associated with an acute change in management (ACM). Methods: This is a retrospective cohort study of all pediatric patients presenting to an ED from 2008 to 2018 with a NIS, excluding repeat febrile seizures, who underwent neuroimaging. Clinical characteristics were extracted from the electronic medical record. The primary outcome was new abnormal neuroimaging resulting in an ACM, defined as admission to the hospital, neurosurgical intervention, or new nonseizure medication administration. Results: We identified 492 encounters. Neuroimaging revealed new findings in 21% of encounters and led to ACMs in 5% of encounters. ACMs included admissions, neurosurgical interventions, and nonseizure medication changes. Factors associated with ACM included new seizure type (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.3-8.0), new focal examination finding (OR 3.0, 95% CI 1.3-7.1), altered mental status (OR 2.9, 95% CI 1.2-7.0), and a history of only provoked seizures (OR 2.8, 95% CI 1.0-7.5). Patients with 2 risk factors had an OR of 6.9 (95% CI 1.8-26.5) for an ACM, and those with 3-4 risk factors had an OR of 45.8 (95% CI 9.8-213.2). The negative predictive value for ACM in a patient with no risk factors was 98.6% (95% CI 95.9-99.5). Discussion: Patients with a NIS who have abnormal neuroimaging associated with an ACM present with unique risk factors. Prospectively validating these factors may allow for a prediction tool for NIS in EDs where reduced exposure to ionizing radiation, sedation, and resource utilization are critically important.

Multicenter Study of the Impact of COVID-19 Shelter-In-Place on Tertiary Hospital-based Care for Pediatric Neurologic Disease.

Objective: To describe changes in hospital-based care for children with neurologic diagnoses during the initial 6 weeks following regional Coronavirus 2019 Shelter-in-Place orders. Methods: This retrospective cross-sectional study of 7 US and Canadian pediatric tertiary care institutions included emergency and inpatient encounters with a neurologic primary discharge diagnosis code in the initial 6 weeks of Shelter-in-Place (COVID-SiP), compared to the same period during the prior 3 years (Pre-COVID). Patient demographics, encounter length, and neuroimaging and electroencephalography use were extracted from the medical record. Results: 27,900 encounters over 4 years were included. Compared to Pre-COVID, there was a 54% reduction in encounters during Shelter-in-Place. COVID-SiP patients were younger (median 5 years vs 7 years). The incidence of encounters for migraine fell by 72%, and encounters for acute diagnoses of status epilepticus, infantile spasms, and traumatic brain injury dropped by 53%, 55%, and 56%, respectively. There was an increase in hospital length of stay, relative utilization of intensive care, and diagnostic testing (long-term electroencephalography, brain MRI, and head CT (all P<.01)). Conclusion: During the initial 6 weeks of SiP, there was a significant decrease in neurologic hospital-based encounters. Those admitted required a high level of care. Hospital-based neurologic services are needed to care for acutely ill patients. Precise factors causing these shifts are unknown and raise concern for changes in care seeking of patients with serious neurologic conditions. Impacts of potentially delayed diagnosis or treatment require further investigation.

Why the Maternal Medication List Matters: Neonatal Toxicity From Combined Serotonergic Exposures.

Serotonergic medications are used for the prevention and treatment of depression during pregnancy. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause poor neonatal adaptation, which has been attributed to withdrawal versus toxicity. Bupropion, a norepinephrine-dopamine reuptake inhibitor, is often used as an adjunctive agent to selective serotonin reuptake inhibitors or SNRIs for refractory depression. Quetiapine, an atypical antipsychotic, may also be used in more complex cases. When combined with serotonergic drugs, bupropion and quetiapine are associated with increased risk of serotonin syndrome in adults. We describe a neonate exposed to venlafaxine (an SNRI), bupropion, and quetiapine in utero who presented nearly immediately after birth with encephalopathy and abnormal movements. The severity and rapidity of symptoms may be attributable to potentiation of venlafaxine's serotonergic effects by bupropion and quetiapine. Neonatal providers should be aware of maternal medications and prepare for possible adverse effects, particularly from common psychotropic exposures.

Infantile Spasms: Opportunities to Improve Care.

Infantile spasm (IS) is a distinct epilepsy syndrome characterized by epileptic spasms (the clinical seizure type) and hypsarrhythmia (the electrographic abnormality). IS is frequently accompanied by impaired neurodevelopment and is often associated with structural, genetic, or metabolic etiologies. Prompt treatment of this severe epileptic encephalopathy improves long-term outcomes but remains elusive in many situations. Despite common misconceptions, even patients with identified etiologies or preexisting developmental delay benefit from proven standard therapies, including adrenocorticotropic hormone (ACTH), oral corticosteroids, or vigabatrin. Treatment efficacy should be assessed with electroencephalography at 2 weeks, and an alternative therapy is indicated if epileptic spasms or hypsarrhythmia have not resolved. Collaboration with primary care providers is critical to mitigate the potentially serious adverse effects of standard treatments and also to provide developmental interventions. Although new approaches are on the horizon, addressing current challenges and opportunities now can dramatically improve patient outcomes.

Incidence of Hypertension Among Children Treated With Adrenocorticotropic Hormone (ACTH) or Prednisolone for Infantile Spasms.

Children with infantile spasms are often treated with hormonal therapies including adrenocorticotropic hormone (ACTH) and prednisolone. These have numerous systemic side effects including hypertension and, rarely, fatal cardiomyopathy; however, the incidence of these side effects has not been well described. This study aims to quantify the incidence and short-term sequelae of hypertension in this population. A retrospective chart review was performed at a single institution. Children 2 months to 2 years old with newly diagnosed infantile spasms treated from 2013 to 2017 were included. Variables collected included age, sex, etiology and treatment of infantile spasms, documented or missed diagnosis of hypertension, treatment of hypertension, echocardiogram results, referrals for hypertension, and persistence of hypertension 2 to 4 months after treatment. Analyses included descriptive statistics with percentiles, means, and medians. Differences between groups were assessed using Fisher exact tests. Hypertension occurred in 34/77 children (44%) during treatment with ACTH and 4/11 children (36%) during treatment with prednisolone. No child developed hypertension during treatment with nonhormonal therapies. The incidence of hypertension between ACTH and prednisolone groups was not significantly different (P = .75). The incidence of hypertension was significantly higher in the ACTH and prednisolone groups compared to the nonhormonal group (P < .001 for each). Sixteen children received echocardiograms, with no cases of cardiomyopathy. Two children had persistent hypertension at 2 months after discontinuation of hormonal therapy. Hypertension is a very common side effect of hormonal therapy for infantile spasms; however, few developed long-term hypertension and none developed cardiomyopathy. Further study is needed to determine the role of antihypertensive treatment for hormone-related hypertension.

Clinical characteristics of enterovirus A71 neurological disease during an outbreak in children in Colorado, USA, in 2018: an observational cohort study.

BACKGROUND: In May, 2018, Children's Hospital Colorado noted an outbreak of enterovirus A71 (EV-A71) neurological disease. We aimed to characterise the clinical features of EV-A71 neurological disease during this outbreak. METHODS: In this retrospective observational cohort study, children (younger than 18 years) who presented to Children's Hospital Colorado (Aurora, CO, USA) between March 1 and November 30, 2018, with neurological disease (defined by non-mutually exclusive criteria, including meningitis, encephalitis, acute flaccid myelitis, and seizures) and enterovirus detected from any biological specimen were eligible for study inclusion. The clinical characteristics of children with neurological disease associated with EV-A71 were compared with those of children with neurological disease associated with other enteroviruses during the same period. To explore the differences in clinical presentation of acute flaccid myelitis, we also used a subgroup analysis to compare clinical findings in children with EV-A71-associated acute flaccid myelitis during the study period with these findings in those with enterovirus D68 (EV-D68)-associated acute flaccid myelitis at the same hospital between 2013 and 2018. FINDINGS: Between March 10 and Nov 10, 2018, 74 children presenting to Children's Hospital Colorado were found to have enterovirus neurological disease; EV-A71 was identified in 43 (58%) of these children. The median age of the children with EV-A71 neurological disease was 22·7 months (IQR 4·0-31·9), and most of these children were male (34 [79%] children). 40 (93%) children with EV-A71 neurological disease had findings suggestive of meningitis, 31 (72%) children showed evidence of encephalitis, and ten (23%) children met our case definition of acute flaccid myelitis. All children with EV-A71 disease had fever and 18 (42%) children had hand, foot, or mouth lesions at or before neurological onset. Children with EV-A71 disease were best differentiated from those with other enteroviruses (n=31) by the neurological findings of myoclonus, ataxia, weakness, and autonomic instability. Of the specimens collected from children with EV-A71, this enterovirus was detected in 94% of rectal, 79% of oropharyngeal, 56% of nasopharyngeal, and 20% of cerebrospinal fluid specimens. 39 (93%) of 42 children with EV-A71 neurological disease who could be followed up showed complete recovery by 1-2 months. Compared with children with EV-D68-associated acute flaccid myelitis, children with EV-A71-associated acute flaccid myelitis were younger, showed neurological onset earlier after prodromal symptom onset, had milder weakness, showed more rapid improvement, and were more likely to completely recover. INTERPRETATION: This outbreak of EV-A71 neurological disease, the largest reported in the Americas, was characterised by fever, myoclonus, ataxia, weakness, autonomic instability, and full recovery in most patients. Because EV-A71 epidemiology outside of Asia remains difficult to predict, identification of future outbreaks will be aided by prompt recognition of these distinct clinical findings, testing of non-sterile and sterile site specimens, and enhanced enterovirus surveillance. FUNDING: None.

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy.

OBJECTIVE: The early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage-gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872. Our goal was to determine the functional effects of these mutations on channel properties. METHODS: Clinical exome sequencing was carried out on patients with early-onset seizures, developmental delay, and cognitive impairment. Two mutations identified here, p.Arg1872Leu and p.Arg1872Gln, and two previously identified mutations, p.Arg1872Trp and p.Arg1617Gln, were introduced into Nav1.6 cDNA, and effects on electrophysiological properties were characterized in transfected ND7/23 cells. Interactions with FGF14, G-protein subunit Gßγ, and sodium channel subunit ß1 were assessed by coimmunoprecipitation. RESULTS: We identified two patients with the novel mutation p.Arg1872Leu and one patient with the recurrent mutation p.Arg1872Gln. The three mutations of Arg1872 and the mutation of Arg1617 all impaired the sodium channel transition from open state to inactivated state, resulting in channel hyperactivity. Other observed abnormalities contributing to elevated channel activity were increased persistent current, increased peak current density, hyperpolarizing shift in voltage dependence of activation, and depolarizing shift in steady-state inactivation. Protein interactions were not affected. INTERPRETATION: Recurrent mutations at Arg1617 and Arg1872 lead to elevated Nav1.6 channel activity by impairing channel inactivation. Channel hyperactivity is the major pathogenic mechanism for gain-of-function mutations of SCN8A. EIEE13 differs mechanistically from Dravet syndrome, which is caused by loss-of-function mutations of SCN1A. This distinction has important consequences for selection of antiepileptic drugs and the development of gene- and mutation-specific treatments.

Epileptiform activity in the CA1 region of the hippocampus becomes refractory to attenuation by cannabinoids in part because of endogenous γ-aminobutyric acid type B receptor activity.

The anticonvulsant properties of marijuana have been known for centuries. The recently characterized endogenous cannabinoid system thus represents a promising target for novel anticonvulsant agents; however, administration of exogenous cannabinoids has shown mixed results in both human epilepsy and animal models. The ability of cannabinoids to attenuate release of both excitatory and inhibitory neurotransmitters may explain the variable effects of cannabinoids in different models of epilepsy, but this has not been well explored. Using acute mouse brain slices, we monitored field potentials in the CA1 region of the hippocampus to characterize systematically the effects of the cannabinoid agonist WIN55212-2 (WIN) on evoked basal and epileptiform activity. WIN, acting presynaptically, significantly reduced the amplitude and slope of basal field excitatory postsynaptic potentials as well as stimulus-evoked epileptiform responses induced by omission of magnesium from the extracellular solution. In contrast, the combination of omission of magnesium plus elevation of potassium induced an epileptiform response that was refractory to attenuation by WIN. The effect of WIN in this model was partially restored by blocking γ-aminobutyric acid type B (GABA(B) ), but not GABA(A) , receptors. Subtle differences in models of epileptiform activity can profoundly alter the efficacy of cannabinoids. Endogenous GABA(B) receptor activation played a role in the decreased cannabinoid sensitivity observed for epileptiform activity induced by omission of magnesium plus elevation of potassium. These results suggest that interplay between presynaptic G protein-coupled receptors with overlapping downstream targets may underlie the variable efficacy of cannabinoids in different models of epilepsy.