Long-Term Increases in Mental Disorder Diagnoses After Invasive Mechanical Ventilation for Severe Childhood Respiratory Disease: A Propensity Matched Observational Cohort Study.

OBJECTIVES: To evaluate neurodevelopmental and mental disorders after PICU hospitalization in children requiring invasive mechanical ventilation for severe respiratory illness. DESIGN: Retrospective longitudinal observational cohort. SETTING: Texas Medicaid Analytic eXtract data from 1999 to 2012. PATIENTS: Texas Medicaid-enrolled children greater than or equal to 28 days old to less than 18 years old hospitalized for a primary respiratory illness, without major chronic conditions predictive of abnormal neurodevelopment. INTERVENTIONS: We examined rates of International Classification of Diseases, 9th revision-coded mental disorder diagnoses and psychotropic medication use following discharge among children requiring invasive mechanical ventilation for severe respiratory illness, compared with general hospital patients propensity score matched on sociodemographic and clinical characteristics prior to admission. Children admitted to the PICU for respiratory illness not necessitating invasive mechanical ventilation were also compared with matched general hospital patients as a negative control exposure. MEASUREMENTS AND MAIN RESULTS: Of 115,335 eligible children, 1,351 required invasive mechanical ventilation and were matched to 6,755 general hospital patients. Compared with general hospital patients, children requiring invasive mechanical ventilation had increased mental disorder diagnoses (hazard ratio, 1.43 [95% CI, 1.26-1.64]; p < 0.0001) and psychotropic medication use (hazard ratio, 1.67 [1.34-2.08]; p < 0.0001) following discharge. Seven-thousand seven-hundred eighty children admitted to the PICU without invasive mechanical ventilation were matched to 38,900 general hospital patients and had increased mental disorder diagnoses (hazard ratio, 1.08 [1.02-1.15]; p = 0.01) and psychotropic medication use (hazard ratio, 1.11 [1.00-1.22]; p = 0.049). CONCLUSIONS: Children without major comorbidity requiring invasive mechanical ventilation for severe respiratory illness had a 43% higher incidence of subsequent mental disorder diagnoses and a 67% higher incidence of psychotropic medication use. Both increases were substantially higher than in PICU patients with respiratory illness not necessitating invasive mechanical ventilation. Invasive mechanical ventilation is a life-saving therapy, and its application is interwoven with underlying health, illness severity, and PICU management decisions. Further research is required to determine which factors related to invasive mechanical ventilation and severe respiratory illness are associated with abnormal neurodevelopment. Given the increased risk in these children, identification of strategies for prevention, neurodevelopmental surveillance, and intervention after discharge may be warranted.

Rapid exome sequencing in PICU patients with new-onset metabolic or neurological disorders.

BACKGROUND: Genomic assessment previously took months to result and was unable to impact clinical care in the pediatric intensive care unit (PICU). The advent of rapid exome sequencing potentially changes this. We investigated the impact of rapid exome sequencing in a pilot study on pediatric patients admitted to a single PICU with new-onset metabolic/neurologic disease. METHODS: Rapid exome sequencing (7 days to verbal result) was performed on (n = 10) PICU patients age < 6 years admitted with new-onset metabolic/neurologic disease. The primary outcome of interest was inpatient LOS, which served as a proxy for inpatient cost. RESULTS: A significant reduction in median LOS was identified when comparing PICU patients who underwent rapid exome sequencing to historical controls. From those patients who underwent rapid sequencing, five had likely pathogenic variants. In three cases with diagnostic genetic results, there was a modification to clinical care attributable to information provided by exome sequencing. CONCLUSIONS: This pilot study demonstrates that rapid exome sequencing is feasible to do in the PICU, that genetic results can be returned quickly enough to impact critical care decision-making and management. In a select population of PICU patients, this technology may contribute to a decrease in hospital length of stay. IMPACT: Ten prospectively enrolled PICU patients with defined clinical criteria and their parents underwent rapid exome sequencing. Fifty percent received a genetic diagnosis, and medical management was affected for 60% of those patients. Median hospital LOS was significantly decreased in this selective subset of PICU patients. Genetic disorders and congenital anomalies are a leading cause of pediatric mortality. Genomic assessment previously took weeks to months for results and was therefore unable to acutely impact clinical care in the pediatric intensive care unit (PICU). The recent advent of rapid exome sequencing changes this in selected patients. Rapid exome sequencing is feasible to do in a PICU. Genetic results can be returned quickly enough to impact critical care decision-making. When done in a carefully selected subset of pediatric patients, rapid exome sequencing can potentially decrease hospital LOS.

Pediatric Anti-N-Methyl-d-Aspartate Receptor Encephalitis: A Review with Pooled Analysis and Critical Care Emphasis.

PURPOSE: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is being recognized with increasing frequency among children. Given the paucity of evidence to guide the critical care management of these complex patients, we provide a comprehensive review of the literature with pooled analysis of published case reports and case series. METHODS: We performed a comprehensive literature search using PubMed, Scopus, EMBASE, and Web of Science for relevant published studies. The literature search was conducted using the terms NMDA, anti-NMDA, Anti-N-methyl-d-aspartate, pediatric encephalitis, and anti-NMDAR and included articles published between 2005 and May 1, 2016. RESULTS: Forty-eight references met inclusion criteria accounting for 373 cases. For first-line treatments, 335 (89.8%) received high-dose corticosteroids, 296 received intravenous immunoglobulin (79.3%), and 116 (31%) received therapeutic plasma exchange. In these, 187 children (50.1%) had a full recovery with only minor deficits, 174 patients (46.7%) had partial recovery with major deficits, and 12 children died. In addition, 14 patients were reported to require mechanical ventilation. CONCLUSION: Anti-NMDA encephalitis is a formidable disease with great variation in clinical presentation and response to treatment. With early recognition of this second most common cause of pediatric encephalitis, a multidisciplinary approach by physicians may provide earlier access to first- and second-line therapies. Future studies are needed to examine the efficacy of these current therapeutic strategies on long-term morbidity.

Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination.

BACKGROUND: L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. METHODS AND RESULTS: Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. CONCLUSIONS: The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

Loss of function mutation in glutamic pyruvate transaminase 2 (GPT2) causes developmental encephalopathy.

Intellectual disability is genetically heterogeneous, and it is likely that many of the responsible genes have not yet been identified. We describe three siblings with isolated, severe developmental encephalopathy. After extensive uninformative genetic and metabolic testing, whole exome sequencing identified a homozygous novel variant in glutamic pyruvate transaminase 2 (GPT2) or alanine transaminase 2 (ALT2), c.459 C > G p.Ser153Arg that segregated with developmental encephalopathy in the family. This variant was predicted to be damaging by all in silico prediction algorithms. GPT2 is the gene encoding ALT2 which is responsible for the reversible transamination of alanine and 2-oxoglutarate to form pyruvate and glutamate. GPT2 is expressed in brain and is in the pathway to generate glutamate, an excitatory neurotransmitter. Functional assays of recombinant wild-type and mutant ALT2 proteins demonstrated the p.Ser153Arg mutation resulted in a severe loss of enzymatic function. We suggest that recessively inherited loss of function GPT2 mutations are a novel cause of intellectual disability.

Anesthesia in children: perspectives from nonsurgical pediatric specialists.

The Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) study investigates the potential neurotoxicity of anesthetics in the pediatric population. At a recent symposium, a panel of nonsurgical physicians from the disciplines of radiology, neurology, cardiology, and critical care discussed the role anesthesia plays in their respective practices. To execute diagnostic studies and/or therapeutic interventions in each of these disciplines, general anesthesia is oftentimes required for pediatric patients. Given recent publications in the literature suggesting the potential for neurotoxicity following anesthesia in pediatric patients, physicians, parents, and other stakeholders are now challenged to continue to balance safety with efficacy in caring for children. This paper summarizes the panelist presentations and the ensuing discussion at the 2014 PANDA symposium.

Advances in pediatric neurocritical care.

Because pediatric intensive care units (PICUs) improve survival for a range of acute diseases, attention has turned toward ensuring the best possible functional outcomes after critical illness. The neurocritical care of children is of increasing interest. However, the pediatric population encompasses a heterogeneous set of neurologic conditions, with several possible models of how best to address them. This article reviews the special challenges faced by PICUs with regards to diseases, technologies, and skills and the progress that has been made in treatment, monitoring, and prognostication. Recent advances in translational research expected to modify the field in the near-term are described.

Initial surgical experience with a dense cortical microarray in epileptic patients undergoing craniotomy for subdural electrode implantation.

OBJECTIVE: Detailed investigations of cortical physiology require the ability to record brain electrical activity at a submillimeter scale. Standard intracranial electrodes result in significant averaging of potentials generated by large numbers of neurons. In contrast, microelectrode arrays allow for recording of local field potentials and single-unit activity. We describe our initial surgical experience with the NeuroPort microelectrode array (Cyberkinetics Neurotechnology Systems, Inc., Salt Lake City, UT) in a series of patients undergoing subdural electrode implantation for epilepsy monitoring. METHODS: Seven patients were implanted with and underwent semichronic recording from the NeuroPort array during standard subdural electrode monitoring for epilepsy. The electrode was placed according to company specifications in putative noneloquent epileptogenic cortex. After the monitoring period, microelectrode arrays were removed during explantation of subdural electrodes and resection of epileptogenic tissue. RESULTS: Successful implantation of the microelectrode array was achieved in all patients, with minor operative difficulties. Robust and durable local field potentials and single-unit recordings were obtained from all implanted individuals. Implantation times ranged from 3 to 28 days; histological analysis of implanted tissue demonstrated no significant tissue injury or inflammatory response. There were no neurological complications or infections associated with electrode implantation or prolonged monitoring. Two patients developed postresection issues with wound healing at the site of scalp egress, with 1 requiring operative wound revision. CONCLUSION: Our experience demonstrates that semichronic microelectroencephalographic recording can be safely and effectively achieved using the NeuroPort microarray. Although significant tissue injury, infection, or cerebrospinal fluid leak was not encountered, the large profile of the connection pedestal resulted in suboptimal wound closure and healing in several patients. We predict that this problem will be easily addressed in second-generation devices.

Long-term outcome of symptomatic infantile spasms established by video-electroencephalography (EEG) monitoring.

In this study, we examine the long-term clinical outcome of children with symptomatic infantile spasm. The children between 2 and 18 years of age diagnosed with symptomatic infantile spasms were reviewed. Sixty-eight children (age range, 2-13 years; mean, 4.5 years) met the inclusion criteria. Children who underwent epilepsy surgery were excluded. Age of onset for infantile spasms ranged from 1 to 24 months (mean, 7.1 months). Developmental delay was noted in all; there was seizure freedom in 14 children (20.5%). Infantile spasms were reported as the only seizure type in 10 (14.5%) children older than age 2 years. During the follow-up; symptomatic generalized epilepsy was diagnosed in 23 children (34%) and focal epilepsy in 21 (31%). The long-term outcome of these children remains unchanged in the majority of the children with symptomatic infantile spasms. We could not establish any risk factor that might be related to favorable or adverse outcome.

Microphysiology of epileptiform activity in human neocortex.

The authors report the use of dense two-dimensional microelectrode array recordings to characterize fine resolution electrocortical activity ("microEEG") in epileptogenic human cortex. A 16-mm(2) 96 microelectrode array with 400-mum interelectrode spacing was implanted in five patients undergoing invasive EEG monitoring for medically refractory epilepsy. High spatial resolution data from the array were analyzed in conjunction with simultaneously acquired data from standard intracranial electrode grids and strips. microEEG recorded from within the epileptogenic zone demonstrates discharges resembling both interictal epileptiform activity ("microdischarges") and electrographic seizures ("microseizures") but confined to cortical regions as small as 200 microm(2). In two patients, this activity appeared to be involved in the initiation or propagation of electrographic seizures. The authors hypothesize that microdischarges and microseizures are generated by small cortical domains that form the substrate of epileptogenic cortex and play important roles in seizure initiation and propagation.

The frequency of non-epileptic spells in children: results of video-EEG monitoring in a tertiary care center.

RATIONALE: the diagnosis of non-epileptic spells (NES) in children can be challenging, even for experienced clinicians. Our objective was to describe the characteristics of such events. METHODS: this was a retrospective study conducted from January 2004 to December 2006. Inclusion criteria were age >1 month and <18 years and the diagnosis of NES established by video-EEG monitoring. RESULTS: among 746 monitored children (1203 recorded video-EEG sessions), 109 (14.6%) had NES. The mean age of patients with NES was 6.6 years (range 0.1-18). Seventy patients were diagnosed with NES alone; the remaining 39 with both NES and epilepsy. Developmental delay was more frequent among patients with a co-morbid diagnosis of epilepsy (p<0.001). Similar clinical events were reported in both of these groups, save for crying spells/irritability which was more common in children with epilepsy. Frequent manifestations of NES included staring spells in preschool children, crying/irritability, tremor and eye deviation in young children and preschoolers, and limb shaking in adolescents. All of the patients with epilepsy and 19 (27%) of those without epilepsy were receiving antiepileptic drugs. CONCLUSION: our data highlights the importance of accurate diagnosis of NES toward the appropriate treatment of affected children.

Magnetoencephalography in epilepsy: tailoring interpretation and making inferences.

Although the ability of magnetoencephalography (MEG) to detect epileptiform discharges noninvasively has long been known, only recently has it become a common tool in clinical settings. Whether MEG or electroencephalography (EEG) is superior has been controversial; MEG has a theoretic edge over EEG for precise localization, but EEG has many practical advantages. Experience has shown that they often provide different and complementary information. Although the results of careful MEG analysis can be quite precise, MEG interpretation, like that of EEG, is partly subjective and reader dependent. Therefore, the appearance of well-defined foci on MEG should not reflexively be regarded as conclusive, but weighed by judgment, experience, and an understanding of the assumptions and behavior of the localization model. We review selected studies in the past 2 years that are relevant to epilepsy. In particular, studies are described that provide insights into MEG's relation to EEG, its contribution to preoperative decision making, its application to benign Rolandic epilepsy, and analysis of secondary generalization.

Interactive use of cerebral angiography and magnetoencephalography in arteriovenous malformations: technical note.

OBJECTIVE: To minimize the risks associated with treating cortical cerebral arteriovenous malformations (AVMs), we developed a technique combining functional imaging and cerebral angiography. The functional loci obtained by performing magnetoencephalography (MEG) are projected onto stereoscopic pairs of a stereotactically derived digital subtraction angiogram. The result is a simultaneous three-dimensional perspective of the angioarchitecture of an AVM and its relationship to the sensorimotor cortex. METHODS: Eight patients underwent multimodality brain imaging, including magnetic resonance imaging, functional mapping via MEG, and stereotactic angiography using a modified Compass fiducial system (Compass International, Rochester, MN). The coordinates derived by performing MEG were superimposed onto stereotactic, stereoscopic, angiographic pairs using custom-made distortion correction and coordinate transfer software. RESULTS: The magnetoencephalographic angiogram allowed simultaneous viewing of the angioarchitecture of the AVM nidus, the feeding vessels, and the draining veins and their relationship to the normal cerebral vasculature and functional cortex. This imaging technique was particularly valuable in identifying en passant vessels that supplied functional cortex and was used during the treatment of these lesions. CONCLUSION: The techniques of MEG and cerebral angiography were combined to provide simultaneous viewing of both modalities in a three-dimensional perspective. This technique can aid in risk stratification in the management of patients with cerebral AVMs. In addition, this technique can facilitate the selective targeting of vessels, thus potentially reducing the risks associated with embolization of these formidable lesions.