Cynthia F. Salorio

Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood.

IMPORTANCE Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand. OBJECTIVE To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood. DESIGN, SETTING, AND PARTICIPANTS Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data. EXPOSURES A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months. MAIN OUTCOMES AND MEASURES The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior. RESULTS Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale = 111; performance = 108; verbal = 111) and unexposed siblings (scores: full scale = 111; performance = 107; verbal = 111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale = -0.2 (95% CI, -2.6 to 2.9); performance = 0.5 (95% CI, -2.7 to 3.7); and verbal = -0.5 (95% CI, -3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior. CONCLUSIONS AND RELEVANCE Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.

Gut vagal afferent lesions increase meal size but do not block gastric preload-induced feeding suppression

Subdiaphragmatic vagal afferent (SVA) signals arising from gut sites may provide critical feedback for the control of food intake within a meal. To evaluate the role of SVAs in both spontaneous and scheduled meals, food intake was assessed in two paradigms in male Sprague-Dawley rats. In the first study, control (Con) rats (n = 6) and rats with subdiaphragmatic vagal deafferentation (SDA) (n = 7) had 12-h nightly access to Ensure liquid diet (1 kcal/ml). SDA rats had larger and fewer meals and maintained initial rapid rates of licking, yet total numbers of licks were unaffected. In the second study, Con (n = 8) and SDA (n = 7) rats had scheduled access to 12. 5% liquid glucose after overnight food deprivation. Glucose intake was assessed after 5-ml gastric preloads of 0.9% saline or glucose, peptone, and Intralipid solutions at three concentrations (0.5, 1, and 2 kcal/ml). Glucose and peptone preloads suppressed intake similarly in Con and SDA rats, whereas Intralipid was ineffective. These results suggest that meal-related SVA signals 1) are not critical in determining preload-induced feeding suppression after deprivation, yet 2) contribute to satiety during spontaneous meals.Subdiaphragmatic vagal afferent (SVA) signals arising from gut sites may provide critical feedback for the control of food intake within a meal. To evaluate the role of SVAs in both spontaneous and scheduled meals, food intake was assessed in two paradigms in male Sprague-Dawley rats. In the first study, control (Con) rats ( n = 6) and rats with subdiaphragmatic vagal deafferentation (SDA) ( n = 7) had 12-h nightly access to Ensure liquid diet (1 kcal/ml). SDA rats had larger and fewer meals and maintained initial rapid rates of licking, yet total numbers of licks were unaffected. In the second study, Con ( n = 8) and SDA ( n = 7) rats had scheduled access to 12.5% liquid glucose after overnight food deprivation. Glucose intake was assessed after 5-ml gastric preloads of 0.9% saline or glucose, peptone, and Intralipid solutions at three concentrations (0.5, 1, and 2 kcal/ml). Glucose and peptone preloads suppressed intake similarly in Con and SDA rats, whereas Intralipid was ineffective. These results suggest that meal-related SVA signals 1) are not critical in determining preload-induced feeding suppression after deprivation, yet 2) contribute to satiety during spontaneous meals.

Neuroimaging correlates of anxiety after pediatric traumatic brain injury

BACKGROUND Anxiety disorders are common after traumatic brain injury (TBI). Data on the neural correlates of these conditions are lacking. This study examines the relationship between brain damage, particularly to the orbitofrontal cortex (OFC) and temporal lobe, and anxiety symptoms and disorders. METHODS Ninety-five children and adolescents were followed for one year postinjury. Preinjury and one-year postinjury anxiety status were obtained from the parent. Magnetic resonance imaging was performed to evaluate brain lesions. The primary analysis used regression models to determine relationships between brain lesions and anxiety outcomes. As a secondary analysis, previously reported posttraumatic stress disorder (PTSD) data were reanalyzed using similar methods for purposes of comparison. RESULTS The primary analysis showed that greater volume and number of OFC lesions correlated with decreased risk for anxiety, whereas lesions in other brain areas did not correlate with anxiety. Consistent with prior data, the secondary analysis showed an inverse correlation between OFC damage and PTSD; temporal lobe damage was positively correlated with PTSD. CONCLUSIONS After pediatric TBI, greater damage to the OFC is associated with decreased risk for anxiety outcomes. Similar to adult data, these findings implicate OFC dysfunction in childhood anxiety. Temporal lobe damage did not correlate with anxiety, in contrast to the findings for PTSD.

Characterization of bombesin binding sites in the rat stomach

We characterized the bombesin receptor population in the rat stomach and determined the receptor subtype mediating the contractile effect of bombesin in the gastric fundus. Using in vitro receptor autoradiography, we evaluated the ability of the specific gastrin-releasing peptide-preferring receptor antagonist [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester to inhibit binding of 125I-[Tyr4]bombesin to the gastric fundus, corpus and antrum. Binding to these regions was completely inhibited by [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester suggesting that these receptors are the gastrin-releasing peptide-preferring subtype. We found that the rank order of potency for the contractile effect of bombesin, and the related mammalian peptides neuromedin C and neuromedin B, was bombesin > neuromedin C > neuromedin B. [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester was equipotent in antagonizing contractions produced by all three peptides. Furthermore, receptor tachyphylaxis to either neuromedin C or neuromedin B abolished the subsequent contractile response elicited by neuromedin C and neuromedin B, suggesting that one bombesin receptor subtype mediates rat gastric fundal contractions. Together, these results demonstrate that the bombesin receptor subtype in the rat stomach is gastrin-releasing peptide-preferring subtype and that this subtype is responsible for the effects of bombesin-like peptides on fundal smooth muscle contraction.

Parent-rated emotional-behavioral and executive functioning in childhood epilepsy.

The present study examined clinical and demographic risk factors associated with parent-rated emotional-behavioral and executive functioning in children and adolescents with epilepsy. The medical records of 152 children and adolescents with epilepsy referred for neuropsychological evaluation were reviewed. Results indicated that the sample displayed significantly elevated symptoms across the emotional-behavioral and executive domains assessed. Executive functioning and behavioral symptoms had the highest rates of clinically elevated scores, with lowest rates of elevated scores in internalizing and externalizing emotional problems. Only 34% of those participants with clinically significant emotional-behavioral or executive functioning difficulties had a history of psychological or counseling services, highlighting the underserved mental health needs of this population. In regard to clinical factors, the majority of seizure-related variables were not associated with emotional-behavioral or executive functioning. However, the frequency of seizures (i.e., seizure status) was associated with behavioral regulation aspects of executive functioning, and the age at evaluation was associated with externalizing problems and behavioral symptoms. Family psychiatric history (with the exception of ADHD) was associated with all domains of executive and emotional-behavioral functioning. In summary, emotional-behavioral and executive functioning difficulties frequently co-occur with seizures in childhood epilepsy, with both seizure-related and demographic factors contributing to the presentation of such neurobehavioral comorbidities. The present findings provide treatment providers of childhood epilepsy with important information to assist in better identifying children and adolescents who may be at risk for neurobehavioral comorbidities and may benefit from intervention.

Functional outcomes in children with abusive head trauma receiving inpatient rehabilitation compared with children with nonabusive head trauma.

OBJECTIVE To compare clinical features and functional outcomes of age- and sex-matched children with abusive and nonabusive head trauma receiving inpatient rehabilitation. STUDY DESIGN Children with abusive head trauma (n = 28) and age- and sex-matched children with nonabusive head trauma (n = 20) admitted to an inpatient pediatric rehabilitation unit from 1995-2012 were studied. Acute hospitalization and inpatient rehabilitation records were retrospectively reviewed for pertinent clinical data: initial Glasgow Coma Scale score, signs of increased intracranial pressure, neuroimaging findings, and presence of associated injuries. Functional status at admission to and discharge from inpatient rehabilitation was assessed using the Functional Independence Measure for Children. Outcome at discharge and outpatient follow-up were described based on attainment of independent ambulation and expressive language. RESULTS Children with abusive and nonabusive head trauma had similar levels of injury severity, although associated injuries were greater in those with abusive head trauma. Functional impairment upon admission to inpatient rehabilitation was comparable, and functional gains during inpatient rehabilitation were similar between groups. More children with nonabusive than with abusive head trauma attained independent ambulation and expressive language after discharge from rehabilitation; the difference was no longer significant when only children aged >12 months at injury were examined. There was variability in delay to obtain these skills and in the quality of gained skills in both groups. CONCLUSIONS Despite more associated injuries, children with abusive head trauma make significant functional gains during inpatient rehabilitation, comparable with an age- and sex-matched sample with nonabusive head trauma. Key functional skills may be gained by children in both groups following discharge from inpatient rehabilitation.

Physical Abilities and Mobility Scale: reliability and validity in children receiving inpatient rehabilitation for acquired brain injury.

OBJECTIVE To investigate the psychometric properties of the Physical Abilities and Mobility Scale (PAMS) in children receiving inpatient rehabilitation for acquired brain injury (ABI). DESIGN Admission and discharge PAMS item and total scores were evaluated. The WeeFIM was used as the criterion standard. A case study was used to illustrate the complementary nature of the PAMS and WeeFIM. SETTING A single, free-standing, academically affiliated pediatric rehabilitation hospital. PARTICIPANTS Children (N=107) aged 2 through 18 years receiving inpatient rehabilitation for ABI between March 2009 and March 2012. Forty-two additional children treated during this time were excluded because of missing PAMS data. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Internal consistency was evaluated using Cronbach alpha. Interrater reliability was evaluated through overall agreement, Pearson correlations, and intraclass correlations. Construct validity was examined through exploratory factor analysis. Criterion validity was explored through correlations of PAMS overall and factor scores with WeeFIM total and subscale scores. Sensitivity to recovery was examined using paired t tests, examining differences between admission and discharge scores for each item and for the total score. RESULTS Internal consistency and interrater reliability were high. Factor analysis revealed 2 factors: lower-level skills and higher-level mobility skills. Correlations with the WeeFIM ranged from moderate to very strong; total PAMS score most strongly correlated with the WeeFIM mobility subscore. Total PAMS score and each item score significantly increased between admission and discharge. CONCLUSIONS The PAMS is a reliable and valid measure of progress during inpatient rehabilitation for children with ABI. By capturing fine-grain progress toward both lower-level and higher-level mobility skills, the PAMS complements the WeeFIM in assessing functional gains during the rehabilitation stay.

Use of a Cumulative Risk Scale to Predict Poor Intellectual and Academic Outcomes in Childhood Epilepsy

Discrete risk factors for poor outcomes in childhood epilepsy have been identified, but it is unclear whether the combined effect of several risk factors better predicts outcome. The Epilepsy Cumulative Risk Scale was developed to quantify cumulative risk for poor outcomes in childhood epilepsy. Participants included 156 clinic-referred children with epilepsy. The Epilepsy Cumulative Risk Scale was developed using variables previously associated with functional outcomes. Scale utility was examined through its association with intellectual and academic functioning. All Epilepsy Cumulative Risk Scale variables were significantly associated with functioning. The Total Score (ie, cumulative effect) was most strongly correlated with cognition and academic skills. A Total Score ≥ 5 had the best sensitivity and specificity for differentiating those at high risk for poor outcomes. The Epilepsy Cumulative Risk Scale shows promise as a practical, data-driven tool for quantification of cumulative risk for poor outcomes in childhood epilepsy and may be helpful in detecting those needing referral for additional services.

The influence of comorbid asthma on the severity of symptoms in children with attention-deficit hyperactivity disorder

ABSTRACT Objective: The current study examined the association between asthma and attention-deficit hyperactivity disorder (ADHD) symptoms in a clinical pediatric sample. Methods: Demographic and neuropsychological data for children with a billing diagnosis of ADHD were extracted from a clinical database. Families completed standard rating scales. Seventy-one patients with a co-morbid asthma diagnosis were identified and matched by age to a group of 71 patients with only ADHD. Results: Children with asthma and ADHD were more likely to display clinically elevated levels of hyperactivity, externalizing behaviors, anxiety, and hyperactive/impulsive behaviors compared to children with ADHD alone. Boys with asthma and ADHD had more symptoms than boys with only ADHD of somatization and emotional internalizing, while girls with asthma and ADHD had more symptoms of hyperactivity/impulsivity, conduct problems, anxiety, and emotional internalizing compared to girls with only ADHD. Conclusions: Findings suggest that in children with ADHD, co-morbid asthma is associated with increased behavioral and internalizing symptoms, with distinct gender differences present. Increased behavioral and internalizing symptoms seen in children with both asthma and ADHD may be due to the burden of their medical condition. No difference was found on cognitive variables, suggesting chronic hypoxia may be less influential in explaining these differences. Future research should determine the specific mechanisms of these differences.

Injury Severity Variables as Predictors of WeeFIM Scores in Pediatric TBI: Time to Follow Commands Is Best

After pediatric traumatic brain injury (TBI), early prognosis of expected function is important for optimizing care. The power of several common brain injury severity measures for predicting functional outcome in children with TBI was investigated; the severity variables studied were Glasgow Coma Scale (GCS) score, time to follow commands (TFC), duration of post-traumatic amnesia (PTA), and total duration of impaired consciousness (TFC+PTA). Outcome was assessed using the Functional Independence Measure for Children (WeeFIM) at discharge from inpatient rehabilitation (n = 120) and, in a subset of children, at 3 months following discharge. Correlations and multiple linear regression analyses were conducted using GCS, TFC, PTA, and TFC+PTA to predict age-corrected WeeFIM scores. Models in which TFC and PTA duration were entered as separate variables and as a combined variable (TFC+PTA) were all significantly predictive of WeeFIM scores at discharge; however, TFC accounted for the greatest portion of variance in WeeFIM scores. Among children with moderate to severe TBI who received inpatient rehabilitation, TFC was the best predictor of general functional outcome at discharge and follow-up. Our findings highlight the need for careful and consistent assessment of TFC to assist in predicting functional outcomes as early and accurately as possible.