Extracapsular versus intracapsular tonsillectomy: Outcomes in children with a focus on developmental delay.

INTRODUCTION: Outcomes following intracapsular tonsillectomy (IT) have not been well established in children with developmental delays. The objective of this study was to compare outcomes and complications between intracapsular and extracapsular tonsillectomy (TT) in pediatric patients with developmental delay (DD) in comparison to non-developmentally delayed children. METHODS: This is a retrospective study of pediatric patients with DD undergoing tonsillectomy between 2016 and 2019 at a tertiary care hospital. This group included patients with Down Syndrome, Autism Spectrum Disorder, other genetic syndromes, and patients with a diagnosis of global developmental delay. Outcomes and complications were analyzed for IT and TT. RESULTS: 2267 charts were reviewed, and 320 patients were identified with DD. Of those, 72 patients underwent IT and 248 underwent TT. In the DD cohort, the IT group had a shorter length of stay (0.97 vs 1.7 days, p < .0001) and was less likely to receive post-operative narcotic medication (2.8% vs 35%, p < .0001) and corticosteroids (9.7% vs 64%, p < .0001) during their hospital stay. Reductions in emergency room (ER) visits (5.6% vs 10%, p = .21) and post-op bleeding (PTH) (1.4% vs 4.8%, p = .31) for IT vs TT were not statistically significant in the DD group. In the NDD group, fewer patients undergoing IT returned to the ER (11% vs 2.3%, p < .0001) or had PTH (4.8% vs 0.25%, p, 0.0001) as compared to those children undergoing TT. There was no difference between parental report of symptom improvement between the groups (39% vs 33%, p = .39). Analysis of 180 patients with preoperative and postoperative sleep study data revealed post-op Apnea Hypopnea Index (AHI) improved with both techniques (74% TT vs 79% IT, p = .7). There were no differences noted for persistent obstructive sleep apnea (OSA) among the two techniques for both study groups (p = .63). CONCLUSION: Children with DD undergoing IT have reduced length of stay and reduced inpatient administration of post-operative opioids and steroids. IT has comparable efficacy to TT in treating symptoms of pediatric sleep apnea with a better safety profile. Overall, children undergoing IT return to the operating room less frequently than those undergoing TT. Longer follow-up studies will be needed to evaluate rate of tonsil regrowth, risk of revision surgery and persistence of OSA in these patients.

Point of care, clinician-performed laryngeal ultrasound and pediatric vocal fold movement impairment.

INTRODUCTION: Vocal fold movement impairment (VFMI) is a well-known sequela of cervical and thoracic procedures performed in the vicinity of the recurrent laryngeal nerve. Interpretation of flexible nasolaryngoscopy (FNL) can be difficult in young children due to crying, secretions, and obstructing supraglottic structures. We have previously published on the use of radiologist performed and interpreted, laryngeal ultrasound (LUS) to evaluate vocal fold mobility with substantial agreement with FNL in infants in the cardiovascular intensive care unit. The purpose of this study was to evaluate point of care, clinician performed, LUS for vocal fold mobility in a pediatric voice clinic. METHODS: LUS and FNL were performed and recorded on 30 consecutive patients (11 with a clinical diagnosis of VFMI and 19 with clinically normal mobility) in a pediatric voice clinic. All LUS was performed by a single clinician (reviewer 1) with a GE logiq P9 and 12 MHz linear probe. Deidentified recordings of the LUS and FNL (without sound) were reviewed in random order by 2 fellowship trained pediatric otolaryngologists who were blinded to the vocal fold mobility. Cohen's kappa was used to determine agreement. RESULTS: There was substantial agreement (κ  = 0.7) between the reviewers regarding interpretation of LUS as well as regarding interpretation of FNL κ  = 0.7802. In addition, each reviewer had near perfect to substantial agreement between their interpretation of the LUS and FNL (reviewer 1 κ  = 0.9294 and reviewer 2 κ  = 0.8413). CONCLUSION: Point of care, clinician performed, LUS can be used for the identification of VFMI with substantial agreement with FNL with good inter-rater reliability. This provides clinicians with another tool in their armamentarium for the evaluation of challenging larynges.

Vortioxetine Reduces Marble Burying but Only Transiently Enhances Social Interaction Preference in Adult Male BTBR T+Itpr3tf/J Mice.

Vortioxetine is a multimodal antidepressant with agonist activity at serotonin (5-HT)1A and 5-HT1B receptors that blocks the 5-HT transporter (SERT). Previously in male BTBR T+Itpr3tf/J (BTBR) mice, the 5-HT1A partial agonist buspirone and SERT blocker fluoxetine enhanced social interaction but did not reduce marble burying. We hypothesized that vortioxetine through its actions at SERT and 5-HT1A could improve BTBR sociability and via 5-HT1B could reduce burying better than sertraline, a selective SERT blocker. Vortioxetine (5-10 mg/kg) or sertraline (2 mg/kg) was administered 30 min presociability and 75 min prior to marble burying tests. Vortioxetine (10 mg/kg) occupancy (%) was 84 ± 1 for SERT, 31 ± 12 for 5-HT1A, and 80 ± 5 for 5-HT1B in brain at 110 min postinjection, and serum oxytocin was 24% lower (p < 0.01) in vortioxetine-treated mice. Vortioxetine reduced novel object investigation, whereas sertraline enhanced overall sociability. However, the vortioxetine-induced increase in social sniffing was transient, as it was lost with 60-120 min presociability test delays in subsequent experiments. Vortioxetine and sertraline both reduced BTBR marble burying. Based on vortioxetine occupancy, actions at SERT and/or 5-HT1B are more likely to underlie its behavioral effects than 5-HT1A. Overall, vortioxetine has great potential for suppressing restrictive-repetitive behaviors, but it appears less promising as a sociability enhancer.

Prenatal metformin exposure or organic cation transporter 3 knock-out curbs social interaction preference in male mice.

Poorly managed gestational diabetes can lead to severe complications for mother and child including fetal overgrowth, neonatal hypoglycemia and increased autism risk. Use of metformin to control it is relatively new and promising. Yet safety concerns regarding gestational metformin use remain, as its long-term effects in offspring are unclear. In light of beneficial findings with metformin for adult mouse social behavior, we hypothesized gestational metformin treatment might also promote offspring sociability. To test this, metformin was administered to non-diabetic, lean C57BL/6 J female mice at mating, with treatment discontinued at birth or wean. Male offspring exposed to metformin through birth lost social interaction preference relative to controls by time in chambers, but not by sniffing measures. Further, prenatal metformin exposure appeared to enhance social novelty preference only in females. However due to unbalanced litters and lack of statistical power, firm establishment of any sex-dependency of metformin's effects on sociability was not possible. Since organic cation transporter 3 (OCT3) transports metformin and is dense in placenta, social preferences of OCT3 knock-out males were measured. Relative to wild-type, OCT3 knock-outs had reduced interaction preference. Our data indicate gestational metformin exposure under non-diabetic conditions, or lack of OCT3, can impair social behavior in male C57BL6/J mice. Since OCT3 transports serotonin and tryptophan, impaired placental OCT3 function is one common mechanism that could persistently impact central serotonin systems and social behavior. Yet no gross alterations in serotonergic function were evident by measure of serotonin transporter density in OCT3, or serotonin turnover in metformin-exposed offspring brains. Mechanisms underlying the behavioral outcomes, and if with gestational diabetes the same would occur, remain unclear. Metformin's impacts on placental transporters and serotonin metabolism or AMPK activity in fetal brain need further investigation to clarify benefits and risks to offspring sociability from use of metformin to treat gestational diabetes.

Acute dietary tryptophan manipulation differentially alters social behavior, brain serotonin and plasma corticosterone in three inbred mouse strains.

Clinical evidence indicates brain serotonin (5-HT) stores and neurotransmission may be inadequate in subpopulations of individuals with autism, and this may contribute to characteristically impaired social behaviors. Findings that depletion of the 5-HT precursor tryptophan (TRP) worsens autism symptoms support this hypothesis. Yet dietetic studies show and parents report that many children with autism consume less TRP than peers. To measure the impact of dietary TRP content on social behavior, we administered either diets devoid of TRP, with standard TRP (0.2 g%), or with 1% added TRP (1.2 g%) overnight to three mouse strains. Of these, BTBRT(+)Itpr3(tf)/J and 129S1/SvImJ consistently exhibit low preference for social interaction relative to C57BL/6. We found that TRP depletion reduced C57BL/6 and 129S social interaction preference, while TRP enhancement improved BTBR sociability (p < 0.05; N = 8-10). Subsequent marble burying did not differ among diets or strains. After behavior tests, brain TRP levels and plasma corticosterone were higher in TRP enhanced C57BL/6 and BTBR, while 5-HT levels were reduced in all strains by TRP depletion (p < 0.05; N = 4-10). Relative hyperactivity of BTBR and hypoactivity of 129S, evident in self-grooming and chamber entries during sociability tests, were uninfluenced by dietary TRP. Our findings demonstrate mouse sociability and brain 5-HT turnover are reduced by acute TRP depletion, and can be enhanced by TRP supplementation. This outcome warrants further basic and clinical studies employing biomarker combinations such as TRP metabolism and 5-HT regulated hormones to characterize conditions wherein TRP supplementation may best ameliorate sociability deficits.

Enhanced novelty-induced corticosterone spike and upregulated serotonin 5-HT1A and cannabinoid CB1 receptors in adolescent BTBR mice.

Hypothalamic pituitary adrenal (HPA) axis responses to change and social challenges during adolescence can influence mental health and behavior into adulthood. To examine how HPA tone in adolescence may contribute to psychopathology, we challenged male adolescent (5 weeks) and adult (16 weeks) BTBR T(+)tf/J (BTBR) and 129S1/SvImJ (129S) mice with novelty in sociability tests. In prior studies these strains had exaggerated or altered HPA stress responses and low sociability relative to C57BL/6J mice in adulthood. In adolescence these strains already exhibited similar or worse sociability deficits than adults or age-matched C57 mice. Yet BTBR adolescents were less hyperactive and buried fewer marbles than adults. Novelty-induced corticosterone (CORT) spikes in adolescent BTBR were double adult levels, and higher than 129S or C57 mice at either age. Due to their established role in HPA feedback, we hypothesized that hippocampal Gαi/o-coupled serotonin 5-HT1A and cannabinoid CB1 receptor function might be upregulated in BTBR mice. Adolescent BTBR mice had higher hippocampal 5-HT1A density as measured by [(3)H] 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) binding than C57 mice, and adult BTBR 8-OH-DPAT-stimulated GTPγS binding was higher than in either C57 or 129S mice in this region. Further, BTBR hippocampal CB1 density measured by [(3)H]CP55,940 binding was 15-20% higher than in C57. CP55,940-stimulated GTPγS binding in adult BTBR dentate gyrus was 30% higher then 129S (p<0.05), but was not a product of greater neuronal or cell density defined by NeuN and DAPI staining. Hence hyperactive HPA responsiveness during adolescence may underlie 5-HT1A and CB1 receptor up-regulation and behavioral phenotype of BTBR mice.