Effect of inter-swallow interval on striated esophagus peristalsis; a comparative study with smooth muscle esophagus.

BACKGROUND: Effect of inter-swallow interval on the contractility of smooth muscle esophagus is well-documented. However, the effects on peristalsis of the striated esophagus have not been systematically studied. A better understanding of striated esophagus motor function in health and disease may enhance the interpretation of manometric studies and inform clinical care. The aim of this study was to assess the effect of inter-swallow interval on striated esophagus compared to findings with that of the smooth muscle esophagus. METHODS: We performed two sets of studies to (1) determine the effect of various inter-swallow interval in 20 healthy volunteers and (2) assess the effect of ultra-short swallow intervals facilitated by straw drinking in 28 volunteers. We analyzed variables using ANOVA with Tukey's pairwise comparison and paired t-test. KEY RESULTS: Unlike smooth muscle esophagus, the striated esophagus contractile integral did not change significantly for swallow intervals ranging from 30 to 5 s. On the contrary, striated esophagus demonstrated absent or reduced peristalsis in response to ultra-short (<2 s) intervals during straw-facilitated multiple rapid swallows. CONCLUSIONS AND INFERENCES: Striated esophagus peristalsis is subject to manometrically observed inhibition during swallows with ultra-short intervals. Inter-swallow intervals as short as 5 s that inhibit smooth muscle esophagus peristalsis do not inhibit striated muscle peristalsis. The mechanisms of these observations are unknown but may relate to central or myenteric nervous system influences or the effects of pharyngeal biomechanics.

Clinical characteristics and long-term outcomes in patients with cyclic vomiting syndrome: A 15-year experience at a tertiary referral center.

BACKGROUND: Cyclic vomiting syndrome (CVS) is a disorder of gut-brain interaction (DGBI) characterized by recurrent episodes of nausea and vomiting. Most children outgrow their CVS symptoms and develop migraine headaches, but there are limited data in adults. We thus sought to determine the natural history of CVS in adults. METHODS: We conducted a retrospective analysis of patients at a specialized tertiary care clinic. Frequency of CVS episodes, emergency department (ED) visits, and hospitalizations were recorded at the index visit and at follow-up. KEY RESULTS: Of 455 CVS patients with complete data, mean age was 33 ± 13 years, 294 (65%) were female, and 392 (86%) were Caucasian. Mean duration of follow-up was 47.4 ± 37.2 months. There was a significant reduction in frequency of CVS episodes/year (18 to 6.8), ED visits (6.1 to 2), and hospitalizations (2.3 to 0.7) (all p-values < 0.001) but only 88 (19%) of patients had complete resolution of episodes at follow-up. On multivariable regression analysis, non-white race [0.33 (0.11-0.98) p = 0.01], comorbidity count [0.77 (0.62-0.95) p = 0.01], cannabis use [0.36 (0.2-0.65) p = 0.0007], and aprepitant use [0.2 (0.08-0.005) p < 0.001] were associated with a reduced odds of complete resolution of CVS episodes. Of note, 19 patients (4%) died. CONCLUSIONS AND INFERENCES: While most adults with CVS improved with specialized care, in contrast to children, only a small subset (~1 in 5) had complete resolution of symptoms. Reasons for the effects of race, cannabis use, and comorbidity burden on outcomes in CVS are unclear and warrant further investigation.

Efficacy of aprepitant as a prophylactic medication in adults with cyclic vomiting syndrome.

BACKGROUND: Aprepitant is a neurokinin-1 receptor antagonist, and recent guidelines by the American Neurogastoenterology and Motility Society recommend its use as prophylaxis in moderate-to severe cyclic vomiting syndrome (CVS). Data are limited to small studies in children. We aimed to determine its efficacy in adults with CVS. METHODS: A retrospective review of CVS patients diagnosed using Rome criteria at a tertiary referral center was conducted. Drug response was defined as >50% reduction in symptoms and/or healthcare utilization. An intent-to-treat (ITT) analysis was conducted. KEY RESULTS: Of 96 patients prescribed aprepitant, 26 (27%) were unable to start due to cost/lack of insurance coverage. Of 70 receiving therapy, mean age was 33 ± 11 years; 51 (73%) were female and 56 (80%) Caucasian. The majority (93%) were refractory to other prophylactic medications. Aprepitant was taken thrice weekly in 51 (73%), daily in 16 (23%) and a few times a month in 3 (4%) due to cost. Fifty (71.4%) had a global symptom response to aprepitant. There was significant reduction in the number of CVS episodes (14.5 ± 11.7 to 6.2 ± 8.0, p < 0.0001), emergency department visits (4.2 ± 7.7 to 1.8 ± 3.4, p = 0.006), and hospital admissions (1.6 ± 3.9 to 0.8 ± 2.1, p = 0.02) in patients treated with aprepitant. Seven (10%) discontinued the drug due to minor side effects. CONCLUSIONS AND INFERENCES: Aprepitant is a safe and effective prophylactic medication in adults with refractory CVS. Adequate insurance coverage is a major barrier preventing its use.

Natural History of Pediatric Cyclic Vomiting Syndrome: Progression to Dysautonomia.

BACKGROUND: The clinical features of pediatric cyclic vomiting syndrome (CVS) often evolve over time. Many patients develop a constellation of chronic symptoms that suggest autonomic nervous system (ANS) dysfunction during adolescence. We aimed to determine the proportion of children with CVS who develop chronic rather than episodic symptoms consistent with ANS dysfunction. METHODS: Retrospective chart review of children ages 0-18 years followed in an outpatient tertiary care CVS center. Patients completed standardized questionnaires at intake and follow-up visits, documenting clinical symptom pattern. Continuous variables are summarized as median [interquartile range (IQR)]. A Mann-Whitney test was used for group comparisons. RESULTS: One hundred subjects were included. A total of 40% developed symptoms of ANS dysfunction (ANS+); 20% were confirmed by comprehensive ANS testing, 11% by orthostatic vital sign abnormalities, and 9% by clinical symptoms. The median (IQR) age at onset of chronic symptoms was 14 (10.02, 15) years. The presence of another disorder of gut-brain interaction ( P = 0.018) and a greater number of comorbidities ( P = 0.031) were more common in the ANS+ group. ANS+ subjects missed more school days ( P = 0.047) and were seen less frequently in the emergency department ( P = 0.023). CONCLUSIONS: Many children with CVS (40%) develop symptoms consistent with clinical dysautonomia in adolescence. These patients experience more comorbid conditions and a greater impact on school attendance, possibly representing a worsened quality of life as their disease course transitions to daily symptoms. When symptoms of CVS change over time, therapeutic interventions may need to be adjusted and targeted accordingly.

Cardiac Vagal Regulation Is Impeded in Children With Cyclic Vomiting Syndrome.

INTRODUCTION: The pathophysiology underlying cyclic vomiting syndrome (CVS) remains undefined. Scant data and distinct clinical features point to altered autonomic nervous system function. Autonomic signaling can be noninvasively assessed through cardiac indices of parasympathetic vagal regulation, which is reduced in children with disorders of gut-brain interaction. We aimed to examine dynamic cardiac vagal regulation in children with CVS compared with that in healthy controls (HC). METHODS: A total of 31 children with CVS evaluated in a tertiary care CVS center and 66 HC (ages 8-18 years) underwent cardiac autonomic function assessment. Electrocardiogram recordings were conducted during 3-minute sit/stand/sit posture challenges. The electrocardiogram-derived variables heart period, respiratory sinus arrhythmia (RSA), and vagal efficiency (VE) were analyzed using linear regression and mixed-effects modeling. RESULTS: After exclusion of medication confounders, 23 patients with CVS were included in analyses. Both groups were comparable in age, gender, and body mass index. Compared with HC, children with CVS had shorter heart period (standardized mean difference range: 1.15-1.22, all P values < 0.05) and lower RSA (SMD range: 0.66-0.88, all P values < 0.05). Patients with CVS had significantly lower VE during the entire course of posture shifts, compared with HC ( B = -19.87, SE = 6.95, t = -2.86, P = 0.005, SMD = 0.76). DISCUSSION: Children with CVS have suboptimal parasympathetic autonomic regulation compared with HC, indexed by reduced RSA and VE, even during their interepisodic well phase. Abnormal vagal modulation may underlie CVS pathophysiology, comorbidities, and triggers. Assessing VE during posture stressors could inform therapeutic interventions.

Cyclic Vomiting Syndrome-Related Hospitalizations Trends, Comorbidities & Health Care Costs in Children: A Population Based Study.

AIM: To analyze the clinical characteristics, trends in hospitalization and health care resource utilization of pediatric patients with cyclical vomiting syndrome (CVS). METHODS: We analyzed the latest 5 Healthcare Cost and Utilization Project-Kids Inpatient Database (HCUP-KID) datasets including years 2003, 2006, 2009, 2012 and 2016 for patients aged 1-20 years with a primary diagnosis of CVS and were compared with Age/gender-matched controls for comorbidities, clinical outcomes, and healthcare resource utilization. RESULTS: A total of 12,396 CVS-related hospitalizations were analyzed. The mean age of CVS patients was 10.4 ± 6.7 years. CVS was associated with dysautonomia (OR: 12.1; CI: 7.0 to 20.8), dyspepsia (OR: 11.9; CI: 8.8 to 16.03), gastroesophageal reflux disease (OR: 6.9; Confidence Interval (CI): 6.4 to 7.5), migraine headaches (OR: 6.8; CI: 5.9 to 7.7) and irritable bowel syndrome (OR: 2.08; CI: 1.2 to 4.3) (all p < 0.001). CVS was also associated with increased cannabis use (OR: 5.26, 4.6 to 5.9; p < 0.001), anxiety disorder (OR: 3.9; CI: 3.5 to 4.4) and stress reaction (OR: 3.6; CI: 2.06 to 6.3), p < 0.001. Mean CVS-related hospitalization costs (inflation adjusted) more than doubled from $3199 in 2003 to $6721 in 2016, incurring $84 million/year in total costs. CONCLUSION: Hospitalized CVS patients have increased prevalence of DGBIs, dysautonomia, psychiatric conditions and cannabis use compared to non-CVS controls. CVS-related hospitalizations in U.S. is associated with increasing health care costs. Better management of CVS and comorbid conditions is warranted to reduce health care costs and improve outcomes.

Development and Assessment of a Low Literacy, Pictographic Cyclic Vomiting Syndrome Action Plan.

OBJECTIVE: To develop and assess an evidence-based, individualized Cyclic Vomiting Syndrome Action Plan (CVSAP) to optimize both preventative and acute care. STUDY DESIGN: This implementation science project synthesized a combination of clinical practice guidelines, published literature, and clinical experience by a team of CVS clinicians to develop the CVSAP. The tool was developed to include validated pictograms and an automatic, embedded, weight-based dosing calculator to output acute management recommendations. The final version of the CVSAP was tested by patients/caregivers, readability calculators, medical librarians, and clinicians using validated metrics. RESULTS: All pictograms met the criteria for inclusion in the CVSAP. A composite readability score of 5.32 was consistent with a fifth-grade level. Patients/caregivers (n = 70) judged the CVSAP to be of high quality with consumer information rating form rating of 84.2%. Six medical librarians rated the CVSAP to have 93% understandability and 100% actionability, and 33 clinicians completing the SAM generated a suitability rating of 87.5%. CONCLUSIONS: The CVSAP visually highlights individualized care plan components to facilitate optimized preventative and acute CVS care. Further investigation will determine if CVSAP increases caregiver confidence and compliance in home management and improves quality of life and clinical outcomes for patients with CVS.

Cardiac autonomic regulation and joint hypermobility in adolescents with functional abdominal pain disorders.

BACKGROUND: Joint hypermobility (JH) is associated with autonomic nervous system dysregulation and functional abdominal pain disorders (FAPDs). Understanding the neurophysiological processes linking these conditions can inform clinical interventions. Autonomic activity regulates gastrointestinal (GI) sensorimotor function and may be a key mechanism. The aims of this study were to examine the relation of JH with dynamic autonomic activity and parasympathetic regulation in adolescents with FAPDs and identify optimal JH cutoff scores that best index autonomic regulation in FAPDs. METHODS: A total of 92 adolescents with FAPDs and 27 healthy controls (age 8-18 years; 80% female) were prospectively enrolled. JH was assessed by Beighton scores. ECG recordings were conducted during supine, sitting, and standing posture challenges. ECG-derived variables-heart period (HP), respiratory sinus arrhythmia (RSA), and vagal efficiency (VE)-were analyzed using linear regression and mixed effects modeling. KEY RESULTS: Beighton scores of ≥4 optimally distinguished autonomic function. Adolescents with FAPD and JH had reduced VE compared to adolescents with FAPDs without JH (B = 18.88, SE = 6.25, p = 0.003) and healthy controls (B = 17.56, SE = 8.63, p = 0.044). These subjects also had lower and less dynamic RSA and HP values during posture shifts, with strongest differences in supine position and using the VE metric. CONCLUSIONS & INFERENCES: Suboptimal autonomic regulation indexed by reduced vagal efficiency may be a mechanism of symptoms in hypermobile FAPD patients with Beighton score ≥ 4. Autonomic disturbance may serve as potential intervention target for patients with JH and functional GI disorders.

Cyclic vomiting syndrome: A narrative review and guide to management.

OBJECTIVES/BACKGROUND: Cyclic vomiting syndrome (CVS) is a disabling disorder of gut-brain interaction manifested by stereotypical and severe episodes of nausea and vomiting. Prevalence data indicate that CVS affects 1-2% of children and there has been a recent dramatic rise in diagnosed adults. METHODS: This narrative review summarizes relevant literature pertaining to pediatric and adult CVS and provides a guide to management based on extensive clinical experience. RESULTS: More timely diagnosis is facilitated by an expert consensus diagnostic approach and limited testing. Some diagnostic tests of exclusion remain essential. These include an upper gastrointestinal (GI) contrast study to exclude intestinal malrotation and basic laboratory screening. An abdominal ultrasound is recommended to exclude renal hydronephrosis in children and biliary disease in adults. Exclusion of metabolic/genetic conditions is warranted in those with specific warning signs, presentation in infants/toddler age, and in those with refractory disease. In the absence of chronic GI symptoms, referral to a GI specialist for upper endoscopy is generally not necessary in children but recommended in adults. A large subset termed migraine-equivalent CVS display strong clinical and genetic features of migraine. A unifying pathophysiologic core concept involves neuronal hyperexcitability and aberrant central modulation of autonomic signals. This is coupled with multiple susceptibility factors including mitochondrial dysfunction/cellular energy deficits, a hyper-responsive hypothalamic-pituitary-adrenal axis and many comorbidities that increase vulnerability to triggering events. CVS episodes are frequently triggered by stressors and intercurrent illnesses. Lifestyle and non-pharmacological interventions thus play a pivotal role in successful management. Pharmacological therapies are categorized into abortive, supportive/rescue, and prophylactic treatments. The majority respond particularly well to migraine-focused treatment strategies. CONCLUSION: Despite improved characterization and understanding, CVS remains classified as a functional disorder of brain-gut interaction that is often disjointly managed by generalists and subspecialists. Early recognition, evaluation, and management will facilitate care and improve outcomes. Further research into its natural history with common progression to migraine headaches, neuroendocrine mechanisms, and the pathophysiologic relation to migraine diathesis is much needed.

Gastric emptying in healthy children using the Spirulina breath test: The impact of gender, body size, and pubertal development.

BACKGROUND: There are no pediatric norms for gastric emptying (GE) measured by nuclear scintigraphy. The 13 C-labeled, stable isotope GE breath test (GEBT) is a non-radioactive alternative. We aimed to determine normative GEBT ranges in a cohort of healthy children and examine the influence of age, gender, puberty, and body surface area (BSA). METHODS: Healthy children ages 8-18 years completed the [13 C]-Spirulina platensis GEBT after an overnight fast. Breath samples were collected at baseline, every 15 min × 1 h, then every 30 min for 4 h total. The 13 CO2 excretion rate was determined by the change in 13 CO2 /12 CO2 over time in each breath sample, expressed as kPCD (Percent 13 C Dose excreted/min). A mixed model with random time was used for multivariable analysis and outcome fit into a quadratic model. KEY RESULTS: The 100 subjects completed the test meal within allotted time. Median (IQR) age was 13.5 (11.3-15.5) years; 51% were female. Females had lower 13 CO2 excretion rates (slower GE) than males across time (p < 0.001) while decreased excretion rates correlated with higher BSA (p = 0.015). Gender differences were also noted within pubertal stages with females showing slower GE. Multivariable analysis suggested that pre-pubertal children have faster GE than both peri- and post-pubertal groups (p < 0.0001). CONCLUSIONS & INFERENCES: Gender, puberty, and BSA influence GE rates in healthy children more than age. Although further data are needed, pubertal stage and hormonal influences may be unique factors to consider when assessing GE in children.

Impaired Vagal Efficiency Predicts Auricular Neurostimulation Response in Adolescent Functional Abdominal Pain Disorders.

INTRODUCTION: To determine whether pretreatment vagal efficiency (VE), respiratory sinus arrhythmia, and heart period can predict pain improvement with auricular neurostimulation in pediatric functional abdominal pain disorders. METHODS: A total of 92 adolescents with functional abdominal pain disorders underwent a 4-week randomized, double-blinded, sham-controlled auricular neurostimulation trial. Electrocardiogram-derived variables at baseline were used to predict pain using mixed effects modeling. RESULTS: A 3-way interaction (95% confidence intervals: 0.004-0.494) showed that the treatment group subjects with low baseline VE had lower pain scores at week 3. There was no substantial change in the placebo or high VE treatment group subjects. This effect was supported by a significant correlation between baseline VE and degree of pain reduction only in the treatment group. DISCUSSION: Impaired cardiac vagal regulation measured by VE predicts pain improvement with auricular neurostimulation.

Nutrition Management in Pediatric Gastrointestinal Motility Disorders.

Gastrointestinal (GI) motility disorders are associated with suboptimal nutrition in children, mainly because of malabsorption and symptoms limiting dietary intake. Apart from medical therapy, nutrition support has a crucial role in maintaining growth and improving clinical outcomes in children. Based on recent data and guidelines, this review provides an overview of nutrition assessment and specific interventions for common pediatric GI disorders including gastroesophageal reflux disease, esophageal motility disorders, gastroparesis, chronic intestinal pseudo-obstruction, and constipation. Several approaches including diet modification, enteral nutrition (gastric vs post-pyloric, temporary vs permanent access, bolus vs continuous), and parenteral nutrition need to be tailored based on patient's nutrition and clinical assessment.

Update on pediatric gastroparesis: A review of the published literature and recommendations for future research.

BACKGROUND: Due to scarcity of scientific literature on pediatric gastroparesis, there is a need to summarize current evidence and identify areas requiring further research. The aim of this study was to provide an evidence-based review of the available literature on the prevalence, pathogenesis, clinical presentation, diagnosis, treatment, and outcomes of pediatric gastroparesis. METHODS: A search of the literature was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines with the following databases: PubMed, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, and Web of Science. Two independent reviewers screened abstracts for eligibility. KEY RESULTS: Our search yielded 1085 original publications, 135 of which met inclusion criteria. Most articles were of retrospective study design. Only 12 randomized controlled trials were identified, all of which were in infants. The prevalence of pediatric gastroparesis is unknown. Gastroparesis may be suspected based on clinical symptoms although these are often non-specific. The 4-hour nuclear scintigraphy scan remains gold standard for diagnosis despite lack of pediatric normative comparison data. Therapeutic approaches include dietary modifications, prokinetic drugs, and postpyloric enteral tube feeds. For refractory cases, intrapyloric botulinum toxin and surgical interventions such as gastric electrical stimulation may be warranted. Most interventions still lack rigorous supportive data. CONCLUSIONS: Diagnosis and treatment of pediatric gastroparesis are challenging due to paucity of published evidence. Larger and more rigorous clinical trials are necessary to improve outcomes.

Efficacy of Auricular Neurostimulation in Adolescents With Irritable Bowel Syndrome in a Randomized, Double-Blind Trial.

BACKGROUND & AIMS: Auricular neurostimulation therapy, in which a noninvasive device delivers percutaneous electrical nerve field stimulation (PENFS) to the external ear, is effective in pediatric patients with functional abdominal pain disorders. Preclinical studies showed that PENFS modulates central pain pathways and attenuates visceral hyperalgesia. We evaluated the efficacy of PENFS in adolescents with irritable bowel syndrome (IBS). METHODS: We analyzed data from pediatric patients with IBS who participated in a double-blind trial at a tertiary care gastroenterology clinic from June 2015 through November 2016. Patients were randomly assigned to groups that received PENFS (n = 27; median age, 15.3 y; 24 female) or a sham stimulation (n = 23; median age, 15.6 y; 21 female), 5 days/week for 4 weeks. The primary endpoint was number of patients with a reduction of 30% or more in worst abdominal pain severity after 3 weeks. Secondary endpoints were reduction in composite abdominal pain severity score, reduction in usual abdominal pain severity, and improvement in global symptom based on a symptom response scale (-7 to +7; 0 = no change) after 3 weeks. RESULTS: Reductions of 30% or more in worst abdominal pain were observed in 59% of patients who received PENFS vs 26% of patients who received the sham stimulation (P = .024). The patients who received PENFS had a composite pain median score of 7.5 (interquartile range [IQR], 3.6-14.4) vs 14.4 for the sham group (IQR, 4.5-39.2) (P = .026) and a usual pain median score of 3.0 (IQR, 3.0-5.0) vs 5.0 in the sham group (IQR, 3.0-7.0) (P = .029). A symptom response scale score of 2 or more was observed in 82% of patients who received PENFS vs 26% of patients in the sham group (P ≤ .001). No significant side effects were reported. CONCLUSIONS: Auricular neurostimulation reduces abdominal pain scores and improves overall wellbeing in adolescents with IBS. PENFS is a noninvasive treatment option for pediatric patients with functional bowel disorders. ClinicalTrials.gov no: NCT02367729.

Nausea exacerbates symptom burden, quality of life, and functioning in adolescents with functional abdominal pain disorders.

BACKGROUND: Nausea frequently co-exists with functional abdominal pain disorders (FAPDs) and may be linked to a higher disease burden. This study aimed to prospectively compare multisystem symptoms, quality of life, and functioning in FAPDs with and without nausea. METHODS: Adolescents ages 11-18 years fulfilling Rome III criteria for a FAPD were grouped by the presence or absence of chronic nausea. Subjects completed validated instruments assessing nausea (Nausea Profile Questionnaire = NPQ), quality of life (Patient-Reported Outcome Measurement Information System), functioning (Functional Disability Inventory), and anxiety (State-Trait Anxiety Inventory for Children). Group comparisons were performed for instruments, multisystem symptoms, school absences, and clinical diagnoses. KEY RESULTS: A total of 112 subjects were included; 71% reported chronic nausea. Patients with Nausea compared to No Nausea had higher NPQ scores (P ≤ 0.001), worse quality of life (P = 0.004), and greater disability (P = 0.02). State and trait anxiety scores were similar (P = 0.57, P = 0.25). A higher NPQ score correlated with poorer quality of life, more disability, and higher anxiety. Specific comorbidities were more common in Nausea vs No Nausea group: dizziness (81% vs 41%; P ≤ 0.001), concentrating difficulties (68% vs 27%; P ≤ 0.001), chronic fatigue (58% vs 20%; P = 0.01), and sleep disturbances (73% vs 48%; P = 0.02). The Nausea group reported more school absences (P = 0.001) and more commonly met criteria for functional dyspepsia (P = 0.034). CONCLUSION AND INFERENCES: Nausea co-existing with FAPDs is associated with a higher extra-intestinal symptom burden, worse quality of life, and impaired functioning in children. Assessing and targeting nausea therapeutically is essential to improve outcomes in FAPDs.

Traumatic stress and the autonomic brain-gut connection in development: Polyvagal Theory as an integrative framework for psychosocial and gastrointestinal pathology.

A range of psychiatric disorders such as anxiety, depression, and post-traumatic stress disorder frequently co-occur with functional gastrointestinal (GI) disorders. Risk of these pathologies is particularly high in those with a history of trauma, abuse, and chronic stress. These scientific findings and rising awareness within the healthcare profession give rise to a need for an integrative framework to understand the developmental mechanisms that give rise to these observations. In this paper, we introduce a plausible explanatory framework, based on the Polyvagal Theory (Porges, Psychophysiology, 32, 301-318, 1995; Porges, International Journal of Psychophysiology, 42, 123-146, 2001; Porges, Biological Psychology, 74, 116-143, 2007), which describes how evolution impacted the structure and function of the autonomic nervous system (ANS). The Polyvagal Theory provides organizing principles for understanding the development of adaptive diversity in homeostatic, threat-response, and psychosocial functions that contribute to pathology. Using these principles, we outline possible mechanisms that promote and maintain socioemotional and GI dysfunction and review their implications for therapeutic targets.

Cyclic Vomiting Syndrome in Children and Adults: What Is New in 2018?

PURPOSE OF REVIEW: Cyclic vomiting syndrome (CVS) is a disabling functional gastrointestinal disorder characterized by severe vomiting episodes that alternate with symptom-free periods. The purpose of this review is to summarize current knowledge and highlight most recent data on prevalence, diagnosis, management, and impact of CVS in children and adults. RECENT FINDINGS: Originally thought to be a pediatric disorder, the past decade has witnessed a considerable increase in CVS diagnosed in adults. Despite improved recognition of CVS, without a delineated pathophysiology and specific biomarker, it remains classified as a functional gastrointestinal disorder. Migraines and CVS share a common pathway based on several studies and response to migraine therapy. Recent work has begun to expand the list of comorbidities and identify plausible mechanisms and new therapeutic avenues. This review seeks to highlight best practices and novel therapies for CVS based on expert consensus and review of available literature.

Healthcare Utilization and Comorbidities Associated with Anorectal Malformations in the United States.

OBJECTIVE: To determine nationwide prevalence and healthcare utilization in children with anorectal malformations and associated anomalies over a 6-year period. STUDY DESIGN: We used the Kids' Inpatient Database for the years 2006, 2009, and 2012 for data collection. International Classification of Diseases, Ninth Revision codes were used to identify patients with anorectal malformations and associated anomalies. RESULTS: A total of 2396 children <2 years of age with anorectal malformations were identified using weighted analysis; 54.3% of subjects were male. The ethnic subgroups were 40.1% white, 23.6% Hispanic, 9.3% African American, and 27% other ethnicity. Other congenital anomalies were reported in 80% of anorectal malformations and were closely associated with increased length of stay and costs. A genetic disorder was identified in 14.1% of the sample. Urogenital anomalies were present in 38.5%, heart anomalies in 21.2%, and 8.6% had vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula and/or esophageal atresia, renal anomalies, and limb defects association. Anorectal malformations with other anomalies including vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula and/or esophageal atresia, renal anomalies, and limb defects association incurred significant hospital charges when compared with anorectal malformations alone. The average annual healthcare expenditure for surgical correction of anorectal malformations and associated anomalies for the 3 years was US $45.5 million. CONCLUSIONS: This large, major nationally representative study shows that majority of children with anorectal malformations have additional congenital anomalies that deserve prompt recognition. The high complexity and need for lifelong multidisciplinary management is associated with substantial healthcare expenditure. This information complements future healthcare resource allocation and planning for management of children with anorectal malformations.

Trends of Cholecystectomies for Presumed Biliary Dyskinesia in Children in the United States.

BACKGROUND: Biliary dyskinesia (BD) is a controversial clinical entity. Standardized diagnostic test and management guidelines are lacking in children. Published data suggest that long-term outcomes of surgical and medical management are similar. We sought to determine national population-based trends of cholecystectomies performed in children for BD and associated healthcare expenditure in the United States during a 10-year period. METHODS: Using Nationwide Inpatient Sample and the International Classification of Diseases, the 9th revision clinical modification codes, we identified children who had a cholecystectomy for BD from 2002 to 2011 in the United States. RESULTS: A total of 66,380 cholecystectomies were identified as primary procedural diagnosis using weighted analysis from 2002 to 2011 in children. BD was the primary indication for cholecystectomy in 6674 (10.8%) of the patients. During the study period, the number of cholecystectomies performed for BD in children increased from 6.6% in 2002 to 10.6% in 2011, and a majority were adolescent white females. The annual health care expenditure for surgical management of BD for children in the US was estimated to almost $16 million/year. CONCLUSIONS: Despite lack of standardized diagnostic criteria and variable outcomes of surgical intervention reported in pediatric literature, cholecystectomies are commonly performed for children with BD in the United States. Consensus guidelines for the diagnosis and management of this controversial disorder in children are needed.

Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial.

BACKGROUND: Development of safe and effective therapies for paediatric abdominal pain-related functional gastrointestinal disorders is needed. A non-invasive, US Food and Drug Administration-cleared device (Neuro-Stim, Innovative Health Solutions, IN, USA) delivers percutaneous electrical nerve field stimulation (PENFS) in the external ear to modulate central pain pathways. In this study, we evaluated the efficacy of PENFS in adolescents with abdominal pain-related functional gastrointestinal disorders. METHODS: In this randomised, sham-controlled trial, we enrolled adolescents (aged 11-18 years) who met Rome III criteria for abdominal pain-related functional gastrointestinal disorders from a single US outpatient gastroenterology clinic. Patients were randomly assigned (1:1) with a computer-generated randomisation scheme to active treatment or sham (no electrical charge) for 4 weeks. Patients were stratified by sex and presence or absence of nausea. Allocation was concealed from participants, caregivers, and the research team. The primary efficacy endpoint was change in abdominal pain scores. We measured improvement in worst abdominal pain and composite pain score using the Pain Frequency-Severity-Duration (PFSD) scale. Participants with less than 1 week of data and those with organic disease identified after enrolment were excluded from the modified intention-to-treat population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT02367729. FINDINGS: Between June 18, 2015, and Nov 17, 2016, 115 children with abdominal pain-related functional gastrointestinal disorders were enrolled and assigned to either PENFS (n=60) with an active device or sham (n=55). After exclusion of patients who discontinued treatment (n=1 in the PENFS group; n=7 in the sham group) and those who were excluded after randomisation because they had organic disease (n=2 in the PENFS group; n=1 in the sham group), 57 patients in the PENFS group and 47 patients in the sham group were included in the primary analysis. Patients in the PENFS group had greater reduction in worst pain compared with sham after 3 weeks of treatment (PENFS: median score 5·0 [IQR 4·0-7·0]; sham: 7·0 [5·0-9·0]; least square means estimate of change in worse pain 2·15 [95% CI 1·37-2·93], p<0·0001). Effects were sustained for an extended period (median follow-up 9·2 weeks [IQR 6·4-13·4]) in the PENFS group: median 8·0 (IQR 7·0-9·0) at baseline to 6·0 (5·0-8·0) at follow-up versus sham: 7·5 (6·0-9·0) at baseline to 7·0 (5·0-8·0) at follow-up (p<0·0001). Median PFSD composite scores also decreased significantly in the PENFS group (from 24·5 [IQR 16·8-33.3] to 8·4 [3·2-16·2]) compared with sham (from 22·8 [IQR 8·4-38·2] to 15·2 [4·4-36·8]) with a mean decrease of 11·48 (95% CI 6·63-16·32; p<0·0001) after 3 weeks. These effects were sustained at extended follow-up in the PENFS group: median 24·5 (IQR 16·8-33·3) at baseline to 12 (3·6-22·5) at follow-up, compared with sham: 22·8 (8·4-38·2) at baseline to 16·8 (4·8-33·6) at follow-up (p=0·018). Ten patients reported side-effects (three of whom discontinued the study): ear discomfort (n=6; three in the PENFS group, three in the sham group), adhesive allergy (n=3; one in the PENFS group, two in the sham group), and syncope due to needle phobia (n=1; in the sham group). There were no serious adverse events. INTERPRETATION: Our results show that PENFS with Neuro-Stim has sustained efficacy for abdominal pain-related functional gastrointestinal disorders in adolescents. This safe and effective approach expands treatment options and should be considered as a non-pharmacological alternative for these disorders. FUNDING: American Neurogastroenterology and Motility Society.