Lubiprostone for Pediatric Functional Constipation: Randomized, Controlled, Double-Blind Study With Long-term Extension.

BACKGROUND & AIMS: Pediatric functional constipation (PFC) is a common problem in children that causes distress and presents treatment challenges to health care professionals. We conducted a randomized, placebo-controlled trial (study 1) in patients with PFC (6-17 years of age) to evaluate the efficacy and safety of lubiprostone, followed by an open-label extension for those who completed the placebo-controlled phase (study 2). METHODS: Study 1 (NCT02042183) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 12-week study evaluating the efficacy and safety of lubiprostone 12 µg twice daily (BID) and 24 µg BID. Study 2 (NCT02138136) was a phase 3, long-term, open-label extension of study 1. In both studies, lubiprostone doses were based on patients' weight. Efficacy was assessed solely based on study 1, with a primary endpoint of overall spontaneous bowel movement (SBM) response (increase of ≥1 SBM/wk vs baseline and ≥3 SBMs/wk for ≥9 weeks, including 3 of the final 4 weeks). RESULTS: 606 patients were randomized to treatment (placebo: n = 202; lubiprostone: n = 404) in study 1. No statistically significant difference in overall SBM response rate was observed between the lubiprostone and placebo groups (18.5% vs 14.4%; P = .2245). Both the 12-µg BID and 24-µg BID doses of lubiprostone were well tolerated in the double-blind and extension phases, with a safety profile consistent with that seen in adult studies. CONCLUSIONS: Lubiprostone did not demonstrate statistically significant effectiveness over placebo in children and adolescents with PFC but did demonstrate a safety profile similar to that in adults. (ClinicalTrials.gov: Number: NCT02042183; Number: NCT02138136).

Characteristics of high-resolution esophageal manometry in children without dysphagia.

BACKGROUND: The absence of high-resolution esophageal manometry (HREM) norms in pediatrics limits the assessment of children with dysphagia. This study aimed to describe HREM parameters in a cohort of children without dysphagia. METHODS: Children ages 9-16 years with a negative Mayo Dysphagia Questionnaire screen and normal histologic findings underwent HREM after completion of esophagogastroduodenoscopy. Ten swallows of 5 ml 0.45% saline boluses per subject were captured in supine position. Analyzed data included resting and integrated relaxation pressures (IRP) of lower (LES) and upper (UES) esophageal sphincters, peristaltic contractile integrals, transition zone (TZ) breaks, velocities, and lengths associated with proximal and distal esophagus. KEY RESULTS: 33 subjects (15 female) with mean (range) age 12.9 (9-16) years completed the study. Two of 330 analyzed swallows failed. The UES mean resting pressure, and its 0.2 s and 0.8 s IRPs were 48.3 (95% CI 12.9) mmHg, 2.9 (95% CI 1.9) mmHg, and 12.1 (95% CI 2.5) mmHg, respectively. The LES mean resting pressure and its 4 s IRP were 29.0 (95% CI 4.0) mmHg and 9.2 (95% CI 1.3) mmHg. The mean proximal (PCI) and distal (DCI) esophageal contractile integrals were 231 (95% CI 54.8) mmHg-s-cm and 1789.3 (95% CI 323.5) mmHg-s-cm, with mean TZ break 0.5 (95% CI 0.3) cm. CONCLUSIONS & INFERENCES: This is the first study to describe HREM parameters in children without dysphagia. Most of the reported measurements were significantly different and less variable from reported adult norms. This emphasizes the need for child-specific catheters, norms, and protocols to define pediatric esophageal motility disorders.

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.

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.

Variability in the Method of Gastrostomy Placement in Children.

Although gastrostomy placement is one of the most common procedures performed in children, the optimal technique remains unclear. The purpose of this study was to evaluate variability in the method of gastrostomy tube placement in children in the United States. Patients <18 years old undergoing percutaneous endoscopic gastrostomy (PEG) or surgical gastrostomy (SG) (including open or laparoscopic) from 1997 to 2012 were identified using the Kids' Inpatient Database. Method of gastrostomy placement was evaluated using a multivariable mixed-effects logistic regression model with a random intercept term and a patient-age random-effect term. A total of 67,811 gastrostomy placements were performed during the study period. PEG was used in 36.6% of entries overall and was generally consistent over time. PEG placement was less commonly performed in infants (adjusted odds ratio [aOR] 0.30, 95%CI 0.26-0.33), children at urban hospitals (aOR: 0.38, 95%CI 0.18-0.82), and children cared for at children's hospitals (aOR 0.57, 95%CI 0.48-0.69) and was more commonly performed in children with private insurance (aOR 1.17, 95%CI 1.09-1.25). Dramatic variability in PEG use was identified between centers, ranging from 0% to 100%. The random intercept and slope terms significantly improved the model, confirming significant center-level variability and increased variability among patients <1 year old. These findings emphasize the need to further evaluate the safest method of gastrostomy placement in children, in particular among the youngest patients in whom practice varies the most.

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.

Chronic Intestinal Pseudo-obstruction.

Chronic intestinal pseudo-obstruction (CIP) is defined by either continuous or intermittent symptoms of bowel obstruction in the absence of fixed lumen excluding lesion. CIP includes a heterogeneous group of disorders which result either from diseases affecting the enteric neurons and smooth muscle lining or those involving the autonomic innervation of the bowel. Symptoms associated with CIP are nonspecific, which can sometimes contribute to the delay in recognizing the condition and making the correct diagnosis. The diagnostic workup should include imaging and manometry studies and, occasionally, full-thickness bowel biopsies for histopathological examination may be required. Multidisciplinary team approach for the management of these patients is recommended, and the team members should include a gastroenterologist, surgeon, chronic pain specialist, clinical nutritionist, and a psychologist. The treatment goals should include optimizing the nutritional status and preventing or delaying the development of intestinal failure. The majority of the patients require enteral or parenteral nutrition support, and chronic pain is a common and distressing symptom. Small bowel transplantation may be required if patients develop liver complications due to parenteral nutrition, have difficult central line access, or have poor quality of life and worsening pain despite aggressive medical management.

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.

Reduced Functional Connectivity Between the Hypothalamus and High-order Cortical Regions in Adolescent Patients With Irritable Bowel Syndrome.

The hypothalamus plays a critical role in maintaining visceral homeostasis. Altered hypothalamus activation has been implicated in functional gastrointestinal disorders, including irritable bowel syndrome (IBS). One important aspect of homeostatic regulation is the cortical modulation of limbic and paralimbic subsystems, including the hypothalamus, which in turn affects the descending regulatory processes mediating visceral homeostasis. Using neuroimaging, we evaluated hypothalamus functional connectivity in adolescent patients with IBS and age-matched healthy controls who received rectal distension stimulations. More extensive hypothalamus connectivity was observed in liminal than subliminal condition in controls, but not in patients with IBS. Compared with controls, patients with IBS showed significantly reduced hypothalamus connectivity in the bilateral prefrontal cortices, supplementary motor and premotor areas, bilateral sensorimotor cortex, and limbic subareas, which are specifically involved in homeostatic regulation. The findings support the generalized homeostatic regulation model that reduced cortical and limbic modulations of hypothalamus functioning underlies disrupted visceral homeostasis in patients with IBS.

Empirically Derived Patterns of Pain, Stooling, and Incontinence and Their Relations to Health-Related Quality of Life Among Youth With Chronic Constipation.

Objective: Chronic constipation is associated with pain, stress, and fecal incontinence, which negatively impact health-related quality of life (HRQoL); however, it is unclear if patterns of pain, stool frequency, and incontinence are differentially associated with HRQoL in youth with chronic constipation. Methods: 410 caregivers completed a demographics and symptoms form, the Parental Opinions of Pediatric Constipation, Pediatric Symptom Checklist, and the Functional Disability Inventory. Results: Stooling patterns were derived using Latent Variable Mixture Modeling. A three-class model emerged: withholding/avoiding ( WA ), pain , and fecal incontinence ( FI ). The pain class reported the greatest amount of disease burden/distress, greatest impairments in illness-related activity limitations, more psychosocial problems, and, along with the FI class, elevated levels of family conflict. The FI class reported the greatest amount of parental worry of social impact. Conclusions: Youth with chronic constipation who experience pain or fecal incontinence may be at a greater risk for specific HRQoL problems such as illness-related activity limitations, psychosocial issues, disease burden and worry, and family conflict.

Approach to a Child with Functional Abdominal Pain.

Functional abdominal pain (FAP) is one of the most common functional gastrointestinal disorders (FGIDs) of childhood. Only a minority of patients with FAP seek medical attention, often presenting to the primary care physician while symptoms are still evolving. The bio-psychosocial model of treatment not only aims to alleviate the illness symptoms but also identifies and remedies the psychological comorbidities and social factors that contribute to illness behavior. Many patients with a mild illness can be managed in the primary care setting. However those with chronic, severe, frequently relapsing, and disabling illness usually are referred to a pediatric gastroenterologist. One of the reason for referral is to exclude organic disorders such as peptic ulcer disease, celiac disease or inflammatory bowel disease which can present with chronic abdominal pain. Recent data suggest that psychological therapy is very effective in alleviating symptoms, a subset of patients may require dietary modification and medications as an adjunct to psychological treatment.

A multicenter study on childhood constipation and fecal incontinence: effects on quality of life.

OBJECTIVE: To describe the effects of childhood functional constipation compared with functional constipation plus fecal incontinence on quality of life, evaluating effects on physical, psychosocial, and family functioning. STUDY DESIGN: This prospective, multicenter study collected data from 5 regional children's hospitals. Children meeting Rome III criteria for functional constipation were included. Parents completed the following 5 instruments: Pediatric Quality of Life Inventory (PedsQL), PedsQL-Family Impact Module, Functional Disability Inventory-Parent Version, Pediatric Inventory for Parents (PIP), and Pediatric Symptom Checklist-Parent Report. RESULTS: Families of 410 children aged 2-18 years (mean [SD], 7.8 [3.5] years; 52% male) were included. Children with functional constipation+fecal incontinence had worse quality of life than children with functional constipation alone (PedsQL Total Score, P ≤ .03). Older children with functional constipation + fecal incontinence had lower quality of life than their younger counterparts (PedsQL Total Score, P ≤ .047). Children with functional constipation+fecal incontinence had worse family functioning (PedsQL-Family Impact Module Total Score, P ≤ .012), greater parental stress (PIP-F Total Score, P ≤ .016; PIP-D Total Score, P ≤ .013), and poorer psychosocial functioning (Pediatric Symptom Checklist Total Score, P ≤ .003). There were no statistically significant between-group differences in physical functioning based on the functional Disability Inventory. CONCLUSION: Fecal incontinence significantly decreases quality of life compared with functional constipation alone in children. Older children with functional constipation+fecal incontinence may be at particular risk. Strategies for early identification and treatment of constipation along with diagnosis and treatment of related adjustment difficulties may mitigate the negative impact of this highly prevalent condition.

Measuring Health-Related Quality of Life With the Parental Opinions of Pediatric Constipation Questionnaire.

OBJECTIVES: The purpose of this study was to develop a caregiver-completed constipation condition-specific health-related quality of life (HRQL) instrument. METHODS: 410 caregivers of children aged 2-18 years completed the Parental Opinions of Pediatric Constipation (POOPC), the PedsQL Generic Core Scales, PedQL Family Impact Module, Pediatric Symptom Checklist, the Functional Disability Inventory, the Pediatric Inventory for Parents, and a demographic questionnaire. Exploratory and confirmatory factor analyses were conducted to assess the psychometric properties of the POOPC. RESULTS: Analyses yielded four factors called Parental Burden/Distress, Family Conflict, Difficulties with the Medical Team, and Worry about Social Impact that reflect problems in HRQL secondary to constipation and soiling, which were generally more strongly correlated with similar measures relative to a general measure of youth's psychosocial functioning. CONCLUSION: The POOPC is a psychometrically sound measure, which may be useful to clinicians and researchers identifying domains of treatment needs for children and their families.

Joint hypermobility: a common association with complex functional gastrointestinal disorders.

OBJECTIVE: To evaluate the prevalence of joint hypermobility (JH) and comorbid conditions in children and young adults referred to a tertiary care neurogastroenterology and autonomic disorders clinic for functional gastrointestinal complaints. STUDY DESIGN: This was a retrospective chart review of 66 new patients aged 5-24 years who fulfilled at least 1 pediatric Rome III criteria for a functional gastrointestinal disorder (FGID) and had a recorded Beighton score (n = 45) or fibromyalgia tender point score (n = 45) based on physician examination. Comorbid symptoms were collected and autonomic testing was performed for evaluation of postural tachycardia syndrome (POTS). RESULTS: The median patient age was 15 years (range, 5-24 years), 48 (73%) were females, and 56% had JH, a significantly higher rate compared with population studies of healthy adolescents (P < .001; OR, 10.03; 95% CI, 5.26-19.13). POTS was diagnosed in 34% of patients and did not correlate significantly with hypermobility. Comorbid conditions were common, including sleep disturbances (77%), chronic fatigue (93%), dizziness (94%), migraines (94%), chronic nausea (93%), and fibromyalgia (24%). CONCLUSION: JH and other comorbid symptoms, including fibromyalgia, occur commonly in children and young adults with complex FGIDs. POTS is prevalent in FGIDs but is not associated with hypermobility. We recommend screening patients with complex FGIDs for JH, fibromyalgia, and comorbid symptoms such as sleep disturbances, migraines, and autonomic dysfunction.

Colon high-resolution manometry: using pressure topography plots to evaluate pediatric colon motility.

OBJECTIVES: Colon manometry is usually performed using the 8-pressure sensor water-perfused manometry system. High-resolution manometry (HRM), using closely spaced solid-state pressure recording sensors, provides more detailed information of gut luminal pressure changes, and, by displaying the HRM data as a pressure topography plot (PTP), helps with data interpretation. Our aim was to compare the colon and rectal luminal pressure data obtained using 8 pressure sensors and displayed as conventional line plot (CLP) with data obtained using a custom-made solid state manometry catheter with 36 pressure recording sensors and displayed as PTP. METHODS: We evaluated colon manometry patterns during fasting, response to meal, and bisacodyl stimulation in 10 patients with constipation and stool expulsion disorders. The data from 8 pressure sensors were displayed as CLP and data from 36 pressure sensors as PTP. Two gastroenterologists independently interpreted these studies. We calculated variability in interpreting colon, rectal, and anal manometry data. RESULTS: Intermode, interobserver, and intraobserver reliability were good to excellent for recognizing colon contraction patterns when data are displayed as PTP compared with when displayed as CLP, whereas the reliability for recognizing anal contractions were poor to excellent. CONCLUSIONS: Colonic and anal manometry patterns are easily recognized when HRM data are expressed as PTP. Obtaining information of colonic luminal pressure changes with rectum and anal pressure changes using HRM can help better understand the pathophysiology of pediatric constipation and stool expulsion disorders.

Comparison of light and electron microscopy in measurement of esophageal intercellular space in children.

OBJECTIVES: A good objective marker of esophageal mucosal damage from gastroesophageal reflux disease (GERD) is lacking in children. Increased esophageal epithelial intercellular (EEIC) space measured using electron microscopy (EM) has been proposed as a surrogate of esophageal mucosal damage in adults with GERD. The aim of the present study was to compare EEIC space measured using EM and light microscopy (LM) in children with nonerosive reflux disease (NERD) with asymptomatic controls. METHODS: Distal esophageal mucosal biopsy was used to measure EEIC space using EM in 35 NERD subjects and 8 controls. In a subset of these patients we used phase contrast LM to measure EEIC space area (26 NERD subjects and 8 controls). RESULTS: The median (range) EEIC space measured using EM in the NERD group was 1.15 (0.74-1.64) µm compared with 0.93 (0.67-1.11) µm in the control group (P = 0.002). The median (range) EEIC space measured using LM was 14.4% (9.6%-26.3%) in the NERD group and 9.6% (8.5%-17.2%) in controls (P = 0.003). Using a cutoff value of 1.02 µm for normal EEIC space measured by EM, we obtained 73% sensitivity and 75% specificity to distinguish the NERD group from the control group, and using a cutoff value of 11.1% for EEIC space measured by LM, we obtained 96% sensitivity and 75% specificity. CONCLUSIONS: EEIC space is increased in children with NERD compared with that in controls, suggesting that changes in EEIC space can be a useful marker of esophageal mucosal injury in children with NERD. Our results suggest that the accuracy of EM and LM to evaluate EEIC space changes in NERD is comparable, and LM may be a more cost-effective option.