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Journal of Pediatric Gastroenterology & Nutrition:
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Research Agenda for Pediatric Gastroenterology, Hepatology and Nutrition: Motility Disorders and Functional Gastrointestinal Disorders: Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation

Li, B. U. K.; Altschuler, Steven M.; Berseth, Carol L.; Di Lorenzo, Carlo; Rudolph, Colin D.; Scott, R. Brent

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Address requests for reprints to: Executive Director, Children's Digestive Health and Nutrition Foundation, PO Box 6, Flourtown, PA, 19031, U.S.A. (e-mail: NASPGHAN@naspghan.org).

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RATIONALE

Motility disorders and functional gastrointestinal (GI) disorders are interrelated. The first category refers to disordered esophageal, gastric, intestinal and colonic motility and encompasses achalasia, gastroparesis, Hirschsprung's disease and chronic idiopathic intestinal pseudo-obstruction (CIIP). The second category encompasses disordered swallowing, vomiting, diarrhea, defecation and functional abdominal pain syndromes such as functional dyspepsia and irritable bowel syndrome (IBS).

Both motility disorders and functional GI disturbances are exciting and fertile areas of current research. New Rome diagnostic criteria for pediatric functional GI disorders were published in 1999 and require validation and correlation with pathophysiologic findings. There has been an explosion of relevant basic science investigations in enteric neurobiology, genetics, brain-gut mapping and receptor physiology.

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Clinical research infrastructure.

Progress in our understanding of pathophysiology and in the development of effective therapies will be facilitated by establishment of a clinical research infrastructure to support collaborative interdisciplinary research endeavors. In particular, such an infrastructure can provide long-term support for urgently needed prospective multicenter trials that can serve as the evidence base for development of diagnostic and therapeutic algorithms.

In addition, consensus conferences are recommended to establish a) standardized diagnostic criteria for symptom-based diagnoses, b) subgrouping/stratification schemes, as well as c) clinical and pathophysiologic testing protocols for both motility disorders and functional disorders. Efforts in some of these areas have begun with the aid of the American Motility Society, Cyclic Vomiting Syndrome Association, National Institutes of Health (NIH), and the Rome Committee for functional GI disorders.

Diagnostic tests and techniques used to evaluate motility disorders and functional GI disorders would be more widely accepted if technical protocols and methods of interpretation were validated and standardized. Such techniques include electrogastrography (EGG) for gastric dysrhythmias, impedance measurement in gastroesophageal reflux (GER), the barostat for visceral hyperalgesia and antroduodenal and colonic manometry for motility disorders.

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Fellowship and post-fellowship training.

To develop a cadre of future clinical and basic science researchers, opportunities must be created for young pediatric gastroenterology investigators for training and mentoring in motility, functional GI and laboratory research. Fellowship and post-fellowship training with senior investigators is recommended in the areas of GI motility, sensory evaluation, functional neuroimaging and functional GI disorders.

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Centers of excellence.

There is a need to develop regional and national centers of excellence with combined clinical expertise and ongoing research protocols in motility disorders and functional bowel disorders.

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AREAS OF EMPHASIS

Define Mechanisms Leading to Feeding Intolerance in Preterm Infants and Evaluate Potential Interventions to Improve Feeding
Research Goals

The study of oropharyngeal development and GI motility in preterm infants can identify mechanisms that underlie feeding intolerance and assist in discovering means of optimizing maturation of these mechanisms. In addition, intervention trials are needed to improve feeding in these patients. Studies could determine the optimal macronutrient composition of feeding regimens, use of bolus or continuous infusion, and nutritional manipulations to enhance gastric emptying and antroanal motility. In preterm infants with comorbid disorders (e.g., congenital anomalies or bronchopulmonary dysplasia with intubation) who cannot tolerate oral feeding, the barriers to normal oromotor development must be defined: Is there a narrow window of normal development? Or does aversion to oral feeding result from use of instrumentation?

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Research Strategies

Feeding intolerance can be studied by means of retrospective and case-control trials in which antroduodenal motility and swallowing studies are done. Interventions can be evaluated in prospective randomized controlled trials.

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Projected Timetable and Funding Requirements

Single-center studies and multicenter collaborations may be undertaken with NIH funding. Applications can be made for R01 (individual award) grants, investigator-initiated interactive research project grants (IRPG), R03 (small clinical trials) grants, F32 grants (or National Research Service Awards, NRSA, for training fellows) and PHS 6246-2 grants (small business innovation research, SBIR, for innovative technologies and approaches).

Consensus conferences could be convened to establish diagnostic criteria and standardized evaluation and treatment protocols. Efforts may be funded by combined support from the NIH (R13 grants for support of scientific meetings), interested foundations and the pharmaceutical industry.

Research efforts should be encouraged in partnership with societies and foundations such as the American Motility Society, Cyclic Vomiting Syndrome Association and International Foundation for Functional Gastrointestinal Disorders.

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Evaluate Oromotor Discoordination and Feeding Aversion in the Older Child and in Neurologically Impaired Children
Research Goals

Studies are needed to evaluate and develop treatments for oromotor discoordination and feeding aversion in these patient subgroups. Key research questions in dysphagia include the role (and reliability) of videofluoroscopic swallowing studies, the role of interdisciplinary evaluation, and whether medical and behavioral approaches affect long-term outcome.

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Research Strategies

Antroduodenal motility and swallowing studies are recommended. Potential interventions can be evaluated in prospective randomized controlled trials.

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Characterize the Pathogenesis of Post-Nissen Fundoplication Complications
Research Goals

The long-term efficacy and safety profile of fundoplication in children has not been definitively studied. Studies are needed to determine the incidence and underlying mechanisms of intractable retching, bloating and feeding intolerance following fundoplication. Can children at risk be identified prior to surgery through a combination of tests? Which techniques are recommended—esophageal biopsies, prolonged pH monitoring, esophageal emptying studies, gastric emptying tests, EGG, gastric barostat, antroduodenal motility testing?

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Research Strategies

Retrospective and case-control studies can be done. Multicenter studies evaluating children with refractory GER prior to antireflux surgery, coupled with long-term clinical outcomes, would be appropriate.

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Characterize the Pathophysiology of Chronic Idiopathic Intestinal Pseudo-Obstruction and Evaluate Diagnostic Techniques and Potential Treatments
Research Goals

Further studies are needed in the areas of pathogenesis, subclassifications of CIIP, diagnosis and treatment. The prevalence of extraintestinal (e.g., gallbladder, pancreas and bladder) involvement of smooth muscle; the role of antroduodenal and colonic manometry in diagnosis and subclassification; the efficacy of new prokinetic agents; the utility of jejunal feedings versus parenteral nutrition—all are important clinical research questions. Basic research questions are reviewed below.

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Research Strategies

For uncommon disorders such as pseudo-obstruction (and Hirschsprung's disease), a centralized tissue bank of appropriately preserved muscle tissue and blood samples should be available for cellular and histochemical studies.

The clinical research questions can be investigated by means of multicenter and individual investigator studies, using manometry, radiographic and nuclear medicine transit studies, and intestinal tissue samples (banked). Prospective randomized controlled trials can be performed to evaluate therapeutic agents and feeding approaches.

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Characterize the Pathophysiology of Functional Constipation, Hirschsprung's Disease, and Other Neurocristopathies and Neuronal Dysplasias; Evaluate Diagnostic Techniques and Potential Treatments
Research Goals

Studies are needed to define the pathophysiology, long-term outcome, diagnosis and treatment of these conditions. Important research questions include the role of motility testing (colonic manometry, radioopaque marker transit studies, anorectal manometry) in diagnosis; its utility in subclassifying patients; and the efficacy of current and novel therapeutic agents, evaluated in prospective controlled trials.

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Research Strategies

For uncommon disorders such as Hirschsprung's disease, a centralized tissue bank of appropriately preserved muscle tissue and blood samples should be available for cellular and histochemical studies.

The clinical research questions can be investigated by means of multicenter and individual investigator studies, using manometry, radiographic and nuclear medicine transit studies, and intestinal tissue samples (banked). Prospective randomized controlled trials can be performed to evaluate therapeutic agents and feeding approaches.

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Assess Utility of Rome Criteria for Functional Disorders and Visceral Pain Syndromes
Research Goals

Do the Rome criteria correctly discriminate between organic and functional disorders? Studies are needed to determine the frequency of missed diagnoses of organic disorders and whether the Rome criteria reduces the need for testing to rule out potentially serious disorders, shortens the time to diagnosis, and directs appropriate treatment. An interesting question is whether the Rome criteria apply cross-culturally. Other research questions include the role of the barostat in evaluating and classifying children with visceral hyperalgesia and IBS; the natural history of IBS (is there a progression from toddler's diarrhea to IBS?); a comparison of efficacy of pharmacotherapy versus cognitive and behavioral treatments; and the synchronous and metachronous incidence of different functional bowel disorders.

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Research Strategies

A variety of studies can be performed, including case-control and outcome studies, cross-cultural studies, longitudinal studies, interdisciplinary studies and randomized controlled therapeutic trials.

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Evaluate Pathophysiologic Mechanisms and Potential Interventions in Patients with Cyclic Vomiting Syndrome
Research Goals

A number of factors may contribute to the onset of cyclic vomiting syndrome, including migraine, mitochondriopathy, autonomic dysfunction and stress axis activation. Studies are needed to determine whether patients can be grouped into clinical phenotypes, with overlapping or distinct pathophysiologic mechanisms. Interventional studies are needed to evaluate the efficacy of current and new pharmacologic agents for prophylaxis and treatment.

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Research Strategies

Questions of pathophysiology may be examined in multicenter and individual investigator studies, utilizing mitochondrial deoxyribonucleic acid (DNA) analysis, autonomic function testing and measurement of corticotropin-releasing factor (CRF). Therapeutic agents may be evaluated in prospective randomized controlled trials.

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Encourage Expansion of Basic Research in Enteric Neurobiology and Development of the Enteric Nervous System (ENS)
Research Goals

Increased involvement by pediatric gastroenterologists is recommended in areas of basic research related to GI motility and functional disorders in children. Studies are needed to:

Identify factors regulating development of the ENS. Studies can target the role of interstitial cells of Cajal and intestinal stem cells in such disorders as achalasia, pyloric stenosis, CIIP, Hirschsprung's disease and constipation. The effects of actins and gut peptides also should be studied.

Characterize molecular, cellular and physiologic defects in mutant mouse strains and transgenic knockout mouse lines that are relevant to the study of motility disorders in humans.

Identify neuroendocrine interactions, e.g., the effect of mast cells (histamine) on motor function in antigen-sensitized animal models. Afferent and efferent central nervous system and ENS pathways can be mapped using immunohistochemical stains (e.g., cholera toxin horseradish peroxidase).

Evaluate the role of CRF in gastric stasis and vomiting using specific antagonists.

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Identify Histopathologic and Ultrastructural Features of Neurocristopathies and Other Lineage Defects of Intestinal Nerve and Muscle
Research Goals

Histopathology studies can evaluate the role of interstitial cells of Cajal in the pathogenesis of CIIP. In addition, these research findings will help to determine whether full-thickness biopsies are necessary in the evaluation of patients with CIIP.

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Research Strategies

Collaboration with pediatric pathologists is recommended to define appropriate guidelines for the histopathologic evaluation of neurocristopathies. By correlating histopathologic findings with clinical patterns and results of functional testing, investigators can determine the subclassification of patients with CIIP and their kindreds.

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Identify Genetic Markers of Neurocristopathies and Neuronal Dysplasias
Research Goals

In 20% of patients, Hirschsprung's disease has a genetic component, and some kindreds display a dominant inheritance with mutations identified in the receptor tyrosine kinase gene (ret) and endothelin receptor-B gene (ENDR-B). Studies in mutant mouse strains (piebald lethal and lethal spotted) have demonstrated mutations in the same regions (ENDR-B gene and endothelin-3).

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Research Strategies

Two transgenic “knockout” mouse lines have been developed, including the ret-k- (functional-loss mutation of ret gene) and ENDR-B null. Introduction of a Lac-Z reporter gene into neural crest cells of these mice allows study of enteric neuroblasts affected by Hirschsprung-type mutations.

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HEALTH AND ECONOMIC OUTCOMES

Disordered GI motility and functional GI disorders cause substantial medical morbidity in a large proportion of the pediatric population. Combined, these disorders constitute more than 50% of a pediatric gastroenterology practice. Recurrent abdominal pain accounts for 25% of pediatric gastroenterology consultations. In one report, irritable bowel syndrome affected 17% of a high school-aged population, matching the prevalence in the adult population. Constipation accounts for 3% of visits to a general pediatrician's office and 25% of referrals to a pediatric gastroenterologist. Less prevalent disorders also have significant economic consequences: health care costs for cyclic vomiting syndrome (2% of school-aged children) can total more than $17,000 per patient annually. Each year, pseudo-obstruction (100 new cases each year) accounts for more than $50,000 in parenteral nutrition costs alone. The medical consequences of prolonged parenteral nutrition in infants and children with long-segment Hirschsprung's disease and pseudo-obstruction include repeated catheter-related sepsis and total parenteral nutrition-related liver disease (with end-stage liver failure and liver transplantation).

Feeding intolerance occurs in 50% to 70% of preterm infants (weighing <1500 g and 1250 g at birth, respectively). Thus, approximately 20,000 infants are affected each year in the US. An advance by 1 week in the placement of preterm infants on full enteral feeding would save an estimated $1 billion annually in parenteral nutrition costs in the US alone.

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© 2002 Lippincott Williams & Wilkins, Inc.

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