Functional Gastrointestinal Disorders: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

SUMMARY OF THE PROBLEM Functional gastrointestinal disorders are defined as conditions in which a variable combination of chronic or recurrent gastrointestinal symptoms are present in the absence of known structural or biochemical abnormalities. There is no apparent organic disease or objective evidence of a pathologic condition. In clinical practice, most children with chronic gastrointestinal complaints have functional disorders. Despite their common occurrence, we know very little about the pathophysiology of most of these conditions. A diagnosis of a functional disorder is largely based on a patient's report of symptoms. Whereas adults can offer accurate histories, this is not necessarily the case in children, especially those who are young. Moreover, parents often play a large role in reporting their child's symptoms as well as in making the decision about whether to seek health care. Often the child–parent unit must be evaluated when addressing functional disorders. Considerable effort has been spent in defining pediatric functional gastrointestinal disorders. A multinational team of senior clinicians suggested working definitions (1). A recent monograph has described the spectrum of these disorders (2). It has been observed that some pediatric functional gastrointestinal disorders accompany normal development (e.g., infant regurgitation), or may be triggered by behavioral responses to age-appropriate activities (functional fecal retention during toilet training). It was also suggested that some children could inherit a temperament characterized by a predilection to gastrointestinal reactivity to stress, thereby constituting a genetic susceptibility to functional gastrointestinal disorders. At the same time it is recognized that environmental factors (parental health care seeking, stress, culture, geographic location) might play a role in the pathogenesis of functional gastrointestinal disorders. In the biopsychosocial model of clinical practice, symptoms represent the end result of autonomic nervous system reactivity and recovery, environmental stressors, and the child's ability to cope. They are also influenced by parental responses and coping. In this report, we address functional gastrointestinal disorders associated with vomiting, abdominal pain, and disordered defecation. We have not considered infant regurgitation, which is discussed in another Working Group report. CYCLIC VOMITING SYNDROME I. Summary of the Problem The cyclic vomiting syndrome (CVS) is characterized by recurrent, severe, discrete episodes of acute nausea and vomiting lasting from hours to days, with intervals of baseline normal function lasting weeks to months between episodes (3,4). Age of onset is quite variable, with most children between 6 and 10 years of age at the start of symptoms. Younger and older children also can be affected. There is no apparent metabolic, gastrointestinal, central nervous system, biochemical, or other disease causing vomiting. The frequency of episodes averages 12 per year (range, 1–70), and intervals between attacks may be regular or sporadic. Episodes tend to begin at the same time of the day, predominantly during the night or early morning. The duration of episodes tends to be similar in individual patients. Samuel Gee published the original description of cyclic vomiting syndrome in the 1880s. Although the cause and pathogenesis are unknown, cyclic vomiting syndrome appears to be related to migraine headache and abdominal migraine in that it is a paroxysmal disorder of brain–gut interaction. Currently, treatment consists of antiemetic medications for relief of nausea and vomiting, as well as prophylaxis with medications used to prevent recurrent migraine. In most children, the disorder is self-limited or resolves before adulthood. However, the episodes of vomiting are intense and disabling, often require parenteral medications and hospitalization, and leave the patient and family feeling distraught and helpless. Patients may be prevented from attending school or holding a job. Fluid and electrolyte disturbances, Mallory-Weiss tears, and inappropriate secretion of antidiuretic hormone can complicate episodes. Recurrent vomiting can lead to chronic esophagitis and erosion of dental enamel. II. Major Issues Requiring Investigation and Implementation The cause and pathogenesis of CVS need to be determined. Although in many patients CVS appears to be associated with migraine, in a significant portion it does not. There is no objective marker for migraine, and the criteria for the diagnosis of migraine-associated CVS have not been validated. It has not been established that migraine-associated CVS has a different cause than non–migraine-associated CVS. To determine whether there is a causative link with migraine, it is necessary to perform prospective studies, with standardized information-gathering tools, systematic testing, established criteria, and collaboration between pediatric neurologists as well as pediatric gastroenterologists There is an urgent need to improve the efficacy of treatment and prophylaxis of CVS. Treatment of acute episodes has included ondansetron, lorazepam, chlorpromazine, and droperidol. Prophylactic therapy has included amitriptyline, cyproheptadine, propranolol, sumatriptan, erythromycin, anticonvulsants, dietary measures, and psychotherapy. No randomized controlled trials have been performed to establish the efficacy of any therapy. III. Proposed Plan to Achieve Goals Randomized double blind placebo-controlled trials of the most promising medications are needed for both migraine-associated and non–migraine-associated groups. Both antiemetic and prophylactic medications should be studied. Multicenter studies may be necessary to enroll an adequate number of patients. Studies should be performed on several continents to determine whether differences in cause and response to therapy exist in various locales. A task force composed of pediatric gastroenterologists, neurologists, physiologists, and behavioral specialists should be formed to develop a multicenter database to systematically examine CVS, determine whether subtypes exist, and longitudinally follow a large cohort of patients. FUNCTIONAL DISORDERS ASSOCIATED WITH ABDOMINAL PAIN I. Summary of the Problem Almost four decades ago, Apley and co-workers defined recurrent abdominal pain as 3 or more bouts of pain, severe enough to affect activities, occurring over a period of not less than 3 months (5). Apley suggested that most children with this problem were suffering from pain associated with psychological difficulties. We now know that recurrent abdominal pain is a description and not a diagnosis. Moreover, the constraint of 3 months' duration is not regarded as relevant by all clinicians. Since Apley's work we have come to appreciate a long list of organic diseases associated with recurrent abdominal pain as well as the spectrum of functional gastrointestinal disorders. Pain has a nociceptive and an affective component, so that we recognize that many children have intolerance for mild discomfort, but others may cope better with pain, and not necessarily interrupt activities. The pain may be intermittent or continuous. Only a minority of cases of recurrent abdominal pain in childhood and adolescence are caused by organic disease. In most cases there is no demonstrable structural or biochemical abnormality. In studies from North America and Scandinavia, recurrent abdominal pain may affect 10% to 30% of children and adolescents. Approximately 5% to 15% of middle school and high school students have symptoms consistent with irritable bowel syndrome. The prevalence of functional dyspepsia in the general pediatric population is unknown, but approximately 5% of middle and high school students note dyspeptic symptoms. There are no epidemiologic data from other parts of the world. There are characteristic symptom patterns that appear to correlate with different clinical disorders. A recent publication proposed definitions for subtypes of recurrent abdominal pain in children (1). These definitions, presented here, may be helpful for both research and clinical care. Although the definitions imply sharply defined differences, some patients have features of more than one subtype. For example, a patient may have symptoms of both irritable bowel syndrome and functional dyspepsia, although often one symptom complex is predominant. Because the definition of a functional condition depends on the patient's report of symptoms, diagnosis in very young children depends on the caretaker's history. Whereas functional abdominal pain may occur in infancy, for this discussion we will assume the child is mature enough to provide an accurate pain history, the duration of symptoms is at least 12 weeks, which need not be consecutive, and the problem has occurred within the preceding 12 months. Functional dyspepsia is defined as persistent or recurrent pain or discomfort centered in the upper abdomen (above the umbilicus) in the absence of evidence (including upper endoscopy) that organic disease is likely to explain the symptoms. In the past this condition was often referred to as non-ulcer dyspepsia, but that term has largely been abandoned. Based on the predominant symptom, subgroups of functional dyspepsia have been suggested. These include ulcer-like dyspepsia in which pain centered in the upper abdomen is the predominant symptom, and dysmotility-like dyspepsia which is characterized by an unpleasant or troublesome nonpainful sensation (discomfort) centered in the upper abdomen often associated with upper abdominal fullness, early satiety, bloating, or nausea. The potential relationship of chronic infection with Helicobacter pylori and functional dyspepsia remains an area of controversy. There is no evidence that dyspepsia is related to defecation. Irritable bowel syndrome (IBS) is defined as abdominal discomfort or pain that has at least two of the following three features: relieved with defecation, onset associated with a change in frequency of stool, onset associated with a change in form (appearance) of stool. In addition, there are no inflammatory, structural, or metabolic abnormalities to explain the symptoms. Functional abdominal pain is defined as continuous or nearly continuous abdominal pain in a school-aged child or adolescent with no or only occasional relation of the pain with physiologic events (e.g., eating, menses, or defecation), and usually some loss of daily functioning (6). The pain is not faked (e.g., malingering) and the patient has insufficient criteria for other functional gastrointestinal disorders or diseases that would explain the abdominal pain. In some patients with functional abdominal pain, the symptom is intermittent rather than continuous. Abdominal migraine is defined as three or more paroxysmal episodes of intense, acute midline abdominal pain lasting 2 hours to several days, with intervening symptom-free intervals lasting weeks to months, in the preceding 12 months (7). There is no evidence of metabolic, gastrointestinal, or central nervous system disease. In addition, there are at least two of the following features: headache during episodes, photophobia during episodes, family history of migraine, headache confined to one side only, or an aura or warning period consisting of either visual disturbances (blurred or restricted vision), sensory symptoms (numbness or tingling), or motor abnormalities (e.g., slurred speech, inability to speak, paralysis). The precise pathophysiology of IBS, functional dyspepsia, functional abdominal pain, and abdominal migraine is not known. It is thought that symptoms may arise from changes in the brain–gut axis, which links the central and enteric nervous systems (ENS) (8). The ENS controls motor and secretory functions of the gastrointestinal system. It is semiautonomous in that the parasympathetic and sympathetic nervous systems modify its actions. Neurotransmitters in the ENS include serotonin (5HT), acetylcholine, substance P, vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP). 5-HT receptors appear to participate in mucosal sensory processing within the gut. Clinical experience suggests that IBS and functional dyspepsia occasionally follow bouts of presumed gastrointestinal infection. Patients with inflammatory bowel disease may manifest IBS-like symptoms even when bowel inflammation is quiescent. This visceral hyperalgesia (or hypersensitivity) may result from alterations in gut wall sensory receptors, abnormal modulation of sensory transmissions in the peripheral or central nervous system, or changes in cortical perception of afferent signals. Primary hyperalgesia refers to afferent gut nociceptors becoming hypersensitive after repetitive painful stimuli (e.g., inflammation), so that they transmit a pain signal after stimuli that were formerly sub-threshold (hyperalgesia) or after stimuli that do not normally cause pain (allodynia). 5HT is thought to play a role in the generation of these nociceptive impulses. Secondary hyperalgesia refers to changes in the central nervous system at and above the synapses between sensory afferent neurons and spinal cord interneurons. The role of motility abnormalities in the pathogenesis of IBS, functional dyspepsia, or functional abdominal pain is not clear. Therapy may be offered at several levels, including reassurance, dietary manipulation, psychotherapy, and pharmacologic measures. There are limited controlled trials of different treatment modalities of IBS, functional dyspepsia, or functional abdominal pain in childhood and adolescence. One study demonstrated a beneficial effect of fiber supplementation in recurrent abdominal pain, and the other demonstrated the efficacy of cognitive and behavioral modification therapy. Current medications used for IBS include anti-cholinergics, tricyclic antidepressants, and selective serotonin re-uptake inhibitors (SSRI). The 5HT3 -receptor antagonist alosetron (Lotronex, Glaxo Wellcome) which showed efficacy in the treatment of IBS in adult females with diarrhea-predominant symptoms was recently withdrawn from the United States market because of concerns of ischemic colitis. Tegaserode, a partial 5HT4-agonist, is currently being considered for approval as a treatment for constipation-predominant IBS in adults. For functional dyspepsia, antacids, H2-receptor antagonists, proton pump inhibitors, cisapride, metoclopramide, and tricyclic antidepressants are used. Cisapride has been withdrawn from the United States market because of reported adverse cardiovascular side effects but will continue to be available in Canada, Latin America, and Europe. For abdominal migraine, therapy is similar to that used for migraine prophylaxis and may include propranolol, cyproheptadine, and amitriptyline. II. Major Issues in Need of Investigation or Implementation Criteria for irritable bowel syndrome and functional dyspepsia need to be validated in childhood. The prevalence of IBS and functional dyspepsia in different ethnic groups and in different locations around the world should be investigated. The pathogenesis of IBS, functional dyspepsia, and functional abdominal pain should be investigated using emerging techniques such as the barostat, brain imaging (positron emission tomography (PET), functional magnetic resonance imaging (MRI), and molecular investigation of brain–gut peptides. The relationship of IBS and functional dyspepsia to previous enteric infection (e.g., postinfectious IBS) and inflammatory bowel disease should be defined. The role of early childhood risk factors for IBS, functional dyspepsia, and functional abdominal pain, including infantile colic, allergy, depression, anxiety, somatization, abuse, and family history of functional gastrointestinal disorders, need to be clarified. This should include a study of whether a genetic component is important in these disorders. There is a need to develop drugs to modulate abnormalities in sensorimotor function of the enteric nervous system in functional disorders to relieve specific symptoms and to assess the proper role of these drugs in the treatment of children and adolescents. The role of antidepressants (tricyclics, selective serotonin reuptake inhibitors) in the treatment of functional gastrointestinal disorders associated with abdominal pain needs to be assessed. The educational, social, and economic consequences of functional gastrointestinal disorders such as school absenteeism, inability to concentrate on studies, inability to participate in age-appropriate activities, health-care seeking, and lost time from parental employment should be studied. The relationship between H. pylori infection and functional dyspepsia should be clearly defined. Standard and novel psychological interventions need to be evaluated in symptom management, particularly promotion of coping through behavior modification to determine whether these patients can be treated nonmedically. Comorbid psychological disorders are often associated with functional gastrointestinal disorders, and there is a need to improve understanding of psychosocial processes and interventions. III. Proposed Plan to Achieve Goals It is important to build on the previous work of the Rome committee and validate or modify working definitions for the functional gastrointestinal disorders associated with abdominal pain. Attempts should be made to better define the concept of visceral hypersensitivity in functional abdominal pain. Cooperative studies with gastrointestinal physiologists and neurogastroenterologists need to be completed in patients of different ages. Newly emerging medications for the treatment of functional gastrointestinal disorders need to be evaluated in multicenter, multinational trials. Cooperative studies with mental health professionals and developmental specialists need to be devised to systematically evaluate behavioral therapies in the treatment of functional abdominal pain. Primary care physicians must be educated about the relationship of the central and enteric nervous systems. Moreover, primary care physicians need to be taught the criteria for functional gastrointestinal disorders. DISORDERS OF DEFECATION I. Summary of Problem Constipation is a symptom defined by the occurrence of any of the following, of of or or painful of large that may the or frequency less than 3 per the child is At chronic for at least 2 as recurrent abdominal pain, or fecal may of a feeling of Irritable bowel syndrome with and chronic many usually has no structural, or metabolic disease and is functional or The cause of functional is largely and is 5HT and 5-HT receptors may play a are being evaluated for efficacy for treatment of is the of associated with to which to a reported sensory at the fecal is the inappropriate of a other than the in a child older than clinicians it may be necessary to an abdominal before fecal retention to of can be In the United is the term often used to whether to or not. is defined as and before of in an infant than 6 months of Constipation has been reported to for about of primary care and of to pediatric The reported prevalence of pediatric is 15% in in Canada, and to in with a prevalence of before age 2 in the have a on tend to have than on or The early onset of symptoms to factors in some of and the of various can affect It has been suggested that can be associated with in may occur in different In children with year of painful can result in because of of painful defecation. This will or dietary which may have in in the In other children, may occur at the time of toilet or the child is from the time to in the toilet when in other activities. However, some this behavior in to of at the time of of toilet In this the is a primary in the pathogenesis of It has been proposed that a in fiber is an important to in some Despite data about dietary fiber in children are in than in children has been in and in but its role as a has not been determined. it has been for but not for children, that dietary the is beneficial in such as and may cause The treatment of chronic is based on the following relief of with either consistent of or therapy to establish normal bowel and prevent with or in over and of the child and The chronic of should be the of in the treatment of chronic with variable efficacy in different of are now being used in some for therapy. A with adequate and is to adequate of and and are This the family to normal bowel and so that and its treatment are with of a regular toilet is and a system of and may be used. The of can be because a for the child and the children may present with severe abdominal pain, or vomiting, which can lead to or psychological alterations to school absence or II. Major Issues in Need of Investigation or Implementation showed that most on functional is based on studies and which needs to now be by controlled There is a need for more prevalence studies, in and also in the has been on disease. Studies are needed on the role of dietary fiber and in the and treatment of are on and of fiber in the of being from that of and fiber in would clinical care as well as There is a need to define the relationship of and intolerance to chronic The role of including primary in and and need to be factors need to be behavior and of the that may be helpful in interventions. must be defined as a primary or in the pathogenesis of functional studies of with should be performed to define whether it is a symptom complex that in The efficacy and role of novel such as in the treatment of in children needs to be studied. The and efficacy of in the treatment of in children should be studied. III. Proposed Plan to Achieve Goals studies need to be performed to assess the prevalence and of in Studies need to be performed to examine the of parents and health care the and of and various treatment Randomized controlled trials are to evaluate the efficacy and of currently used and novel including and Randomized controlled trials to evaluate the efficacy of dietary fiber and fiber supplementation in the and treatment of should be I. Summary of the Problem or chronic children from to years of The children are they 3 to per The frequency can be as many as 10 per day, and may and The in the is usually large in formed or of the bowel occur in the of the day, and no are at The are often described as particularly The general condition of the children is to or of At their may be by dietary measures. Abdominal pain may be present but is a is by an of acute or another infection. that before the onset of many of the children or Although is to be one of the of chronic in the in the general population is There is a of epidemiologic studies of this common condition both in the and Current understanding of the is that intestinal motility is in children with at the time of diagnosis. result in in the and they in response to a In one these were not after This may result in a intestinal time when with normal factors are recognized as an important role in the pathogenesis of with often or very high with very high especially from and has been reported has also been suggested as a Although it is very likely that dietary and are of the spectrum of factors it is that the is often although may in some children by the or by many children of more than who are bowel intestinal intestinal of and also may be important in the pathogenesis of The of treatment is to such as dietary abnormalities. For those with no treatment with and has been by no treatment at the may be the is than are of by months of II. Major Issues in of Investigation and Implementation Although is well recognized as one of the most common of in and the remains both in and There is a of prevalence data in large data are needed to assess the of the problem in the general The relationship of to ethnic and of the parents is The of remains the primary cause of chronic is the role of dietary is the role of have been used in children with However, it is to an of the intestinal as the of Moreover, one could also that in during and could be related to an of In the is used in Although there are no clinical data this that this should be evaluated and the for this treatment is that the an of the of the intestinal and improve There is a need to the general behavior and of the child with and gastrointestinal and gastrointestinal III. Proposed Plan to Achieve Goals prospective studies should be performed to more about normal bowel in and It may well appear that there are many children in the population that have similar and bowel to those with It is that epidemiologic studies will a to a about a problem in with an studies defining normal patterns in different parts of the world from through childhood should be Multicenter trials of in the treatment of chronic should be There is a need to the history of chronic to determine whether children develop functional gastrointestinal disorders including irritable bowel syndrome in could be by to similar to improve and I. Summary of the Problem is the of of and is of the spectrum of functional symptoms The most common is abdominal However, abdominal also as a of gastrointestinal of as in or as a of in abdominal colic, and The of large of in the is or In abdominal during the and is in the of the to and even intestinal Patients with that is the of can be in two in the the is to severe or such as and Patients with chronic such as develop because of The as of functional such as when children during children large of may be associated with even in the absence of pathologic The treatment of is largely behavioral of and from during can all be In the of behavioral is II. Major Issues Investigation or Implementation Studies need to be performed to develop data on the and of gastrointestinal in pediatric patients. There is a need to determine whether is an cause of recurrent abdominal pain in children, especially the that in the The relationship of to should be studied. III. Proposed Plan to Achieve Goals and investigation techniques should be to the frequency and of We need to whether pathogenesis are should be to of to patients and their because it is to patients and their that is to a clinical The and who as and and who as