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Motility Disorders in Childhood: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

2002; Lippincott Williams & Wilkins; Volume: 35; Linguagem: Inglês

10.1097/00005176-200208002-00017

1536-4801

Peter J. Milla, Salvatore Cucchiara, Carlo DiLorenzo, Norberto Mata Rivera, Colin D. Rudolph, Takeshi Tomomasa,

Infant Health and Development

I. SUMMARY OF THE PROBLEM Gastrointestinal disorders result in a limited number of symptoms, including recurrent vomiting, abdominal pain and distension, constipation, and loose stools. A large body of evidence has accumulated in both adults and children to suggest that these functional symptoms may be largely caused by disordered gastrointestinal motility. The pathophysiology of the above symptoms is best understood by considering their production by disturbances of the control mechanisms of gut motor activity. Such disturbances may be produced by organic disease involving enteric nerves and muscle, alteration of the humoral environment of the nerves and muscle of the gut, and altered central nervous system input. The current body of information regarding the physiology of gastrointestinal motor activity started at the end of the last century with Bayliss and Starling's description of peristaltic movement. It soon became apparent that there were complex patterns of motor activity but it was not until the late 1960s and 70s that great impetus occurred in the understanding of the organization of gastrointestinal motor activity with the description of the migrating myoelectric complex by Szurszewski. In the late 1970s and early 1980s, systematic study of gastrointestinal motor activity started in children. Motility disorders occur across the ethnic spectrum and are commonest in infancy. Approximately 50% of mothers with healthy infants between the ages of 2 and 8 months report that their infants regurgitate two or more times daily, indicating that gastroesophageal reflux is an extremely common disturbance of foregut motility. If the United States alone is considered, then more than four million babies are born each year and at least half of them will have gastroesophageal reflux at some time during the first 2 years of life. Thus, what often seems to be a relatively minor problem has important economic and public health implications. Apart from constipation all the other motility disorders discussed in this report are much less common—even functional constipation, only accounting for perhaps 3% of pediatric outpatient visits and 25% of pediatric gastroenterology consultations. However, it is likely that every child at some time during their childhood may have an episode of constipation particularly associated with dehydration or an infection. The remaining disorders all account for less than 5% of children. In childhood, both congenital and acquired disease processes may produce the pathogenetic mechanisms resulting in symptoms that vary in severity from the chronic and recurrent obstruction of chronic intestinal pseudo-obstruction to the repeated passage of loose stools in chronic nonspecific diarrhea. In children, it is particularly important to consider that these disease processes operate on a background of the developmental processes that the child undergoes and also may be the result of the interaction of children with their parents and society. Increasing understanding of the above concepts and basic principles has resulted in the emergence of neurogastroenterology. Neurogastroenterology is a new and advancing subspecialty of clinical gastroenterology and digestive science. It embraces the innervation of the gut from brain and spinal cord through sympathetic parasympathetic divisions of the autonomic nervous system to the intrinsic enteric nervous system. Also included are smooth muscle, mucosal epithelium and the gut-associated lymphoid tissue of the immune system, which interact with the neural elements of the gut. Enteric innervation neural networks with control of gut function are positioned in the brain, spinal cord, prevertebral sympathetic ganglia, and in the walls of the organs that make up the gut. A hierarchy of four neural centers is involved in the control of gut motility (1). Level One is the enteric nervous system, which has local circuitry for integrated function and is independent of extrinsic nervous connections. Level Two includes the prevertebral sympathetic ganglia, which are influenced by preganglionic sympathetic fibers in the spinal cord. Levels Three and Four are within the central nervous system and consist of the sympathetic and parasympathetic outflow to the gut and the higher brain centers. Disease and malfunction of these systems are increasingly recognized as underlying motility disorders of the gut. The enteric nervous system coordinates the activity of primary effectors to produce meaningful patterns of behavior of the gut for the whole organ. It is a local mini-brain within which are stored a library of programs for different patterns of gut behavior. Such programs include emesis, swallow-induced peristalsis, and fasting small intestinal motor activity, amongst others. The enteric nervous system in many respects resembles the central nervous system, and indeed the neurones involved are essentially the same. The enteric nervous system works with three functional categories of neurones—sensory, inter, and motor neurones—and these are connected by synapses into networks that process sensory information and control the behavior of motor neurones. Multiple connections for logic circuits that decipher codes from sensory neurones and signals from elsewhere in the nervous system interact to produce an integrated motor output. Abnormalities in the inhibitory or excitatory input may lead to different disease states. A functional obstruction occurs in any condition in which inhibitory motor neurones are destroyed or the muscle coats have lost contractile activity. Without inhibitory controls, the self-excitable smooth muscle contracts continuously and behaves as an obstructing element. Loss or malfunction of inhibitory motor neurones is the pathophysiologic basis of this type of condition, and it underlies several forms of chronic intestinal pseudo-obstruction, Hirschsprung disease, and achalasia of the esophagus. In early life, this may be due to congenital maldevelopment of the enteric nervous system and in later life neuropathic degeneration. Neuropathic degeneration in its early stages may be manifest as symptoms that can be confused with the irritable bowel syndrome and other functional gastrointestinal disorders. An increasing body of evidence shows the interaction between mucosal-associated lymphoid tissue and the motor apparatus of the gut. The enteric immune system is colonised by populations of immune and inflammatory cells that are constantly changing according to luminal conditions and pathophysiological states. Due to the inability of the physical and chemical barrier of the luminal interface to entirely exclude antigens, the immune system is daily exposed to dietary antigens, bacteria, viruses, and toxins, causing the mucosal associated lymphoid tissue to be chronically challenged. The motor and secretory responses in the gut of animals sensitized to antigens such as food or bacterial toxins, together with the effects of infection in the human, show a direct link between the immune system and the motor apparatus. Immunoneural integration starts with either detection by epithelial cells of antigen or immunocytes in the lamina propria (2). The signal is transferred to the enteric nervous system, and the appropriate response occurs from the program library of the enteric nervous system. In general, detection by the enteric immune system and signal transmission to the enteric nervous system initiates a defensive behaviour analogous to the emetic response in the upper gastrointestinal tract, resulting in the forceful and rapid propulsion of ingested material over long distances (2). Several kinds of immune and inflammatory cells, including lymphocytes, macrophages, mast cells, and polymorphonuclear cells, are putative sources of paracrine signaling to the enteric nervous system. The use of signaling between mast cells and the enteric nervous system is best understood. Antigen-evoked degranulation of sensitized mast cells releases a wide variety of paracrine signals that include 5-hydroxytryptamine, histamine, platelet activating factor, tachykinins, prostaglandins, cytokines, and leukotrienes. Recurrent Vomiting Three functionally based syndromes resulting in recurrent vomiting occur. Infant regurgitation or gastroesophageal reflux, rumination, and cyclical vomiting. Regurgitation and rumination are both examples of gastroesophageal reflux. Cyclical vomiting is due to recurrent activation of the emetic reflex. Gastroesophageal Reflux Infant regurgitation or gastroesophageal reflux occurs commonly in infants during the first 18 months to 2 years of life. In 90%, symptoms resolve at this time (3). When gastroesophageal reflux causes or contributes to tissue damage or inflammation as in esophagitis, apnea, bronchospasm, pulmonary aspiration, failure to thrive, iron deficiency, anemia, or hematemesis and stricture of the esophagus, it is called gastroesophageal reflux disease. The episodes of reflux are most usually due to transient relaxation of the lower esophageal sphincter (4). However, several other mechanisms also may play a part, including low basal tone of the lower esophageal sphincter and prolonged opening of the lower esophageal sphincter during swallowing. Although dysfunction of the sphincter and loss of the barrier to a pressure gradient from abdomen to esophagus causes reflux whether gastroesophageal reflux disease occurs or not is mostly due to lack of acid clearance from the esophagus because of to impaired peristaltic activity of the body of the esophagus. Due to the improvement with age, it has generally been considered that the reflux is associated with the development of control of the neuromusculature of the lower esophagus and stomach. However, recent evidence suggests that in some children organic disease of enteric nerve and muscle is present and in others that modulation of the humoral environment of the esophageal and gastric neuromusculature by food allergic responses results in regurgitation taking place. This latter is particularly true in atopic infants or those with minor immunodeficiency. Regurgitation also may occur in association with occult anatomic abnormality such as malrotation and altered central nervous system input such as that which occurs in cerebral palsy or occult cerebral tumours. The diagnostic approach to the infant or child with possible GERD varies depending on the symptom presentation. Infants with GER but no symptoms of oesophageal inflammation or extra-esophageal GERD do not require diagnostic evaluation. If there is a question of esophagitis, either empiric therapy or diagnostic endoscopy and biopsy is reasonable. Other disorders such as eosinophilic or allergic esophagitis may be identified by biopsy. The approach to evaluation of airway complications of GER remains enigmatic. Abnormal esophageal pH monitoring increases the likelihood that GER is causing respiratory symptoms, but a negative test certainly cannot exclude GER as a cause of recurrent pneumonia, asthma exacerbation or laryngeal symptoms such as stridor. Other techniques such as bronchoalveolar lavage for lipid-laden macrophages, laryngoscopy to identify “characteristic reflux changes” or nuclear scintigraphy lack adequate specificity for definitive diagnosis. The best diagnostic approach for supra-oesophageal complications of GER remains unclear. New techniques using intraluminal impedance measurements to detect non-acid GER may prove more effective in the evaluation for GERD. Treatment Because infant gastroesophageal reflux is a transient problem, for the most part treatment goals are to provide effective reassurance and symptom relief. Symptoms often improve with positioning after meals, thickening of formulas, and small feeding volumes. In the last year the safety of prokinetic drugs such as cisapride has been called into question and as a consequence prokinetic agents should not be used for simple spitting up or possetting but may be necessary where there is gastroesophageal reflux disease. In such instances, combination with anti-acid secretory drugs such as H2 blockers and protein pump inhibitors should also be used. In uncontrolled gastroesophageal reflux disease, surgery may be necessary, and fundoplication either by open surgery or laparoscopy is the procedure of choice. However, fundoplication has a definite morbidity and mortality. As a consequence, most surgeons would reserve surgery for those who have severe intractable esophagitis, life-threatening respiratory symptoms, Sandifers syndrome, stricture, or severe failure to thrive that does not respond to medical treatment. Rumination The mechanism for all forms of rumination appears to be voluntary abdominal contraction when the lower esophageal sphincter is open, which is usually induced by swallowing. This appears to be a self-stimulating behavior occurring in infants, neurodevelopmentally retarded individuals, and older children (5). Recent evidence suggests that it may be easier for these children to induce reflux because of a decreased threshold for lower esophageal sphincter relaxation during gastric distension. Treatment Treatment effort should be directed toward caregivers as well as the child. The goal of therapy is to provide a nurturing environment and comfort and care to the infant or child to avoid the necessities of self-stimulating behavior. This can often be achieved by improving caregivers' ability to recognise and respond sensitively to the infant's physical and emotional needs. However, in mentally handicapped children, providing a nurturing caregiver may not be sufficient, and behavioral therapy such as aversive techniques and surgery may be necessary. In older children and adolescents, intensive therapy or inpatient hospitalization for behaviour modification may be effective. A better understanding of the underlying mechanisms triggering this stereotypic behavioral pattern is necessary before pharmacologic therapies can be appropriately selected. It is possible that in some children with rumination, an aberrant interaction between the central nervous system and the enteric nervous system leads to the relief of pain or discomfort resulting from normal amounts of gastric distension. Cyclical Vomiting Syndrome Cyclical vomiting consists of repeated episodes of activation of the emetic reflex. Activation of the emetic reflex may occur after a number of known conditions, including intracranial space-occupying lesions, obstructive nephropathy, inborn errors of metabolism, especially urea cycle defects and organic acidurias, and gastrointestinal mucosal inflammation. In those in whom there is not an obvious underlying pathologic process, approximately 80% are able to identify specific conditions that precipitate most of their episodes, and these include heightened emotional states, infections, allergy, or physical exhaustion. About one third of these patients have clinically significant psychiatric conditions, such as anxiety disorder or depression (6). The paradigm of the emetic reflex appears to be a useful means of understanding cyclical vomiting, and the known causes of cyclical vomiting will all provide either central or peripheral input into the emetic reflex arc. The nature of psychiatric and psychogenic input into the emetic reflex arc is as yet unknown but almost certainly results from altered central neurotransmitter profiles. Treatment The major role played by 5HT3 receptors in the vagal afferent input into the emetic reflex results in ondansetron and granisetron being extremely effective agents in a proportion of children with cyclical vomiting. In those with an identifiable prodrome, oral administration of these drugs before the onset of nausea may abort episodes. In others, intravenous infusion of ondansetron and granisetron during an episode may interrupt the crisis. A variety of other prophylactic treatments, including amitryptiline, propranalol, sumitryptan, and cipraheptadine, have all be shown to reduce the frequency or even eliminate episodes. In addition to pharmacologic treatment, emotional conditions that trigger episodes should be identified and treated, as should electrolyte deficit, hypertension, and inappropriate secretion of vasopressin. Oesophageal Motility Disorders Achalasia is characterised by failure of the LES to relax during swallows. High-amplitude, “vigorous,” simultaneous contractions of the esophageal body may be observed during the early evolution of this disease. Subsequently, the esophagus distends and becomes completely dysfunctional. LES tone usually is elevated in achalasia. The disorder results from a lack of inhibitory innervation of the LES. Achalasia is rare in childhood, usually occurring after 15 years of age; however, it may present in the first month or years after birth and then is frequently associated with an autosomal recessive syndrome of deafness, vitiligo, short stature, and muscle weakness, or with the syndrome of alacrima and corticotrophin insensivity. In Latin America, Chagas' disease must be considered. Similarly, leiomyoma or other tumors of the stomach may masquerade as achalasia. Diagnosis of achalasia is usually suspected based on findings of radiographic contrast studies that show poor esophageal transit and usually a dilated esophageal body. Confirmation by esophageal manometry is desirable. Treatment with pharmacotherapy (e.g., nifedipine) is variably effective and rarely provides an option for long-term management. Similarly, injection of the lower esophageal sphincter with botulinum toxin provides transient relief, but the requirement for repeated injection makes this therapy less attractive for treatment of childhood achalasia. Pneumatic balloon dilation of the LES ruptures the muscle and may provide long-term relief from symptoms. If frequent pneumatic dilation is required to prevent symptom recurrence, a laparascopic Heller myotomy with an anti-reflux procedure provides definitive surgical therapy. Diffuse esophageal spasm is characterized by prolonged (i.e., >5.5 seconds) simultaneous contractions in at least 30% of the esophageal body waveforms. These contractions have multiple peaks, and, often, increased amplitude. High-pressure (mean amplitude, >180 mm Hg) and prolonged (>5.5 seconds) organized peristaltic waves characterize a nutcracker esophagus. These disorders are rarely described in children. A variety of nonspecific esophageal motility disorders characterized by varying combinations of simultaneous contractions, abnormal wave forms, and decreased wave amplitudes are common; the pathophysiologic significance of these findings remains obscure. No consistently effective treatment for esophageal motility disorders are available except for achalasia. Approaches have included calcium channel blocking drugs, botulinum toxin injection into the esophageal muscle, and dilation with inconsistent responses. Chronic Nonspecific Diarrhoea A child with loose, frequent, foul-smelling stools who is thriving, is probably the commonest problem to present to the pediatric gastroenterologist. A variety of mechanisms have been implicated in chronic nonspecific diarrhea, including changes in intestinal transport and brush border enzymes, prostaglandin synthesis, food intolerance, and intestinal motor activity (7). It is only in the last of these that there is convincing evidence that they may play a role. In a survey of children with chronic nonspecific diarrhea, one third of such patients have evidence of food allergy, and all were atopic. Treatment of the food allergy commonly results in cessation of the diarrheal symptoms. Disturbed intestinal motor activity appears to be an important mechanism for the production of the symptoms, with particularly lack of suppression of fasting small intestinal motor activity by food resulting in a shortened small bowel transit time. The cause of the inadequate postprandial response is not clear but could be expected to be involved in the observed, shortened, small bowel transit time. There is no information as yet as to whether this is caused by abnormal secretion of postprandial polypeptide hormones or an immune response such as immediate hypersensitivity to a constituent of the food consumed or maldigestion of a food resulting in an osmotic diarrhoea. Clearly a variety of mechanisms may cause nonspecific diarrhea, and treatment is that of the underlying condition in most cases. Treatment In those that have minor immunodeficiency or who are atopic, food exclusion diets (commonly excluding cow's milk and eggs) may be extremely effective. In others, nonspecific treatment with Loperamide may control their symptoms. Constipation and Recurrent Intestinal Pseudo-obstruction Up to 25% of outpatient visits to a pediatric gastroenterologist are for problems with defecation (8). In most constipated children, the condition results from a behavioral disorder triggered by the fear of painful defecation. After months of withholding the passage of stools, constipated children develop a megarectum. A minority of children presenting with constipation may have potentially serious underlying pathology with organic disease of the enteric neuromusculature (15) For those with functional constipation due to a behavioral disorder, a number of factors appear important (9). A bout of constipation is associated with loss of appetite due to an acute infection with the development of a rectum full of hard, large stool that is difficult to pass. Pain on defecation from an anal fissure, difficult toilet training due to unpleasant toilet facilities, e.g., inadequate provision at school or due to persistent negative developmental phase in some toddlers. None of these adequately explain the relatively common scenario of the development of constipation in toddlers and infants that stem from the introduction of solids into their diet. In this context, the recent description of constipation occurring in atopic individuals is of particular interest, and this may be mediated by an eosinophilic rectosigmoiditis that results in increased anal sphincteric tone. The use of an exclusion diet, which may exclude cow's milk and eggs or wheat, results in normalization of defecation in as many as 70% of atopic individuals (10). Recent evidence also shows that, in up to 25% of those that have the irritable bowel syndrome that may include bouts of constipation, this occurs after an enteric infection. Spiller et al. have shown both the presence of an intraepithelial lymphocitosis and entero-endocrine cell hyperplasia in the rectal biopsies of such individuals. It is of interest that the population of endocrine cells that are involved are those that produce 5-hydroxytriptaline, neurotensin, and neuropeptide Y. In a minority, occult enteric neuromuscular disease may cause severe constipation or recurrent functional obstruction, which may be both congenital and acquired (11). The acquired disorders in childhood appear to be mostly autoimmune disorders affecting either nerve or muscle of the bowel. Interestingly these may also occur after an apparent enteric infection. Degenerative inflammatory enteric neuropathies or myopathies are characterized by dense inflammatory infiltrates confined to either the myenteric plexus or to the muscle coats of the bowel—usually the circular muscle coat. Initially there may also be mucosal inflammation perhaps originally associated with the enteric infection. This pattern appears to occur most frequently in the idiopathic degenerative disease and Chagas' disease whereas para-neoplastic syndrome usually does not exhibit a mucosal inflammatory process. In both conditions an autoimmune process is often present that arises as part of a T-cell–mediated inflammatory process. Both CD4 and CD8 positive T-lymphocytes are present in the inflammatory process and circulating antibodies against enteric neurones similar to those found in secondary inflammatory neuropathies with anti-Hu and anti-Yo protein or smooth muscle antibodies. The immunolabeling pattern of the idiopathic inflammatory neuropathy is different from that of the para-neoplastic syndrome with rather prominent cytoplasmic rather nuclear staining. In diagnostic motility studies, degenerative loss of enteric neurones is reflected by hypermotility and spacticity due to the loss of inhibitory motor neurones. In the myopathic disease, there are low-amplitude contractions. These disorders are important for two reasons: 1) the early complaints with these conditions are either similar to functional gastrointestinal disease or are of an enteric infection; 2) these conditions are treatable with immunosuppressive drugs which that the T-cell–mediated process. Ontogeny of Intestinal Motility A variety of studies over the last 10 years, especially of the esophagus and small intestine, have shown a clear ontogenic process involving the development of the muscle coat and the enteric nerve. Three major phases of development appear to occur: an early period of proliferation and morphogenesis; an intermediate period of differentiation when many different and distinctive cell types appear, and a later period of maturation. Only this latter period is considered in this report. Although by the end of the second trimester the gut is morphologically complete, the function of the enteric neuromusculature develops over the last trimester with adult patterns of contractile activity in most areas of the gut by term. Esophagus Functional studies of esophageal motor activity have been restricted to premature infants during the last trimester, and several studies have shown that nonperistaltic motor patterns are common in premature infants but they all have a high pressure zone, certainly by 33 weeks of gestation, at the lower esophageal sphincter (4). Both swallow-related and transient inappropriate relaxation of the lower esophageal sphincter occurs, but the relative preponderance of nonperistaltic pressure wave sequences in the body of the esophagus of premature infants means that they have poorer acid clearance when reflux episodes occur and are thus more likely to develop gastroesophageal reflux related disease. A number of studies of gastric motor activity either measuring gastric emptying or gastric antral myoelectric activity using surface electrogastrography have shown that gastric emptying, although poor before 28 weeks' gestation, after that period is relatively normal. Where there is gastroesophageal reflux, often gastric emptying is delayed, and this appears to be exacerbated by respiratory distress syndrome and ventilation. Small Intestinal Motor Activity Over the last 10 years, a number of studies have been done into the development of small intestinal motor function, and all have identified four stages of fasting motor activity: one—a disorganized stage; two—clusters of phasic activity; three—prolonged phasic activity, and four—a regular cyclical migrating motor complex pattern (12). It seems clear that the development of intestinal motor activity changes toward a more mature pattern within increasing postconceptional age. Mechanisms involved in this, however, are not entirely clear and probably involve both the development of secretion of paracrine polypeptide hormones from entero-endocrine cells and the development of the muscular plexuses of the Interstitial Cells of Cajal. Of practical importance to the neonatologist is the time that infants will develop tolerance to enteral feeds. A variety of studies have shown that this is determined by the length of time on enteral feeds, the development of clustered phasic motor activity, and the development of motilin receptors, which appears to occur at around 32 weeks of gestation (13,14). This period appears to be quite critical and in addition to the development of motilin receptors is also associated with the development of a cyclical clustered phasic activity in the fasting state and a continuous pattern of activity in response to food (15). As food releases a variety of polypeptide hormones it is almost certainly the development of receptors to these hormones that is important in developing the tolerance to enteral feeds. Thus, postprandial events appear to be dependent on the nature of the humoral response to food provided that the muscle-coats of the guts and the enteric neurones have developed sufficiently to be able to respond to the hormones secreted. The Interstitial Cells of Cajal may play an important role in this. The nature of these maturational changes, however, remain poorly explored but increasing knowledge is allowing the development of more logical feeding regimens for premature infants. II MAJOR ISSUES IN NEED OF INVESTIGATION OR IMPLEMENTATION The pathophysiological mechanisms responsible for the major motility disorders are similar to those seen in adult disorders. In the child, however, some mechanisms may be more obviously involved than others by virtue of the developmental stage that he or she is at. It is clear that the enteric neuromusculature goes through several stages of development, which occur prenatally and in early infancy. This is at present poorly explored, and the age range at which milestones of development occur are incompletely understood. There is a little or no information regarding the ontogeny of the central modulation of gastrointestinal activity, but some information is emerging to show that immunomodulation of the enteric neuromusculature may occur and that this might be particularly associated with transient immunodeficiencies of childhood resulting in an altered humoral environment for the enteric neuromusculature. There are thus a number of clear research directions at the basic and clinical level. These include: The molecular genetics and cell biology of enteric neuromuscular development and the identification of the defects causing congenital enteric neuromuscular disease. It