Pediatric gastroparesis

Epidemiology

Due to a lack of epidemiological studies, both the incidence and prevalence of pediatric GP remain unknown. However, based on a nationwide pediatric hospital database, the rate of pediatric GP hospitalizations increased significantly from 2004 to 2013 at a rate of 130 additional hospitalizations per year . The number of unique patients hospitalized with a diagnosis of GP increased from 174 to 723 during those same years . Females and adolescents appeared to have more repeat hospitalizations . Median age was 8 years (range 2–14 years), with children younger than 5 years of age having the most hospitalizations, followed by those 11–15 years of age, 6–10 years of age, and 16–21 years of age . When divided by regions, GP hospitalizations were most common in the South. The reasons why hospitalizations increased are unknown; possibilities include an increase in the prevalence of GP and/or increase in overall severity of GP .

Interestingly, hospitalizations for dyspepsia and other “specified disorders of function of the stomach” (ICD-9 536.8) also increased during this time . Though hospitalizations provide insight into the potential increase in incidence of more severe pediatric GP and/or other functional disorders of the stomach, further studies are needed to determine the overall incidence and prevalence of pediatric GP. It may be of note that cisapride was removed from the market in July 2000, some years before the rate of hospitalizations began to increase . However, whether this is a potential contributor to the increased hospitalizations is unclear.

Etiologies

In adults, most cases of GP are idiopathic with diabetes mellitus, drugs, and postsurgical causes following in frequency . Other etiologies include Parkinson’s disease and connective tissue diseases . It is estimated that as many as 25%–55% of adult patients with type 1 diabetes have GP . Most idiopathic cases are believed to occur as a post-viral syndrome, since at least 23% of patients with idiopathic GP had a viral illness prior to GP presentation . Females are more likely to have idiopathic GP, while nonwhites are more likely to have diabetic GP .

One of the proposed mechanisms for GP in adults is macrophage driven loss of, or functional abnormalities in, the interstitial cells of Cajal ( ICCs ), which can lead to gastric dysmotility . Histologic specimens from patients with diabetic and idiopathic GP showed: a decrease in the number of ICCs, with remaining ICCs showing injury; an abnormal immune infiltrate containing macrophages; and a variable decrease in nerve fibers on immunohistochemistry and electron microscopy . Whether these same pathophysiologic findings are present in children with GP is unknown. Studies using full thickness biopsies will be required to address this question.

Different pediatric retrospective studies have assessed possible GP etiologies. Table 22.1 contrasts the two largest studies to date. In contrast to adults, diabetic GP was one of the least common causes for GP in both studies. Given the small relative contribution of diabetes mellitus as an etiology of GP in children, current research paradigms directed at diabetes mellitus related GP in adults may not translate well to the pediatric GP population. Furthermore, given the extremely large predominance of an idiopathic etiology (or more likely, etiologies) in pediatric GP, particular efforts in this area are sorely needed.

Whether diabetes mellitus even is responsible for delayed gastric emptying in children is unsettled. A number of studies have evaluated gastric emptying in children with diabetes mellitus but interpretation is limited by differences in methodology for measuring emptying, the test meal administered, and ages of the children studied . Two studies were able to show slower gastric emptying time in children with diabetes mellitus type 1 when compared to controls; however, the meal ingested for these studies was not the standardized meal (Tougas) routinely used to assess emptying and methodology was varied . Multiple hypotheses have been postulated to identify the cause of emptying delay in diabetic children, including deficiency in amylin peptide hormone, uncontrolled glucose, and autonomic dysfunction; unfortunately results have been mixed . In adolescents a positive correlation has been found between the duration of diabetes type 1 and gastric emptying . Indeed, there is evidence it can take approximately 10 years for a patient with diabetes mellitus to develop GP . This delay between diabetes onset and the onset of GP may be one of the reasons why delayed gastric emptying is more prevalent in adults than in children.

Connective tissue disorders and postural tachycardia syndrome

GI symptoms are among the most common complaints in patients with connective tissue disorders including benign joint hypermobility syndrome, Ehlers-Danlos syndrome ( EDS ), Marfan Syndrome, as well as postural tachycardia syndrome ( POTS ) . Several theories have been proposed as to why patients with connective tissue disorders have increased GI complications; including abnormal gut wall connective tissue that allows increased visceral compliance, which promotes hollow organ distention and interferes with gut mechanoreceptors .

The available literature on GP and connective tissue disorders/POTS is scarce. Connective tissue disorders such as EDS have been associated with multiple GI complaints. A large retrospective study found abdominal pain, nausea, and constipation were the most common complaints . In the same study, 378 patients (n=687 with a diagnosis of EDS) complained of GI symptoms, of which 76 had a gastric emptying scan and 9 had delayed gastric emptying . Interestingly, 8 had accelerated gastric emptying, alluding to a possible different mechanism accounting for this, such as decreased gastric accommodation . To date, no studies are available in the pediatric population assessing EDS and GP. Further prospective studies are needed to understand the pathophysiology of GP and what mechanisms may be responsible for causing dysmotility in children.

Multiple retrospective studies have assessed the presence of dysmotility in patients with POTS, with most showing more rapid rather than delayed emptying . Unfortunately these studies are small, and thus larger cohorts are needed in order to confirm these results.

POTS often is associated with hypermobility joint syndrome and in fact, GP has been reported in around 20% of patients with POTS, with an even greater increase in prevalence in GI symptoms in patients with both POTS and autonomic neuropathy . However, it seems that rapid emptying is more common than delayed emptying in this subset of the population . A recent study by Velasco-Benitez et al. found that children with functional GI disorders have a greater prevalence of symptoms of orthostatic intolerance; however, children with joint hypermobility did not have a greater prevalence of orthostatic intolerance or POTS when compared to children without joint hypermobility .

Diagnostic considerations

As noted in Table 22.1 , there are a number of conditions associated with pediatric GP. Because of significant overlap in symptoms between GP and functional dyspepsia, these disorders can be difficult to differentiate based on clinical grounds alone . Both disorders can manifest as postprandial bloating or fullness and/or pain, nausea, emesis, anorexia, and/or early satiation . Presumably, measurement of gastric emptying should differentiate the two, with the strong caveat related to the use of gastric emptying scintigraphy in children (see below).

Gastroesophageal reflux disease and peptic ulcer disease should be considered and usually can be excluded based on endoscopy, and in the case of reflux, by esophageal pH probe and/or impedance monitoring . Cyclic vomiting can be distinguished on clinical grounds given its characteristic of symptom-free periods . Rumination syndrome should be suspected based on clinical history and physical examination .

Of particular relevance to pediatrics are mitochondrial disorders and chronic intestinal pseudoobstruction as these more commonly present in childhood. Mitochondrial disorders such as mitochondrial encephalopathy, lactic acidosis, and stroke like episodes (MELAS) and mitochondrial neurogastrointestinal encephalopathy (MNGIE) can present with vomiting with the latter also associated with delayed gastric emptying .

Most cases of pseudoobstruction in children are idiopathic but they also can occur secondary to systemic diseases such as muscular dystrophy, hypothyroidism, hypoparathyroidism, and Chagas disease . Symptoms may overlap with GP and result in delay in diagnosis. The term pseudoobstruction can subsume a number of etiologies such as degenerative neuropathies and immune mediated disorders .

Symptoms and symptom assessment

In children, age significantly influences GP symptom expression ( Table 22.1 ) , a finding that is seen in a number of other pediatric disorders . Vomiting is most common in infants and young children whereas abdominal pain predominates in older children and adolescents ( Table 22.1 ) . The most common symptoms that appear to prompt medical evaluation are vomiting (42%), abdominal pain (35%), and nausea (29%) . It appears symptom duration was longer in patients with mitochondrial disease and shorter in patients with post-viral GP when compared with subjects not presenting with these conditions . Presenting symptoms between girls and boys appear to be similar . These data highlight that symptom assessment in children should be tailored to the age of the child.

Sex

In adults, GP is more predominant in females . In contrast, the female: male ratio in pediatric GP varies by age ( Table 22.1 ) . It is unknown why these age-related gender differences exist in the pediatric population, but they may suggest different pathophysiologic factors playing a role in the development of GP, particularly prior to adolescence. A large retrospective pediatric study (n=239) had an almost equal distribution between female and male patients (51.5% and 48.5%, respectively), as well as similar etiologies for each sex. However, it seemed that as age increased, female predominance increased suggesting a potential hormonal involvement as is postulated in adults ( Table 22.1 ) . Whether gender influences etiology and/or symptom severity in children with GP, to our knowledge, remains to be clarified.

Comorbidities

Rodriguez et al. found that the most common comorbidities in children with GP (n=320) were viral (18%), gastroesophageal reflux (14%), mitochondrial disease (8%), diabetes mellitus (2%), and hypothyroidism (0.4%) . When divided by age group, the most common associated disease in the infant group (n=36) was cow’s-milk protein allergy (33%), followed by viral (17%) . Children aged 1–12 years of age (n=109) reported viral (19%), gastroesophageal reflux (9.6%), and mitochondrial disease (9%) as the most common co-morbidity. In contrast, children aged >12 years of age (n=85) more commonly presented with post-viral symptoms (18%), irritable bowel syndrome (11%), and depression (8%) .

Another study by Waseem et al. found that 38.5% (n=92) of pediatric patients with GP had comorbidities as well . These included, in no particular order, seizure disorder, cerebral palsy, developmental delay, and prematurity .