Etiology of gastroparesis in children is most often idiopathic or postviral. Together, both have been associated with up to 70 % of cases of gastroparesis in children [20]. Surgery and medication effects are the next most common factors implicated in pediatric gastroparesis. Multiple other etiological factors have been described in children of various ages (Table 23.1).

Intestinal development continues to occur during the third trimester of gestation, and interruption of this development, most commonly by preterm birth, may result in symptomatic disorders. Normal gastric liquid emptying, both electrical rhythm and motor activity, has been demonstrated in 32–34-week gestation infants [21, 22]. Gastric electrical activity and motor function continues to develop postnatally with enteral nutrition stimulating continued maturation of intestinal motor function [23]. Gastric electrical activity develops further in the first decade of life before achieving normal adult patterns [24].

In children, gastroparesis has been reported following rotavirus, EBV, CMV, and mycoplasma infection [25–27]. An infectious etiology is suspected frequently in the course of clinical care of a child with gastroparesis, but the infecting agent is rarely identified. Postinfectious gastroparesis is suspected when a previously healthy individual has acute onset of gastrointestinal symptoms characteristic of infectious enteritis—nausea, vomiting, diarrhea, fever, or abdominal pain. At presentation, the clinical findings of children who develop postinfectious gastroparesis can be mild or severe and identical to other children with acute gastroenteritis. However, in children with gastroparesis, the gastrointestinal symptoms persist for months to years. Long-term outcomes are excellent, with resolution of symptoms typically between 6 months and 2 years [25, 28]. Evaluation of adults with gastroparesis demonstrates abnormalities of enteric neurons and interstitial cells of Cajal (ICC), and it is hypothesized that viral infections could cause such injury. Although several types of infection can result in gastroparesis, not every infectious agent that affects the stomach is associated with delayed emptying. A study on adult patients found a lower prevalence of Helicobacter pylori infection in patients with gastroparesis than controls [29].

Diabetes mellitus is an uncommon cause of delayed gastric emptying in children . In contrast, up to 30 % of adults with type 2 diabetes mellitus (T2DM) have gastroparesis [30]. Poor glucose control, vagal parasympathetic dysfunction, and depletion/dysfunction of ICC and gastric enteric neurons are postulated to alter gastric physiology in diabetics [31]. Relaxation of the fundus and gastric capacity are decreased in diabetics. Uncontrolled diabetes may cause gastric dysrhythmias; ineffective contractions of the fundus, corpus, and antrum; and pyloric hypercontractility [32–34]. Similar to adults with T2DM, children with type 1 diabetes mellitus (T1DM) may have antral hypomotility, gastroparesis, and gastric electrical dysrhythmias [35, 36]. A study comparing children with T1DM to children with chronic dyspepsia or chronic constipation (but no T1DM) identified lower serum motilin concentrations among diabetics, but found no difference in autonomic function, gastric emptying, or total intestinal transit time [37]. Other studies found delayed gastric emptying [35, 36], autonomic dysfunction [38], and even rapid gastric emptying [39], underscoring the need to study the gastric function of T1DM patients who present with gastrointestinal symptoms to establish individual therapeutic plans .

Autonomic peripheral neuropathies may occur secondary to diabetes mellitus, primary and hereditary amyloidosis, toxins (organic solvents, vincristine), infection (Chagas disease, HIV), hereditary disorders (hereditary and sensory autonomic neuropathies, Fabry disease, Allgrove syndrome ), immune-mediated and autoimmune disorders (Guillain-Barré syndrome , systemic lupus erythematosus, myasthenia gravis), and paraneoplastic syndrome [40]. Symptoms typically affect multiple organs with variable severity although upper gastrointestinal symptoms are common.

Autoimmune gastrointestinal dysmotility presents with subacute onset of autonomic dysfunction . Clinical findings may be generalized or limited to the gastrointestinal organs and include nausea, vomiting, and/or gastroparesis. Involvement of the esophagus (including achalasia), pyloric stenosis, intestinal pseudo-obstruction, and anal spasm have been reported [41]. A case series of adults with ganglionic acetylcholine receptor antibodies found gastroparesis, constipation, anhidrosis, dry eyes and dry mouth, a neurogenic bladder, and orthostatic hypotension [42]. Although there were few patients, significant variability in disease severity and the potential for chronic duration were demonstrated. A case series screening sera of patients with autoantibodies and gastrointestinal disease identified 12 patients with delayed gastric emptying [41]. The patients had antibodies to ganglionic acetylcholine receptor [7], voltage-gated calcium channels N-type [3], thyroperoxidase [3], thyroglobulin [3], glutamic acid decarboxylase 65 kDa isoform [2], islet cell antigen 512 [2], antineuronal nuclear autoantibody, type 1/anti-Hu [1], and muscle acetylcholine receptor [1].

Disturbances in gastrointestinal motility including delayed esophageal, gastric, and small intestinal transit, as well as delayed or accelerated colonic transit, have been described in patients with celiac disease [43, 44]. A study on adult celiac disease patients found delayed gastric emptying that normalized after 1 year of gluten-free diet (GFD) [45]. A study in children with celiac disease showed near-complete resolution of antroduodenal dysmotility after 6 months of GFD [46]. However, another study in adult patients found altered antroduodenal manometry in the fasting and fed state even in those adherent to a GFD [47]. Persisting autonomic dysfunction, peripheral neuropathy, and antineuronal antibodies found in a series of celiac disease patients on GFD could explain these findings [48].

Gastric emptying is delayed in some patients with inflammatory bowel disease, and prolonged emptying times may be associated with disease activity through a GLP-1-mediated pathway [49]. Interestingly, the location of disease activity does not necessarily correlate with altered gastric motility. Gastrointestinal neurohumoral mediators (including GLP-1 and CCK) may be altered even in distal small intestinal or colonic inflammation and associate with gastric emptying delay [50]. Further, as in treated celiac disease, gastroparesis may persist in patients even with inactive inflammatory bowel disease [51, 52].

Children with chronic illnesses including central nervous system disorders have a high incidence of gastric dysrhythmias, gastroparesis, and abnormal antroduodenal motility [53–55]. In one study, 31/50 children had gastric dysrhythmias [53], while in another study all children had abnormal antroduodenal manometry and half of them had delayed gastric emptying of liquids [54]. Although not all children with central nervous system disorders have abnormalities of gastrointestinal motility, the possibility of gastroparesis, gastroesophageal reflux disease, feeding disorders, and constipation should always be considered.

Gastrointestinal manifestations of mitochondrial disease are varied and complex [56]. Several case series identify gastroparesis in the setting of specific mitochondrial disorders. Eighteen of 26 children with mitochondrial disease had delayed gastric emptying with delays persisting in most despite prokinetic therapy [57]. Four patients with upper gastrointestinal symptoms consistent with gastroparesis were identified to have 3243A>G mtDNA mutation in specific stomach regions [58]. This mutation is implicated in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). Three of the patients were further studied and found to have abnormal EGG and gastric emptying, although gold-standard scintigraphy was not used. Six children with defects in mitochondrial electron transport chain enzymes of oxidative phosphorylation (OXPHOS), but no specific mtDNA mutation, were found to have abnormal antroduodenal manometry indicative of neuropathy, and four had delayed gastric emptying [59].

Although Hirschsprung disease (HD ) is generally considered a disorder of the lower gastrointestinal tract, abnormalities of upper intestinal motility have been identified years after repair. Specifically, esophageal body abnormalities were found on manometry of 12 children with HD [60]. Similar findings were identified in 11 children with total colonic aganglionosis who had abnormalities in esophageal body contractions and propagation, but generally preserved UES and LES tone [61]. Antroduodenal manometry in these HD patients found a mix of abnormal propagation, distribution, or occurrence of phase III activity in the MMC.

Gastric emptying function is also affected in children with HD. HD patients have significantly longer total gastrointestinal transit times than controls even after surgical repair. In only few cases does the delay in gastrointestinal transit relate to prolonged colonic transit [62]. Patients with HD had longer gastric isotope retention than controls at 60 and 90 min, with 12/21 HD patients having >60 % retention at 60 min (>2SD from mean). Although HD patients frequently reported persistent vomiting and/or abdominal distension, the symptoms did not predict gastroparesis. Similarly, the frequency of bowel movements had poor correlation with gastric emptying times. Forty percent of HD patients with normal bowel frequency had delayed gastric emptying .

Infants sensitized to cow’s milk (cow’s milk protein allergy—CMPA) had significant gastric electrical dysrhythmias and delayed gastric emptying measured by electrical impedance tomography when compared to controls with gastroesophageal reflux [63]. A positive food challenge in children identified resultant electrogastrographic changes and mast cell degranulation in proximity to gastric nerve fibers [64]. In children with FD, increased antral mast cell density is associated with slower gastric emptying [65]. Gastrointestinal eosinophils and mast cells, in animal and human studies, are increasingly associated with alterations in gastric motor and electrical function [66].

Gastroparesis may follow specific surgical procedures including fundoplication, bariatric surgery, and heart or lung transplantation [67]. Although purposeful vagotomy is infrequently performed, inadvertent vagal injury may occur during the course of other upper abdominal or thoracic procedures. Gastroparesis-related symptoms following vagal injury can improve with time, possibly due to enteric nervous system adaptation or vagal nerve reinnervation [67]. Fundoplication may result in accelerated or delayed gastric emptying, underscoring the complex interplay of factors associated with surgery. Multiple pathophysiological mechanisms may result in abnormal function following surgery. Antireflux procedures may affect sensorimotor function of the proximal stomach. Motor abnormalities that have been most frequently described in patients with fundoplication include alterations in antral peristalsis and receptive relaxation [68].

Many other factors are related to delays in gastric emptying. In children, constipation is often associated with upper gastrointestinal symptoms (including nausea) [69] possibly through the reflex inhibition (cologastric brake) of upper gastrointestinal motor activity. Constipated dyspeptic children have more frequent delays in gastric emptying than non-constipated dyspeptic subjects, and their gastric emptying time improves after osmotic laxative treatment [70]. Activation of the cologastric brake may explain delays in gastric emptying associated with both rectal distension [71, 72] and voluntary suppression of defecation [73].

Endocrinopathies including hypo- and hyperthyroidism, hyperparathyroidism, Addison’s disease, and hypopituitarism have been associated with gastroparesis. Myopathies including myotonic dystrophy and Duchenne muscular dystrophy are associated with severely symptomatic gastroparesis [74, 75].

Critically ill patients frequently exhibit severe gastroparesis which may be exacerbated by endogenous mediators, sepsis, mechanical ventilation, and medications. Over 50 % of mechanically ventilated critically ill adults have delays in gastric emptying [76], potentially increasing morbidity and mortality due to inability to administer adequate enteral nutrition. Multiple potential pathophysiologic mechanisms of ICU-associated gastroparesis have been explored including the roles of cholecystokinin, secretin, oxyntomodulin, GLP-1, GLP-2, pancreatic polypeptide, and peptide YY [77].

Psychological stress also has effects on electromechanical function. Experimentally induced stress has been shown to increase symptoms and inhibit normal postprandial EGG responses in some, but not all, studies [78, 79]. Stress is further shown to impair accommodation and to delay gastric emptying [80]. The stress effect on gastric emptying appears to be mediated at least in part via CRH [81].

Ingestions of caustic substances, medications, and marijuana have also been related to delays in gastric emptying. Although patients with caustic ingestion and chronic injury did not demonstrate symptoms of gastroparesis, studies have shown that the orocecal transit time [82] and scintigraphic gastric emptying [83] were delayed. Multiple medications including anticholinergics, opioids, tricyclic antidepressants, proton-pump inhibitors, H2 receptor antagonists, antacids, sucralfate, octreotide, beta-adrenergic agonists, calcium channel blockers, and levodopa can lead to delayed gastric emptying [84–86]. Endocannabinoids exert multiple effects on enteric neurons that may inhibit neuronal activity, synaptic transmission, and axonal mitochondrial transport [87, 88]. Delta-9-tetrahydrocannibinol (THC) slows gastric emptying in adults suggesting putative antiemetic effects are centrally mediated rather than related to alterations in gastric motor function [89].

Eating disorders also have a variety of potential gastrointestinal manifestations including gastroparesis [90]. Patients with anorexia nervosa have increased gastric dysrhythmias [91] and increased antral distension during meals with maximal dilation reached more quickly than controls [92]. Many case reports suggest the association of gastroparesis in anorexia [90]. Severity of malnutrition may be associated with gastroparesis in anorexia nervosa [92], although the relation of body weight to gastroparesis is unclear given contradictory data. Treatment of anorexia nervosa with refeeding may improve gastric emptying time [92, 93].

Patients with rumination syndrome are demonstrated to have normal EGG, scintigraphic gastric emptying, and MMCs on antroduodenal manometry [94]. However, rumination syndrome is at times related to gastroparesis through “conditioned vomiting” that can occur in the setting of delayed gastric emptying [95].

Treatment of gastroparesis includes a variety of pharmacologic, interventional, and complementary therapies including prokinetic agents, pyloric botulinum toxin injection, implanted gastric neuromodulator, acupuncture, and herbal substances. Importantly, symptom resolution correlates very weakly with diagnostic measures of gastric emptying including 4-h scintigraphy.

Prokinetic agents effective for gastroparesis include serotonergic agonists, dopaminergic antagonists, and antibiotics. Cisapride [96] and tegaserod [97] are serotonergic agonists found to be efficacious in the treatment of gastroparesis, but are currently not available (aside from compassionate use) in the USA due to an increased risk of cardiac side effects. Metoclopramide and domperidone are dopamine antagonists with gastric prokinetic effects. However, the use of metoclopramide has declined in pediatric patients secondary to an FDA warning related to the risk for tardive dyskinesia with prolonged use. Domperidone does not have the same central nervous system risks, but in the USA is available only for compassionate use due to risk of cardiac dysrhythmias. Bethanechol, a muscarinic agonist, also stimulates gastric contractions [98]. Erythromycin, a macrolide antibiotic, activates motilin receptors in the stomach and small intestine, increases antral contraction amplitude and frequency, and induces phase III MMCs [99, 100]. Azithromycin, a related macrolide antibiotic, may also be useful for treatment of gastroparesis [101]. Other motilin receptor agonists [102], acyl-ghrelin agonists [103], as well as other novel agents [104] are being investigated for treatment of gastroparesis, but are not frequently utilized in clinical care of pediatric patients.

Endoscopic pyloric botulinum toxin A injection has been used in children with gastroparesis refractory to prokinetic therapy [105]. Botulinum toxin was shown to be effective in approximately 2/3 of patients; however, the effects are generally transient and limited to several months’ duration. Neuromodulation with the implanted gastric electrical stimulator was shown effective for symptom reduction in a series of pediatric patients with gastroparesis and dyspepsia [106] and is increasingly used for patients nonresponsive to medical therapy. The mechanism of action of gastric stimulation is not completely understood. Low-frequency, high-energy stimulation is thought to entrain the gastric slow wave, increase slow-wave amplitude, and improve gastric emptying in adults with gastroparesis [107]. High-frequency, low-energy stimulation, such as that used in recent clinical trials [108], is shown to increase slow-wave propagation velocity, enhance the amplitude of postprandial slow waves [109], and lessen sensitivity to gastric distension [110], but does not improve gastric emptying rate [109].

Alternative therapies including acupuncture additionally were found to be effective in select adult gastroparetics [111–113], but large-scale and pediatric studies are yet to be performed. Ginger [114, 115] and peppermint oil [116] enhance gastric emptying, but their effect on upper gastrointestinal symptoms remains unclear.

Given the interaction between the stress response, visceral hypersensitivity, and electromechanical dysfunction, treatment of stress and anxiety may have a role in the management of gastroparesis. Interventions effective in children with chronic GI symptoms , but not necessarily gastroparesis, include cognitive behavioral therapy, gut-directed hypnotherapy [117], yoga [118], and biofeedback-assisted relaxation therapy (BART) [119]. An in-depth discussion of diagnostic testing and therapeutic options is provided in other chapters of this book.

Dumping syndrome is a disorder of postprandial gastrointestinal and vasomotor symptoms related to rapid gastric emptying. Rapid gastric emptying results in delivery of an osmotic load to the small intestine with accompanying fluid shifts, as well as nutrient delivery and subsequent disordered glucose regulation. Dumping syndrome may be idiopathic, iatrogenic, postinfectious, or related to diabetes mellitus. Classically it was identified after surgical procedures of the upper GI tract including fundoplication in children and gastrojejunostomy, pyloroplasty, and Roux-en-Y bypass in children and adults. It is reported in up to 30 % of children undergoing fundoplication [120], 35 % of adults with CVS, 13 % with diabetes mellitus, and 10 % with IBS [121].

Dumping syndrome symptoms has “early” and “late” patterns . Early dumping begins within 30 min after a meal and may include abdominal pain/cramps, diarrhea, borborygmi, nausea, and bloating, as well as vasomotor symptoms of fatigue, flushing, palpitations, tachycardia, hypotension, lightheadedness, sweating, and syncope. Early dumping is attributable to bowel distension, gastrointestinal hormone secretion, and autonomic dysfunction [122]. Late dumping occurs 1–3 h after a meal and consists of a reactive hypoglycemia and vasomotor symptoms (including sweating, confusion, palpitations, fatigue) rather than predominant GI symptoms. Symptoms may be severe and disabling and can result in malnutrition and avoidance of eating. The two patterns of symptoms can coexist in the same patient. Many of these symptoms, particularly GI symptoms of early dumping, are also present in patients with gastroparesis, and many dumping syndrome patients may be first diagnosed with gastroparesis.

Dumping syndrome can be distinguished from gastroparesis by radionuclide scintigraphy and clinical presentation. Rapid gastric emptying with a standardized meal typically finds <35 % gastric retention at 1 h in early dumping syndrome and <20 % at 2 h in late dumping syndrome, although variable normative values are used. Clinical presentation remains key to diagnosis, with exclusively postprandial symptoms and the lack of history suggestive of other diseases (including carcinoid syndrome, pancreatic insufficiency, or other causes of hypoglycemic episodes). Sigstad’s clinical scoring system can be utilized in adults with graded rating of symptoms [123] to aid in distinguishing from other disorders and to follow symptom course/response to therapy. The oral glucose challenge is a provocative test that can also assist in diagnosis of dumping syndrome. After a 10-h fast, 50 g glucose is ingested. Heart rate (HR) and blood pressure before, during, and 3 h after ingestion are recorded. An increase in HR >10BPM after 30 min is indicative of dumping syndrome [124]. Associated tests of hematocrit (increase greater than 3 % in first 30 min) and serum glucose (hypoglycemia 2–3 h after ingestion) can also be performed. In adults, the oral glucose challenge has sensitivity of 100 % and specificity of 94 %. All tests listed above are limited by lack of validation in pediatric patients, but continue to serve as useful clinical tools [124].

Treatment of dumping syndrome is typically through dietary modification. To prevent symptoms, the portion size is reduced, and frequent small meals composed of few monosaccharides and high fiber are recommended. Other dietary strategies include increasing viscosity of food with addition of uncooked cornstarch, guar gum, or pectin [125–127]. Continuous enteral feeding can be considered when initial dietary strategies are ineffective. Acarbose is an alpha-glucosidase inhibitor useful for treatment of late dumping syndrome [128]. It competitively inhibits brush-border enzymes, delaying glucose and fructose absorption and preventing significant postprandial hypoglycemia. Acarbose was shown to be effective in adults with T2DM-associated late dumping syndrome [129], as well as children with late dumping who are refractory to dietary management [130, 131]. Potential adverse effects of acarbose include diarrhea and bloating.

Octreotide has been reported to be beneficial in a systematic review of dumping syndrome patients refractory to dietary management [132]. Octreotide slows gastric emptying, inhibits insulin release, decreases enteric peptide secretion, increases intestinal absorption of water and sodium, and prevents hemodynamic changes, thereby alleviating dumping syndrome symptoms. Octreotide is typically given by subcutaneous injection three times daily, although long-acting (depot) octreotide also is effective [133, 134].