Clinical management of motility disorders in children

Seminars in Pediatric Surgery (2009) 18, 224-238

Clinical management of motility disorders in children Cheryl E. Gariepy, MD, FAAP,a,b,c Hayat Mousa, MD, FAAPb,c From the aCenter for Cell and Developmental Biology, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio; b Center for Advanced Research in Neuromuscular Gastrointestinal Disorders at Nationwide Children’s Hospital, Columbus, Ohio; and the c Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, Ohio. KEYWORDS Fundoplication; Gastroparesis; Chronic intestinal pseudoobstruction; Constipation; Fecal incontinence; Imperforate anus

We review the current clinical evaluation and management of the most common esophageal and gastrointestinal motility disorders in children based on the literature and our experience in a pediatric motility center in the United States. The disorders discussed include esophageal achalasia, pre- and post-fundoplication motility disorders, gastroparesis, motility disorders occurring after repair of congenital atresias, motility disorders associated with gastroschisis, chronic intestinal pseudo-obstruction, motility after intestinal transplantation, motility disorders after colonic resection for Hirschsprung’s disease, chronic functional constipation, and motility disorders associated with imperforate anus. © 2009 Elsevier Inc. All rights reserved.

Esophageal and gastrointestinal motility disorders produce nutritional and electrolyte deficiencies, chronic and recurrent vomiting, fecal incontinence, chronic and recurrent pain or discomfort, diarrhea and/or constipation, reduced independence in daily life, and reduced mobility. A wide range of clinical skills is required to optimally treat these patients. Centers specializing in the care of patients with these disorders generally establish a multidisciplinary team approach. Our goal is to review the current management of the most common motility disorders identified in our practice. We concentrate on nutritional, pharmacologic, and surgical approaches, but this does not diminish the importance of psychological and social support efforts to achieve optimal outcomes.

Address reprint requests and correspondence: Cheryl E. Gariepy, MD, FAAP, Center for Cell and Developmental Biology, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, WA2015, Columbus, OH 43205. E-mail address: [email protected].

1055-8586/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2009.07.004

Esophageal achalasia Esophageal achalasia (EA) is a primary esophageal motility disorder characterized by impaired relaxation of the lower esophageal sphincter (LES) in response to swallowing. The esophageal body also lacks effective peristalsis. EA is a rare disorder in adults and is even less common in children, most often identified in teenagers. EA in young children is associated with trisomy 21, the triple A syndrome, and familial dysautonomia.1,2 The symptoms of EA are dysphagia for both liquids and solids, chest pain, and regurgitation. Typically, an EA esophagram will show a dilated esophagus with retained contrast and a smooth tapering of the distal esophagus (“bird beak” appearance). A normal contrast esophagram does not rule out early disease. Esophageal manometry showing poor relaxation of the LES and aperistalsis of the esophageal body establishes the diagnosis. The LES may also be hypertensive (Figure 1). Endoscopy may demonstrate a distended esophagus with retained food, but there should be no obstruction to the scope in the distal esophagus.3

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Figure 1 Esophageal motility in achalasia. Contrast esophagram demonstrates typical findings in achalasia: gradual narrowing of the distal esophagus to obstruction at the LES; dilation of the body of the esophagus with retention of contrast (A,B); and an abnormal contraction pattern with a loss of coordinated peristalsis in the body of the esophagus (arrows in A). Esophageal manometry shows a lack of distal progression of contraction waves in the body of the esophagus after a water swallow (WS) at the upper esophageal sphincter (UES) and a failure of the LES to relax in response to WS (C). The pressure topography plot of the same study using high-resolution manometry also reveals simultaneous low-pressure contractions throughout the body of the esophagus and persistent high pressures in the LES (D).

226 Although the triggering events to the development of primary achalasia remain undetermined, the motility abnormality results from a reduction in the number of inhibitory neurons in the esophageal myenteric plexus.4 Directed treatment to the underlying abnormality would require restoring the damaged neurons. As this is not yet possible, current treatment is directed at relieving the distal esophageal obstruction to allow food bolus passage into the stomach by gravity.

Pharmacologic treatment Available pharmacologic agents are of very limited use in EA, and we recommend them only in patients unwilling or unable to undergo other procedures. Calcium channel blockers, nitrites, and phosphodiesterase inhibitors are sometimes used. Two small, double-blind, placebo-controlled trials of nifedipine in adults with EA demonstrated modest improvements in esophageal manometry with at most a modest improvement in clinical symptoms.5,6 Botulinum toxin A injections into the LES block the release of the excitatory neurotransmitter, acetylcholine, from visceral motor efferent nerve terminals. This reduces the pressure in the LES and allows esophageal emptying. Botulinum toxin injection is a relatively low-risk procedure compared with dilations and surgical interventions (discussed below) and can be repeated in responding patients if the effect wears off.7 We use this procedure in those patients unwilling or unable to undergo a surgical myotomy. Injections last 6-12 months in responding patients. Patients who do not respond to the initial injections are unlikely to benefit from repeated injections.

Pneumatic balloon dilation Dilation in EA is meant to rupture the muscle fibers of the LES and carries a significant risk (2%-15%) of perforation.8 Although some practitioners report good long-term results, it is difficult to balance the desire to disrupt the LES with the desire to avoid esophageal perforation, particularly in small patients. Graded dilation using a 30- to 35-mm balloon to efface the waist created by the LES is generally recommended in adults. Repeated dilations may be needed to maintain symptomatic improvement. Given the need for long-term results in children and data from some recent studies demonstrating better outcomes with surgical myotomy,9 we currently rarely recommend this approach for our patients.

Surgical LES myotomy Surgical myotomy relieves the obstruction at the LES by longitudinal transection of the sphincter. Laparoscopic Heller myotomy has comparable results to the open procedure and has reduced perioperative morbidity. An antireflux procedure, usually a partial wrap using the Toupet tech-

Seminars in Pediatric Surgery, Vol 18, No 4, November 2009 nique, can reduce gastroesophageal reflux (GER) and result in less postoperative dysphagia than full wrap procedures. Even with this procedure, a significant proportion of patients will experience reflux symptoms and require proton pump inhibitor therapy. In a large study of adults, ⬃97% of patients reported good to excellent results at 1 year. However, at ⱖ15 years postprocedure, only 75% of patients reported good to excellent results. This reduction in outcome success was primarily due to increased symptoms related to reflux. Endoscopic peptic esophagitis developed in 11% of patients, with half of these being asymptomatic.10 These results underline the importance of lifelong follow-up in patients with achalasia. The incidence of long-term complications after laparoscopic myotomy for achalasia in children is unknown, but persistent dysphagia is reported. Possible causes include incomplete myotomy, esophageal dysmotility, relative obstruction from a fundoplication, or postsurgical fibrosis in the distal esophagus. Evaluation should include a barium esophagram to exclude the presence of anatomic obstruction and to evaluate the emptying of the esophagus. If abnormal esophageal emptying is identified, esophageal manometry should be done to evaluate the effectiveness of the myotomy. Postsurgical LES pressures of ⬍10 mm Hg predict a good long-term clinical response.11 In dysphagic patients with persistently elevated LES pressures after laparoscopic myotomy (with or without fundoplication), we usually recommend pneumatic dilations and consider repeat surgical intervention only if this fails. Pensabene and Nurko proposed a detailed algorithm to evaluate and treat children with this condition.12

Pre- and post-fundoplication motility disorders Transient relaxation of the LES underlies most GER, but other potential contributors include increased intra-abdominal pressure, reduced esophageal clearance, and decreased gastric compliance.13-15 Medical management of GER disease (GERD) can suppress gastric acid secretion, but reflux of gastric contents may persist. Fundoplication and gastrojejunal feeding tubes are frequently employed to reduce GER. There is no significant difference between these two modalities in preventing aspiration pneumonia or improving overall survival for children.16 Nissen fundoplication (NF) is the most widely used surgery for the treatment of GERD. It is designed to prevent GER by correcting hiatal herniation, lengthening the intraabdominal portion of the esophagus, tightening the crura, and increasing the pressure at the level of the LES. It permanently alters gastroesophageal anatomy and function and leads to a variety of complications. Post-fundoplication problems are more common in special categories of children, such as those with neurologic or respiratory diseases, esophageal atresia, or a generalized motility disorder. As

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Figure 2 Antroduodenal motility in rumination syndrome. Manometry in a teenage patient with persistent postprandial regurgitation (A) demonstrates simultaneous pressure spikes on all sensors known as “R” waves (arrows), consistent with rumination syndrome. “R” waves are an artifact on the manometric tracing caused by an increase in intra-abdominal pressure resulting from contraction of the abdominal muscles and are present in ⬃50% of patients with rumination syndrome. In contrast, vomiting produces a retrograde contraction pattern (B).

concluded by Spechler and coworkers, “Antireflux surgery should not be advised with the expectation that patients with GERD will no longer need to take antisecretory medications or that the procedure will prevent cancer among those with GERD and Barrett’s esophagus.”17

Pre-fundoplication evaluation Evaluation before antireflux surgery should, as much as possible, eliminate any other etiology for the vomiting. A

thorough history should evaluate for cyclic vomiting syndrome or rumination. Upper gastrointestinal imaging should be done to detect intestinal malrotation, partial obstructions, or other congenital anomalies. Esophagogastroduodenoscopy with biopsies should be done to look for eosinophilic esophagitis or other mucosal disease because symptoms will persist after surgery and may worsen. In addition, antroduodenal motility is indicated in unusual cases where the diagnosis of rumination based on clinical history is not possible (Figure 2). In general, failure to

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improve in response to optimal antireflux pharmacotherapy should raise suspicion that GERD may not be the sole cause of the symptoms. There are conflicting data regarding the benefits of esophageal motility studies before fundoplication. Strate and coworkers found that tailoring antireflux surgery according to the esophageal motility is not indicated, as motility disorders are not correlated with postoperative dysphagia.18

Post-Nissen fundoplication complications Dysphagia Dysphagia is a well-known complication of NF. Dysphagia during the first 4 weeks after surgery might be related to edema of the esophagogastric junction or transient esophageal dysmotility. Dysphagia persisting 6 months after surgery suggests a very tight wrap, small bowel adhesions, or herniated wrap/para-esophageal hernia. Esophageal motility should be performed. Balloon dilatation of the wrap should be done if resting pressure is above 5-10 mm Hg or if there is evidence of obstruction on contrast study. Also, distal esophageal foreign bodies should be looked for as they are relatively common in children after NF (Figure 3).19 Gastric hypersensitivity After NF, patients may suffer from increased pain or discomfort related to volume or pressure inside the stomach. Fundoplication, like any other surgical intervention, may

Figure 3 Distal esophageal foreign body. Contrast esophagram demonstrates a foreign object in the esophagus (arrow) of a child who presented with dysphagia after having undergone a NF.

Figure 4 Fundoplication significantly reduces gastric compliance. An electronic barostat was used to measure gastric motor activity as a function of the changes in intragastric volume at a constant intragastric pressure. Compliance (the ability of the organ to expand in response to pressure) was determined for each distension by plotting volume (y axis) vs pressure (x axis) and was defined as the slope of the curve. The compliance slopes are plotted in the figure for patients pre-fundoplication (circles) and post-fundoplication (triangles). The difference between compliance slopes before and after NF is significant (P ⫽ 0.001).20

cause sensitization of nerve receptors at the site of surgery. Gastric accommodation decreases significantly after surgery. Using the electronic barostat, we found that after NF, children had a lower threshold for postprandial discomfort and abnormal gastric postprandial relaxation,20 similar to what is reported in adults (Figure 4).21,22 Children with visceral hypersensitivity suffer from gagging and retching when small volumes are placed in the stomach, usually volumes that were tolerated well prior to surgery. Feeding continuously into the stomach or jejunum helps to minimize symptoms. Sumatriptan, a 5-HT1D agonist, or buspirone, a 5HT1A agonist (used for treating anxiety disorders), significantly increases postprandial fundic relaxation in dyspeptic patients.23,24 We also use cyproheptadine for impaired gastric accommodation. Gas-bloat syndrome After fundoplication, children with “gas-bloat syndrome” or “post-fundoplication syndrome” may present with gagging, retching, nausea, food refusal, and abdominal distension alternating with lethargy, pallor, and exhaustion. Symptoms are aggravated by meals. Venting the stomach via G-tube offers limited relief. Pathophysiologically, “gas-bloat syndrome” is related to a combination of poor fundic accommodation, visceral hypersensitivity, delayed gastric emptying, and pyloric distension. Gastric compliance is reduced in children after NF, and poor compliance is associated with an increased pain score.20 Evaluation of the symptomatic patient after fundoplication should include antroduodenal motility. Symptomatic children have abnormal motility with an absence of the

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Clinical Management of Motility Disorders in Children

interdigestive migrating motor complex, postprandial antral hypomotility, and delayed gastric emptying.25-28 It is often difficult to know whether the motility abnormality predated, or is a result of, the surgical procedure. Dumping syndrome NF is associated with dumping syndrome (DS). Early DS classically occurs in children within 60 minutes of feeding and is characterized by abdominal distension, tachycardia, and diaphoresis. Hypoglycemia may occur 1-4 hours later (late DS). Precipitous emptying of hyperosmolar carbohydrate-containing solutions into the small bowel shifts fluid into the bowel lumen, resulting in hypovolemia, rapid glucose absorption, and hyperglycemia followed by reactive hypoglycemia. Results of oral glucose tolerance tests do not correlate with the severity of symptoms.29 To establish diagnosis of DS, we perform a glucose tolerance test and check meal-stimulated pancreatic polypeptide release to verify the vagal damage. Children with DS may be treated with continuous intragastric feeding until boluses of a carbohydrate-modified diet are tolerated. Cornstarch, pectin, octreotide, and diet manipulations can be used. Acarbose is also beneficial in delaying the conversion of oligosaccharides to monosaccharides. Diagnosis of DS is often delayed despite characteristic clinical signs. Close follow-up after antireflux surgery is important in children.29,30

Gastroparesis Gastroparesis is symptomatic delayed gastric emptying in the absence of mechanical obstruction. Symptoms include nausea, vomiting, early satiety, fullness, bloating, and abdominal discomfort or pain. In the pediatric population, the most common causes of gastroparesis are postviral illness, idiopathic, and postsurgical. Diabetes mellitus is the most common cause of gastroparesis in adults. Postinfectious gastroparesis tends to improve or resolve spontaneously over several months,31 whereas idiopathic disease tends to be more severe and intractable. Rarely, gastroparesis is an autoimmune or paraneoplastic process. Postinfectious gastroparesis has been linked to parvovirus-like agents, lyme disease, and rotavirus.32 A wide range of histologic abnormalities are reported in postinfectious and idiopathic gastroparesis. These include reduced numbers of interstitial cells of Cajal (ICCs) and myenteric neurons, gastric myopathy, and eosinophilic and lymphocytic infiltrates.33-37 Because gastroparesis is associated with many systemic conditions, a careful history and physical are particularly important. Upper gastrointestinal barium study can evaluate for mechanical obstruction, and upper endoscopy is useful in detecting mucosal lesions and retained food or bezoar in the stomach. We assess gastric emptying in children using the protocol and norms developed as the consensus of the

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American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine.38 Antroduodenal manometry is considered for patients who do not respond to medical therapy. Gastroparesis is characterized by the loss of normal fasting migrating motor complexes and reduced antral contraction in the fed state. Occasionally, pylorospasm is noted.39 Manometry can help exclude an associated small intestinal dysmotility, and it can also be used to assess response to treatment. Treatment is first aimed at ensuring that fluid, electrolyte, and nutritional deficiencies are corrected. Because it is unusual that the underlying cause can be identified and corrected, further treatment is largely symptomatic. Mild disease may respond to frequent small, low-fat, low-fiber meals. Patients are encouraged to walk 1-2 hours after a meal. Because emptying of liquids is usually preserved, liquid forms of nutrition may be better tolerated. Glycemic control should be optimized in diabetics as acute hyperglycemia slows gastric emptying and reduces the efficacy of prokinetics.40 Gastric or jejunal drip feeds may be necessary in severe cases, at least temporarily. Jejunal feeds may be accompanied by continuous gastric drainage via a gastrostomy. For patients with nausea, vomiting, and bloating, a prokinetic agent may be useful. We use erythromycin, domperidone (which is available in the USA only through an FDA investigational new drug application), or metoclopramide. Of these, erythromycin, a motilin receptor agonist, is the most potent stimulator of gastric emptying and improves symptoms in many patients, though these two events are not necessarily related.41 Patients need to be warned to not simultaneously take other inhibitors of cytochrome P-450 3A as an increased risk of death is reported in adults.42 Domperidone, a peripheral dopamine D2 receptor antagonist, also gives symptomatic improvement in some patients. Domperidone has strong anti-emetic effects via D2 receptors in the brainstem and some peripheral prokinetic effects in the proximal gut. It has fewer side effects than metoclopramide because it does not cross the blood– brain barrier. Metoclopramide, like domperidone, is an antiemetic through brain stem D2 receptor antagonism. It also directly stimulates gut smooth muscle. It increases esophageal, gastric fundal, and antral contractions and increases LES pressures. Use is limited to short-term due to side effects, particularly irreversible tardive dyskinesia, which needs to be discussed in detail with the patient and family.43 Tricyclic antidepressants have shown promise in reducing symptoms in adults with delayed gastric emptying,44 and we have found low-dose amitriptyline to be helpful in children with gastroparesis. Cyproheptadine and ondansetron also provide symptomatic improvement in some children. Endoscopic injection of the pylorus with botulinum toxin A can improve gastric emptying and reduce symptoms when other therapies have failed to adequately improve symptoms.45 A newer option is gastric electrical stimulation

230 (GES) using an implantable stimulator. Temporary pacing through endoscopically placed leads can help determine which patients are likely to respond.46 The implanted device involves two electrodes placed on the serosal surface of the gastric body that are connected to a pulse generator similar to a cardiac pacemaker. The body of the pacer is placed in the subcutaneous tissue of the abdominal wall. The pulses are not strong enough to stimulate gastric smooth muscle contraction but do excite gastric nerves. GES does not improve gastric emptying, but significantly improves nausea and vomiting in patients.46

Motility disorders after repair of congenital intestinal atresias Children with congenital intestinal atresias commonly experience intestinal dysmotility following surgical resection of the atretic segment and primary anastamosis.47 Longer and more distended bowel proximal to the atretic segment appears to predispose to dysmotility. Antroduodenal manometry after resection of an atretic duodenal segment shows low-amplitude contractions in the dilated segment.48 Several investigators had documented the existence of segmental intestinal muscular49 and neural50,51 defects in dilated segments. Khen identified evidence of delayed maturation of the myenteric plexus below the atretic segment and suggested that the fetal intestinal obstruction impairs development of the enteric nervous system.51 Because the dilated segment is generally identified as the main actor in the dysmotility and because patients often have multiple atretic segments, physicians caring for these patients struggle with the risks of leaving a dilated segment versus the risk that the patient will have insufficient gut for nutrient absorption. Some have advocated tapering procedures for the dilated segment to balance these risks, whereas others feel that this is only leaving in place a dysmotile segment and argue for resection. Decisions to taper versus resect are individualized based on the enteral feeding tolerance and the length of involved intestine. Symptoms of dysmotility associated with congenital atresias are very similar to those found in chronic intestinal pseudo-obstruction and include recurrent episodes of abdominal pain, abdominal distension, constipation or diarrhea, vomiting, and decreased ability to tolerate enteral nutrition. Treatments include probiotics in an attempt to prevent bacterial overgrowth and antimicrobial agents (most commonly metronidazole or sulfamethoxazole with trimethoprim) to reduce microbial overgrowth. When oral feedings are not tolerated or not sufficiently tolerated to support growth, continuous feeding into the stomach may be tolerated. If proximal motility is severely affected, it may be necessary to give jejunal feeds with continuous gastric decompression through a gastrostomy. Prokinetic agents, particularly erythromycin, may improve gastric emptying. Amoxicillin with clavulanic acid improves small bowel

Seminars in Pediatric Surgery, Vol 18, No 4, November 2009 motility and can facilitate jejunal feedings in severely affected patients.52 Nutritional support is critical, and parenteral nutrition is frequently necessary.

Motility disorders associated with gastroschisis Infants with gastroschisis generally have significant feeding problems despite surgical repair. These problems are compounded by associated intestinal atresia, ischemia, and resections. The specific nature of the motility issues associated with gastroschisis are not well defined. GERD is reported in about half of gastroschisis patients, and enteral feeding tolerance is delayed.53-55 Infants after gastroschisis repair lack pharyngoesophageal peristalsis and adaptive peristaltic reflexes compared with normal infants. They also have impaired responses in the upper and LES.53 Symptoms of gastroschisis-related motility disorder include vomiting, bloating, abdominal pain, chronic diarrhea, and enteral feeding intolerance. Treatment first should concentrate on adequate nutrient support via drip feels into the jejunum if not tolerated into the stomach. Parenteral nutrition is often needed, at least temporarily. Motility agents may be helpful, but there are little objective data. Bethanecol can be used to improve esophageal motor function. A multicenter, randomized, double-blind, placebo-controlled trial of enteral erythromycin in infants after repair of uncomplicated gastroschisis failed to show efficacy in reducing the time to full enteral feedings.56 Antibiotics and probiotics can treat and prevent bacterial overgrowth in dilated intestinal segments improving nutrient absorption and enteral feeding tolerance, and preventing D-lactic acidosis.57

Chronic intestinal pseudo-obstruction Chronic intestinal pseudo-obstruction (CIP) is characterized by chronic or repetitive episodes of bowel obstruction in the absence of a lumen-occluding lesion (Figure 5). CIP often results in intestinal failure and requires lifelong medical care. Data from the American Pseudo-Obstruction and Hirschsprung’s Society suggested that approximately 100 infants with CIP are born each year in the USA. More boys than girls are affected.58,59 The most common symptoms include vomiting, abdominal distension, and constipation. Other symptoms are the result of complications and associated abnormalities: diarrhea from bacterial overgrowth, jaundice from parenteral nutrition-related liver injury, and urinary voiding disorders due to involvement of the nerves and muscles of the urinary tract, for example. CIP related to mitochondrial disorders may be associated with myopathy, stroke, and encephalopathy.60 Medical treatment in CIP remains limited, and most children with the most severe forms of the disease require parenteral nutrition.61

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Figure 5 Chronic intestinal pseudoobstruction. Plain abdominal x-ray films in a 3-year-old girl with pseudo-obstruction after placement of ileostomy show extremely dilated intestinal loops with gaseous detention (A) and air-fluid levels (B). Intestinal manometry demonstrates reduced and disorganized interdigestive contractions (C). (Color version of figure is available online.)

Although total parenteral nutrition (TPN) has extended the lives of infants and children with CIP,62 complications related to TPN, including central venous catheter-associated sepsis, cholestasis, and end-stage liver disease, are major contributing factors to CIP mortality and morbidity. Patients with CIP are at high risk for irreversible intestinal failure, major fluid/electrolyte imbalances associated with proximal gastrointestinal stomas or fistula, extreme bowel dilatation with bacterial overgrowth, intractable abdominal pain, frequent central venous catheter infections due to multidrug-resistant organisms with loss of the central venous access sites, and severe liver disease with cholestatic liver cirrhosis. The management goals of CIP are to restore proper nutrition and fluid balance, relieve symptoms, improve intestinal motility, and treat complications. When medical management is unsuccessful in maintaining the enteral feeds, decompressing the bowel through a gastrostomy or

jejunostomy is very beneficial. Gastrostomies and jejunostomies are also used for drip feeding before committing to parenteral nutrition. Placing an ileostomy is also recommended. Every patient with pseudo-obstruction should have a trial of jejunal feeding and receive an ileostomy before considering intestinal transplantation. When constipation is the predominant symptom, use of antegrade enemas through a cecostomy or an appendicostomy may also be beneficial. Surgical bypass of diseased segments63 and loop enterostomies64 benefit carefully selected patients. Best results occur in the rare situations where disease is limited to an isolated segment of the bowel. Surgical implantation of gastric and intestinal pacemakers aimed at improving motility constitutes a promising investigational approach in patients with severe motility disorders. Use of the gastric pacemaker has been associated with significant improve-

232 ment in nausea and vomiting.65 As with its use in gastroparesis, gastric emptying is not improved, suggesting that the electrical stimulation may act on sensory rather than motor nerves. Small bowel pacing is more challenging and this approach still in its infancy. In patients with clear clinical improvement after ileostomy placement and tolerance of enteral feeding for more than 2 years, total colectomy and ileorectal anastomosis should be considered; two-third of the patients who undergo this procedure remain off parenteral nutrition for long periods, if not definitively. Children with gastrointestinal motility disorders are considered candidates for small bowel transplantation if they are dependent on TPN and have recurrent episodes of sepsis, limited intravenous access, or TPN-related liver failure (in which case, a liver transplant is performed as well).

Motility disorders after intestinal transplantation CIP was the underlying diagnosis in 9% of individuals undergoing intestinal transplant according to the International Intestinal Transplant Registry (children and adults) as of May 2003. Other motility disorders accounted for 2% of transplants. Outcome of small bowel transplantation is improved because of changes in surgical technique, immunosuppressive medication, and perioperative care. Pre-transplant evaluation in patients with motility disorders should include the evaluation of gastric and colonic function. Multivisceral transplantation should be done instead of isolated intestinal transplantation whenever the gastric motility is abnormal. Repeated episodes of urosepsis may occur in patients with CIP-associated bladder dysfunction. Chronic visceral pain post-transplant may be related to long-term narcotic use for CIP symptoms. Studies on dogs undergoing intestinal autotransplantation revealed no extrinsic reinnervation of the allografted bowel until 12 months.66 Extrinsic reinnervation occurs along the vascular anastomosis and does not cross the intestinal anastomosis. We performed antroduodenal motility studies on patients 3-23 months after they received small bowel transplantation. We found: (1) Allograft bowel generates a migrating motor complex (MMC). (2) MMCs dissociate across duodenojejunal anastomosis (Figure 6). (3) The allograft bowel fails to change from the interdigestive to the fed motility pattern. (4) Giant waves are propagated from native bowel to allograft. (5) Only patients who had undergone multivisceral transplant, including stomach and duodenum, were found to have a normal fed pattern. (6) Patients who suffered from exfoliative rejection had no MMC.59 In conclusion, extrinsic innervation of allograft small bowel is not necessary for generation of MMC, and rejection adversely affects motility.

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Figure 6 Small intestinal motility in transplantation. Antroduodenal manometry in a 4.5-year-old child 1 year after intestinal transplant demonstrates spontaneous MMCs during fasting that are propagated distally. MMCs arising in the allograft small bowel (red arrows) are dissociated from those in the native small bowel (yellow arrows). (Color version of figure is available online.)

Acute cellular rejection in the gastrointestinal tract is a regional process. It can be confined to one anatomic lesion, and it can be spotty in its distribution. Ileum and duodenum appear to be the most commonly involved areas in the gastrointestinal tract for acute rejection. Acute cellular rejection is divided into three grades: mild (I), moderate (II), and severe (III). The degree of neuronal loss is closely correlated with the grade of rejection with 0% loss in mild rejection, 19.3% loss in moderate rejection, and 61% neuronal loss in severe rejection.67 In classic chronic rejection, ischemic changes result in focal stricturing and patchy villous atrophy along with patchy intimal fibrosis of submucosal arteries. Obstruction tends to not improve with steroids and progressively worsens. Limited resection is generally not very successful. Post-transplantation, we also see sclerosing peritonitis resulting in a thick constricting peal and “frozen” bowel. Obstruction may transiently improve with steroids, but recurrence is the rule. Limited resection is unsuccessful. Management of post-transplantation patients includes regular screening/monitoring and management of dysmotility. As a screening tool, we follow serum citrulline levels; levels ⬎13 have a negative predictive value for moderate or severe rejection of 96% and 99%, respectively.68 We also follow fecal calprotectin; levels ⬎92 mg/kg detect rejection with a sensitivity of 83% and specificity of 77%.69 For hypersecretion, we use loperamide, clonidine, and octreotide. For slow transit and obstructive symptoms, we use erythromycin or metaclopramide, and for symptoms thought to be related to bacterial overgrowth, we alternate metronidazole with amoxicillin-clavulanate. After exfoliative rejection, patients may benefit from continuous enteral feedings and elemental feedings. If patients become TPNdependent, retransplantation may be necessary. Small bowel transplantation is evolving from a “rescue” procedure to a true therapeutic option.

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Hirschsprung’s disease

Diagnosis

Hirschsprung’s disease is the congenital absence of the myenteric and submucosal plexuses for a variable length of distal intestine. The lack of enteric neurons leads to tonic contraction of the aganglionic segment and functional obstruction. Enteric nervous system progenitors colonize the developing gut in a cranial to caudal direction. Hirschsprung’s disease occurs when these progenitors fail to colonize a distal segment. It is a multigenic disorder with complex inheritance and is often associated with other congenital anomalies. Hirschsprung’s disease can be familial or sporadic and is generally categorized by the length of involved intestine, with ⬃75% of cases only involving colon distal to the splenic flexure (short-segment disease), ⬃20% of cases involving colon proximal to the splenic flexure and 5% of cases involving the entire colon and rarely involving the small intestine as well.70 Typically, Hirschsprung’s disease presents as constipation in the neonate. Of children with Hirschsprung’s disease, 60% to 90% fail to pass meconium in the first 48 hours of life. Occasionally, the disease is not recognized until the child is older, but in these cases, a history of stooling difficulties in the neonatal period can almost always be elicited. Children with Hirschsprung-associated enterocolitis will present with chronic diarrhea.71 Until methods to repair the enteric nervous system are developed, the first stage of treatment for Hirschsprung’s disease is surgical resection of the aganglionic segment.72 Unfortunately, a majority of patients will continue to have disordered defecation after resection. These patients require careful evaluation. The postresection defecation disorders are generally categorized as those primarily presenting with fecal incontinence or constipation. Rarely, Hirschsprung’s disease is associated with intestinal neuronal dysplasia and CIP. The treatment of these disorders is discussed separately. Incontinence can be the result of abnormal sphincter function or sensation, overflow incontinence from chronic constipation, or the propagation of high-amplitude colonic contractions (HAPCs) through the neorectum to the anal sphincter. Postresection enterocolitis may also present with incontinence, though this is usually associated with diarrhea and abdominal pain. Chronic constipation can be the result of mechanical obstruction, persistent or acquired aganglionosis, absence of HAPCs in the colon, a hypertensive internal anal sphincter, or functional constipation. Abnormal sphincter function or sensation is generally secondary to damage to the anal canal during the resection procedure. Aganglionic segment resection techniques and their complications are discussed in detail elsewhere.73 Overflow incontinence and chronic functional constipation are discussed in another section of this article and anal achalasia is discussed in a separate article. Here, we discuss treatment of the most common chronic motility disorders affecting patients after colonic resection for Hirschsprung’s disease.

Patients reporting defecation disorders ⬎3 months after resection should generally have a contrast enema, a digital rectal examination, and a detailed examination of the anal canal. Loose stool, particularly that containing gross or occult blood, should be further evaluated with rectal and colonic biopsies. Patients with obstructive symptoms but without a mechanical lesion on contrast study should undergo a rectal biopsy to evaluate the myenteric plexus. Colonic motility testing is useful in patients in whom the physical examination, contrast study, and biopsy are unrevealing.

Distal propagation of HAPCs Colonic manometry can identify HAPCs and determine the appropriateness of the internal anal sphincter pressures. The healthy colon produces HAPCs that originate in the proximal colon and sweep distally to the rectosigmoid junction. These contractions are triggered by eating (gastrocolic reflex), are more frequent in children than adults, and do not occur during sleep. Normally, only 14% of HAPCs are propagated to the rectum.74 When the rectum is resected, the contractions may move colon content to the anal verge, where pressures within the neorectum exceed the anal sphincter pressure leading to fecal incontinence. The patient’s efforts to avoid incontinence may produce abdominal pain or discomfort. A portion of Hirschsprung patients after resection experience more frequent contractions as well as contractions at night. This type of incontinence can improve with fiber therapy, the institution of structured meals, and the avoidance of between-meal oral intake. Anticholinergic medications can also be very helpful and likely work by reducing the force and frequency of the propagating contractions as well as increasing internal anal sphincter pressures.75,76 We usually start with loperamide but have also found amitriptyline, and occasionally clonidine, to be very useful.

Hypomotility Rarely, colonic manometry will demonstrate weak or ineffective HAPCs in all or part of the ganglion containing colon of patients with Hirschsprung’s disease. These patients benefit from diversion of the fecal stream and resection of the abnormal segment if the motility abnormality is persistent.

Motility issues in chronic functional constipation Chronic constipation is common in childhood. In the vast majority of case, it is caused by slow colonic transit and/or paradoxical contraction of the anal and pelvic floor muscles

234 exacerbated by functional fecal retention.77 Childhood chronic constipation usually responds to stool softeners or stimulant laxatives with behavior interventions and education. With a consistent history, normal stooling in the neonatal period, normal rectal examination except for the presence of a large amount of firm stool in the rectal vault, and the absence of other neurologic findings, treatment can generally begin with a stool softener. PEG 3350 is significantly better than placebo in producing more frequent bowel movements and decreasing overflow fecal incontinence compared with placebo.78,79 In a double-blind, randomized trial, PEG 3350 was more successful in reducing fecal incontinence and producing frequent bowel movements than lactulose. The PEG 3350 group also reported less abdominal pain and less difficulty defecating than those on lactulose.80 PEG 3350 is available either with or without electrolytes. Giving the formulation with electrolytes reduces some of the concern regarding possible electrolyte imbalances, but also reduces compliance. Observational studies suggest that PEG 3350 without electrolytes is safe when taken with a regular diet, even with prolonged use.79,81-83 Children whose symptoms are not completely resolved with high-dose PEG 3350 and behavioral interventions, particularly those with a very dilated colon, may benefit from chronic use of a stimulant laxative, such as bisacodyl or senna. There are very little data to support the popular concern that chronic use of these medications causes colonic neuromuscular injury. Three large, double-blind, cross-over, randomized studies in adults using two different species of probiotics showed improvement in constipation symptoms. Two studies used a Bifidobacterium animalis strain and reported a significant reduction of colonic transit time, although no change was observed in the number of stools per week.84,85 The other study used Lactobacillus casei Shirota and showed significant improvement in self-reported severity of constipation and stool consistency with a small but significant increase in stool frequency.86 In contrast to these studies, a doubleblind, placebo-controlled, randomized study in children of the effectiveness of Lactobacillus GG failed to show any additional benefit when it was used as an adjunct to lactulose.87 Intestinal bacteria may play an important role in modulating intestinal motility through neuroendocrine activation. An enteroendocrine cell receptor for Microbiota-derived shortchain fatty acids alters intestinal transit though expression of neuropeptide YY.88 Lubiprostone is an oral bicyclic fatty acid that selectively activates type 2 chloride channels of the gastrointestinal epithelium, resulting in increased fluid secretion and softer stool.89 Lubiprostone can be of benefit in older children with chronic functional constipation unresponsive to other therapies, though in our experience the benefit is generally short-lived. Nausea is a significant side effect, and adequate fluid intake must be stressed with the patient and family. Patients with a history or atopy may have food intolerance-

Seminars in Pediatric Surgery, Vol 18, No 4, November 2009 related constipation and may benefit from the elimination of milk protein from the diet.90-93 The goal of pharmacologic treatment is to keep the stool very soft and frequent while giving the child and family an opportunity to address the behavioral issues—particularly the avoidance of defecation. A child psychologist is an extremely important member of the management team. Patients not responsive to standard treatment, patients with very early-onset disease, and patients with palpable abdominal fecal masses but an empty rectum may need further evaluation. This would include rectal biopsies to evaluate for Hirschsprung’s disease, imaging of the colon to evaluate the presence and extent of dilation, and screening blood work for electrolyte imbalances, thyroid disease, and celiac disease. Spinal MRI should at least be done in patients with a patulous anal sphincter, loss of reflexes, and/or urinary incontinence.94 Colonic manometry can help discriminate severe functional constipation from colonic neuromuscular diseases. Children with functional fecal retention will have a dilated colon but normal manometry. In severe cases, colonic dysmotility may be found associated with extreme dilation of the colon (Figure 7). In some cases, the colon is severely and diffusely dilated to the point that the colonic manometry is uninterpretable. These patients benefit from a decompressing colostomy or ileostomy. After 6-12 months of decompression, colonic manometry can be done to determine whether reanastomosis and/or colonic resection should be undertaken. The presence of HAPCs predicts good outcome with reanastomosis. Colon segments proximal to the rectosigmoid junction that do not demonstrate HAPCs may need to be resected.95 Marker transit studies are helpful in differentiating between nonretentive fecal incontinence and retentive functional constipation with overflow incontinence. Children with nonretentive fecal incontinence will pass markers quickly, whereas those with functional constipation will show very delayed passage. Special testing is helpful in isolated cases. Defecography and functional MRI defecography can demonstrate pelvic floor dysfunction related to rectoceles, peritoneceles, or enteroceles (Figure 8).

Imperforate anus Imperforate anus is a congenital anorectal malformation of the hindgut with incomplete separation of the cloaca leaving most patients with a fistula. The repair procedure generally used is a posterior sagittal anorectoplasty. Despite careful preservation of the sphincter muscle and reconstruction of an anorectum, a high proportion of individuals experience disordered defection after surgical repair. Approximately 10% of patients with perineal fistula are incontinent, and 40% of patients with a vestibular or rectourethral fistula are incontinent.96 Like Hirschsprung patients, patients with im-

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Figure 7 Severely dilated and dysmotile colon in a child with functional constipation. Constipation leading to a widely dilated sigmoid colon (SIG) and fecal impaction demonstrated on CT (A) and plain radiograph (B). Colonic dysmotility in the distal colon in the same patient (C). High-amplitude propagated contractions progress distally in the proximal colon (thin arrows) but do not propagate through the dilated descending and sigmoid colon (thick arrow). (Color version of figure is available online.)

perforate anus experience HAPCs propagated into the neorectum, often associated with subnormal internal anal sphincter pressures.97 Fecal soiling may also be associated with good anal sphincter function and stool withholding. Evaluation of chronic fecal incontinence following imperforate anus repair includes radiographic studies to define

the anatomy and anorectal manometry. Colonic motility studies aid in defining the pathophysiology and can guide clinical management. For patients with low internal anal sphincter pressures or frequent HAPCs propagated to the neorectum, a trial of loperamide or other anticholinergic medications with enemas or suppositories may be helpful.

Figure 8 Enterocele in an infant. A 3-month-old male who had an imperforate anus repair as a newborn underwent functional MRI due to continue stooling difficulties. During initial defecation, a small enterocele forms (A, arrow). During a postdefecation Valsalva maneuver (B), the enterocele (long arrow) increases to 4.6 ⫻ 6.5 ⫻ 5 cm, compresses the distal rectum (short arrow), and obstructs the flow of stool.

236 Patients with constipation and overflow incontinence may benefit for stool softeners, behavioral interventions, and stimulant laxatives. Frequently, these patients benefit greatly from routine daily antegrade enema therapy usually achieved via an appendicostomy98 or a cecostomy, which can be placed percutaneously.99,100

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