Preface

Article Outline

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Two years ago, I corresponded with Professor Jay Grosfeld about the lack of evidence-based medicine concerning gastrointestinal motility disorders. In a prompt reply, he described it as one of the “black box” areas in surgery and how little is known about this spectrum of disorders. A lot of experimental work has unravelled the mysteries of the “enteric nervous system (ENS),” and there is a growing interest in the management of these disorders by pediatricians, gastroenterologists, and neurogastroenterologists that seems very far removed from the realms of the general pediatric surgeon.

My interest in this condition began about 15 years ago with a patient who was born with numerous congenital abnormalities, including esophageal atresia and tracheoesophageal fistula, cleft palate, Tetralogy of Fallot, and bilateral duplex kidneys with ureteroceles, who was successfully surgically corrected shortly after birth. Over the subsequent 4 years, gastroesophageal reflux gastroesophageal reflux disease (GERD) became problematic despite maximum medical therapy. At this time, new symptoms began to emerge, including severe spasmodic abdominal pain, gaseous distension, and loud borborygmi heralded by excess salivation. A typical attack was witnessed and described extremely well by her general practitioner: “She would become distressed, pulled on her dress and started scratching her lower abdomen then proceeded to scream and sometimes head banging … At the end of the attack she would pass a lot of wind.” Numerous investigations were performed, including barium swallow, 24-hour pH monitoring, and esophagoscopy. These were unhelpful, and a trial of antispasmodics and valproate to alleviate possible intestinal dysmotility provided little relief. A Thal fundoplication was then performed. She temporarily improved after this, and all medication was stopped. A year later, however, severe spasmodic abdominal pain returned. Various medications were tried, including amitryptiline, Buscopan, and clonidine; these and dietary manipulation showed little benefit. A redo-fundoplication and pyloroplasty were performed, again with little symptomatic relief. Features of intestinal pseudo-obstruction with bile draining from her gastrostomy, abdominal distension, and dilated loops of bowel with fluid levels were seen on abdominal radiographs. At the age of 15 years, she began to lose weight and was suffering from daily paralyzing painful spasms requiring opiates, including intravenous morphine. Shortly after her 16th birthday, the decision was made to undertake a celiac plexus block to attempt to block any overactivity of her sympathetic nervous system to see if this would improve her symptoms. This was performed under general anesthesia by our lead pain consultant. The first block was such a success that she was discharged shortly after the procedure, tolerating oral diet and fluids and remained pain-free for the first time in months. This block lasted 16 days, at which time she was readmitted and the block repeated. This pattern continued with monthly blocks for a period of 12 months, at which time a thoracoscopic splanchnicectomy was performed. Follow-up is now 13 years, and she has had no further symptoms. At 29 years old, she maintains a good weight and is now living a comfortable, happy, and pain-free life (Scottish Medical Journal, 2009;54:58).

There are a number of clinical conditions that deserve consideration, some of which are common and resolve, whereas others are lifelong problems. Post-operative ileus is a form of motility disorder that resolves 24-48 hours after surgery; however, for reasons unexplained, this may be prolonged on occasions and results in second-look operations to try to resolve it. Irritable bowel syndrome is a very common problem among the adolescent age group, but in children it can be a major problem with psychological consequences. This condition is poorly understood and often treated anecdotally and empirically. Chronic constipation with slow transit time is another motility disorder now more and more recognized affecting the childhood years. This does resolve once adolescence and adulthood is reached but is still a source of great frustration for carers and children alike.

Cerebral palsy is well recognized as a contributing factor to GERD and motility disorders in that group of patients. This is one of the major groups that pediatric surgeons are asked to treat by minimal invasive fundoplication and gastrostomy for venting. This procedure is often successful, but there is a high failure rate in this group of patients with postoperative bloat, autonomic problems, sweating, excessive borborygmi, and especially severe pain from bowel spasm which may go unrecognized. Some other conditions are associated with dysmotile bowel, such as gastroschisis and neonatal necrotizing enterocolitis. This could be due to underlying pathology in this condition affecting the motility mechanisms. Most institutions have a few patients with recurrent pseudo intestinal obstructions, and these patients end up with more and more resections of the bowel, which is a lifelong problem often treated by total parenteral nutrition (PN) and now increasingly the possibility of small bowel transplantation. Achalasia, neuronal intestinal dysplasia, megacystis, microcolon hypoperistalsis syndrome, and Hirschsprung's disease (HSCR) are the best recognized pathologic entities with motility disorders, and there is an abundance of genetic and immunohistochemistry information about these conditions. Over the last decade, a lot of research has clearly established and identified the patterns of motor activity in the gastrointestinal tract. These studies have attempted to clarify the effects of chemical neurotransmitters and hormones, and in recent times, the importance of the ENS gut brain on motility.

Twenty-five experts from 10 international centers of excellence [Australia, Switzerland, USA (Seattle, Ohio), Toronto, Ireland, South Africa, London, Manchester, and Glasgow] have contributed to this issue of Seminars.

“Development of the enteric nervous system and its role in intestinal motility during fetal and early postnatal stages” by Heather M. Young and her team sets the scene for the understanding of gastrointestinal motility disorders. In the early human gut, the wavefront of migrating neural crest cells (NCC) reaches the midgut by week 5 of development, and the entire length of the gut is colonized by week 7. Not only do NCC migrate rostrocaudally along the gut, but there is also a rostrocaudal gradient of maturation within the ENS. NCC-derived precursors coalesce along the length of the gut to form the myenteric plexus, first in the foregut, then the midgut, and finally the hindgut. The submucosal plexus forms 2-3 days after the myenteric plexus and arises from cells that migrate centripetally from the myenteric plexus. A well-defined band of circular muscle is apparent within the esophagus at week 8 of development and in the hindgut at week 11. By week 14, the smooth muscle layers of the hindgut are well defined with concentric muscularis mucosae, circular muscle, and longitudinal muscle apparent. By week 14, the human fetal gut has a relatively mature appearance due to the presence of concentric muscle layers, submucosal and myenteric plexuses, and interstitial cell of Cajal (ICC) networks that are associated with the ENS. In this review the complex nature of ENS development has been highlighted; NCC colonize the lengthening gut and undergo extensive migration, proliferation, and differentiation to form a functional ENS, processes which are controlled, or influenced by, a bewildering range of genes, molecules, signaling pathways, and developmental mechanisms. Failure in these processes can result in aganglionic gut conditions, such as HSCR in humans.

“The histopathology of gastrointestinal motility disorders in children” by S. Feichter, W. Meier-Ruge, and E. Bruder describes gastrointestinal motility disorders and chronic constipation as common pediatric problems. Normal peristalsis depends on the interaction between muscles, nerve cells, and tendinous connective tissue of muscularis propria. Malfunction of any of these components results in a motility disorder:

Aganglionosis, typically of the left distal colon, is the cause of (HSCR). Hypoganglionosis constitutes another gastrointestinal motility disorder. In hypoplastic hypoganglionosis, the number of nerve cells and the size of ganglia of the ENS are reduced, resulting in symptoms similar to aganglionosis. In intestinal neuronal dysplasia type B, submucous plexus development is disturbed.

Immaturity of the ENS, but also ganglioneuromatosis, can be the underlying cause of chronic constipation. Chronic constipation may be caused by a myopathy. Aplasia or atrophy of the tendinous connective tissue of muscularis propria may cause desmosis, which may result in an aperistaltic syndrome.

In severe chronic constipation, a histopathological diagnosis of the underlying cause is useful. In the diagnostic approach for most of these causes of chronic constipation, enzyme histochemistry is an efficient tool to complement conventional immunohistochemical and selected molecular technologies. An interdisciplinary approach of a gastrointestinal working group is beneficial in the management of these difficult patients.

“Practical pathology and genetics of Hirschsprung's disease” by Raj P. Kapur describes the diagnosis and management of HSCR. Rectal biopsies, intraoperative frozen sections, and resection specimens provide invaluable information. Extraction of these data requires thoughtful biopsy technique, adequate histologic sections, histochemistry, and collaboration of surgeon and pathologist. Critical consideration of transition zone anatomy and published studies of “transition zone pull through” indicate more research is needed to determine how much ganglionic bowel should be resected from HSCR patients. Many HSCR-susceptibility genes have been identified, but mutational analysis has limited practical value unless family history or clinical findings suggest syndromic HSCR.

“Clinical management of motility disorders in children” by Cheryl E. Gariepy and Hayat Mousa describes a review of 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 USA. 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 after intestinal transplantation, following colonic resection for HSCR, chronic functional constipation, and imperforate anus.

“Omega-3 lipids for intestinal failure associated liver disease” by Paul W. Wales and coworkers describes intestinal failure associated liver disease (IFALD) as one of the most common and devastating complications in infants with intestinal failure. Although multifactorial, its pathophysiology is clearly related to the administration of PN, with a recent focus on the role of PN lipid emulsions. This paper reviews the evidence for the use of omega-3 fatty acid PN lipid emulsions, which are proposed to have efficacy in the treatment of IFALD. Mechanisms explaining their effects are considered as well as future research directions.

“Internal anal sphincter achalasia” by Prem Puri and Reshma Doodnath describes a clinical condition with a presentation similar to HSCR but with the presence of ganglion cells on rectal suction biopsy. The diagnosis is made by anorectal manometry, which demonstrates the absence of the rectosphincteric reflex on rectal balloon inflation. The internal anal sphincter is regulated by several neurogenic mechanisms and so its pathogenesis is thought to be multifactorial, including the absence of nitrergic innervations, defective innervation of the neuromuscular junction, and altered distribution of ICC. In internal anal sphincter achalasia, the recommended treatment of choice is posterior internal anal sphincter myectomy. Recently, however, the use of intrasphincteric botulinum toxin has been used to treat this condition, but further long-term studies are needed to determine its effectiveness.

“The dilated bowel: A liability and an asset” by A. Bianchi and A. Morabito describes how the gastrointestinal tract responds to significant mechanical or functional obstruction by dilatation and hypertrophy of the segment proximal to the obstruction. Excessive dilatation compromises motility and absorption and is associated with considerable morbidity (intraluminal stasis, sepsis) such that bowel dilatation represents a major liability that predisposes the patient to intestinal failure. The dilated bowel proximal to an obstruction provides valuable autologous material for reconstruction with “tissue appropriate to the part.” Bowel elongation and dilatation are integral to the natural intestinal adaptation response to loss of small bowel and can also be induced through a structured “bowel expansion” program. The additional absorptive tissue that is progressively generated is essential for reconstruction of the bowel (tailoring and lengthening), to restore gastrointestinal dynamics (effective propulsion and absorption), and to reduce morbidity (intraluminal stasis, sepsis). In enhancing the prospects for enteral autonomy, dilatation and elongation of the residual autologous bowel are crucial to long-term survival and good quality life, and represent a most welcome asset. This paper reviews the impact and management of bowel dilatation along the gastrointestinal tract.

“Intestinal transplantation for motility disorders” by Alastair J.W. Millar and coworkers describes how transplantation has now become an accepted form of replacement therapy for intestinal failure and its complications, namely loss of central venous access, line sepsis, and the adverse effects of PN. The concept of intestinal failure has emerged in the last two decades, due to the success of long-term PN. The incidence of children with intestinal failure is estimated to be 1-2 per million population. Causes of intestinal failure can be subdivided into three categories: short bowel syndrome, disorders of bowel motility, and primary mucosal disease. When bowel motile dysfunction has evolved to a stage of intestinal failure along with complications from PN and central venous access, intestinal transplantation is indicated.

“Potential of cell therapy to treat pediatric motility disorders” by Nikhil Thapar and coworkers describes the management of children suffering from gut motility disorders and presents significant challenges. Although current treatments, such as surgery and PN, have revolutionized management, they remain palliative and associated with significant morbidity. The considerable advances in the study and application of cellular therapies have provided new hope for curative treatments and show particular promise with regard to replenishment of the ENS. The putative tools for such therapy include stem cells sourced from a range of tissues, including postnatal gut. To date, numerous studies have shown that such stem cells have the capacity to generate a neo-ENS in vitro and upon transplantation into experimental models of human gut motility disorders. Herein we review the progress that has been made, including the sourcing of putative stem cells for therapy and how key challenges are being addressed on the road to establishing definitive curative treatments for gut motility disorders in the clinical setting.

“Metoclopramide, celiac axis block, and thoracic splanchnectomy: New tools in the treatment of motility disorders in children” by Robert Carachi and coworkers describes how gastrointestinal motility disorders can develop in neurologically impaired children with a history of GERD and congenital malformations of the gut. It is characterized by moderate to severe abdominal pain, vomiting, and failure to thrive. Antral dysmotility after fundoplication and increased sympathetic over activity are two factors associated with this condition. Once this condition develops, it is difficult to treat. It can be a result of the operative procedures used to treat the condition (ie, fundoplication or laparotomy). The cause is complex and probably multifactorial. This paper proposes a management strategy using metaclopramide, celiac plexus blockade, and thoracic splanchnicectomy.

I have endeavored to contact colleagues around the globe who I knew ran programs on motility disorders, whether they have to do with basic research or clinical programs, and have been overwhelmed by the response and the high standard of the manuscripts received. I hope you will find this issue on motility disorders of educational value and practical help when such patients present to your practice.