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. Author manuscript; available in PMC: 2018 Jun 1.
Published in final edited form as: Curr Opin Pediatr. 2017 Jun;29(3):347–353. doi: 10.1097/MOP.0000000000000486

Pediatric enteric neuropathies: diagnosis and current management

Maggie L Westfal 1, Allan M Goldstein 2,3,*
PMCID: PMC5475271  NIHMSID: NIHMS865942  PMID: 28319561

Abstract

Purpose of Review

Neurointestinal diseases are increasingly recognized as causes of significant gastrointestinal morbidity in children. This review highlights the most common pediatric enteric neuropathies and their diagnosis and management, emphasizing insights and discoveries from the most recent literature available.

Recent Findings

The embryologic and histopathologic causes of enteric neuropathies are varied. They range from congenital aganglionosis in Hirschsprung disease, to autoimmune-mediated loss of neuronal subtypes in esophageal achalasia and Chagas disease, to degenerative neuropathies in some cases of chronic intestinal pseudo-obstruction and gastroparesis. Increased awareness of the clinical presentation and diagnostic evaluation of these conditions is essential as it allows for earlier initiation of treatment and improved outcomes. Most current therapies, which include medical management, neurostimulation, and operative intervention, aim to minimize the symptoms caused by these conditions. The evidence base for many of these treatments in children is poor, and multi-institutional prospective studies are needed. An innovative therapy on the horizon involves using neuronal stem cell transplantation to treat the underlying pathology by replacing the missing or damaged neurons in these diseases.

Summary

While recent advances in basic and clinical neurogastroenterology have significantly improved our awareness and understanding of enteric neuropathies, the efficacy of current treatment approaches is limited. The development of novel therapies, including pharmacologic modulators of neurointestinal function, neurostimulation to enhance gut motility, and neuronal cell-based therapies, is essential to improve the long-term outcomes in children with these disorders.

Keywords: Enteric neuropathy, neurointestinal disease, enteric nervous system, Hirschsprung disease

Introduction

Normal gastrointestinal (GI) function relies on the enteric nervous system (ENS), a complex network of neurons and glia in the gut wall that regulate motor, sensory, absorptive, secretory, and multiple other aspects of GI homeostasis. Comprised of cells that arise from the embryonic neural crest, the ENS is organized in two major ganglionated plexuses, myenteric and submucosal, and functions independently of central nervous system input (Figure 1). Many diseases of the GI tract have a neuropathic cause (Table 1) and lead to significant morbidity due to abnormalities in motor and/or sensory GI function. Some conditions are developmental in origin, caused by abnormal formation of the ENS. Others are acquired in later life due to infection, immune-mediated inflammation, or neuronal degeneration. In this review we highlight the most common enteric neuropathies affecting children, review our present understanding of their pathophysiology, and discuss current and emerging approaches to their diagnosis and treatment.

Figure 1. Enteric nervous system.

Figure 1

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Immunohistochemistry shows the enteric nervous system organized in two concentric rings of ganglia located in the myenteric and submucosal plexuses (A). Magnified views of a myenteric ganglion (B) and a submucosal ganglion (C) demonstrate the presence of both enteric neurons (Tuj1 antibody) and glial cells (S100 antibody), with nuclei stained with DAPI.

Table 1. Enteric neuronal phenotype associated with pediatric neurointestinal diseases.

Enteric neuropathy Enteric neuronal phenotype
Hirschsprung disease Enteric ganglia absent along variable lengths of distal bowel
Intestinal neuronal dysplasia, type B Colonic submucosal hyperganglionosis in children >1 year of age
Esophageal achalasia Autoimmunity leading to loss of inhibitory enteric neurons in esophageal myenteric plexus
Gastroparesis Variable findings, including loss of ICC, hypoganglionosis, or neuronal inflammation (myenteric ganglionitis) in stomach
CIPO Neuropathic cases are associated with neuronal inflammation, usually affecting the myenteric plexus
Neurogenic constipation Variable histology, with some cases exhibiting reduced neurons, glial cells, or ICCs; neurotransmitter imbalance may also contribute
Chagas disease Autoimmune-mediated inflammatory enteric neuropathy leading to degeneration of neurons in the gastrointestinal tract
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CIPO, chronic intestinal pseudo-obstruction

ICC, interstitial cells of Cajal

Hirschsprung disease

Hirschsprung disease (HSCR) is the most common congenital neurointestinal disease with an incidence of 1 in 5000 live-births. It is caused by the failure of enteric neural crest-derived cells, which give rise to the ENS, to complete their cranio-caudal migration from the foregut to the end of the bowel [1], leaving the distal end aganglionic and therefore devoid of motility. Recent work has demonstrated that abnormal proliferation, differentiation, and migration of the neural crest-derived cells underlie the development of HSCR. [2,3] This disease usually presents in newborns with failure to pass meconium within the first 48 hours of life, abdominal distension, emesis, and feeding difficulty. The aganglionosis is “short-segment” (i.e. limited to the rectosigmoid) in 80% of cases, with the remainder extending more proximally, sometimes involving the whole colon or even the entire intestine. [2]

HSCR has a complex, non-Mendelian inheritance pattern complicated by variable penetrance and clinical expression. Mutations in greater than 10 genes have been identified, but nearly all patients have a coding or noncoding mutation in the RET gene, which is critical for ENS development. Several genetic syndromes are associated with HSCR, including Down syndrome in 10% of cases, Shah-Waardenburg, Haddad syndrome, and Mowat-Wilson syndrome. [2] While a contrast enema showing a caliber change between proximal dilated bowel and distal aganglionic bowel raises suspicion in the appropriate clinical setting, the diagnosis is established by rectal biopsy showing absence of ganglion cells and often the presence of hypertrophic nerves. Ancillary tests are helpful and recently calretinin immunohistochemistry, showing absent calretinin-immunoreactive fibers in the submucosa and lamina propria, is replacing the traditional acetylcholinesterase histochemical stain that has been fraught with unreliability. [4]

The treatment of HSCR remains surgical, with single-stage transanal endorectal pullthrough procedures, with or without laparoscopy, representing the most common approach for short-segment disease. Both Soave and Swenson transanal procedures are performed and no significant difference in outcomes (hospital stay, obstructive symptoms, enterocolitis incidence) has been observed. [5] Current research is focusing on long-term outcomes and the recognition that bowel function is not nearly as good as previously thought. In a meta-analysis of transanal pullthroughs, 14% experienced persistent bowel dysfunction, including 53% with constipation, 29% with Hirschsprung-associated enterocolitis (HAEC), and 18% with incontinence or soiling. [6] A recent longer-term study of transanal endorectal pullthroughs with 15-year follow-up found that 54% of patients had soiling and 44% developed post-operative HAEC, with bowel function reduced in children with an associated syndrome. [7] The same group analyzed long-term bowel function and quality of life with matched controls and found significant impairment in fecal control during childhood. Control improved with age, but stooling frequency remained persistently higher. Quality of life was satisfactory, but the importance of psychosocial support for the child and the family is emphasized. [8]

One cause of post-pullthrough morbidity is the “transition zone pullthrough,” in which the proximal resection margin contains abnormally ganglionated bowel. The transition zone, defined by partial circumferential aganglionosis, hypoganglionosis, and/or submucosal nerve hypertrophy, was shown to extend up to 5cm proximal to the aganglionic segment [9]. Based on this observation, routine resection of a 5cm proximal margin should be performed and may improve outcomes. Post-pullthrough complications, including fecal incontinence, obstructive symptoms, and HAEC, adversely impact not only GI function but also quality of life, including psychological, behavioral and/or developmental outcomes. [10] Early identification and treatment of these complications utilizing multidisciplinary teams is of critical importance, including involvement of adult specialists as these children transition to adulthood.

Intestinal neuronal dysplasia

Intestinal neuronal dysplasia (IND) type B, which comprises >95% of IND cases, presents as chronic constipation usually during childhood. The diagnosis is made by biopsy showing submucosal hyperganglionosis in the colon. The specific histopathologic criteria have been controversial. One set of criteria based on expert opinion includes the presence of giant submucosal ganglia defined as containing >8 ganglion cells per ganglion in at least 20% of submucosal ganglia examined. The diagnosis must be made on frozen section and should not be made before one year of age because submucosal hyperganglionosis occurs normally in infants. [11]

IND has been found in isolation or in the transition zone proximal to the aganglionic segment in HSCR. In the latter scenario, it has been proposed to cause persistent obstructive symptoms after pullthrough surgery [12] but whether this is true is debated. [13] IND remains a controversial entity, with some suggesting that its histologic features are secondary to chronic obstruction rather than a primary cause of constipation. Regardless, treatment is similar to that of chronic constipation, with some severe cases requiring surgery, including sphincterotomy, diverting colostomy, or colectomy. [14]

Esophageal achalasia

Esophageal achalasia is uncommon in children, with an incidence of 0.1 per 100,000 [15,16] and an average age at diagnosis of 11 years. [17,18] The disease is characterized by impaired relaxation of the lower esophageal sphincter (LES) and abnormal esophageal motility, resulting in dysphagia and regurgitation, often with retrosternal chest discomfort and weight loss. Its pathophysiology is due to the loss of inhibitory neurons in the esophageal myenteric plexus that release nitric oxide, which is required for LES relaxation. [2] The disease is thought to be autoimmune, with auto-antibodies reacting against enteric neurons and leading to an imbalance of excitatory (cholinergic) over inhibitory (nitrergic) innervation. [19]

The diagnosis is made by esophagram and manometry. A contrast study typically shows a dilated esophagus with abnormal peristalsis and delayed emptying through a narrow esophagogastric junction, giving a “bird's beak” appearance. [19] Characteristic manometric findings include high resting LES pressure, failure of LES relaxation after swallowing, and absence of peristaltic contractions in the esophagus. The optimal treatment in children remains controversial due to inadequate comparative data on which to base recommendations. [20] Initial treatment with botulinum toxin injection into the LES is only temporizing, requiring subsequent Heller myotomy in 85% of cases in a recent retrospective review. [17] Endoscopic pneumatic dilatation is commonly performed, but has been associated with a high rate of retreatment for persistent or recurrent symptoms, ranging from 71-88% [16,18], leading some to recommend Heller myotomy as first-line therapy for newly diagnosed children.

A Heller myotomy has long been the gold standard among pediatric surgeons. The procedure is usually laparoscopic and often includes a partial fundoplication to minimize the risk of post-myotomy reflux. However, reported results after Heller myotomy are mixed, with repeat myotomy or pneumatic dilation required in 15-29% of patients for recurrent dysphagia. [16,21] In a prospective double-blind trial, laparoscopic myotomy and pneumatic dilation yielded equivalent results at 2-year follow-up in 184 patients. [22] Interestingly, in subgroup analysis younger patients (under 40 years) were more likely to require re-dilation after pneumatic dilation, suggesting age-dependent differences in outcome and consistent with the poorer long-term results observed in children.

Peroral endoscopic myotomy (POEM) is a new approach that leverages natural orifice transluminal endoscopic surgery (NOTES) to perform endoscopic myotomy. Experience in children is limited. A recent study comparing pediatric laparoscopic myotomy and POEM found that the latter had shorter operative time, longer myotomy, fewer complications, faster time to feeding, and shorter hospital stay, with equivalent outcomes. [15] Another study of 10 children included Eckhardt score, timed barium swallow, and high-resolution manometry one year after POEM and found significantly improved scores on these measures and complete symptom resolution. [23] The current lack of evidence supporting one treatment approach over another, combined with the rarity of achalasia in children, has led to wide variation in practice. [24] Well-designed multi-institutional studies are needed to improve treatment and prevent the adverse impact this disease has on a child's long-term quality of life. [16]

Gastroparesis

Gastroparesis refers to delayed gastric emptying in the absence of mechanical obstruction. Symptoms include post-prandial bloating and pain, early satiety, nausea, and vomiting. While the prevalence among children is unknown, the past decade has seen a dramatic increase in gastroparesis-associated hospitalizations. [25] In children 70% of gastroparesis is idiopathic or post-viral, with the remaining 30% due to medications or post-surgery. Various pathophysiologic causes have been proposed, including abnormalities of extrinsic gastric innervation, loss of interstitial cells of Cajal (ICCs), hypoganglionosis, and inflammatory degeneration of myenteric neurons. [2] The diagnosis is suspected clinically and confirmed by gastric emptying scintigraphy, which measures the time to empty a 99Tc sulfur colloid meal from the stomach. A 4-hour solid meal scan is the optimal test and can be completed by most children, excluding the very young. [26]

The mainstay of treatment for pediatric gastroparesis includes dietary modification and medications (prokinetic drugs, antiemetics, appetite stimulants) with the goal of maintaining fluid and nutrition status and relieving symptoms. For intractable cases, surgical options include gastrostomy, jejunostomy, gastric emptying procedures, and intrapyloric Botox injection, but these have met with limited success. [27] Gastric electrical stimulation (GES) is a promising new approach that has been shown to be effective in treating the nausea and vomiting, even while not improving gastric emptying. GES involves delivery of low-energy electrical stimulation via electrodes implanted into the stomach. [28] The largest pediatric study to date included 97 children, 67 of whom had permanent pulse generators implanted and exhibited significant and sustained symptomatic improvement. [29] Additional studies are needed to confirm these findings and to determine mechanisms of action, predictors of success, and long-term efficacy.

Chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction (CIPO) is a rare and severe motility disorder characterized by recurrent or continuous symptoms of intestinal obstruction in the absence of a fixed obstructive lesion. [3] Symptoms are often non-specific, delaying the diagnosis and contributing to morbidity. CIPO accounts for 15% of cases of chronic intestinal failure in children. Most cases are idiopathic, while some occur secondary to systemic disease, including myxedema, Duchenne muscular dystrophy, hypothyroidism, hypoparathyroidism, celiac disease, Chagas disease, and mitochondrial disorders. [2] The pathophysiology of primary CIPO can be neuropathic, mesenchymopathic, or myopathic, depending on whether the abnormality lies with the enteric neurons, ICCs, or smooth muscle, respectively. Neuropathic CIPO is often due to degenerative loss of enteric neurons or to an inflammatory neuropathy within the enteric ganglia and/or nerve processes. [30] While the prognosis in children is better for neuropathic, rather than myopathic, CIPO, [31] the disease remains chronic and often debilitating, often with no definitive therapy available.

Treatment requires a multidisciplinary team of surgeons, gastroenterologists, pathologists, nutritionists, and psychologists aimed at avoiding the many associated complications, including intestinal failure, small intestinal bacterial overgrowth (SIBO), central line-associated bloodstream infections (CLABSI), sepsis, and, when possible, improving gut motility and function. [32] Treatment therefore includes nutritional support with enteral nutrition, parenteral nutrition when needed, non-opioid analgesics, antibiotics, and prokinetics. The role of surgery is limited to central venous access, ostomy for intestinal decompression, feeding tubes, appendicostomy or cecostomy for antegrade enemas [3], and, in end-stage CIPO, bowel transplantation. Immunomodulatory therapy may have a role in treating immune-mediated neuropathies, but the evidence remains limited to small case series. [2]

Neurogenic constipation

Chronic constipation is a common functional GI disorder that affects up to 30% of children. Three principal subtypes exist: normal transit (functional constipation), slow transit constipation (STC), and obstructed defecation. Tissue obtained from colectomies performed for severe STC show an underlying enteric neuropathy in some patients, including reductions in neuronal cell bodies and processes, enteric glia, and ICCs. [2] A study of children with severe STC showed that abnormal colonic manometry was associated with histopathological findings involving neurons, ICCs, and smooth muscle. [33] Colonic dysmotility may be due to neurotransmitter imbalance, such as an excess of nitric oxide in the myenteric plexus, which could inhibit contractile activity. [34] However, the role of neurotransmitters remains unclear as multiple studies on a variety of mediators have yielded contradictory results.

Treatment of chronic constipation begins with medical management using laxatives, including bulk-formers (fiber), stool softeners, lubricants (mineral oil), hyperosmotic agents (lactulose, polyethylene glycol), stimulants (bisocodyl, senna), serotonin agonists (prucalopride), and other newer agents (5-HT4 agonists, ileal bile acid transporters, and ghrelin agonists). [35,36] Cases refractory to medications may benefit from surgical intervention, but a thorough diagnostic evaluation is essential prior to embarking on an operation. The workup should be tailored to the individual child and can include anorectal and/or colonic manometry, colon transit study, and contrast enema. Depending on the results, intestinal diversion, various types of colectomy, and antegrade colonic enema (ACE) procedures have all proven to be beneficial, but the evidence supporting each of these is poor and larger, more rigorous studies are needed. [37, 38]

Chagas disease

Chagas disease is caused by the parasite Trypanosoma cruzi and transmitted to humans by Reduviidae beetles, known as “kissing bugs.” Infection can also occur via vertical or blood-borne transmission, non-vectorial modes that represent a major source of infection. [39] Chagas disease is endemic in Central and South America, but present worldwide, with over 6 million people infected and over 12,000 deaths annually. [40] Symptoms during the acute infectious phase, which lasts weeks to months, are mild and self-resolving. In 20-30% of patients, a symptomatic chronic phase occurs, often many years later, with cardiac, neurologic, and GI consequences. [41] While any segment of the GI tract can be affected and result in dysmotility, the esophagus and colon are most often involved, leading to megaesophagus and megacolon, respectively. Interestingly, GI involvement is geographically distinct, with esophageal involvement more common in Brazil and megacolon more often seen in Chile. [42] The megaesophagus is often called “Chagasic achalasia” due to its similarities to idiopathic achalasia, although an important difference is the loss of both excitatory and inhibitory innervation in Chagasic achalasia as opposed to selective loss of inhibitory innervation in the idiopathic form. [43]

Chagas disease is characterized by the degenerative loss of enteric ganglia due to immune infiltration in the myenteric plexus. This results from autoimmunity due to a flagellum-associated surface protein (Fl-160) that mimics a protein expressed by mammalian enteric neurons. [44] Patients with GI disease can also have circulating antibodies against the type 2 muscarinic acetylcholine receptor expressed on smooth muscle cells, leading to muscle contraction and contributing to achalasia. [45]

Treatment of Chagas disease is based on antiparasitic drugs in the acute phase and symptom management in the chronic phase. Drug treatment includes nifurtimox and benznidazole, but these have variable efficacy and significant side effects. [42] Management of chronic GI involvement, such as megaesophagus and megacolon, are similar to idiopathic achalasia and constipation with megacolon, respectively. There is a growing emphasis on prevention through the use of vector control strategies, including insecticides [46], as well as the importance of testing pregnant women and screening and treating infants with congenital Chagas disease. [47]

Future Directions

An area of active and promising investigation is the development of neuronal cell transplantation for HSCR and other neurointestinal diseases. [48] The identification and isolation of neuronal progenitor cells from the human postnatal intestine [49,50] raises the intriguing possibility of transplanting these cells to replace missing or abnormal neurons in patients with enteric neuropathies. Recent studies successfully transplanted enteric neuronal progenitors isolated from the intestine or differentiated from pluripotent stem cells into mouse models of HSCR [51,52], but improvement in gut function has yet to be convincingly demonstrated. The initiation of pilot studies in humans is on the horizon.

Conclusions

Neurointestinal diseases represent a diverse group of conditions associated with significant morbidity. We have presented those most commonly encountered in childhood, but many other enteric neuropathies exist, including hypoganglionosis, ganglioneuromatosis, neuronal intranuclear inclusion disease, ganglionitis, degenerative neuropathy, and more. [53] An increased awareness of these conditions, including their clinical presentation and their pathologic features, is needed to improve the care we deliver to affected patients. Unfortunately, for most of these diseases, definitive treatments are lacking and current therapies aim only to alleviate symptoms. As our understanding of ENS biology and of neurointestinal pathophysiology improves, so too will our ability to treat these challenging clinical conditions.

Key points.

  • Enteric neuropathies result from congenital defects in ENS development or from acquired loss of enteric neurons due to infection, immune-mediated inflammation, or neuronal degeneration.

  • The most common pediatric enteric neuropathies include Hirschsprung disease, esophageal achalasia, gastroparesis, chronic intestinal pseudo-obstruction, and neuropathic constipation.

  • While current therapies aim primarily to alleviate symptoms, neuronal stem cell transplantation is being explored as a way of treating the underlying pathophysiology by replacing damaged or missing neurons in these conditions.

Acknowledgments

None

Financial support and sponsorship: A.M.G. is supported by the National Institutes of Health (R01DK103785).

Footnotes

Conflicts of interest: None

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