Motility Disorders and Hirschsprung Disease

Chronic Intestinal Pseudoobstruction

Asim Maqbool

Kristin N. Fiorino

Chris A. Liacouras

Chronic intestinal pseudoobstruction (CIPO) comprises a group of primary and secondary disorders characterized as a motility disorder with the dominant defect of impaired peristalsis; symptoms are consistent with intestinal obstruction in the absence of mechanical obstruction ( Table 358.1 ). The natural history of primary pseudoobstruction is that of a progressive disorder, although there are occasional cases of secondary pseudoobstruction caused by conditions that can transiently or permanently alter bowel motility. The most common cause of acute pseudoobstruction is Ogilvie syndrome (acute pseudoobstruction of the colon). Pseudoobstruction represents a wide spectrum of pathologic disorders from abnormal myoelectric activity to abnormalities of the nerves (intestinal neuropathy) or musculature (intestinal myopathy) of the gut. The organs involved can include the entire gastrointestinal tract or be limited to certain components, although almost always include the small bowel. The distinctive pathologic abnormalities are considered together because of their clinical similarities. For these reasons, CIPO may be thought of more as a clinical syndrome at times.

Most congenital forms of primary pseudoobstruction occur sporadically, although autosomal dominant (SOX10), autosomal recessive (RAD2I, SGOL1, TYMP, POLG), X-linked (FLNA, L1CAM), and familial patterns of inheritance have been identified. Patients with autosomal dominant forms of pseudoobstruction have variable expressions of the disease. Patients with mutations in TYMP and POLG genes present with mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE); MELAS syndrome is another mitochondrial disorder associated with CIPO. MNGIE is characterized by intestinal dysmotility, abdominal pain and distention, emesis, cachexia, ptosis, leukoencephalopathy, peripheral neuropathy (paresthesia, pain), and myopathy. Sixty percent have symptoms (often subtle) before age 20 yr (see Chapter 358.2 ). Acquired pseudoobstruction can follow episodes of acute gastroenteritis, presumably resulting in injury to the myenteric plexus.

In congenital pseudoobstruction, abnormalities of the muscle or nerves can be demonstrated in most cases. In myopathies, the smooth muscle is involved, in which the outer longitudinal muscle layer is replaced by fibrous material. These manifestations of visceral myopathies may be primary or secondary phenomenon. The enteric nervous system is usually altered in neuropathies and may involve disorganized ganglia, hypoganglionosis, or hyperganglionosis. Abnormalities in the interstitial cells of Cajal, the intestinal pacemaker, are classified as mesenchymopathies. In others, mitochondrial defects have been identified.

Diagnosis

The diagnosis of pseudoobstruction is based on the presence of compatible symptoms in the absence of mechanical obstruction ( Fig. 358.1 ). Plain abdominal radiographs demonstrate air-fluid levels in the intestine. Neonates with evidence of obstruction at birth may have a microcolon. Contrast studies demonstrate slow passage of barium; water-soluble agents should be considered. Esophageal motility is abnormal in about half the patients. Antroduodenal (small intestinal) motility and gastric emptying studies have abnormal results if the upper gut is involved ( Table 358.3 ). The clinical manifestations depend in large part to the areas of the gastrointestinal tract that are involved, with milder forms more common in older children. Although counterintuitive, older children with CIPO may present with both abdominal distention and diarrhea, related to small bowel bacterial overgrowth because of altered motility. Other presentations may include constipation and bilious emesis, as well as failure to thrive, as a consequence of decreased enteral feeding tolerance.

Table 358.3

Findings in Pseudoobstruction

From Steffen R: Gastrointestinal motility. In Wyllie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver disease, ed 3, Philadelphia, 2006, WB Saunders, p. 66.

GI SEGMENT	FINDINGS *
Esophageal motility	Abnormalities in approximately half of CIPO, although in some series up to 85% demonstrate abnormalities
	Decreased LES pressure
	Failure of LES relaxation
	Esophageal body: low-amplitude waves, poor propagation, tertiary waves, retrograde peristalsis, occasionally aperistalsis
Gastric emptying	May be delayed
EGG	Tachygastria or bradygastria may be seen
ADM	Postprandial antral hypomotility is seen and correlates with delayed gastric emptying
	Myopathic subtype: low-amplitude contractions, <10-20 mm Hg
	Neuropathic subtype: contractions are uncoordinated, disorganized
	Absence of fed response
	Fasting MMC is absent, or MMC is abnormally propagated
Colonic	Absence of gastrocolic reflex because there is no increased motility in response to a meal
ARM	Normal rectoanal inhibitory reflex

ADM, antroduodenal manometry; ARM, anorectal manometry; CIPO, chronic intestinal pseudoobstruction; EGG, electrogastrography; GI, gastrointestinal; LES, lower esophageal sphincter; MMC, migrating motor complex.

* Findings can vary according to the segment(s) of the GI tract that are involved.

The initial focus is to rule out anatomic obstruction and to assess for bladder involvement, because that is a frequent and significant extraintestinal manifestation of concern. Manometric evidence of a normal migrating motor complex and postprandial activity should redirect the diagnostic evaluation. CIPO due to an intestinal myopathy may demonstrate manometry evidence of low-amplitude contractions, whereas CIPO due to enteric neuropathy demonstrates normal amplitude but poorly organized contractions (nonperistaltic or tonic). Anorectal motility is normal and differentiates pseudoobstruction from Hirschsprung disease. Full-thickness intestinal biopsy might show involvement of the muscle layers or abnormalities of the intrinsic intestinal nervous system.

The differential diagnosis is broad and includes such etiologies as Hirschsprung disease, mitochondrial neurogastrointestinal encephalomyopathy, mechanical obstruction, psychogenic constipation, neurogenic bladder, and superior mesenteric artery syndrome. Secondary causes of ileus or pseudoobstruction that should be considered include medication side effects, infectious etiologies, metabolic disturbances, immunologic disorders, oncologic processes, vasculitides, neuropathies, and myopathies (see Table 358.1 ). Examples include use of opiates hypokalemia, hypothyroidism, hypokalemia, diabetic neuropathy, porphyria, amyloidosis, Chagas disease, scleroderma, hereditary angioedema, mitochondrial disorders, and radiation, and these must be excluded. Other causes of abdominal distention such as small bowel bacterial overgrowth and aerophagia may present similarly and should be considered. Small bowel bacterial overgrowth is a complication of CIPO.

Treatment

Nutritional support is the mainstay of treatment for pseudoobstruction. Thirty to 50% of patients require partial or complete parenteral nutrition. Some patients can be treated with intermittent enteral supplementation, whereas others can maintain themselves on selective oral diets. Prokinetic drugs are generally used, although studies have not shown definitive evidence of their efficacy. Isolated gastroparesis can follow episodes of viral gastroenteritis and spontaneously resolves, usually in 6-24 mo. Erythromycin, a motilin receptor agonist, and cisapride, a serotonin 5-HT ₄ receptor agonist, may enhance gastric emptying and proximal small bowel motility and may be useful in this select group of patients. Metoclopramide, a prokinetic and antinausea agent, is effective in gastroparesis, although side effects, such as tardive dyskinesia, limit its use. Domperidone, an antidopaminergic agent, is a prokinetic agent that can be considered. Pain management is difficult and requires a multidisciplinary approach.

Symptomatic small bowel bacterial overgrowth is usually treated with rotated nonabsorbable oral antibiotics and/or probiotics. Bacterial overgrowth can be associated with steatorrhea and malabsorption. Octreotide, a long-acting somatostatin analog, has been used in low doses to treat small bowel bacterial overgrowth. Patients with acid peptic symptoms are generally treated with acid suppression. Many patients with CIPO benefit from a gastrostomy, and some benefit from decompressive enterostomies ( Fig. 358.2 ). Colectomy with ileorectal anastomosis is beneficial if the large bowel is the primary site of the motility abnormality. Bowel transplantation may benefit selected patients with CIPO. The prognosis is better for patients without urinary tract involvement and for those with neuropathic etiologies over myopathic disorders.

Mitochondrial Neurogastrointestinal Encephalomyopathy

Asim Maqbool

Chris A. Liacouras

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystem autosomal recessive disease that initially presents with severe gastrointestinal disturbances; the neurologic manifestations usually occur later in the illness and may initially be subtle or asymptomatic.

MNGIE is caused by a mutation in the nuclear DNA TYMP gene encoding thymidine phosphorylase that results in abnormalities in intergenomic communication with resulting instability of mitochondrial DNA (some patients have mutations on POLG1 ). There are at least 50 individual mutations with a poor genotype-phenotype correlation and varying manifestations within each family. Consanguinity is present in 30% of families.

MNGIE affects both males and females and is usually diagnosed in the 2nd and 3rd decade (average age: 18 yr; range: 5 mo-35 yr). Onset is usually around age 12 yr, but there is often a 5- to 10-yr delay in the diagnosis.

MNGIE initially presents with gastrointestinal symptoms. Severe intestinal dysmotility and gastroparesis are associated with early satiety, postprandial emesis, episodic pseudoobstruction, diarrhea, constipation, and abdominal pain and cramping, which leads to significant cachexia. Because of the age of onset, emesis, early satiety, and cachexia patients are often misdiagnosed with an eating disorder.

Most often, following the onset of gastrointestinal manifestations, ptosis, progressive external ophthalmoplegia, hearing loss, myopathy, and peripheral neuropathy may develop. The neuropathy is either demyelinating or a mixed axonal demyelinating type and manifests as weakness, decreased or absent deep tendon reflexes, and paresthesias. Leukoencephalopathy is initially asymptomatic and noted on MRI as patchy lesions predominantly in the cortex but also in the basal ganglia and brainstem. Eventually the central nervous system lesions become diffuse and confluent. A small number of patients develop cognitive impairment or dementia.

The diagnosis is suggested by the constellation of gastrointestinal and neurologic symptoms, lactic acidosis, ragged red fibers, and cytochrome C oxidase–deficient fibers seen in most patients on muscle biopsy. Reduced activity of thymidine phosphorylase enzyme and elevated plasma levels of thymidine and deoxyuridine are often diagnostic; genetic testing for the mutation or other genes (POLG1) is recommended.

Treatment is focused on providing sufficient nutritional support and avoidance of infectious complications and of nutritional deficiencies. Domperidone has been used for nausea and emesis, antibiotics for small bowel bacterial overgrowth, amitriptyline or gabapentin for neuropathic pain, and parenteral alimentation for nutritional support. Opiates and any medications that affect intestinal motility or mitochondrial function must be avoided. Stem cell transplantation has been successful in a small number of patients.

Overall the prognosis is poor, with few surviving into the 4th or 5th decade.