Ondine's curse

The primary care physician faces the challenge of differentiating potentially serious conditions from self-limited conditions. Hirschsprung's disease is a serious condition that may present as constipation.

Illustrative Case

A 24-year-old woman (gravida 3 para 2), had a male child by spontaneous vaginal delivery. The infant's physical examination at birth was unremarkable. During his first day of life he fed poorly and had two small episodes of emesis. He did not pass a stool until 39 hours of life, but subsequently passed four stools before 48 hours of life. He was discharged home in good condition. When he was 11 days old he was brought to the office because he had not had a bowel movement for six days. He was treated with glycerin suppositories and subsequently had five loose green bowel movements during the next day.

However, two days later he was brought to the clinic because of a one-day history of fever and irritability. The parents reported that he had intermittent postprandial abdominal distention that resolved spontaneously within a few hours. The parents denied any vomiting or lethargy.

On examination he was found to be irritable but easily consoled. His temperature was 38.2[degrees]C (100.9[degrees]F), and he appeared mildly dehydrated. Abdominal examination revealed normal bowel sounds with guarding. There was no abdominal distention. The rectal ampulla held firm stool that did not pass with stimulation.

He was admitted to the neonatal intensive care unit, where he was given intravenous antibiotics and fluids. Radiographs of the abdomen showed a paucity of bowel gas, except for a large dilated loop in the right lower quadrant, and one air-fluid level. There was no pneumatosis or free air.

Barium enema showed a segment of spastic colon and a grossly dilated distal sigmoid colon. A pediatric surgeon performed a rectal biopsy that revealed no ganglionic cells in the bowel wall. A diagnosis of Hirschsprung's disease was made. Two days later a diverting colostomy was performed, at the level of the sigmoid colon. During the surgery, multiple biopsies were taken to determine the level of aganglionosis. At six months of age, the child had a Soave pull-through procedure, with an incidental appendectomy. At 10 months of age, he was doing well.

Definition

Hirschsprung's disease, or congenital megacolon, obtains its name from a Danish physician who described two cases at the 1888 Pediatric Congress in Berlin.(1) Since that time, progress in diagnosis and treatment of Hirschsprung's disease has led to a marked decrease in morbidity and mortality from this condition.

Hirschsprung's disease is now recognized as one of several disorders of intestinal innervation. Collectively known as "dysganglionoses," these disorders include aganglionosis of the bowel wall, hypoganglionosis, neuronal dysplasia (hyperganglionosis), absence of intrinsic innervation of the colon and absence of innervation of the intestine.(2)

Hirschsprung's disease is characterized by the absence of intramural ganglionic cells at the submucosal (Meissner's plexus) and myenteric (Auerbach's plexus) levels of the intestines, for a distance greater than 4 cm proximal to the pectinate line(2)(3) (Figures 1a and 1b). Absence of intramural ganglion cells interferes with the normal relaxation of peristalsis in the bowel wall and the internal sphincter. The abnormally innervated segment of intestine becomes hypertonic and behaves as a functional stenosis, leading to partial or complete colonic obstruction.(2) Immediately proximal to the aganglionic segment, the intestine becomes markedly dilated with feces and gas.(4)

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Etiology

The etiology of Hirschsprung's disease is thought to be multifactorial. Intramural ganglion cells are thought to arise from neuroblasts that migrate from their neural crest origin via the vagus nerve to the distal colon during the seventh to 12th weeks of gestation.(2)(5) Genetic predisposition and microenvironmental factors, such as trophic substances, intra-uterine intestinal ischemia or infections, may interrupt the migration and development of these neuroblasts, resulting in aganglionosis of the bowel wall.(2)(5) Hirschsprung's disease occurs in one of 5,000 to 8,000 live births, with a male-to-female predominance of 3:1 or 4:1.(2) A family history of Hirschsprung's disease is found in 3 to 7 percent of affected children, and in these children, longer segments of bowel tend to be involved.(4)(6)(7) Hirschsprung's disease has been associated with various congenital defects, such as Down syndrome, mental retardation, Ondine's curse (congenital central hypoventilation syndrome), Waardenburg's syndrome, pheochromocytoma, meningomyelocele, distinctive facies, microcephaly and other defects involving almost all organ systems.(5)(8)

Genetic transmission of Hirschsprung's disease varies, depending on the presence of certain features.(6) Aganglionosis of the entire bowel often appears to have an autosomal recessive pattern. However, when Hirschsprung's disease is associated with sensorineural deafness and Waardenburg's syndrome, a dominant inheritance pattern has been demonstrated.(6)

Clinical Course

Hirschsprung's disease can present in one of five distinct patterns, with varying degress of severity.(8) One pattern, occurring soon after birth, consists of complete intestinal obstruction with emesis and failure to pass meconium. In the second pattern, repeated bowel obstruction occurs, with emesis, dehydration and delayed passage of meconium. The episodes of obstruction resolve spontaneously. In the third pattern, the infant presents with signs of persistent mild constipation and suddenly develops complete intestinal obstruction with abdominal distention and emesis. In the fourth pattern, diarrhea is followed by obstruction, fever and enterocolitis. Children presenting with the fifth pattern have persistent mild constipation that never results in complete intestinal obstruction.

The newborn with Hirschsprung's disease is usually a full-term infant, with an uneventful prenatal course and delivery, and normal birth weight.(8) The most common symptoms and physical findings in infants with Hirschsprung's disease, as found in a review of 501 cases, are summarized in Tables 1 and 2.(1) Rectal examination may result in an explosive discharge of feces and gas; the infant may appear pale and listless, and fail to gain weight.(8) Uncommonly, periorbital edema secondary to protein-losing enteropathy may be a presenting sign of Hirschsprung's disease.(8) The presence of diarrhea may indicate early enterocolitis that may rapidly progress to sepsis and death.(8)

TABLE 1

Signs and Symptoms of Hirschsprung's Disease

(*)--Number of respondents.

Adapted from Swenson O, Sherman JO, Fisher JH. Diagnosis of congenital megacolon: an analysis of 501 patients. J Pediatr Surg 1973; 8:587-94.

TABLE 2

Presenting Findings in Patients with Hirschsprung's Disease

(*)--Total number of patients in study was 501.

Adapted from Swenson O, Sherman JO, Fisher JH. Diagnosis of congenital megacolon: an analysis of 501 patients. J Pediatr Surg 1973; 8:587-94.

Bowel involvement in Hirschsprung's disease extends proximally from the anus for a variable distance. Table 3(7) summarizes the findings in 874 cases of Hirschsprung's disease throughout the world. The frequency of vomiting as a presenting sign is directly proportional to the length of aganglionic bowel.(1) The incidence of spontaneous perforation of the gastrointestinal tract is thought to increase as the length of aganglionic bowel increases.(7)

TABLE 3

Aganglionic Bowel Segments in Patients with Hirschsprung's Disease

Adapted from Sherman JO, Snyder ME, Weitzman JJ, Jona JZ, Gillis DA, O'Donnell B, et al. A 40-year multinational retrospective study of 880 Swenson procedures. J Pediatr Surg 1989; 24:833-8.

Differential Diagnosis

Normal stooling patterns in neonates and children vary in frequency from three times a day to once a week. Constipation can be defined as intestinal dysfunction in which feces are difficult or painful to evacuate. Ninety percent of neonates pass meconium within the first 24 hours of life.

A thorough history and physical examination are important to differentiate Hirschsprung's disease from other causes of intestinal obstruction, constipation and delayed passage of meconium. In a review of 10 years' experience at Cook County Hospital, Chicago, it was found that the four most common causes of neonatal intestinal obstruction were intestinal atresia (35 percent), imperforate anus (28 percent), malrotation (27 percent) and Hirschsprung's disease (11 percent).(9) Table 4(10) presents a differential diagnosis of constipation in infants and children. Table 5 lists distinguishing features of Hirschsprung's disease and functional constipation.(4)

TABLE 4

Differential Diagnosis of Constipation

Dietary causes Excessive intake of cows' milk Lack of bulk in diet Undernutrition, dehydration

Drugs Magnesium sulfate Opiates Ganglion blockers

Structural defects Tracheoesophageal fistula Duodenal atresia/anal, rectal stenosis Small colon syndrome Intussusception Volvulus/malrotation Presacral teratoma Meconium plug Rectal prolapse

Smooth muscle disease Scleroderma Dermatomyositis Systemic lupus erythematosus

Absence of abdominal musculature

Abnormal mysenteric ganglion cells Dysganglionosis Hirschsprung's disease Chagas' disease von Recklinghausen's disease Multiple endocrine neoplasm type 28

Spinal cord defects Spina bifida occulta Myelomeningocele Meningocele Diastematomyelia Paraplegia Cauda equina tumor Sacral agenesis Cerebral palsy

Metabolic and endocrine disorders Hypothyroidism Hypoparathyroidism Renal tubular acidosis Diabetes insipidus Vitamin D intoxication Idiopathic hypercalcemia Hypokalemia

Infectious conditions Infant botulism Necrotizing enterocolitis

Neurologic and psychiatric conditions Myotonic dystrophy Amyotonia congenita Mental retardation Psychosis

Adapted from Oski F, ed. Principles and practice of pediatrics. Philadelphia: Lippincott, 1994:1845.

TABLE 5

Distinguishing Features of Hirschsprung's Disease and Functional

Constipation

Adapted from Behrman RE, Kliegman RM, Nelson WE, Vaughan VC III, eds.

Nelson Textbook of pediatrics. 14th ed. Philadelphia: Saunders, 1992:955.

Approach to Diagnosis

Early diagnosis of Hirschsprung's disease is essential, because curative therapy is available. Evaluation of an infant or child with constipation or intestinal obstruction may include abdominal radiography, barium enema, anorectal manometry and rectal biopsy. The approach to the diagnosis of Hirschsprung's disease depends, to some degree, on the severity of the illness and the particular presentation. The infant who presents with signs of acute intestinal obstruction requires a more aggressive approach to diagnosis than the child with chronic constipation.

Anteroposterior, lateral and upright abdominal radiographs may be nonspecific during the first few days of life and then may begin to show colonic distention with no air in the rectum. Barium enema is the initial screening procedure for assessing patients with symptoms of intestinal obstruction. Classically, barium enema in patients with Hirschsprung's disease reveals signs of a transitional zone in the colon, a sawtooth appearance of the sigmoid area and an elongated, dilated, right-sided sigmoid colon, accompanied by delayed (two to three days) evacuation of the barium.(8) Visualization of a transitional zone (from a narrow rectum to a dilated sigmoid colon) is a reliable sign of Hirschsprung's disease, especially when it is associated with any of the other findings; however, failure to visualize a transitional zone does not rule out Hirschsprung's disease.(11)(12)

Barium enema is less accurate in cases of total colonic aganglionosis or very-short-segment aganglionosis, in infants younger than one month of age or in patients who have had a colostomy.(8) The sensitivity and specificity of a barium enema vary with the degree of intestinal obstruction and age of the patient.(1) Overall, barium enema has a false-negative rate of 5 to 40 percent and a false-positive rate of up to 27 percent, depending on which combination of radiographic signs is present.(1)(11)(12)

In neonates and children without intestinal obstruction, other diagnostic procedures may be more helpful than barium enema in ruling out Hirschsprung's disease. Ultrasonography has been used to identify Hirschprung's disease in a child who presented with a milder form of the disease.(13)

Rectal sphincter manometry aids in the diagnosis of different causes of constipation. In the normally innervated bowel, stimulation of the rectum by stretching results in reflex relaxation of the internal sphincter.(14) However, in patients with Hirschsprung's disease, this reflex is absent. When used in screening circumstances, manometry has a sensitivity of 79 to 90 percent and a specificity of 97 to 100 percent.(14)(15)(16)(17) It serves as the least invasive screening test for infants and children with chronic constipation and has been shown to be more sensitive than barium enema in cases of short-segment aganglionosis.(14) Certain conditions, however, such as sepsis, hypothyroidism, rectal or colonic stenosis, meningocele, enterocolitis and neuronal intestinal dysplasia, may result in absence of recto-anal reflex in patients who do not have Hirschsprung's disease.(16)

Confirmation of the diagnosis of Hirschsprung's disease can be made with rectal biopsy. Rectal biopsy can be done as a partial-thickness (suction) or full-thickness biopsy. Partial-thickness biopsy is simple to perform and requires no anesthesia.(2) The disadvantage of partial-thickness biopsy is that, at best, the technique reaches the submucosal level; at this level, only the presence of Meissner's plexus can be evaluated.(18)

The absence of ganglionic plexus in the bowel wall is associated with thickened bundles of neural fibers.(19) This overgrowth results in an increased presence of acetylcholinesterase (AChE) in the bowel wall(19) (Figures 2a and 2b). When combined with staining for AChE, the sensitivity of partial-thickness biopsy approaches 99 percent.(20) The advantage of AChE staining is that samples with only mucosa and specimens from the anorectal region can provide diagnostically relevant information.(21) False-negative AChE results have been more frequent in biopsies of tissue proximal to the splenic flexure, at colostomy sites, in cases of total colonic aganglionosis, and in infants with ultra--short-segment Hirschsprung's disease.(21) Given the improved accuracy of partial-thickness biopsy, combined with the use of staining for AChE, a two-point biopsy technique has been recommended, taking rectal samples at 5 to 10 mm and at 30 to 50 mm proximal to the dentate line.(22) If the proximal sample shows Meissner's plexus, simple rectal myectomy is adequate treatment. Full-thickness biopsy, which requires general anesthesia, may be required for the precise diagnosis of other intestinal innervation disorders.(2)

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Treatment

Definitive treatment of Hirschsprung's disease is surgery (Figure 3). Swenson developed one of the first surgical procedures used to treat Hirschsprung's disease. His work led to the development of other techniques, most notably the Duhamels and Soave-Boley procedures.

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The Swenson procedure is the most commonly used, as well as the most extensively evaluated. This procedure involves resecting the aganglionic bowel, with reanastomosis of normally innervated intestine at the posterior pectinate line to an aganglionic rectal stump anteriorly.(8) Duhamels' procedure brings normally innervated colon to an end-to-side anastomosis with the rectum at the peritoneal reflexion.(8) The result is a rectum in which half of the circumference is aganglionic and half has normal innervation. The advantage of the Duhamels' procedure is that it requires less pelvic dissection than Swenson's procedure. The original Duhamels' technique has been modified to decrease the incidence of fecalomas, soiling and stenosis.

The Soave-Boley procedure involves dissection to normal colonic mucosa and a pull-through to attach it to the muscular cuff at the anal verge. The procedure avoids pelvic dissection, is relatively easy to perform and is associated with a low incidence of postoperative enterocolitis. Late complications of this procedure include stenosis, perineal fistula and residual-segment symptoms.

It is difficult to compare the results of these procedures and, thus, there is debate within the literature as to which procedure is indicated in a given situation. Variables that affect the outcome of surgery include the extent of aganglionosis, the clinical severity of the disease, the age at which the definitive operation is performed and the presence of enterocolitis, associated anomalies and retardation.(7)(23)(24) For example, children with Down syndrome can safely undergo definitive surgical treatment of Hirschsprung's disease, but their mortality rate is higher and they are at increased risk for developing anastomotic leaks.(7)

Delay in the treatment of Hirschsprung's disease can result in sepsis and death; however, definitive surgery in infants under three months in age is associated with higher complication rates.(24) Improved intensive care techniques and the increased certainty with which the diagnosis can be made have made preoperative medical management of the infant with Hirschsprung's disease a much safer option.(24) Decompression enemas can be used to relieve the obstruction, and parenteral nutrition and antibiotics can be used effectively to treat enterocolitis before surgery. However, enemas have an associated risk of perforation of the thin-walled dilated segment immediately proximal to the aganglionic bowel. Enemas should contain isotonic solutions, since the large colonic surface area results in an increased absorption rate. Other techniques are also being investigated as possible adjunctive treatments for Hirschsprung's disease.

Prognosis

Without recognition and treatment, Hirschsprung's disease has been estimated to carry a 50 percent mortality rate by one year of age.(8) With early diagnosis and appropriate treatment, the outcome is favorable. A review of more than 800 Swenson procedures performed throughout the world revealed that in 70 percent of the surgeries, patients had no early complications and in 61 percent, patients had no late complications.(7) Table 6(7) summarizes the types and frequency of early and late complications. This review demonstrated that the mortality rate was 2.4 percent, with a significant increase in patients with Down syndrome, in patients younger than four months of age and in patients who had postoperative bowel obstruction or an anastomotic leak. Only 0.8 percent of the patients required permanent ileostomy, 0.5 percent required permanent colostomy, and there were no reports of impotence or incontinence on long-term follow-up.

TABLE 6

Postoperative Complications in Patients with Hirschsprung's Disease

(*)--Total number of patients in study was 874.

([dagger])--Does not include 21 bowel obstructions occurring >30 days after the resection.

([double dagger])--Patients with Down syndrome or mental retardation excluded.

Adapted from Sherman JO, Snyder ME, Weitzman JJ, Jona JZ, Gillis DA, O'Donnell B, et al. A 40-year multinational retrospective study of 880 Swenson procedures. J Pediatr Surg 1989; 24:833-8.

REFERENCES

(1.)Swenson O, Sherman JO, Fisher JH. Diagnosis of congenital megacolon: an analysis of 501 patients. J Pediatr Surg 1973; 8:587-94.

(2.)Heitz PU, Komminoth P. Biopsy diagnosis of Hirschsprung's disease and related disorders. Curr Top Pathol 1990; 81:257-75.

(3.)Neilson IR, Yazbeck S. Ultrashort Hirschsprung's disease: myth or reality. J Pediatr Surg 1990; 25:1135-8.

(4.)Behrman RE, Vaughan VC 3d, Nelson WE, eds. Nelson Textbook of pediatrics. 13th ed. Philadelphia: Saunders, 1987.

(5.)Hamilton J, Bodurtha JN. Congenital central hypoventilation syndrome and Hirschsprung's disease in half sibs. J Med Genet 1989; 26:272-4.

(6.)Lipson AH, Harvey J. Three-generation transmission of Hirschsprung's disease. Clin Genet 1987; 32:175-8.

(7.)Sherman JO, Snyder ME, Weitzman JJ, Jona JZ, Gillis DA, O'Donnell B, et al. A 40-year multinational retrospective study of 880 Swenson procedures. J Pediatr Surg 1989; 24:833-8.

(8.)Sieber WK. Hirschsprung's disease. Curr Probl Surg 1978; 15:1-76.

(9.)Reyes HM, Meller JL, Loeff D. Neonatal intestinal obstruction. Clin Perinatol 1989; 16:85-96.

(10.)Oski F, ed. Principles and practice of pediatrics. Philadelphia: Lippincott. 1994:1684.

(11.)Rosenfield NS, Ablow RC, Markowitz RI, DiPietro M, Seashore JH, Touloukian RJ, et al. Hirschsprung disease: accuracy of the barium enema examination. Radiology 1984; 150:393-400.

(12.)Taxman TL, Yulish BS, Rothstein FC. How useful is the barium enema in the diagnosis of infantile Hirschsprung's disease? Am J Dis Child 1986; 140:881-4.

(13.)Oestreich AE. Ultrasound diagnosis of Hirschsprung's disease in the infant with distended abdomen. Radiology 1990; 30:19-20.

(14.)Aaronson I, Nixon HH. A clinical evaluation of anorectal pressure studies in the diagnosis of Hirschsprung's disease. Gut 1972; 13:138-46.

(15.)Tobon F, Schuster MM. Megacolon: special diagnostic and therapeutic features. Johns Hopkins Med J 1974; 135:91-105.

(16.)Yokoyama J, Kuroda T, Matsufugi H, Hirobe S, Hara S, Katsumata K. Problems in diagnosis of Hirschsprung's disease by anorectal manometry. Prog Pediatr Surg 1989; 24:49-58.

(17.)Low PS, Quak SH, Prabhakaran K, Joseph VT, Chiang GS, Aiyathurai EJ. Accuracy of anorectal manometry in the diagnosis of Hirschsprung's disease. J Pediatr Gastroenterol Nutr 1989; 9:342-6.

(18.)Blisard KS, Kleinman R. Hirschsprung's disease: a clinical and pathologic overview. Hum Pathol 1986; 17:1189-91.

(19.)Meier-Ruge W. Hirschsprung's disease: its aetiology, pathogenesis and differential diagnosis. Curr Top Pathol 1974; 59:131-79.

(20.)Ikawa H, Kim SH, Hendren WH, Donahoe PK. Acetylcholinesterase and manometry in the diagnosis of the constipated child. Arch Surg 1986; 121:435-8.

(21.)Schofield DE, Devine W, Yunis EJ. Acetylcholinesterase-stained suction rectal biopsies in the diagnosis of Hirschsprung's disease. J Pediatr Gastroenterol Nutr 1990; 11:221-8.

(22.)Ohi RJ, Tseng SW, Kamiyama T, Chiba T. Two-point rectal mucosal biopsy for selection of surgical treatment of Hirschsprung's disease. J Pediatr Surg 1990; 25:527-30.

(23.)Shermeta DW, Meller JL. Ideal treatment for total colonic Hirschsprung's disease. J Pediatr Surg 1989; 24:88-91.

(24.)Carcassonne M, Guys JM, Morrison-Lacombe G, Kreitmann B. Management of Hirschsprung's disease: curative surgery before 3 months of age. J Pediatr Surg 1989; 24:1032-4.

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