Visceral myopathy of the gastrointestinal and genitourinary tracts in infants

GASTROENTEROLOGY

1988;94:892-8

Visceral Myopathy of the Gastrointestinal and Genitourinary Tracts in Infants MICHAEL RICHARD

D. SCHUFFLER, ROBERTA A. PAGON, and ALEXANDER H. BILL SCHWARTZ,

Departments of Medicine and Surgery, Pacific Medical Center and Children’s Hospital and Medical Center; and the Departments of Medicine and Pediatrics, University of Washington School of Medicine, Seattle, Washington

We describe 4 infants who had chronic intestinal pseudoobstruction caused by visceral myopathy. Three of the 4 were girls. Two were symptomatic at birth and 2 were symptomatic by 3 wk of age. All had abdominal distention and emaciation, 3 of the 4 had severe obstipation and fecal impactions, and 3 had signs of urologic obstruction. All had gaseous distention of the small bowel and colon, and barium studies showed dilated small bowel and colon, with slow transport through the small intestine. Two of 3 had enlarged stomachs and slowed gastric emptying, and 3 had dilated bladders and ureters. The 1 infant studied by esophageal manometry had absence of esophageal contractions. Despite total pare&era1 nutrition in 3, all died within 10-18 mo. The pathologic features of visceral myopathy were identified in variable sample sites from the esophagus, stomach, small intestine, colon, bladder, and ureter of the 4 infants. Of 170 family members related to 3 of the infants, there was no consanguinity and no one appeared to be clinically affected. Thus, an infantile form of visceral myopathy exists which, pathologically, is identical to the familial and sporadic forms of visceral myopathy previously identified in adolescents and adults.

ence of associated problems, such as ptosis and ophthalmoplegia (5-13). The smooth muscle of the genitourinary system may be involved as well (14). The sporadic form of visceral myopathy also involves the gastrointestinal and genitourinary tracts, but differs from the familial form because of the absence of other affected family members. Both the familial and sporadic forms of visceral myopathy are characterized pathologically by vacuolar degeneration and fibrosis of smooth muscle (15). These abnormalities are distinguishable from the smooth muscle involvement of systemic diseases, such as progressive systemic sclerosis and progressive muscular dystrophy. Visceral myopathy usually becomes manifest in adolescence or early adulthood. Its occurrence in infancy is rare, having been reported only once, in association with the megacystismicrocolon-intestinal hypoperistalsis syndrome (16). The purpose of this paper is to report 4 infants who presented with intestinal pseudoobstruction caused by visceral myopathy. Involvement was so severe that they died between the ages of 10 and 18 mo.

Materials and Methods he syndrome of chronic idiopathic intestinal pseudoobstruction is caused by a variety of disorders of the smooth muscle or myenteric plexus (l-4). The primary disorders of smooth muscle, i.e., those not associated with systemic diseases such as progressive systemic sclerosis or muscular dystrophy, are referred to as “visceral myopathies,” whereas the degenerative disorders of the myenteric plexus are known as “visceral neuropathies.” Familial visceral myopathies are subdivided into five distinct syndromes based on the pattern of inheritance, the distribution and nature of involvement within the gastrointestinal tract, and the pres-

T

Three infants with visceral myopathy were treated on the surgical service of the Children’s Hospital and Medical Center in Seattle between 1972 and 1974. Despite extensive medical and surgical efforts, all 3 infants died of complications of their disease. Hospital records were searched, and a fourth infant was added from 19%. Because visceral myopathy was not described until 1977 (5), these 4 cases were recognized only in retrospect after a review of their histopathology in 1978. After recognition of the correct pathologic diagnosis, the infants’ hospital records, radiographic reports, and radio0 1988 by the American

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VISCERAL MYOPATHY IN INFANTS

graphs were reviewed, except for the radiographs of case 1, which no longer were available. One infant had had esophageal manometry. The parents of 3 of the infants were contacted, and detailed family histories were obtained and pedigrees constructed. The diagnosis of intestinal pseudoobstruction was based on a combination of clinical symptoms and signs, radiographic findings, and the results of surgical exploration and autopsy. All cases had evidence of intestinal dilatation without mechanical obstruction. The diagnosis of visceral myopathy was based on light microscopy utilizing hematoxylin and eosin and Masson’s trichrome stains of paraffin-embedded tissue. The pathologic features of visceral myopathy consist of vacuolar degeneration and fibrosis of one or both layers of the muscularis externa (15). No “wet” tissue was available for Smith’s method of staining the myenteric plexus with silver (17,18), a procedure not yet established in our laboratory at the time these patients were seen. Paraffin blocks of surgically obtained full-thickness biopsy specimens of small intestine or colon, or both, were available from each patient, as were paraffin blocks of tissue obtained at autopsy. New sections were cut and stained with hematoxylin and eosin and Masson’s trichrome and sections of the bladder and ureters were stained by Verhoeff’s method for elastic tissue. These sections were compared with sections of intestine obtained at autopsy from 10 infant controls. Not ali areas of the gastrointestinal and genitourinary systems of the 4 patients were sampled at autopsy, so that the exact areas of involvement and their distribution throughout the gut and urinary tract could not be assessed. However, there was sufficient tissue available from each patient to make a firm pathologic diagnosis. The studies of the infant controls were approved by the Human Subjects Review Committee of the University of

893

Washington on September 5, 1984, and by the Institutional Review Board of the Children’s Hospital and Medical Center on September 13, 1984.

Results Clinical

Manifestations

Table 1 summarizes the important clinical manifestations. All of the infants were born with normal birth weights after full-term pregnancies and uncomplicated deliveries. One of the pregnancies was complicated by polyhydramnios. Three of the 4 infants were girls. All had symptoms and signs consistent with gastrointestinal obstruction. Two infants were symptomatic at birth and the other 2 were symptomatic by 3 wk of age. All 4 infants had constipation, but 3 also had diarrhea at some time during their illnesses. The initial diagnostic’impressions were Hirschsprung’s disease in 3 of the 4 and urologic obstruction in the fourth. Three of the 4 infants developed obstipation and fecal impactions so resistant to treatment that a transverse loop colostomy was done in one, a subtotal colectomy in a second, and two separate sigmoidoscopies with removal of stool in the third. All 4 patients had abdominal distention and 3 of the 4 were emaciated at some time during their illnesses. Weights at admission varied from 4400 to 6860 g, an overestimate, as part of the weight was accounted for by large amounts of retained urine. Radiographic findings provided evidence consistent with intestinal pseudoobstruction (Table 2). Plain films showed excessive gas or gaseous distention and/or air-fluid levels throughout the small

Table 1. Patient Characteristics Case 1

Case 2

Age At onset of symptoms At presentation to CHMC At death Sex Weight at presentation Percentile weight for age Symptoms and signs Abdominal distention Vomiting Diarrhea” Constipation” Obstipation Failure to thrive Initial diagnosis

3 wk 3.5 mo 18 mo F 4.5 kg 6%

At birth 30 h 10 mo F 4.5 kg 95%

+ + + + + + Hirschsprung’s

+ + + + + + Hirschsprung’s

Pregnancy Duration Complications Birth weight

9 mo 3.3 kg

9 mo Polyhydramnios 4.9 kg

CHMC, the Children’s

Hospital and Medical Center. a Patients 1, 2, and 4 had predominance

Case 3 2 wk 8 mo 12 mo F 4.4 kg 5% + + _ + + Urologic obstruction 9 mo 3.5 kg of constipation,

Case 4 At birth 5 mo 10 mo M 6.9 kg 40% + + + + + + Hirschsprung’s

9 mo 4.0 kg with occasional

diarrhea.

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Table 2. Radiographic Findings

Plain

films

UGI/small series

Barium

bowel

enema

IVP/cystogram

IVP, intravenous

Air and stool throughout small bowel and colon; marked distention of small bowel. Not done

Normal, but excessive stool present.

Not done

pyelogram;

UGI, upper

Case 3

Case 2

Case 1

Case 4

Air-fluid levels; gas and fluid distention of small bowel and colon.

Gas and fluid distention of stomach and small bowel.

Air-fluid levels; gas and fluid distention of small bowel and colon.

Enlarged stomach with slow gastric emptying. Very active motility in normal-sized duodenum and proximal jejunum. Rest of small bowel dilated, with slow emptying (barium not in colon by sixth day). Redundant and ahaustral, with stool-filled descending colon.

Enlarged stomach with very slow emptying (barium still in stomach at fourth day). Dilated duodenum and jejunum with slow emptying into cecum.

Normal-sized esophagus, stomach, and proximal small bowel. Markedly dilated distal small bowel.

Normal

Markedly enlarged bladder with no reflux. Dilated, tortuous ureters and markedly dilated pelves and calyces.

Markedly enlarged bladder. Mild dilatation and tortuosity of both ureters; slight reflux bilaterally.

Dilated, redundant, and ahaustral; did not pass barium for 14 days and needed two disimpactions. Markedly enlarged bladder; slightly dilated pelvices and slightly dilated right ureter.

gastrointestinal

study.

bowel and colon of 3 infants and within the stomach and small bowel of the fourth. Barium studies of the stomach and small bowel in 3 patients showed an enlarged, slowly emptying stomach in 2 and dilatation of the small bowel in all 3. The dilatation was located in the distal jejunum and ileum in 2 patients and in the duodenum and jejunum in the third. Transport of barium through the small intestine was slow. Barium enemas were normal in 2 and showed dilated, redundant, ahaustral colons in 2. One of the latter 2 patients (case 4) did not pass any barium for 14 days and required two disimpactions by sigmoidoscopy. Three patients had intravenous pyelograms and cystograms and all had megacystis and variable amounts of dilatation of one or both ureters. Two had enlargement of the renal pelves. One infant (case 2) had esophageal manometry, revealing absence of contractions after swallows. Rectal biopsy specimens in the 3 patients thought to have Hirschsprung’s disease revealed normal numbers of neurons in all. Because mechanical bowel obstruction or Hirschsprung’s disease was suspected, all 4 infants had exploratory laparotomies. The operative findings and procedures are summarized in Table 3. During the course of their illnesses, 3 of the infants each had three operations, whereas the fourth had a single operation. At surgery, 3 of the infants had markedly dilated colons and bladders and 2 had enlarged ureters. A variety of surgical procedures, including

colostomy, cecostomy, gastrostomy, Noble plication, and lysis of adhesions, were done in an attempt to either decompress or remove nonfunctioning bowel. Table 3. Operative Findings and Procedures Case No. 1

Operation No. 1

2

3 2

1 2

3

3

1 2

4

3 1

Description Transverse loop colostomy for fecal impaction. Reexplored for suspected mechanical obstruction, with none found. Bowel distended proximally and collapsed distally, but with no point of mechanical obstruction. Noble plication and enterolysis for multiple small bowel adhesions. Bilateral Hynes-Anderson pyeloplasties and ureteral biopsies. Proximal colectomy and terminal ileostomy for obstipation and volvulus of ascending and transverse colons. Atonic. markedly dilated colon. Partial cystectomy and Y-V plasty of bladder neck for continuing bladder dilatation and recurrent infections. Exploratory laparotomy: grossly distended colon, megacystis, and megaloureters. Exploratory laparotomy: small bowel and coionic dilatation interpreted as “Hirschsprung’s disease.” Cecostomy done. Cecostomy closed; appendectomy. Exploratory laparotomy. Markedly dilated colon and bladder. Small bowel normal. Double-barreled transverse colostomy, gastrostomy, and appendectomy done.

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Table

4. Pathologic

VISCERAL

Family

Involvement Number of sites examined

Esophagus Stomach Small bowel Colon Bladder Ureter

Number

abnormal

2 3 3 4 1

1 3 2 4 1

1

1

One of the patients had a subtotal colectomy. This patient also had bilateral Hynes-Anderson pyeloplasties and partial cystectomy and Y-V plasty of the bladder neck to treat continuing bladder dilatation and recurrent urinary tract infections. None of the operative procedures relieved the symptoms and signs of intestinal obstruction. A variety of medications were unsuccessful in producing effective intestinal propulsion. These included reserpine in 2 infants, phentolamine in 1, prostigmine in 2, and urecholine, methylprednisolone, azathioprine, and metoclopramide in 1. Three of the 4 patients were placed on total parenteral nutrition in the hospital; 2 of them developed sepsis presumed to be secondary to the intravenous catheter, Despite total parenteral nutrition, all patients followed a steady, downhill course. The causes of death included wound infection and malnutrition in case 1; enterocolitis and sepsis in case 2; necrotizing enterocolitis with small bowel perforations and peritonitis in case 3; and malnutrition in case 4. The ages at death ranged from 10 to 18 mo.

Table

5. Pathologic

Colon CM LM Bladder Ureter

IN INFANTS

895

Pedigrees

Family histories were obtained from the parents in cases 2-4. Information on chronic gastrointestinal or urinary problems, and more specifically on dysphagia, vomiting, abdominal pain, abdominal distention, constipation, urinary retention, and urinary tract infections was obtained. The parents of patient 4 underwent esophageal manometry to determine if peristaltic abnormalities were present, which might be a more sensitive means of identifying mildly affected individuals (19). Both had normal esophageal motility. The mother of this infant also had a normal upper gastrointestinal study and small bowel follow-through, done by her personal physician for vague gastrointestinal symptoms. Information on a total of 106 individuals in four generations of the family in case 2, 16 individuals in three generations of the family in case 3, and 48 individuals in four generations of the family in case 4 was obtained, and no one appeared to be affected. There was no consanguinity or fetal wastage in any of the families. Pathology The pathologic findings are summarized in Tables 4 and 5. The ages at which the surgical specimens were obtained varied from 1 to 11 mo. In no case had visceral myopathy been recognized in the original hospital pathology reports of the surgical and autopsy specimens. In contrast, our review of newly cut and stained sections revealed findings of visceral myopathy in all 4 infants. This diagnosis was apparent in the specimens from 3 patients

Findings Case

Esophagus” CM LM Stomach CM LM Small bowel” CM LM

MYOPATHY

1

_b

Case 2

Case 3 31

N N

N 4’ VD l+ Fibrosis

1+ VD; 0 Fibrosis 3+ VD; It Fibrosis

V,,“,d

l+ Fibrosis 3+ VW 2+ Fibrosis

2+ VD’ 2+ Fibrosis (#II N 4+ VD l+ Fibrosis

Case 4

(#2) 3+ VD’

N N

N 3+ VD; l+ Fibrosis 2+ VD: 0 Fibrosis N

0 Fibrosis 3+ VD; l+ Fibrosis I+ VD; I+ Fibrosis

N 3+ VD; 1+ Fibrosis

4+ VD; 4+ Fibrosis 2+ VD 3+ Fibrosis

b No tissue available. ” Both muscle layers ’ CM, circular muscle; LM, longitudinal muscle; N, normal; VD, vacuolar degeneration. d l+ = 25% of the muscle layer on the section involved with vacuolar degeneration or fibrosis: 2+ = 25%-50%; equally involved. e Two samples available from patient 2. 50%75%; 4+ = 75%100%.

about 3+ =

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obtained at surgery and from all 4 at autopsy. A full-thickness rectal biopsy specimen obtained from patient 3 had subtle changes of vacuolar degeneration of the circular muscle that easily could have been overlooked. In contrast, the autopsy tissue from this case had obvious features of visceral myopathy. The pathologic features of visceral myopathy were present in all areas of the gastrointestinal tract sampled and in the bladder and ureter of the 1 patient in which this tissue was available (Figures 1 and 2).

Figure

Figure

1. A. Ureter from patient 2. The wall of the ureter is replaced extensively by collagen, with only a small amount of smooth muscle left in this particular area (arrows). The mucosa is not well visualized secondary to traumatic artifacts. Masson’s trichrome, x80. B. Bladder from patient 2. There is prominent vacuolar degeneration and fibrosis of the smooth muscle. Masson’s trichrome, x320.

2. A. Esophagus from patient 3 showing extensive vacuolar degeneration of the longitudinal muscle. Neurons are visible within the myenteric plexus just above this muscle. B. Small intestine from patient 2 showing marked vacuolar degeneration of the longitudinal muscle and normal circular muscle. Neurons are visible within the myenteric plexus between the two muscle layers. A, B: Masson’s trichrome, ~32.0.

These features consisted of vacuolar degeneration (degeneration and dropout of smooth muscle cells producing a vacuolated appearance of the smooth muscle) and variable amounts of fibrosis. Usually, there was a greater amount of vacuolar degeneration than fibrosis except in the bladder and ureters, which had extensive fibrosis. However, there was no increase of elastic tissue in the bladder or ureters. Twelve of 14 sites examined had features of visceral myopathy. None of the 10 controls had any abnormalities of the smooth muscle other than the expected amount of postmortem autolysis.

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Discussion We have demonstrated that visceral myopathy occurs in infants and produces the syndrome of chronic intestinal pseudoobstruction. Because our infants’ clinical symptoms had their onset at or near birth, it is likely that the smooth muscle degeneration began in utero. Despite the fact that chronic intestinal pseudoobstruction has been reported in infants and children (7,20-27), visceral myopathy has been reported only once before as its cause (16). This occurred in 2 infants presenting with the megacystis-microcolon-intestinal hypoperistalsis syndrome, which may be a variant of intestinal pseudoobstruction in which the colon is small rather than enlarged. However, this report did not include illustrations of the histopathology by light microscopy. The cause is unknown, but could be infectious, toxic, metabolic, or genetic. We were unable to find evidence for genetic transmission. However, our findings do not exclude the possibility of autosomal recessive inheritance. The information obtained from the parents was retrospective and limited by their ability to obtain historical information from family members. Unfortunately, we had to be content with a retrospective study, because these infants were recognized as having visceral myopathy only in retrospect. Both symptomatic and asymptomatic family members of future patients could be evaluated by barium contrast studies and esophageal manometry in an attempt to document the presence of the disorder. Abnormalities can be present in the absence of symptoms (5,6). It is of interest that 3 of these cases “clustered” at the Children’s Hospital and Medical Center between 1972 and 1974. They came, however, from widely separated areas, with 1 patient from Seattle, 1 from Olympia, Washington (60 miles from Seattle), and 1 from Montana. This must be a rare illness, because no cases of visceral myopathy have been brought to our attention from among the patients seen at the Children’s Hospital and Medical Center since 1975, although we have evaluated tissue from 4 infants with pseudoobstruction hospitalized at the Children’s Hospital and Medical Center since 1975 who have had abnormalities of the myenteric plexus (unpublished data). Thus, chronic intestinal pseudoobstruction in infants is rare, and etiologically heterogeneous, with visceral myopathy being but one cause. The absence of effective smooth muscle contractions within the gastrointestinal tract was documented manometrically in one of our cases, and visualized radiographically in the cases that had prolonged retention of barium in the stomach, small intestine, and colon. In addition, the urinary tract

VISCERALMYOPATHYININFANTS

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may also be markedly dilated because of smooth muscle degeneration and fibrosis of the bladder and ureteral walls. Either gastrointestinal symptoms or urinary tract involvement may be the reason for original presentation to the physician. The initial working diagnosis in all our cases was incorrectly thought to be Hirschsprung’s disease. Although these patients may have prominent coionic dilatation, the finding of dilatation elsewhere in the gastrointestinal tract, as well as in the genitourinary tract, should immediately raise the possibility of chronic intestinal pseudoobstruction (2). Esophageal aperistalsis is further evidence for this diagnosis. Rectal biopsy easily rules out Hirschsprung’s disease, because patients with visceral myopathy have normal numbers of neurons within the submucosa. Visceral myopathy was not diagnosed on the initial histologic examination of tissue from our patients; at that time visceral myopathy had not yet been described. Since 1974, this disorder has become a recognized entity, and it is unlikely that it would be overlooked today. A diagnosis of chronic intestinal pseudoobstruction in infancy carries a grave prognosis and treatment requires a long-term commitment to home parenteral nutrition. Therefore, accurate diagnosis is mandatory, and exploratory laparotomy is usually required to rule out unequivocally congenital abnormalities producing mechanical obstruction. If no mechanical obstruction is found and the surgeon encounters distended, abnormally contracting bowel, one or more full-thickness samples of intestine should be excised to establish an accurate pathologic diagnosis. Although a conventional full-thickness biopsy specimen is usually sufficient to diagnose visceral myopathy, we favor a limited resection of one or more areas of intestine in order to provide a large enough sample to diagnose a disorder of the myenteric plexus. Although there is some increased risk associated with this recommendation, a large sample (measuring at least 1.5 x 1.5 cm along the smooth muscle of the opened specimen) is required to adequately visualize the myenteric plexus by Smith’s technique, the best method currently available for diagnosing abnormalities of the myenteric plexus (17,18).In fact, maturational abnormalities of the myenteric plexus are more common causes of chronic intestinal pseudoobstruction in infancy than visceral myopathy (unpublished data), so that maturational arrest should be sought whenever tissue is removed for diagnosis. Thus, chronic intestinal pseudoobstruction in infants is suspected on the basis of radiography and motility studies, and is confirmed at laparotomy,

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with a tissue diagnosis of a muscle or neural abnormality made by light microscopy. In conclusion, we report an infantile form of visceral myopathy that is pathologically identical to the visceral myopathy of adolescents and adults, but which is more severe, with earlier onset and fatal outcome. The etiology is unknown. The possibility of genetic transmission is neither established nor excluded.

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Received January 23, 1987. Accepted October 26, 1987. Address requests for reprints to: Michael D. Schuffler. M.D.. Pacific Medical Center, 1200 12th Avenue South, Seattle, Washington 98144. Dr. Bill’s current address is: Route 1. Box 1426, Lopez, Washington 98261. This study was supported by grant AM28180 from the National Institutes of Health. The authors thank Zoe Jonak for technical assistance and Bernita A. McKinion and Alice Joseph for typing the manuscript.