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Familial visceral myopathy: The role of surgery
Familial Visceral Myopathy: The Role of Surgery Anthony Shaw, MD, Duarte, California Hubert A. Shaffer, MD, Charlottesville,
Virginia
Slnn Apuras, MD, Iowa City, Iowa
Chronic intestinal pseudoobstruction includes a diverse group of disorders in which there are recurrent or persistent symptoms and signs of intestinal obstruction in the absence of an actual lesion obstructing the intestinal lumen. In 1970, Maldonado et al [1] reported five cases of chronic intestinal pseudoobstruction with striking clinical and radiographic similarities and no apparent cause, which they named chronic idiopathic intestinal pseudoobstruction. Reports of similar cases tended to confirm chronic idiopathic intestinal pseudoobstruction as a motility disorder, frequently familial, in which the entire alimentary tract might be involved, with usual onset in early adolescence or young adulthood. Recent histologic studies have identified either myopathic or neuropathic lesions in resected intestinal specimens of patients with chronic idiopathic intestinal pseudoobstruction, which permit a crude subdivision of the disease into two symptomatically similar but etiologically dissimilar subgroups [2-41. In 1979, two of us (AS and HAS), with colleagues at the University of Virginia [5], described a large family in which chronic.idiopathic intestinal pseudoobstruction was identified in members of at least four generations. The finding of fibrosis in the resected bowels of two family members allowed acctirate pathologic diagnosis of the disorder as familial visceral myopathy [3]. Because familial visceral myopathy has been characterized only recently, and only a few patients have been diagnosed and followed medically, there is still much to be letied. The purpose of this report is to present what we have learned from an 8 year From ttie Department of Pediatric Surgery, City of Hope National Medical Center, Dwte, Callfomia. the oepatanent of Radiology,Unbrsity of Virginia Medical Center, Charlottesville, Virginia, and the Deljartment of Medicine. University of Iowa Hospitals and Clinics, Iowa City, Iowa. Requests for reprints should be addressed to Anthony Shaw, MD, Department of Pediatric Surgery, City of Hope f4ational Medical Center, 1500 East Duarle Road, Duarte, California 91010. Presented at the 56th Annual Meeting of the Pacific Coast Surgical Assoclatlon. kbnterey, California, February 17-20, 1985.
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follow-up of six living family members with familial visceral myopathy, four of whom have had intestinal bypass or resection, with respect to natural history, pathologic characteristics, heredity, and response to treatment, especially surgery.
Case Reports Patient 1. Original propositus, age 23 years. Since age 13, she experienced bloating and abdominal pain after meals, nocturnal heartburn, and constipation. At age 14,
biweekly severe crampy abdominal pain and bilious vomiting required hospitalization five times for decompression and intravenous hydration. Barium studies showed dysmotility throughout the alimentary tract, sparing only the stomach, with marked redundancy and dilatation of the le$fJside pf the colon, which was considered the probable cause of her dominant symptoms and so was resected. Histologic examination revealed fibrosis of the outer muscle layers (Figures 1 through 3) [5]. Over a 2 year period, severe constipation often alternating with diarrhea recurred, along with worsening dysphagia. Increasingly frequent and severe attacks of abdominal pain associated with bloating and vomiting that became worse during menses were usually relieved by passage of gas and stool but required hospitalization twice. The patient’s appetite has remained good, her weight has not changed, and her abdomen has remained flat, without palpable masses or dilated bowel. Plain films showed a dilated stool fiied colon. On barium swallow, her esophagus was mildly dilated and aperistaltic, emptied only in the upright position, and was without evidence of stricture, hiatal hernia, or gastroesophageal reflux. The stomach was normal in size and emptied promptly. The duodenum was markedly distended to a diameter of 9.5 cm (Figure l), showed no peristaltic activity, and emptied easily only when the patient was on her left side. Barium was present in the dilated duodenum 7 hours later. There was segmental dilatation of jejunum with a marked delay in small intestinal transit time. The cecum was still not reached after 7 hours. Patient 2. Sister of Patient 1, age 25 years. Bloating, vomiting and hematemesis at age 12 led Patient 2 to duodenojejunostomy for what was diagnosed as superior mesenteric artery syndrome, with minimal postoperative
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Figure 1. Patlent 1. Recent barium study shows a dilated flaccid duodenum (d). The vertical band-like defect (arrowheads) is produced by the aortic impress/on.
improvement (Figure 2). Barium swallow at age 17 demonstrated an aperistaltic esophagus and a hypotonic dilated duodenum and was complicated by colonic impaction of barium (Figure 3). A successful pregnancy was complicated by severe bloating, vomiting, and constipation. In mid1984, the patient underwent emergency transverse colostomy for colonic obstruction which was followed 3 months later by a subtotal colectomy with preservation of the cecum. Histopathologic study showed cellular atrophy and increased fibrosis of the circular muscle layer (Figure 4), which were findings similar to those previously reported for her sister 151.At the most recent follow-up, she had one to five loose bowel movements per day and takes no medication. Patient 3. Mother of Patients 1 and 2, age 43 years. Although she has never had any gastrointestinal symptoms, barium study showed generalized alimentary dysmotility with prolonged retention of barium in a greatly dilated, hypotonic duodenum. On most recent follow-up, Patient 3 has remained asymptomatic and her barium swallow is essentially unchanged from her previous examination. Patient 4. Grandmother of Patients 1 and 2, age 58 years. Bloating and constipation have been present since early adolescence. She was operated on for what was diagnosed as duodenal obstruction at age 35, but no obstruction was found. A duodenojejunostomy provided no postoperative improvement. Previous barium studies showed an aperistaltic esophagus, normal stomach, and a dilated duodenum with slightly delayed small intestinal transit. On follow-up, constipation (sometimes lasting 7 to 10 days) and bloating have remained her most serious problems. Long-standing symptoms of dysphagia, nocturnal regurgitation, and abdominal pain remained essentially unchanged. A recent barium swallow revealed an aperistaltic esophagus, marked dilatation of the duodenum
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Figure 2. Patlent 2, age 12 years. Barium study before duodenojejunostomy demonstrates a patulous proximal duodenum.
which emptied through both normal and anastomotic pathways, and mild segmental dilatation of the small bowel with delayed transit time. Patient 5. Brother of Patient 4, age 64 years. He has had bloating and stomach growling most of his life, but has passed three to four stools daily and has never been constipated. A cholecystectomy was performed for symptomatic gallstones at age 33 years. Previous barium swallow studies showed an aperistaltic esophagus, a dilated duodenum, and delayed small bowel transit. The patient has denied serious gastrointestinal symptoms currently and declined follow-up barium studies because of severe difficulty in expelling barium 6 years ago. Patient 6. Sister of Patient 4, age 61 years. Bloating, nocturnal heartburn, and severe constipation have been present since late childhood. Cholecystectomy was performed for symptomatic gallstones at age 51. She underwent two unsuccessful operations for severe rectal prolapse. Previous studies showed dysmotility of the esophagus, the duodenum, and the small bowel, with prolonged duodenal retention of barium. On follow-up, her chief complaints have been continuing rectal prolapse and obstipation. On physical examination, she had a reducible rectal prolapse over 12 inches in length. Results of a recent barium swallow and follow-through were essentially unchanged from her previous examination 8 years earlier.
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Flgure 3. Pafieni 2, age 17 years. Abdominal radkqraph several days alter small bowel examination shows barkrm lmpacllon In the colon and volvulus of the splenlc flexure.
Comments Approximately 6 families with familial visceral myopathy have been identified with certainty on clinical, radiographic, and pathologic grounds since this disorder associated with smooth muscle fibrosis was described in the late 1970s. However, clinical reports can be found as far back as 1938 of familial and sporadic cases of chronic pseudoobstruction that are clinically and radiographically indistinguishable from recently diagnosed cases of familial visceral myopathy [6]. The family members described herein collectively exhibited the entire spectrum of symptoms of disordered alimentary tract motility seen in familial visceral myopathy, including dysphagia, heartburn, bloating, postprandial abdominal pain, vomiting, constipation, and diarrhea. As in other reported kindred, symptoms appeared in the second decade of life and persisted or recurred with varying intensity and chronicity [7]. Within the family described, Patient 3 was asymptomatic, Patient 5 had mild symptoms, symptoms in Patients 4 and 6 were intermediate in severity, and Patients 1 and 2 had severe chronic disease with recurring attacks of dis-
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Figure 4. LongHucllnal secilon of colon with markedly decreased numbers of smooth muscle cells and increased flbrosls ot the circular muscle layer. ( Trichrome stain; magnification X 27, reduced by 32 percent. )
abling and even life-threatening symptoms that required parenteral nutritional support. Constipation was the dominant symptom. Severe attacks requiring repeated hospitalization in Patients 1 and 2, as well as the refractory rectal prolapse in Patient 6, appeared to be due primarily to colonic stasis. Although the basic motility disorder is due to atrophy and fibrosis of the visceral smooth muscle, variations of symptoms have resulted from alterations in the population of enteric gas-forming bacteria, from changes of diet and activity, and probably from hormonal changes related to the menstrual cycle or to pregnancy. Most patients with familial visceral myopathy, including those in our series, favor a bland diet free from spicy foods, citrus fruits, and such gas-producing foods as onions, beans, broccoli, carbonated drinks, and beer. Although a dilated lower urinary tract (megacystis) has been reported in patients with familial visceral myopathy who had symptoms of urinary retention, no one in our family group had evidence of urinary disease. The radiographic findings in patients with familial visceral myopathy are remarkably similar and have been well summarized in recent articles [7,8]. Dy-
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namic studies of each of our patients demonstrated most or all of the following radiographic findings. Dysmotility of most of the alimentary tract, most consistently in the eosphagus, duodenum, and colon, is seen. The esophagus is aperistaltic, normal in caliber or mildly dilated, and empties by gravity or by displacement from above. Gastric motility and emptying are normal. The duodenum is flaccid and dilated with lengthy barium retention-as long as 19 days in one reported case [2]. The small intestine is usually of normal caliber or slightly dilated but may show areas of more severe (usually segmental) dilatation. Transit time is usually delayed, and the colon is usually dilated, hypoperistaltic, and redundant. Expulsion of barium may be very difficult, as it was for all of our patients, including Patient 3. Radiologists must weigh the benefits of barium as a contrast agent when studying patients with pseudoobstruction against the risk of colonic obstruction. Recent studies by Mitros and colleagues [9] from the Universities of Iowa, Washington, and Virginia have shown that familial visceral myopathy was the most common cause of chronic primary (idiopathic) intestinal pseudoobstruction. The lesion, as described by these investigators, characteristically involved muscle cell degeneration, muscle cell loss, and fibrosis of the external layer of smooth muscle, conditions which were seen in Patients 1 and 2 in our series. Such lesions may be difficult to distinguish from those seen in progressive systemic sclerosis; however, familial visceral myopathy and progressive systemic sclerosis can usually be distinguished on clinical grounds. Fibrosis of the smooth muscle of the bladder may also be seen in patients with familial visceral myopathy, producing urinary retention, reflux, and upper tract damage. Mitros et al [9] emphasized the importance of adequate tissue sampling, since the fibrosis may be unevenly distributed, and the use of trichrome stain and electron microscopy in detecting the smooth muscle fibrosis. At the same time that histopathologic studies have identified visceral myopathies as a distinct subgroup of chronic idiopathic intestinal pseudoobstruction, a second and more heterogenous subgroup, the visceral neuropathies, have been distinguished. Using Smith’s silver staining technique, Schuffler et al [4] identified a range of degenerative changes in the myenteric plexus of some patients with chronic idiopathic intestinal pseudoobstruction, as well as some with obstipation alone, which would have been missed by conventional staining techniques. The intestinal smooth muscle has appeared normal in all patients with visceral neuropathy studied thus far. Of nine families with familial visceral myopathy, including the family in this report, whose pedigrees were recently reviewed by Anuras et al [IO], the disease appears to be transmitted by a dominant (autosomal or sex-linked) gene in seven families and by an autosomal recessive gene in two. This information
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suggests that members of identified kindred with familial visceral myopathy could benefit from genetic counseling. Although some patients with familial visceral myopathy have such unremitting symptoms that parenteral nutrition may be required to prevent inanition, most have learned to live with their disease with symptomatic treatment, such as nonfiber laxatives, enemas and antacids, and avoidance of bedtime snacks and gas-forming or constipating foods. For patients with moderate food intolerance and worsening nutritional status, Schuffler et al [If] have reported some success with a low-fat, low-fiber, low-lactose diet, which provides 1,800 to 2,400calories per day supplemented with a liquid formula [2 11. The intermittent use of antibiotics, such as tetracycline and metronidazole, may reduce symptoms of intestinal distention by controlling growth of gastrointestinal flora [8]. Of our patients, only Patient 1 took tetracycline, but for too short a time to evaluate its effectiveness. Although cholinergic drugs have not provided clear improvement in any form of chronic idiopathic intestinal pseudoobstruction [8], Patient 1 has been taking 15 mg of oral neostigmine 3 times a day because neostigmine was observed to stimulate intestinal peristalsis during her fluoroscopic examination. When she has become severely constipated, she has increased the dose to 15 mg every 3 to 4 hours despite unpleasant systemic side effects until she starts to pass gas and liquid stool. Patient 2 took neostigmine for a time but discontinued it because of a toxic reaction to the drug. Surgical treatment of familial visceral myopathy should be reserved for those patients incapacitated by symptoms refractory to dietary and medical management. When the duodenum or colon has been identified clinically and radiographically as the likely source of the most incapacitating symptoms in familial visceral myopathy, operations designed to relieve duodenal or colonic stasis have benefited carefully selected patients. Duodenojejunostomy has been the operation most commonly performed for symptoms attributable to the megaduodenum, often incorrectly diagnosed preoperatively as superior mesenteric artery syndrome. When duodenojejunostomy fails to relieve bloating, abdominal pain, and vomiting, this may be because of either dysmotility of the small bowel or obstruction at a poorly constructed anastomosis. A recent barium study of Patient 4 showed duodenal dilatation and stasis despite outflow through both the normal route and the duodenojejunostomy. A partial duodenectomy may provide better drainage than duodenojejunostomy alone [12]. Several patients who experienced little or only transient relief from side-to-side duodenojejunostomy had considerable improvement when a large portion of the anterior wall of the dilated duodenum was subsequently resected. Unfortunately, the fol-
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low-ups have been short in many reported cases; therefore, it is not known whether the early good results of some duodenojejunostomies have been sustained [12]. The few reported attempts to relieve upper intestinal symptoms by gastrojejunostomy have proved ineffective, with high morbidity and mortality rates [12,13]. Deaths have resulted from intraoperative peritoneal contamination by duodenal contents containing coliform bacteria in concentrations as high as lOls/ml [13]. Therefore, duodenal drainage procedures should be preceded by nasoduodenal drainage, intravenous nutritional support in malnourished patients, and antibiotic prophylaxis. Patients with symptoms primarily due to severe dysmotility of the small bowel are not likely to benefit from resective procedures unless relatively short segments are involved. When the colon has been the major source of symptoms, resection of elongated, dilated, and redundant colon may be beneficial. Anything less than subtotal colectomy may be insufficient. Although Patient 1 seemed to benefit initially from partial colectomy, as previously reported, her most severe symptoms, which are still likely related to colonic stasis, recurred. Because of these observations, we recommended that her sister, Patient 2, undergo resection of most of the colon after emergency colostomy. Patient 6’s rectal prolapse, refractory thus far to segmental resection and suspensory procedures, would probably benefit from a subtotal colectomy to relieve her obstipation, as well as reduce the likelihood of recurrent prolapse. Most patients with visceral neuropathy do not have megaduodenum but do have a more generalized, nonsegmental distribution of the motility disorder through the alimentary tract [8]. However, Krishnamurthy et al [14] have recently described a group of young women who underwent subtotal colectomy for intractable obstipation and were found to have a colonic neuropathy as revealed by Smith’s silver stain technique which suggests that patients with this form of visceral neuropathy may benefit from a resective procedure. Surgeons who begin an abdominal procedure expecting to find acute mechanical obstruction and instead find dilated and redundant bowel should consider the possibility of a visceral myopathy or neuropathy. Suspicion should increase if the patient has had previous negative laparotomies for intestinal obstruction, chronic or recurring gastrointestinal complaints, a large urinary bladder and retention, or if relatives also have had multiple alimentary tract symptoms. Full-thickness biopsy specimens should be taken from the duodenum, jejunum, and colon, and they should be examined with electron microscopy, trichrome stain, and Smith’s silver stain. However, the surgeon must weigh the risk of peritoneal soiling in such cases against the benefit of possibly obtaining opsy.
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a diagnosis
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When a diagnosis of visceral myopathy has been made in a patient with seemingly sporadic symptoms, investigation of the family, particularly one with chronic, baffling symptoms, may result in a diagnosis of familial visceral myopathy. An appropriate management plan for symptomatic relatives may then be devised. Summary Familial visceral myopathy is a form of chronic intestinal pseudoobstruction in which fibrosis of the smooth muscle of the alimentary tract causes protean symptoms of disordered visceral motility. Based on our 8 year observation of six members of one family with familial visceral myopathy and review of the few well-documented case reports of this disease, we have confiied a role for surgeons in tissue diagnosis, case identification, and palliation of incapacitating symptoms of familial visceral myopathy after obtaining dynamic radiographic assessment of the entire alimentary canal. Because the duodenum and colon are the usual sources of major dysmotility symptoms, patients incapacitated by duodenal or colonic pseudoobstruction may benefit from bypass or resective operations. Acknowledgment: We thank Drs. Lowell Secrist, Jonathan L. Shurherg, Robert K. Heide, and Walter Nickin for their help and cooperation and Dr. Frank A. Mitros, Department of Pathology, University of Iowa, for his interpretation of the histopathologic findings in Patient 2.
References 1. Maldonado JE, Gregg JA, Green PA, Brown AL. Chronic idiopathic intestinal pseudoobstruction. Am J Med 1970;49: 203-13. 2. Schuffler MD, Lowe MC, Bill AH. Studies of idiopathic intestinal pseudoobstruction. I. Hereditary hollow visceral myopathy: clinical and pathological studies. Gastroenterology 1977; 73:327-38. 3. Faulk DL, Anuras S, Gardner GD, Mitros FA, Summers RW, Christensen J. A familial visceral myopathy. Ann Intern Med 1978;89:800-6. 4. Schuffler MD, Jonak Z. Chronic idiopathic intestinal pseudoobstruction caused by a degenerative disorder of the myenteric plexus: the use of Smith’s method to define the neuropathology. Gastroenterology 1982;82:478-86. 5. Shaw A, Shaffer H, Teja K, Kelly T, Grogan E, Bruni C. A perspective for pediatric surgeons: chronic idiopathic intestinal pseudoobstruction. J Pediatr Surg 1979;14:719-27. 8. Weiss W. Zur aetiologie des megaduodenums. Dtsch Z Chir 1938;251:317-30. 7. Anuras S, Shaw A, Christensen J. The familial syndromes of intestinal pseudoobstruction. Am J Hum Genet 1981;33: 584-91. 8. S&ruffler MD. Chronic intestinal pseudoobstruction syndromes. Med Clin North Am 1981;65:1331-58. 9. Mllos FA, S&ruffler MD, Teja K, Anuras S. Pathologic features of familial visceral myopathy. Hum Pathol 1982;13:82533. 10. Anuras S, Mitros FA, Nowak TV, et al. A familial visceral myopathy with external ophthalmoplegia and autosomal recessive transmission. Gastroenterology 1983;84:346-53. 11. Schuffler MD, Rohrmann CA, Chaffee RG, Brand DL, Delaney
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JH, Young JH. Chronic intestinal pseudoobstruction: a report of twenty-seven cases and review of the literatue. Medicine (Baltimore) 1981;60:173-96. 12. Schuffler MD, Deitch EA. Chronic idiopathic intestinal pseudoobstruction: a surgical approach. Ann Surg 1980:192: 752-6 1. 13. Anuras S, Shirazi S, Faulk DL, Gardner GD, Christensen J. Surgical treatment in familial visceral myopathy. Ann Surg 1979;189:306-10. 14. Krishnamurthy S, Schuffler MD, Rohrmann CA, Pope CE Il. Severe idiopathic constipation is associated with a distinctive abnormality of the colonic myenteric plexus. Gastroenterology 1985;88:26-34.
Discussion Marshall J. Orloff (San Diego, CA): Chronic idiopathic intestinal pseudoobstruction is a rare category of diseases that has been recognized only recently. The term was first proposed only 15 years ago. Dr. Shaw, I know that YOU and your colleagues have been interested in these disorders since 1979, when you first described Patient 1. The particular value of your report is that you have provided long-term follow-up data of the previously reported patient and, equally important, of the patient’s family so that we can begin to understand the longitudinal course of this disorder. In a review of the cases of chronic intestinal pseudoobstruction of all types seen at the University of California, San Diego Medical Center over a 20 year period, we excluded cases of acute intestinal pseudoobstruction (such as in postoperative adynamic ileus) and acute colonic pseudoobstruction (Ogilvie’s syndrome) observed in elderly patients. Of 15 cases of chronic intestinal pseudoobstruction which have been treated at our center during this period, 6 were associated with scleroderma, or what is now called progressive systemic sclerosis; two with systemic lupus erythematosus; and one case each was associated with dermatomyositis, amyloidosis secondary to multiple myeloma, myxedema, myotonic dystrophy, jejunal diverticulosis, diabetes mellitus with presumed autonomic neuropathy, and jejunal bypass for morbid obesity. Cases of chronic intestinal pseudoobstruction reported in the literature have been related to Chagas’ disease, Parkinson’s disease, adult Hirschsprung’s disease, and long-term intake of various drugs, particularly phenothiaxines. We have not yet encountered any case of idiopathic chronic intestinal pseudoobstruction, such as the ones just described. Two points deserve emphasis. If we consider cases of chronic intestinal pseudoobstruction in which there has been an underlying or associated disease, as well as cases of idiopathic chronic intestinal pseudoobstruction, the disorder is not as rare as has been believed. In addition, surgery should be avoided if at all possible in the management of chronic intestinal pseudoobstruction. With the exception of chronic intestinal pseudoobstruction due to jejunal diverticulosis that can be readily resected, and due to jejunoileal bypass that can be taken down, operations in patients with chronic intestinal pseudoobstruction of either the idiopathic or secondary types have often been followed by recurrence of symptoms and a vicious cycle of repeated operations. Dr. Shaw, your initial patient, for example, had recurrent symptoms despite resection of her colon. Eight of our 15 patients underwent operations for chronic intestinal pseudoobstruction and the results were uniformly unsatisfactory, sometimes disastrous. The surgeon who operates on a patient with chronic intestinal
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pseudoobstruction without first trying every alternative form of therapy and without the most careful investigation and deliberation is asking for trouble. Chronic intestinal pseudoobstruction often involves the entire digestive tract. Finally, Dr. Shaw, regarding your recommendation of duodenojejunostomy when surgical treatment of megaduodenum is necessary, my review of the literature suggests that gastrojejunostomy has not received appropriate consideration on the basis of poor results in a very small number of cases. It appears to me that gastrojejunostomy should work as well or better than duodenojejunostomy, provided stomach motility is normal and the jejunum is not involved with the disease. Carlos A. Pellegrini (San Francisco, CA): Chronic intestinal pseudoobstruction is characterized by periods of remission and exacerbation. Previous reports had had short follow-ups, so the effect of operations on this disease was difficult to evaluate. Dr. Shaw, your report clarifies some aspects of the natural history of chronic intestinal pseudoobstruction and the long-term results of surgery. When managing patients with motility disorders of the bowel, I believe it is important to evaluate the motility of the gut from the mouth to the anus. Although the disorder may appear clinically limited to one area of the bowel, occasionally resection or bypass of an area has revealed a subclinical motility disorder elsewhere. Dr. Shaw, did you perform any other studies, for example, esophageal or coionic manometry, that might further define the motility abnormality in these patients? Conventional radiologic techniques using barium suspension alone are insufficient to evaluate intestinal motility and may even be dangerous, as barium impaction in these patients is frequent. We have recently developed a method to study small bowel transit using technetium 99m tagged chicken liver. Because technetium 99m is neither adsorbed nor absorbed through the mucosa of the gut, transit time between the stomach and the colon can be measured directly, the rate of flow of intestinal contents into the cecum can be determined, and areas of pooling in the bowel can be identified. This technique should be especially useful in patients like those presented, since it can be repeated as needed to evaluate the results of therapy, and has none of the risks associated with barium. Dr. Shaw, I agree that surgery ought to be reserved for patients in whom medical therapy has failed. When surgery is performed, however, the entire segment that is dilated must, in my opinion, be either bypassed or resected. I would not expect, for example, that a duodenojejunostomy would solve the problem if the duodenum, as you showed, is completely atonic. Would you comment on the choice of this operation rather than a gastrojejunostomy, as suggested by Schuffler and Deitch [Annals of Surgery 1980;192:752-61] in patients with atonic duodenum? Have you tried antidopaminergic drugs, such as metoclopramide or domperidone? Roy Cohn (Palo Alto, CA): About 15 years ago, the scientists at Jackson Laboratory, Bar Harbor were working on melanin pigment. The strain of mice they were using as models were white, black and white, and black. They found that all mice of the white strain died in about 3 to 4 weeks, and autopsy findings demonstrated Hirschsprung’s disease. The level of the nerve growth factor in these mice was discussed, and whether the genetic origin of this disease
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was in some way connected with nerve growth factor. The extract is made from the parotid salivary gland of the male mouse, which has a high level of nerve growth factor. The investigators also found what Dr. Winn just mentioned; that there was either a decrease or a complete absence of the nerve cells in the bowel wall generally, and that deficit was the cause of death. The serum nerve growth factor can be measured both at Stanford and at the University of California San Francisco Medical Center, and I suggest that this factor might explain what has happened in your patients, Dr. Shaw. Dean F. Winn, Jr. (Woodland, CA): I will describe a case of subacute intestinal pseudoobstruction. This patient presented last year with symptoms of nausea, vomiting, constipation, and obstipation. Both a gastroenterologist in Arizona and one of my associates performed thorough endoscopic tests. No cause for all of the symptoms could be found, and eventually aspiration pneumonia and a perforated cecum developed. The diagnosis before this event was chronic intestinal pseudoobstruction because we had found no cause for the symptoms. After the patient’s death, autopsy revealed paucity of the myenteric plexus through the colon and, to a lesser extent, throughout the small bowel. The autopsy examination also showed an occult small-cell carcinoma of the left bronchus with metastatic nodes in the mediastinurn and in the periaortic nodes. This is the sixth reported case in which there has
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pseu-
Anthony Shaw (closing): As you have pointed out, Dr. Orloff, most cases of chronic pseudoobstruction have a well-defined cause such as Hirschsprung’s disease, Chagas’ disease, or progressive systemic sclerosis. However, among the population of patients currently being treated for a myriad of gastrointestinal complaints ranging from dysphagia to constipation, there will be some who on more thorough study will be found to have idiopathic intestinal pseudoobstruction. Many of these patients are being misdiagnosed as having a peptic ulcer, achalasia, hiatal hernia, and other more common alimentary tract disorders. Three cases of gastrojejunostomy performed for megaduodenum in familial visceral myopathy have been reported, all with disastrous outcomes, because the huge flaccid duodenum remained undrained. Bacterial counts in the duodenums of patients with familial visceral myopathy have been as high as 1013/ml. Dr. Pellegrini, manometry has been useful in documenting abnormal esophageal peristalsis and lower esophageal sphincter pressures. By and large, drugs such as metoclopramide and bethanechol (Urecholine”) have not benefited patients with familial visceral myopathy. Dr. Cohn, I am not aware of any studies that have correlated serum levels of nerve growth factor with pseudoobstruction.
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Virginia
Slnn Apuras, MD, Iowa City, Iowa
Chronic intestinal pseudoobstruction includes a diverse group of disorders in which there are recurrent or persistent symptoms and signs of intestinal obstruction in the absence of an actual lesion obstructing the intestinal lumen. In 1970, Maldonado et al [1] reported five cases of chronic intestinal pseudoobstruction with striking clinical and radiographic similarities and no apparent cause, which they named chronic idiopathic intestinal pseudoobstruction. Reports of similar cases tended to confirm chronic idiopathic intestinal pseudoobstruction as a motility disorder, frequently familial, in which the entire alimentary tract might be involved, with usual onset in early adolescence or young adulthood. Recent histologic studies have identified either myopathic or neuropathic lesions in resected intestinal specimens of patients with chronic idiopathic intestinal pseudoobstruction, which permit a crude subdivision of the disease into two symptomatically similar but etiologically dissimilar subgroups [2-41. In 1979, two of us (AS and HAS), with colleagues at the University of Virginia [5], described a large family in which chronic.idiopathic intestinal pseudoobstruction was identified in members of at least four generations. The finding of fibrosis in the resected bowels of two family members allowed acctirate pathologic diagnosis of the disorder as familial visceral myopathy [3]. Because familial visceral myopathy has been characterized only recently, and only a few patients have been diagnosed and followed medically, there is still much to be letied. The purpose of this report is to present what we have learned from an 8 year From ttie Department of Pediatric Surgery, City of Hope National Medical Center, Dwte, Callfomia. the oepatanent of Radiology,Unbrsity of Virginia Medical Center, Charlottesville, Virginia, and the Deljartment of Medicine. University of Iowa Hospitals and Clinics, Iowa City, Iowa. Requests for reprints should be addressed to Anthony Shaw, MD, Department of Pediatric Surgery, City of Hope f4ational Medical Center, 1500 East Duarle Road, Duarte, California 91010. Presented at the 56th Annual Meeting of the Pacific Coast Surgical Assoclatlon. kbnterey, California, February 17-20, 1985.
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follow-up of six living family members with familial visceral myopathy, four of whom have had intestinal bypass or resection, with respect to natural history, pathologic characteristics, heredity, and response to treatment, especially surgery.
Case Reports Patient 1. Original propositus, age 23 years. Since age 13, she experienced bloating and abdominal pain after meals, nocturnal heartburn, and constipation. At age 14,
biweekly severe crampy abdominal pain and bilious vomiting required hospitalization five times for decompression and intravenous hydration. Barium studies showed dysmotility throughout the alimentary tract, sparing only the stomach, with marked redundancy and dilatation of the le$fJside pf the colon, which was considered the probable cause of her dominant symptoms and so was resected. Histologic examination revealed fibrosis of the outer muscle layers (Figures 1 through 3) [5]. Over a 2 year period, severe constipation often alternating with diarrhea recurred, along with worsening dysphagia. Increasingly frequent and severe attacks of abdominal pain associated with bloating and vomiting that became worse during menses were usually relieved by passage of gas and stool but required hospitalization twice. The patient’s appetite has remained good, her weight has not changed, and her abdomen has remained flat, without palpable masses or dilated bowel. Plain films showed a dilated stool fiied colon. On barium swallow, her esophagus was mildly dilated and aperistaltic, emptied only in the upright position, and was without evidence of stricture, hiatal hernia, or gastroesophageal reflux. The stomach was normal in size and emptied promptly. The duodenum was markedly distended to a diameter of 9.5 cm (Figure l), showed no peristaltic activity, and emptied easily only when the patient was on her left side. Barium was present in the dilated duodenum 7 hours later. There was segmental dilatation of jejunum with a marked delay in small intestinal transit time. The cecum was still not reached after 7 hours. Patient 2. Sister of Patient 1, age 25 years. Bloating, vomiting and hematemesis at age 12 led Patient 2 to duodenojejunostomy for what was diagnosed as superior mesenteric artery syndrome, with minimal postoperative
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Figure 1. Patlent 1. Recent barium study shows a dilated flaccid duodenum (d). The vertical band-like defect (arrowheads) is produced by the aortic impress/on.
improvement (Figure 2). Barium swallow at age 17 demonstrated an aperistaltic esophagus and a hypotonic dilated duodenum and was complicated by colonic impaction of barium (Figure 3). A successful pregnancy was complicated by severe bloating, vomiting, and constipation. In mid1984, the patient underwent emergency transverse colostomy for colonic obstruction which was followed 3 months later by a subtotal colectomy with preservation of the cecum. Histopathologic study showed cellular atrophy and increased fibrosis of the circular muscle layer (Figure 4), which were findings similar to those previously reported for her sister 151.At the most recent follow-up, she had one to five loose bowel movements per day and takes no medication. Patient 3. Mother of Patients 1 and 2, age 43 years. Although she has never had any gastrointestinal symptoms, barium study showed generalized alimentary dysmotility with prolonged retention of barium in a greatly dilated, hypotonic duodenum. On most recent follow-up, Patient 3 has remained asymptomatic and her barium swallow is essentially unchanged from her previous examination. Patient 4. Grandmother of Patients 1 and 2, age 58 years. Bloating and constipation have been present since early adolescence. She was operated on for what was diagnosed as duodenal obstruction at age 35, but no obstruction was found. A duodenojejunostomy provided no postoperative improvement. Previous barium studies showed an aperistaltic esophagus, normal stomach, and a dilated duodenum with slightly delayed small intestinal transit. On follow-up, constipation (sometimes lasting 7 to 10 days) and bloating have remained her most serious problems. Long-standing symptoms of dysphagia, nocturnal regurgitation, and abdominal pain remained essentially unchanged. A recent barium swallow revealed an aperistaltic esophagus, marked dilatation of the duodenum
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Figure 2. Patlent 2, age 12 years. Barium study before duodenojejunostomy demonstrates a patulous proximal duodenum.
which emptied through both normal and anastomotic pathways, and mild segmental dilatation of the small bowel with delayed transit time. Patient 5. Brother of Patient 4, age 64 years. He has had bloating and stomach growling most of his life, but has passed three to four stools daily and has never been constipated. A cholecystectomy was performed for symptomatic gallstones at age 33 years. Previous barium swallow studies showed an aperistaltic esophagus, a dilated duodenum, and delayed small bowel transit. The patient has denied serious gastrointestinal symptoms currently and declined follow-up barium studies because of severe difficulty in expelling barium 6 years ago. Patient 6. Sister of Patient 4, age 61 years. Bloating, nocturnal heartburn, and severe constipation have been present since late childhood. Cholecystectomy was performed for symptomatic gallstones at age 51. She underwent two unsuccessful operations for severe rectal prolapse. Previous studies showed dysmotility of the esophagus, the duodenum, and the small bowel, with prolonged duodenal retention of barium. On follow-up, her chief complaints have been continuing rectal prolapse and obstipation. On physical examination, she had a reducible rectal prolapse over 12 inches in length. Results of a recent barium swallow and follow-through were essentially unchanged from her previous examination 8 years earlier.
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Flgure 3. Pafieni 2, age 17 years. Abdominal radkqraph several days alter small bowel examination shows barkrm lmpacllon In the colon and volvulus of the splenlc flexure.
Comments Approximately 6 families with familial visceral myopathy have been identified with certainty on clinical, radiographic, and pathologic grounds since this disorder associated with smooth muscle fibrosis was described in the late 1970s. However, clinical reports can be found as far back as 1938 of familial and sporadic cases of chronic pseudoobstruction that are clinically and radiographically indistinguishable from recently diagnosed cases of familial visceral myopathy [6]. The family members described herein collectively exhibited the entire spectrum of symptoms of disordered alimentary tract motility seen in familial visceral myopathy, including dysphagia, heartburn, bloating, postprandial abdominal pain, vomiting, constipation, and diarrhea. As in other reported kindred, symptoms appeared in the second decade of life and persisted or recurred with varying intensity and chronicity [7]. Within the family described, Patient 3 was asymptomatic, Patient 5 had mild symptoms, symptoms in Patients 4 and 6 were intermediate in severity, and Patients 1 and 2 had severe chronic disease with recurring attacks of dis-
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Figure 4. LongHucllnal secilon of colon with markedly decreased numbers of smooth muscle cells and increased flbrosls ot the circular muscle layer. ( Trichrome stain; magnification X 27, reduced by 32 percent. )
abling and even life-threatening symptoms that required parenteral nutritional support. Constipation was the dominant symptom. Severe attacks requiring repeated hospitalization in Patients 1 and 2, as well as the refractory rectal prolapse in Patient 6, appeared to be due primarily to colonic stasis. Although the basic motility disorder is due to atrophy and fibrosis of the visceral smooth muscle, variations of symptoms have resulted from alterations in the population of enteric gas-forming bacteria, from changes of diet and activity, and probably from hormonal changes related to the menstrual cycle or to pregnancy. Most patients with familial visceral myopathy, including those in our series, favor a bland diet free from spicy foods, citrus fruits, and such gas-producing foods as onions, beans, broccoli, carbonated drinks, and beer. Although a dilated lower urinary tract (megacystis) has been reported in patients with familial visceral myopathy who had symptoms of urinary retention, no one in our family group had evidence of urinary disease. The radiographic findings in patients with familial visceral myopathy are remarkably similar and have been well summarized in recent articles [7,8]. Dy-
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namic studies of each of our patients demonstrated most or all of the following radiographic findings. Dysmotility of most of the alimentary tract, most consistently in the eosphagus, duodenum, and colon, is seen. The esophagus is aperistaltic, normal in caliber or mildly dilated, and empties by gravity or by displacement from above. Gastric motility and emptying are normal. The duodenum is flaccid and dilated with lengthy barium retention-as long as 19 days in one reported case [2]. The small intestine is usually of normal caliber or slightly dilated but may show areas of more severe (usually segmental) dilatation. Transit time is usually delayed, and the colon is usually dilated, hypoperistaltic, and redundant. Expulsion of barium may be very difficult, as it was for all of our patients, including Patient 3. Radiologists must weigh the benefits of barium as a contrast agent when studying patients with pseudoobstruction against the risk of colonic obstruction. Recent studies by Mitros and colleagues [9] from the Universities of Iowa, Washington, and Virginia have shown that familial visceral myopathy was the most common cause of chronic primary (idiopathic) intestinal pseudoobstruction. The lesion, as described by these investigators, characteristically involved muscle cell degeneration, muscle cell loss, and fibrosis of the external layer of smooth muscle, conditions which were seen in Patients 1 and 2 in our series. Such lesions may be difficult to distinguish from those seen in progressive systemic sclerosis; however, familial visceral myopathy and progressive systemic sclerosis can usually be distinguished on clinical grounds. Fibrosis of the smooth muscle of the bladder may also be seen in patients with familial visceral myopathy, producing urinary retention, reflux, and upper tract damage. Mitros et al [9] emphasized the importance of adequate tissue sampling, since the fibrosis may be unevenly distributed, and the use of trichrome stain and electron microscopy in detecting the smooth muscle fibrosis. At the same time that histopathologic studies have identified visceral myopathies as a distinct subgroup of chronic idiopathic intestinal pseudoobstruction, a second and more heterogenous subgroup, the visceral neuropathies, have been distinguished. Using Smith’s silver staining technique, Schuffler et al [4] identified a range of degenerative changes in the myenteric plexus of some patients with chronic idiopathic intestinal pseudoobstruction, as well as some with obstipation alone, which would have been missed by conventional staining techniques. The intestinal smooth muscle has appeared normal in all patients with visceral neuropathy studied thus far. Of nine families with familial visceral myopathy, including the family in this report, whose pedigrees were recently reviewed by Anuras et al [IO], the disease appears to be transmitted by a dominant (autosomal or sex-linked) gene in seven families and by an autosomal recessive gene in two. This information
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suggests that members of identified kindred with familial visceral myopathy could benefit from genetic counseling. Although some patients with familial visceral myopathy have such unremitting symptoms that parenteral nutrition may be required to prevent inanition, most have learned to live with their disease with symptomatic treatment, such as nonfiber laxatives, enemas and antacids, and avoidance of bedtime snacks and gas-forming or constipating foods. For patients with moderate food intolerance and worsening nutritional status, Schuffler et al [If] have reported some success with a low-fat, low-fiber, low-lactose diet, which provides 1,800 to 2,400calories per day supplemented with a liquid formula [2 11. The intermittent use of antibiotics, such as tetracycline and metronidazole, may reduce symptoms of intestinal distention by controlling growth of gastrointestinal flora [8]. Of our patients, only Patient 1 took tetracycline, but for too short a time to evaluate its effectiveness. Although cholinergic drugs have not provided clear improvement in any form of chronic idiopathic intestinal pseudoobstruction [8], Patient 1 has been taking 15 mg of oral neostigmine 3 times a day because neostigmine was observed to stimulate intestinal peristalsis during her fluoroscopic examination. When she has become severely constipated, she has increased the dose to 15 mg every 3 to 4 hours despite unpleasant systemic side effects until she starts to pass gas and liquid stool. Patient 2 took neostigmine for a time but discontinued it because of a toxic reaction to the drug. Surgical treatment of familial visceral myopathy should be reserved for those patients incapacitated by symptoms refractory to dietary and medical management. When the duodenum or colon has been identified clinically and radiographically as the likely source of the most incapacitating symptoms in familial visceral myopathy, operations designed to relieve duodenal or colonic stasis have benefited carefully selected patients. Duodenojejunostomy has been the operation most commonly performed for symptoms attributable to the megaduodenum, often incorrectly diagnosed preoperatively as superior mesenteric artery syndrome. When duodenojejunostomy fails to relieve bloating, abdominal pain, and vomiting, this may be because of either dysmotility of the small bowel or obstruction at a poorly constructed anastomosis. A recent barium study of Patient 4 showed duodenal dilatation and stasis despite outflow through both the normal route and the duodenojejunostomy. A partial duodenectomy may provide better drainage than duodenojejunostomy alone [12]. Several patients who experienced little or only transient relief from side-to-side duodenojejunostomy had considerable improvement when a large portion of the anterior wall of the dilated duodenum was subsequently resected. Unfortunately, the fol-
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low-ups have been short in many reported cases; therefore, it is not known whether the early good results of some duodenojejunostomies have been sustained [12]. The few reported attempts to relieve upper intestinal symptoms by gastrojejunostomy have proved ineffective, with high morbidity and mortality rates [12,13]. Deaths have resulted from intraoperative peritoneal contamination by duodenal contents containing coliform bacteria in concentrations as high as lOls/ml [13]. Therefore, duodenal drainage procedures should be preceded by nasoduodenal drainage, intravenous nutritional support in malnourished patients, and antibiotic prophylaxis. Patients with symptoms primarily due to severe dysmotility of the small bowel are not likely to benefit from resective procedures unless relatively short segments are involved. When the colon has been the major source of symptoms, resection of elongated, dilated, and redundant colon may be beneficial. Anything less than subtotal colectomy may be insufficient. Although Patient 1 seemed to benefit initially from partial colectomy, as previously reported, her most severe symptoms, which are still likely related to colonic stasis, recurred. Because of these observations, we recommended that her sister, Patient 2, undergo resection of most of the colon after emergency colostomy. Patient 6’s rectal prolapse, refractory thus far to segmental resection and suspensory procedures, would probably benefit from a subtotal colectomy to relieve her obstipation, as well as reduce the likelihood of recurrent prolapse. Most patients with visceral neuropathy do not have megaduodenum but do have a more generalized, nonsegmental distribution of the motility disorder through the alimentary tract [8]. However, Krishnamurthy et al [14] have recently described a group of young women who underwent subtotal colectomy for intractable obstipation and were found to have a colonic neuropathy as revealed by Smith’s silver stain technique which suggests that patients with this form of visceral neuropathy may benefit from a resective procedure. Surgeons who begin an abdominal procedure expecting to find acute mechanical obstruction and instead find dilated and redundant bowel should consider the possibility of a visceral myopathy or neuropathy. Suspicion should increase if the patient has had previous negative laparotomies for intestinal obstruction, chronic or recurring gastrointestinal complaints, a large urinary bladder and retention, or if relatives also have had multiple alimentary tract symptoms. Full-thickness biopsy specimens should be taken from the duodenum, jejunum, and colon, and they should be examined with electron microscopy, trichrome stain, and Smith’s silver stain. However, the surgeon must weigh the risk of peritoneal soiling in such cases against the benefit of possibly obtaining opsy.
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When a diagnosis of visceral myopathy has been made in a patient with seemingly sporadic symptoms, investigation of the family, particularly one with chronic, baffling symptoms, may result in a diagnosis of familial visceral myopathy. An appropriate management plan for symptomatic relatives may then be devised. Summary Familial visceral myopathy is a form of chronic intestinal pseudoobstruction in which fibrosis of the smooth muscle of the alimentary tract causes protean symptoms of disordered visceral motility. Based on our 8 year observation of six members of one family with familial visceral myopathy and review of the few well-documented case reports of this disease, we have confiied a role for surgeons in tissue diagnosis, case identification, and palliation of incapacitating symptoms of familial visceral myopathy after obtaining dynamic radiographic assessment of the entire alimentary canal. Because the duodenum and colon are the usual sources of major dysmotility symptoms, patients incapacitated by duodenal or colonic pseudoobstruction may benefit from bypass or resective operations. Acknowledgment: We thank Drs. Lowell Secrist, Jonathan L. Shurherg, Robert K. Heide, and Walter Nickin for their help and cooperation and Dr. Frank A. Mitros, Department of Pathology, University of Iowa, for his interpretation of the histopathologic findings in Patient 2.
References 1. Maldonado JE, Gregg JA, Green PA, Brown AL. Chronic idiopathic intestinal pseudoobstruction. Am J Med 1970;49: 203-13. 2. Schuffler MD, Lowe MC, Bill AH. Studies of idiopathic intestinal pseudoobstruction. I. Hereditary hollow visceral myopathy: clinical and pathological studies. Gastroenterology 1977; 73:327-38. 3. Faulk DL, Anuras S, Gardner GD, Mitros FA, Summers RW, Christensen J. A familial visceral myopathy. Ann Intern Med 1978;89:800-6. 4. Schuffler MD, Jonak Z. Chronic idiopathic intestinal pseudoobstruction caused by a degenerative disorder of the myenteric plexus: the use of Smith’s method to define the neuropathology. Gastroenterology 1982;82:478-86. 5. Shaw A, Shaffer H, Teja K, Kelly T, Grogan E, Bruni C. A perspective for pediatric surgeons: chronic idiopathic intestinal pseudoobstruction. J Pediatr Surg 1979;14:719-27. 8. Weiss W. Zur aetiologie des megaduodenums. Dtsch Z Chir 1938;251:317-30. 7. Anuras S, Shaw A, Christensen J. The familial syndromes of intestinal pseudoobstruction. Am J Hum Genet 1981;33: 584-91. 8. S&ruffler MD. Chronic intestinal pseudoobstruction syndromes. Med Clin North Am 1981;65:1331-58. 9. Mllos FA, S&ruffler MD, Teja K, Anuras S. Pathologic features of familial visceral myopathy. Hum Pathol 1982;13:82533. 10. Anuras S, Mitros FA, Nowak TV, et al. A familial visceral myopathy with external ophthalmoplegia and autosomal recessive transmission. Gastroenterology 1983;84:346-53. 11. Schuffler MD, Rohrmann CA, Chaffee RG, Brand DL, Delaney
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JH, Young JH. Chronic intestinal pseudoobstruction: a report of twenty-seven cases and review of the literatue. Medicine (Baltimore) 1981;60:173-96. 12. Schuffler MD, Deitch EA. Chronic idiopathic intestinal pseudoobstruction: a surgical approach. Ann Surg 1980:192: 752-6 1. 13. Anuras S, Shirazi S, Faulk DL, Gardner GD, Christensen J. Surgical treatment in familial visceral myopathy. Ann Surg 1979;189:306-10. 14. Krishnamurthy S, Schuffler MD, Rohrmann CA, Pope CE Il. Severe idiopathic constipation is associated with a distinctive abnormality of the colonic myenteric plexus. Gastroenterology 1985;88:26-34.
Discussion Marshall J. Orloff (San Diego, CA): Chronic idiopathic intestinal pseudoobstruction is a rare category of diseases that has been recognized only recently. The term was first proposed only 15 years ago. Dr. Shaw, I know that YOU and your colleagues have been interested in these disorders since 1979, when you first described Patient 1. The particular value of your report is that you have provided long-term follow-up data of the previously reported patient and, equally important, of the patient’s family so that we can begin to understand the longitudinal course of this disorder. In a review of the cases of chronic intestinal pseudoobstruction of all types seen at the University of California, San Diego Medical Center over a 20 year period, we excluded cases of acute intestinal pseudoobstruction (such as in postoperative adynamic ileus) and acute colonic pseudoobstruction (Ogilvie’s syndrome) observed in elderly patients. Of 15 cases of chronic intestinal pseudoobstruction which have been treated at our center during this period, 6 were associated with scleroderma, or what is now called progressive systemic sclerosis; two with systemic lupus erythematosus; and one case each was associated with dermatomyositis, amyloidosis secondary to multiple myeloma, myxedema, myotonic dystrophy, jejunal diverticulosis, diabetes mellitus with presumed autonomic neuropathy, and jejunal bypass for morbid obesity. Cases of chronic intestinal pseudoobstruction reported in the literature have been related to Chagas’ disease, Parkinson’s disease, adult Hirschsprung’s disease, and long-term intake of various drugs, particularly phenothiaxines. We have not yet encountered any case of idiopathic chronic intestinal pseudoobstruction, such as the ones just described. Two points deserve emphasis. If we consider cases of chronic intestinal pseudoobstruction in which there has been an underlying or associated disease, as well as cases of idiopathic chronic intestinal pseudoobstruction, the disorder is not as rare as has been believed. In addition, surgery should be avoided if at all possible in the management of chronic intestinal pseudoobstruction. With the exception of chronic intestinal pseudoobstruction due to jejunal diverticulosis that can be readily resected, and due to jejunoileal bypass that can be taken down, operations in patients with chronic intestinal pseudoobstruction of either the idiopathic or secondary types have often been followed by recurrence of symptoms and a vicious cycle of repeated operations. Dr. Shaw, your initial patient, for example, had recurrent symptoms despite resection of her colon. Eight of our 15 patients underwent operations for chronic intestinal pseudoobstruction and the results were uniformly unsatisfactory, sometimes disastrous. The surgeon who operates on a patient with chronic intestinal
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pseudoobstruction without first trying every alternative form of therapy and without the most careful investigation and deliberation is asking for trouble. Chronic intestinal pseudoobstruction often involves the entire digestive tract. Finally, Dr. Shaw, regarding your recommendation of duodenojejunostomy when surgical treatment of megaduodenum is necessary, my review of the literature suggests that gastrojejunostomy has not received appropriate consideration on the basis of poor results in a very small number of cases. It appears to me that gastrojejunostomy should work as well or better than duodenojejunostomy, provided stomach motility is normal and the jejunum is not involved with the disease. Carlos A. Pellegrini (San Francisco, CA): Chronic intestinal pseudoobstruction is characterized by periods of remission and exacerbation. Previous reports had had short follow-ups, so the effect of operations on this disease was difficult to evaluate. Dr. Shaw, your report clarifies some aspects of the natural history of chronic intestinal pseudoobstruction and the long-term results of surgery. When managing patients with motility disorders of the bowel, I believe it is important to evaluate the motility of the gut from the mouth to the anus. Although the disorder may appear clinically limited to one area of the bowel, occasionally resection or bypass of an area has revealed a subclinical motility disorder elsewhere. Dr. Shaw, did you perform any other studies, for example, esophageal or coionic manometry, that might further define the motility abnormality in these patients? Conventional radiologic techniques using barium suspension alone are insufficient to evaluate intestinal motility and may even be dangerous, as barium impaction in these patients is frequent. We have recently developed a method to study small bowel transit using technetium 99m tagged chicken liver. Because technetium 99m is neither adsorbed nor absorbed through the mucosa of the gut, transit time between the stomach and the colon can be measured directly, the rate of flow of intestinal contents into the cecum can be determined, and areas of pooling in the bowel can be identified. This technique should be especially useful in patients like those presented, since it can be repeated as needed to evaluate the results of therapy, and has none of the risks associated with barium. Dr. Shaw, I agree that surgery ought to be reserved for patients in whom medical therapy has failed. When surgery is performed, however, the entire segment that is dilated must, in my opinion, be either bypassed or resected. I would not expect, for example, that a duodenojejunostomy would solve the problem if the duodenum, as you showed, is completely atonic. Would you comment on the choice of this operation rather than a gastrojejunostomy, as suggested by Schuffler and Deitch [Annals of Surgery 1980;192:752-61] in patients with atonic duodenum? Have you tried antidopaminergic drugs, such as metoclopramide or domperidone? Roy Cohn (Palo Alto, CA): About 15 years ago, the scientists at Jackson Laboratory, Bar Harbor were working on melanin pigment. The strain of mice they were using as models were white, black and white, and black. They found that all mice of the white strain died in about 3 to 4 weeks, and autopsy findings demonstrated Hirschsprung’s disease. The level of the nerve growth factor in these mice was discussed, and whether the genetic origin of this disease
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was in some way connected with nerve growth factor. The extract is made from the parotid salivary gland of the male mouse, which has a high level of nerve growth factor. The investigators also found what Dr. Winn just mentioned; that there was either a decrease or a complete absence of the nerve cells in the bowel wall generally, and that deficit was the cause of death. The serum nerve growth factor can be measured both at Stanford and at the University of California San Francisco Medical Center, and I suggest that this factor might explain what has happened in your patients, Dr. Shaw. Dean F. Winn, Jr. (Woodland, CA): I will describe a case of subacute intestinal pseudoobstruction. This patient presented last year with symptoms of nausea, vomiting, constipation, and obstipation. Both a gastroenterologist in Arizona and one of my associates performed thorough endoscopic tests. No cause for all of the symptoms could be found, and eventually aspiration pneumonia and a perforated cecum developed. The diagnosis before this event was chronic intestinal pseudoobstruction because we had found no cause for the symptoms. After the patient’s death, autopsy revealed paucity of the myenteric plexus through the colon and, to a lesser extent, throughout the small bowel. The autopsy examination also showed an occult small-cell carcinoma of the left bronchus with metastatic nodes in the mediastinurn and in the periaortic nodes. This is the sixth reported case in which there has
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Anthony Shaw (closing): As you have pointed out, Dr. Orloff, most cases of chronic pseudoobstruction have a well-defined cause such as Hirschsprung’s disease, Chagas’ disease, or progressive systemic sclerosis. However, among the population of patients currently being treated for a myriad of gastrointestinal complaints ranging from dysphagia to constipation, there will be some who on more thorough study will be found to have idiopathic intestinal pseudoobstruction. Many of these patients are being misdiagnosed as having a peptic ulcer, achalasia, hiatal hernia, and other more common alimentary tract disorders. Three cases of gastrojejunostomy performed for megaduodenum in familial visceral myopathy have been reported, all with disastrous outcomes, because the huge flaccid duodenum remained undrained. Bacterial counts in the duodenums of patients with familial visceral myopathy have been as high as 1013/ml. Dr. Pellegrini, manometry has been useful in documenting abnormal esophageal peristalsis and lower esophageal sphincter pressures. By and large, drugs such as metoclopramide and bethanechol (Urecholine”) have not benefited patients with familial visceral myopathy. Dr. Cohn, I am not aware of any studies that have correlated serum levels of nerve growth factor with pseudoobstruction.
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