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Regional Enteritis
Regional Enteritis From the Department of Surgery, University of California Medical Center, San Francisco, California
JAMES C. NEELY, M.D. William P. Kyne Memorial Research Fellow in Surgery
LEON GOLDMAN, M.D., F.A.C.S. Professor and Chairman, Department of Surgery, and Surgeon-in-Chief, Herbert C. Moffitt-University of California Hospitals, San Francisco
BARELY 30 years have passed since Crohn, Ginzburg and Oppenheimer proposed "to describe, in its pathologic and clinical details, a disease of the terminal ileum, affecting mainly young adults, characterized by an acute or chronic necrotizing and cicatrizing inflammation."4 In spite of the generally prompt acceptance of the disease as a pathologic and clinical entity, this important and not uncommon condition, which Crohn called regional ileitis, was for a long time unrecognized as a distinct disease process. Even today, although some investigators believe that the incidence of this disease is increasing and more than 2000 cases have been recorded in the literature, an individual physician's lifetime experience with Crohn's disease is apt to be small. PATHOGENESIS AND PATHOLOGY
The cause of regional enteritis is unknown. All inflammatory diseases of the small bowel have an unexplained predilection for the terminal ileum, and as one progresses distally from the pylorus toward the ileocecal valve a correlative increase in the incidence of disease is demonstrable for all such lesions. Because of its ubiquitous distribution (rare cases have been recorded in the stomach), what was at first called terminal ileitis is now generically referred to as regional enteritis, a descriptive observation, however, which sheds no etiologic light. Nearly all the known non-neoplastic disease-causing agents have been implicated from time to time, including viruses, bacteria, protozoa, toxins, trauma and, more recently, auto-immune mechanisms. Enteric
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sarcoid, tuberculosis and lymphopathia venereum have been specifically implicated. Refvem31 has attributed the disease to a fungus. Frazer12 , 13 has suggested a relationship with nontropical sprue on the basis of similarly altered fecal fat values and bacteria counts. Chess and his associates1 produced chronic enteritis experimentally in dogs and rats by having them ingest sand and talc, which perhaps is what led some investigators to impugn tooth powder for a time. Reichert and Mathes30 demonstrated that lesions simulating regional enteritis can be produced by lymphatic blockage, and they produced an exacerbation of the process by intravenous bacterial injections. Tallarigo and Cacudi33 have called attention to the possible role of histamine following lymph stasis, while Cooke and his co-workers3 emphasized their clinical observation of the consistently high elevation of seromucoids in both regional enteritis and ulcerative colitis. Emsb0 10 first described a disease in swine, prevalent in Scandinavia, that is similar to regional enteritis, and Strande et aJ.32 have recently observed the same in cocker spaniels. Crohn, however, laid this issue to rest somewhat when he stated in a recent panel discussion that, "It is true that all the animals in the zoo have been inoculated with material from cases of regional enteritis and I know of no animal in which the disease has been successfully reproduced."8 Unquestionably too little is known of the composition and specific content of the succus entericus in this disease. As Van Patter and his associates35 point out in their excellent article, our knowledge of the intestinal enzymatic content, bacterial flora, protein by-products, and fat breakdown is too poor to rule out a specific substance in the fecal stream as causative, and it is in this area that future investigation is perhaps most promising. At present we are left with a multiplicity of factors that could combine in a synergistic relationship. These include genetic, metabolic, bacterial, allergic and psychosomatic influences. But, as has most often been the case with unexplained disease in the past, our clinicopathologic knowledge has become extensive, and from this the etiologic agent may eventually emerge. Pathologists distinguish between the acute, subacute and chronic forms of the disease. It is particularly important for the surgeon to recognize the gross characteristics of acute regional enteritis. The involved small bowel is typically reddened from hyperemia and is edematous and thickened and engorged all along its serosa, which is usually covered with a fibrinous exudate. Pathognomonic is a pincers-like circumserosal migration of toughened mesenteric fat. The affected segment is usually abruptly demarcated, frequently just at the ileocecal valve, although in 5 per cent of the cases there is an associated ileocolitis. The latter is a variant of regional enteritis, and is to be emphatically distinguished from segmental colitis, essentially a mild variant of ulcerative colitis, whose limited colonic resection is usually curative. Similarly
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"backwash ileitis" is a variant of ulcerative colitis and is to be carefully distinguished. The remainder of the bowel usually appears normal, but mesenteric thickening and regional lymphadenopathy are marked, and it is this alteration which most observers believe leads to the stasis of chyle which in turn leads to the progressive nature of the disease. A follow-up by Crohn 7 of surgically diagnosed "acute enteritis" shows that in 75 per cent of the cases the patient's disease subsides to a subacute or chronic form. In contrast, the chronic lesions assume a normal serosal hue without cngorgement or exudate. Bowel thickening and actual stiffening from proliferative changes and organizing fibrosis is present. The fatty migration still occurs and, depending upon the extent of the disease, interloop adhesions and kinking may be marked. Lymphadenopathy is often generalized by this time, and mesenteric thickening up to 2 to 3 cm. is common. With further progress of the disease the well-known cutaneous interloop and enterocolic fistulas, abscesses and cicatricial obstructions may occur, the obstructions often leading to dilatation and muscular hypertrophy of the proximal bowel. Intramural irregularity, thickening and intraluminal narrowing are conspicuous at this stage. Intraluminal ulcers, a distinguishing pathologic feature, are typically aligned along the mesenteric border between areas of shaggy, gray mucosa. The histopathologic features of the disease, however, as emphasized by Warren and Sommers,36 have enabled pathologists to split off regional enteritis as a disease entity from its categorization with "benign granuloma" of the small bowel as outlined by Tietze,34 Moschcowitz and Wilensky,26 and Mock24 during the early part of this century. While some observers such as Meyer, 23 in emphasizing the specificity for disproportionate hypertrophy of the muscularis mucosa, have directed their attention to specific bowel layers, all layers seem to be involved. The most typical primary changes occur in the submucosa and the mesentery. Interstitial edema, lymphoid hyperplasia, lymph duct ectasia, plasma cell infiltration, endothelial proliferation, perivascular histiocytosis and excavating ulcerations intersperse with varying degrees of acute cellular elements. Here also the controversial tubercle appears. This microscopic aggregation is composed principally of pale-staining histiocytes and is pathognomonic only insofar as the other clinical and pathologic aspects of the disease are present, since a variety of chronic infectious diseases of the bowel show the same response. The secondary microscopic changes are reparative in nature and all degrees of healing may be evident. Simultaneously, this early lesion in the submucosa is accompanied by edema and lymphatic obstruction of its mesentery. DIAGNOSIS AND THE CLINICAL PICTURE
A poorly publicized fact, one which probably stems from the repeated emphasis placed on the chronicity of regional enteritis and its long
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history of remissions and exacerbations, is that the initial manifestations of this disease may resemble those of the acute surgical abdomen. From a third to a half of the diagnoses of regional enteritis are made during exploration of the acute abdomen. Seven of Crohn's4 original 14 patients were explored for appendicitis, 30 per cent of the 600 patients reported by Van Patter et al.3 5 were so explored, and Neely,28 in reporting a 15-year experience at Cincinnati General Hospital, found that 60 per cent of the diagnoses were established during exploratory operations on the acute abdomen. Priestly and Judd 29 have admonished the surgeon for his lack of diagnostic acumen in this disease, but it seems likely, aR Fergusonl l has recently stated, that the clinical picture of acute regional ileitis or even the exacerbation of a chronic form is often indistinguishable from acute appendicitis. For this reason, and for the fact that the one condition is common and the other comparatively rare, operative intervention should not be withheld in questionable cases. What is most important, as emphasized previously, is that the surgeon must recognize with certainty the pathologic features of the disease process once he encounters them. Approximately two-thirds of the patients with Crohn's disease show evidence of a chronic disease process when they are first seen by the physician. No helpful social, ethnic, sexual or established geographical incidence exists. Cases have been reported in patients from the age of four to the age of 75, but 60 per cent of the patients are between 16 and 35 years old and only 10 per cent of the primary cases are first seen beyond the age of 50. A typical case would be that of a 25 year old white woman with a IS-month history of mild recurrent diarrhea and easy fatigability. Presenting symptoms would be increasing diarrhea, perhaps six to eight stools a day, mostly at night or in the morning, a loss in weight of 10 pounds in the past four months, and possibly a wet, macerating pruritus ani. She would appear well developed and well nourished, perhaps slightly anemic, but her vital signs would be normal. Three physical signs may give the diagnostic clue. One is previous abdominal scars, particularly an appendectomy scar, in which fistulous openings may be present. Fistulas, of course, may occur without scars. Secondly, a mass in the right lower quadrant is present 35 per cent of the time. The mass is moderately tender, may be fixed posteriorly, is firm and represents the inflammatory reaction in the terminal ileum with adjacent bowel, omentum and parietes. Thirdly, anal fissures and fistulas are frequent. Cattell 8 puts the incidence at 20 per cent, Morson and Lockhart-Mummery25 at 50 per cent. The history and physical findings at this point are usually sufficient to make the diagnosis, but other clinical features may be present in varying degrees. These include steatorrhea, myriad manifestations of avitamiinoss, hypocalcemia, arthritis, clubbing of the fingers, erythema nodosum, abdominal and perineal abscesses, and personality changes.
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Regional enteritis may present as a fever of unknown origin. The differential diagnosis may include Hodgkin's disease, lymphosarcoma, lymphopathia, enteric tuberculosis, sarcoid, carcinoid, endometriosis, enterogenous cysts, bacillary dysentery and parisitism. In the routine case it will be sufficient to rule out amebae and salmonella by proctoscopy and appropriate stool examinations before proceeding with roentgenologic examination. The "string sign," first described by Kantor 19 in 1934, is now classic and confirms the diagnosis. It represents the intraluminal narrowing from cicatrizing enteritis and usually refers to the involved 8 to 10 inches of terminal ileum. It is demonstrable by barium enema, small bowel reflux or a small bowel series from above. Depending upon the extent and duration of the disease, radiologists may be able to demonstrate mucosal serrations and bowel stiffening only by fluoroscopy, but they believe a string sign can be found eventually in 95 per cent of all cases. Thus repeated examinations may be indicated. Although death from regional enteritis is rare, an occasional patient seen late in the course of his disease, or who has been untreated or intractable, may develop severe inanition, multiple interloop fistulas, metastatic abscesses, progressive diarrhea, anemia, mineral deficiencies and electrolyte depletion. His condition gradually deteriorates until septicemia and death occur. TREATMENT AND PROGNOSIS
It must be emphasized that the primary treatment of regional enteritis is medical. In general, the surgeon treats only the complications, whether acute or chronic, for this is essentially a chronic recurrent disease that requires the perseverance and adjustments of a conscientiously supervised medical regimen. This includes detailed long-term dietary restrictions, stool bulk-forming preparations, vitamin supplements, enteric antibiosis, and appropriate rest. Eggers,9 and more recently Bargen,8 have employed radiotherapy, but with variable results. Steroids have not been shown to be routinely beneficial, but are probably indicated in the intractable case or during severe exacerbation. At such times bed rest in a hospital with sedation and intensification of all therapy is indicated. The surgeon should be consulted but, as Goldman and Gardner16 point out, it is not advisable to operate until the disease is quiescent or in a "burned out" stage when "the disease pattern is well established." The positive indications for surgery include: progressive symptomatic terminal ileitis, enteric or perirectal fistulas, hemorrhage, intestinal obstruction, postoperative recurrent progressive or recurrent enteritis, perforation and abscesses. The contraindications include: extensive and diffuse enteritis, rapidly progressive mucosal enteritis, and the combined
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ileocolitis recently described by Yarnis et al. 37 Occasionally, although extensive involvement of the bowel may be suspected clinically, one laparotomy may be indicated to confirm and even successfully ameliorate the patient's condition. Since most surgical intervention is carried out for intractability with progression of symptoms, the preoperative preparation is all-important in such a depleting disease. Blood replacement, electrolyte balance, vitamin deficiencies, serum protein alignment and weight stabilization should all be brought under control during a week or more of hospitalization before operation. Decompression with a Miller-Abbott tube is desirable for a few days before carrying out procedures to correct obstruction. Five days of preoperative preparation with either succinylsulfathiazole (Sulfasuxidine) or phthalylsulfathiazole (Sulfathalidine) and neomycin should be carried out, but care should be taken not to exacerbate the diarrhea. Before operative treatment of elective cases is considered, certain questions must be answered that are likely to be more pressing and often acute. How should the anal lesions be handled? The surgeon is cautioned not to do fissurectomies and fistulectomies prior to attacking the primary regional enteritis, since poor healing and recurrence under such circumstances is the rule. For some as yet unexplained reason these lesions nearly all regress when the underlying small-bowel disease is medically abated or surgically corrected. Should the surgeon operate on gastric, duodenal and jejunal lesions? Only if they have failed to respond to thorough medical therapy and are causing obstructive symptoms. The upper reaches of the bowel have repeatedly shown a greater propensity to heal. It is known that gastric resections have been carried out with disastrous results, although the published reports are few. A patient reported by Heffernon and Kepkay18 died from postoperative complications, while studies by Martin and Carr21 clearly show the regressive nature of unmolested gastric lesions. Duodenal lesions have been thoroughly discussed by McGarity,22 who, in analyzing 25 cases, cautioned against resection and pointed to the favorable results following bypass gastrojejunostomy. In the jejunum one may encounter either very long segments of involvement or short, truncated, often multiple areas. In the former instance, as in the case described by Harris, Bell and Brunn,17 there may be difficulty in delineating the extent of the disease process at the operating table. The presence of "skip lesions" must be determined by careful complete abdominal exploration in every case. These short segments, usually associated with disease elsewhere in the ileum, tend to recur at various points throughout the small and occasionally the large bowel, particularly following previous resection. What is the treatment of acute regional enteritis? The surgeon who finds acute regional enteritis in exploring the acute surgical abdomen
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should recognize the extent and severity of the disease process and do no further surgery. The symptoms in 25 per cent of such patients subside on medical therapy with no recurrence of the disease. Should the appendix be removed? Eleven per cent of Marshall and Fechner's2o series of 114 patients who had appendectomies developed abdominal wall fistulas. Cattell 8 states that this was historically true in one-third of such patients seen at the Lahey Clinic. Crohn,6 on the other hand, in analyzing 700 cases, has found a similar incidence of fistula formation whether or not the appendix was removed, and therefore favors its removal. Perhaps the approach of Ferguson,11 who reports that no fistulas have ever developed in his patients, is best. He states that the appendix should not be removed if, in the surgeon's judgment, neither it nor the cecum is grossly involved in the disease process. In any event, regional enteritis may be the only situation in surgery in which the surgeon is operating through a McBurney incision and does not remove the appendix. What is the treatment of obstruction, bleeding, perforation and tender fluctuant abdominal abscess? These four complications, each having an incidence of less than 5 per cent, necessitate emergency surgical intervention. Obstruction is usually heralded by a long, progressive disease. Acute obstruction is not of the strangulating type unless it is caused by adhesions occurring after previous surgery. As stated previously, preoperative long-tube decompression is desirable. The procedure of choice is bypass rather than resection for the obstructed terminal ileum. Bleeding, on the other hand, requires resection. If the extent of involvement of the bowel is questionable, a division at its apparently affected midportion, as advised by Cattell,8 may help localize the pathologic process and the bleeding site with the hope of sparing some length of small bowel. The treatment of perforation has been reviewed by Neely.27 Only six cases of this ominous complication have been reported; each was treated differently, so we have no satisfactory therapeutic criteria. Abscesses, of course, should be drained. No special concern is necessary about iatrogenic fistula formation if the incision is carried out over the maximum area of fluctuation. With abscess, enteric fistulas may already be present, and further treatment will be required after the infection is controlled. What is the cause of recurrent regional enteritis following operation and what are the indications for further operation? Van Patter et al. 35 have studied the effects of various factors on recurrence rates following resection. Those which have been shown to have no bearing include the patient's sex, type of procedure previously carried out, the presence of tubercles at the resection margins, the location of the lesion, the length of the lesion up to 50 cm. and the amount of grossly normal small bowel proximal to the lesion. But the duration of the disease before the initial operation and the age of the patient at the onset of symptoms seem to
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have a direct bearing. Thus, in the event of equivocal medical control of a postoperative recurrence, the surgeon should be aware of the probable necessity for re-resecting those patients whose initial symptoms were of longer than five years' duration or in whom the onset of the disease occurred during the first four decades of life. There seems to be an arithmetical progression of recurrence following re-resection, so again caution is emphasized. The procedure chosen in such cases will obviously depend largely on the nature of the first procedure and the location of the recurrence, but most surgeons agree that bypass is seldom chosen as a secondary procedure, except in extremely poor-risk patients, and that a judicious limited resection is the operation of choice. Finally, what is the best elective surgical procedure in terminal ileitis? This unresolved dispute turns on the rate of recurrence of the disease symtomatology following bypass ileocolostomy versus resectional procedures, and is independent of the operative mortality rate, which now approaches 2 per cent in all major series. Most recurrences may be expected within the first six months. The major proponent of bypass is Garlock et al. 14 who claim a 46 per cent recurrence rate following resection, and less than half that with bypass. The Garlock procedure involves exclusion by complete division of the small bowel above its diseased segment and an end-to-side ileotransverse colostomy with closure of the blind loop end. The statistics of Van Patter et al.,a5 however, show no appreciable difference in the rate of recurrence between this procedure and a simple side-to-side ileocolic anastomosis. Crohn 6 puts forth the following data in favor of bypass: Primary resection-116 cases
Results good Recurrence Death
57.8% 37.7% 9.5%
Bypass-232 cases
Results good Recurrence Death
67.7% 29.0% 3.4%
It should be noted that only a few of these deaths were operative, mostly in the early years of treatment when the operative mortality approached 10 per cent. Marshall and Fechner20 reject the bypass procedure and, on the basis of a 15 per cent recurrence rate in 223 primary resections, advocate resectional surgery whenever possible. In the 600 cases reported by Van Patter et al.3 5 from the Mayo Clinic the recurrence rate was 67 per cent after resection and 71 per cent after bypass. Colp and Dreiling,2 in an exhaustive study in 1952, analyzed the reports from 16 separate series on bypass procedures and from 28 separate series on resection and compared the weighted averages of the incidence of recurrence. For bypass the recurrence rate was 28.9 per cent and for resection, 21.9 per cent. We prefer resection to exclusion except in the presence of obstruction, poor surgical risk, or if the nature or extent of
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the pathologic findings would make resection hazardous. Our follow-up results have indicated a more rapid recovery and lower incidence of recurrence. While the statistics point irrefutably to the difficulties encountered in a smoldering disease, the over-all survival rates are high, probably greater than 95 per cent. Some observers feel that recurrence eventually may be expected in all cases. Age of onset seems to be very important in this regard, since the recurrence rate in patients who develop the disease after the age of 50 is less than 10 per cent; physiological alterations in youth, such as pregnancy,5 have been shown to exacerbate the disease. A compilation of ten different authors puts the over-all recurrence rate at about 30 per cent, with a high of 60 per cent and a low of 20 per cent in a one to 20 year follow-up. Fortunately, however, unlike ulcerative colitis, the incidence of carcinomatous degeneration is small, as pointed out by Ginzburg et al.,15 and only three such cases have been reported. REFERENCES 1. Chess, S., Chess, D., Olander, G., Benner, W. and Cole, W. H.: Production of Chronic Enteritis and Other Systemic Lesions by Ingestion of Finely Divided Foreign Materials. Surgery 27: 221-234, 1950. 2. Colp, R. and Dreiling, D. A.: Peristent or Recurrent Proximal Ileitis Following Surgery. A.M.A. Arch. Surg. 64: 28-46, 1952. 3. Cooke, W. T., Fowler, D. 1., Cox, E. V., Gaddie, R. and Meynell, M. J.: The Clinical Significance of Seromucoids in Regional Ileitis and Ulcerative Colitis. Gastroenterology 34: 910--919, 1958. 4. Crohn, B. B., Ginzburg, L. and Oppenheimer, G. D.: Regional Ileitis; A Pathologic and Clinical Entity. J.A.M.A. 99: 1323-1328, 1932. 5. Crohn, B. B., Yarnis, H. and Korelitz, B. 1.: Regional Enteritis Complicating Pregnancy. Gastroenterology 31: 615-624, 1957. 6. Crohn, B. B.: Current Status of Therapy in Regional Ileitis. J.A.M.A. 166: 14791480,1958. 7. Crohn, B. B.: Life Cycle of Regional Ileitis. Gastroenterology 34: 300--306,1958. 8. Crohn, B. B., Bargen, J. A., Brooke, B. N., Cattell, R. B., Kirsner, J. B. and Templeton, F. E.: Panel Discussion: Regional Enteritis. Gastroenterology 36: 398--408, 1959. 9. Eggers, C.: Transactions of the New York Surgical Society: Discussion on Nonspecific Granuloma of Ileum. Ann. Surg. 97: 132, 1933. 10. Emsbo, P.: Terminal or Regional Ileitis in Swine. Nord. Vet. Med. 3: 1-23,1951. 11. Ferguson, L. K.: Surgical Viewpoint in Regional Ileitis. J.A.M.A. 165: 20482052,1957. 12. Frazer, A. C.: A New Mechanism of Vitamin Deprivation with Special Reference to the Sprue Syndrome. Brit. Med. J. 2: 731-733, 1949. 13. Frazer, A. C.: Fat Metabolism and the Sprue Syndrome. Brit. M. J. 2: 769773,1949. 14. Garlock, J. H., Crohn, B. B., Klein, S. H. and Yarnis, H.: An Appraisal of the Long-Term Results of Surgical Treatment of Regional Ileitis. Gastroenterology 19: 414-423, 1951. 15. Ginzburg, L., Schneider, K. M., Dreizen, R. H. and Levinson, C.: Carcinoma of the Jejunum Occurring in a Case of Regional Enteritis. Surgery 39: 347351,1956. 16. Goldman, L. and Gardner, R. E.: Recent Advances in the Surgical Treatment
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of Diseases of the Gastrointestinal Tract and Abdomen. Arizona Med. 15: 257-262, 1958. Harris, F. 1., Bell, G. H. and Brunn, H.: Chronic Cicatrizing Enteritis. Surg. Gynec. & Obst. 57: 637-645, 1933. Heffernon, E. W. and Kepkay, P. H.: Segmental Esophagitis, Gastritis, and Enteritis. Gastroenterology 26: 83-88, 1954. Kantor, J. L.: Regional (Terminal) Ileitis: Its Roentgen Diagnosis. J.A.M.A.103: 2016-2021, 1934. Marshall, S. F. and Fechner, M. B.: Chronic Regional Ileitis: Surgical Treatment and Complications. Am. Surgeon 20: 337-347, 1954. Martin, F. R. R. and Carr, R. J.: Crohn's Disease Involving the Stomach; A Report on 2 Cases. Brit. M. J. 1: 70G-702, 1953. McGarity, W. C.: Regional Enteritis of the Duodenum. Surg. Gynec. & Obst. 105: 203-209, 1957. Meyer, P. C.: Pathogenesis of Segmental Enteritis. Brit. J. Surg. 47: 375-381, 1960. Mock, H. E.: Infective Granuloma: Nonspecific Chronic Tumor-like Productive Inflammations of the Gastro-intestinal Tract. Surg. Gynec. & Obst. 52: 672-689, 1931. Morson, B. C. and Lockhart-Mummery, H. E.: Anal Lesions in Crohn's Disease. Lancet 2: 1122-1123, 1959. Moschcowitz, E. and Wilensky, A.: Non-specific Granulomata on the Intestine. Am. J. M. Sc. 166: 48-66,1923. Neely, J. C.: Perforation in Regional Enteritis. J.A.M.A. 174: 168G-1682, 1960. Neely, J. C.: A Ten Year Analysis of Primary Small Bowel Pathology Causing Acute Small Bowel Obstruction in Adults. Am. J. Surg. (in press). Priestley, J. T. and Judd, E. S.: The Duodenum, Jejunum, Ileum and Appendix. In Christopher's Textbook of Surgery, 6th ed. Philadelphia, W. B. Saunders Co., 1956, p. 644. Reichert, F. L. and Mathes, M. E.: Experimental Lymphedema of the Intestinal Tract and Its Relation to Regional Cicatrizing Enteritis. Ann. Surg. 104: 601-616, 1936. Refvem, 0.: Enteric Mycosis (Regional Enteritis). Gastroenterology 35: 321325,1959. . Strande, A., Sommers, S. C. and Petrak, M.: Regional Enterocolitis in Cocker Spaniel Dogs. A.M.A. Arch. Path. 57: 357-362, 1954. Tallarigo, A. and Cacudi, G.: Istamina e Linfostasi nella Patogenesi della Enterite Regionale Sperimentale. Gior. Clin. Med. 39: 1925-1943, 1958. Tietze, A.: tJber entziindliche DickdarmgeschwUlste. Ergebun. d. Chir. u. Orthop. 12: 211-273, 1920. Van Patter, W. N., Bargen, J. A., Dockerty, M. B., Feldman, W. H., Mayo, C. W. and Waugh, J. M.: Regional Enteritis. Gastroenterology 26: 347450,1954. Warren, S. and Sommers, S. C.: Cicatrizing Enteritis (Regional Ileitis) as a Pathologic Entity. Am. J. Path. 24: 475-501, 1948. Yarnis, H., Marshak, R. H. and Crohn, B. B.: Ileocolitis. J.A.M.A. 164: 7-13, 1957.
University of California Medical Center San Francisco 22, California
JAMES C. NEELY, M.D. William P. Kyne Memorial Research Fellow in Surgery
LEON GOLDMAN, M.D., F.A.C.S. Professor and Chairman, Department of Surgery, and Surgeon-in-Chief, Herbert C. Moffitt-University of California Hospitals, San Francisco
BARELY 30 years have passed since Crohn, Ginzburg and Oppenheimer proposed "to describe, in its pathologic and clinical details, a disease of the terminal ileum, affecting mainly young adults, characterized by an acute or chronic necrotizing and cicatrizing inflammation."4 In spite of the generally prompt acceptance of the disease as a pathologic and clinical entity, this important and not uncommon condition, which Crohn called regional ileitis, was for a long time unrecognized as a distinct disease process. Even today, although some investigators believe that the incidence of this disease is increasing and more than 2000 cases have been recorded in the literature, an individual physician's lifetime experience with Crohn's disease is apt to be small. PATHOGENESIS AND PATHOLOGY
The cause of regional enteritis is unknown. All inflammatory diseases of the small bowel have an unexplained predilection for the terminal ileum, and as one progresses distally from the pylorus toward the ileocecal valve a correlative increase in the incidence of disease is demonstrable for all such lesions. Because of its ubiquitous distribution (rare cases have been recorded in the stomach), what was at first called terminal ileitis is now generically referred to as regional enteritis, a descriptive observation, however, which sheds no etiologic light. Nearly all the known non-neoplastic disease-causing agents have been implicated from time to time, including viruses, bacteria, protozoa, toxins, trauma and, more recently, auto-immune mechanisms. Enteric
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sarcoid, tuberculosis and lymphopathia venereum have been specifically implicated. Refvem31 has attributed the disease to a fungus. Frazer12 , 13 has suggested a relationship with nontropical sprue on the basis of similarly altered fecal fat values and bacteria counts. Chess and his associates1 produced chronic enteritis experimentally in dogs and rats by having them ingest sand and talc, which perhaps is what led some investigators to impugn tooth powder for a time. Reichert and Mathes30 demonstrated that lesions simulating regional enteritis can be produced by lymphatic blockage, and they produced an exacerbation of the process by intravenous bacterial injections. Tallarigo and Cacudi33 have called attention to the possible role of histamine following lymph stasis, while Cooke and his co-workers3 emphasized their clinical observation of the consistently high elevation of seromucoids in both regional enteritis and ulcerative colitis. Emsb0 10 first described a disease in swine, prevalent in Scandinavia, that is similar to regional enteritis, and Strande et aJ.32 have recently observed the same in cocker spaniels. Crohn, however, laid this issue to rest somewhat when he stated in a recent panel discussion that, "It is true that all the animals in the zoo have been inoculated with material from cases of regional enteritis and I know of no animal in which the disease has been successfully reproduced."8 Unquestionably too little is known of the composition and specific content of the succus entericus in this disease. As Van Patter and his associates35 point out in their excellent article, our knowledge of the intestinal enzymatic content, bacterial flora, protein by-products, and fat breakdown is too poor to rule out a specific substance in the fecal stream as causative, and it is in this area that future investigation is perhaps most promising. At present we are left with a multiplicity of factors that could combine in a synergistic relationship. These include genetic, metabolic, bacterial, allergic and psychosomatic influences. But, as has most often been the case with unexplained disease in the past, our clinicopathologic knowledge has become extensive, and from this the etiologic agent may eventually emerge. Pathologists distinguish between the acute, subacute and chronic forms of the disease. It is particularly important for the surgeon to recognize the gross characteristics of acute regional enteritis. The involved small bowel is typically reddened from hyperemia and is edematous and thickened and engorged all along its serosa, which is usually covered with a fibrinous exudate. Pathognomonic is a pincers-like circumserosal migration of toughened mesenteric fat. The affected segment is usually abruptly demarcated, frequently just at the ileocecal valve, although in 5 per cent of the cases there is an associated ileocolitis. The latter is a variant of regional enteritis, and is to be emphatically distinguished from segmental colitis, essentially a mild variant of ulcerative colitis, whose limited colonic resection is usually curative. Similarly
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"backwash ileitis" is a variant of ulcerative colitis and is to be carefully distinguished. The remainder of the bowel usually appears normal, but mesenteric thickening and regional lymphadenopathy are marked, and it is this alteration which most observers believe leads to the stasis of chyle which in turn leads to the progressive nature of the disease. A follow-up by Crohn 7 of surgically diagnosed "acute enteritis" shows that in 75 per cent of the cases the patient's disease subsides to a subacute or chronic form. In contrast, the chronic lesions assume a normal serosal hue without cngorgement or exudate. Bowel thickening and actual stiffening from proliferative changes and organizing fibrosis is present. The fatty migration still occurs and, depending upon the extent of the disease, interloop adhesions and kinking may be marked. Lymphadenopathy is often generalized by this time, and mesenteric thickening up to 2 to 3 cm. is common. With further progress of the disease the well-known cutaneous interloop and enterocolic fistulas, abscesses and cicatricial obstructions may occur, the obstructions often leading to dilatation and muscular hypertrophy of the proximal bowel. Intramural irregularity, thickening and intraluminal narrowing are conspicuous at this stage. Intraluminal ulcers, a distinguishing pathologic feature, are typically aligned along the mesenteric border between areas of shaggy, gray mucosa. The histopathologic features of the disease, however, as emphasized by Warren and Sommers,36 have enabled pathologists to split off regional enteritis as a disease entity from its categorization with "benign granuloma" of the small bowel as outlined by Tietze,34 Moschcowitz and Wilensky,26 and Mock24 during the early part of this century. While some observers such as Meyer, 23 in emphasizing the specificity for disproportionate hypertrophy of the muscularis mucosa, have directed their attention to specific bowel layers, all layers seem to be involved. The most typical primary changes occur in the submucosa and the mesentery. Interstitial edema, lymphoid hyperplasia, lymph duct ectasia, plasma cell infiltration, endothelial proliferation, perivascular histiocytosis and excavating ulcerations intersperse with varying degrees of acute cellular elements. Here also the controversial tubercle appears. This microscopic aggregation is composed principally of pale-staining histiocytes and is pathognomonic only insofar as the other clinical and pathologic aspects of the disease are present, since a variety of chronic infectious diseases of the bowel show the same response. The secondary microscopic changes are reparative in nature and all degrees of healing may be evident. Simultaneously, this early lesion in the submucosa is accompanied by edema and lymphatic obstruction of its mesentery. DIAGNOSIS AND THE CLINICAL PICTURE
A poorly publicized fact, one which probably stems from the repeated emphasis placed on the chronicity of regional enteritis and its long
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history of remissions and exacerbations, is that the initial manifestations of this disease may resemble those of the acute surgical abdomen. From a third to a half of the diagnoses of regional enteritis are made during exploration of the acute abdomen. Seven of Crohn's4 original 14 patients were explored for appendicitis, 30 per cent of the 600 patients reported by Van Patter et al.3 5 were so explored, and Neely,28 in reporting a 15-year experience at Cincinnati General Hospital, found that 60 per cent of the diagnoses were established during exploratory operations on the acute abdomen. Priestly and Judd 29 have admonished the surgeon for his lack of diagnostic acumen in this disease, but it seems likely, aR Fergusonl l has recently stated, that the clinical picture of acute regional ileitis or even the exacerbation of a chronic form is often indistinguishable from acute appendicitis. For this reason, and for the fact that the one condition is common and the other comparatively rare, operative intervention should not be withheld in questionable cases. What is most important, as emphasized previously, is that the surgeon must recognize with certainty the pathologic features of the disease process once he encounters them. Approximately two-thirds of the patients with Crohn's disease show evidence of a chronic disease process when they are first seen by the physician. No helpful social, ethnic, sexual or established geographical incidence exists. Cases have been reported in patients from the age of four to the age of 75, but 60 per cent of the patients are between 16 and 35 years old and only 10 per cent of the primary cases are first seen beyond the age of 50. A typical case would be that of a 25 year old white woman with a IS-month history of mild recurrent diarrhea and easy fatigability. Presenting symptoms would be increasing diarrhea, perhaps six to eight stools a day, mostly at night or in the morning, a loss in weight of 10 pounds in the past four months, and possibly a wet, macerating pruritus ani. She would appear well developed and well nourished, perhaps slightly anemic, but her vital signs would be normal. Three physical signs may give the diagnostic clue. One is previous abdominal scars, particularly an appendectomy scar, in which fistulous openings may be present. Fistulas, of course, may occur without scars. Secondly, a mass in the right lower quadrant is present 35 per cent of the time. The mass is moderately tender, may be fixed posteriorly, is firm and represents the inflammatory reaction in the terminal ileum with adjacent bowel, omentum and parietes. Thirdly, anal fissures and fistulas are frequent. Cattell 8 puts the incidence at 20 per cent, Morson and Lockhart-Mummery25 at 50 per cent. The history and physical findings at this point are usually sufficient to make the diagnosis, but other clinical features may be present in varying degrees. These include steatorrhea, myriad manifestations of avitamiinoss, hypocalcemia, arthritis, clubbing of the fingers, erythema nodosum, abdominal and perineal abscesses, and personality changes.
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Regional enteritis may present as a fever of unknown origin. The differential diagnosis may include Hodgkin's disease, lymphosarcoma, lymphopathia, enteric tuberculosis, sarcoid, carcinoid, endometriosis, enterogenous cysts, bacillary dysentery and parisitism. In the routine case it will be sufficient to rule out amebae and salmonella by proctoscopy and appropriate stool examinations before proceeding with roentgenologic examination. The "string sign," first described by Kantor 19 in 1934, is now classic and confirms the diagnosis. It represents the intraluminal narrowing from cicatrizing enteritis and usually refers to the involved 8 to 10 inches of terminal ileum. It is demonstrable by barium enema, small bowel reflux or a small bowel series from above. Depending upon the extent and duration of the disease, radiologists may be able to demonstrate mucosal serrations and bowel stiffening only by fluoroscopy, but they believe a string sign can be found eventually in 95 per cent of all cases. Thus repeated examinations may be indicated. Although death from regional enteritis is rare, an occasional patient seen late in the course of his disease, or who has been untreated or intractable, may develop severe inanition, multiple interloop fistulas, metastatic abscesses, progressive diarrhea, anemia, mineral deficiencies and electrolyte depletion. His condition gradually deteriorates until septicemia and death occur. TREATMENT AND PROGNOSIS
It must be emphasized that the primary treatment of regional enteritis is medical. In general, the surgeon treats only the complications, whether acute or chronic, for this is essentially a chronic recurrent disease that requires the perseverance and adjustments of a conscientiously supervised medical regimen. This includes detailed long-term dietary restrictions, stool bulk-forming preparations, vitamin supplements, enteric antibiosis, and appropriate rest. Eggers,9 and more recently Bargen,8 have employed radiotherapy, but with variable results. Steroids have not been shown to be routinely beneficial, but are probably indicated in the intractable case or during severe exacerbation. At such times bed rest in a hospital with sedation and intensification of all therapy is indicated. The surgeon should be consulted but, as Goldman and Gardner16 point out, it is not advisable to operate until the disease is quiescent or in a "burned out" stage when "the disease pattern is well established." The positive indications for surgery include: progressive symptomatic terminal ileitis, enteric or perirectal fistulas, hemorrhage, intestinal obstruction, postoperative recurrent progressive or recurrent enteritis, perforation and abscesses. The contraindications include: extensive and diffuse enteritis, rapidly progressive mucosal enteritis, and the combined
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ileocolitis recently described by Yarnis et al. 37 Occasionally, although extensive involvement of the bowel may be suspected clinically, one laparotomy may be indicated to confirm and even successfully ameliorate the patient's condition. Since most surgical intervention is carried out for intractability with progression of symptoms, the preoperative preparation is all-important in such a depleting disease. Blood replacement, electrolyte balance, vitamin deficiencies, serum protein alignment and weight stabilization should all be brought under control during a week or more of hospitalization before operation. Decompression with a Miller-Abbott tube is desirable for a few days before carrying out procedures to correct obstruction. Five days of preoperative preparation with either succinylsulfathiazole (Sulfasuxidine) or phthalylsulfathiazole (Sulfathalidine) and neomycin should be carried out, but care should be taken not to exacerbate the diarrhea. Before operative treatment of elective cases is considered, certain questions must be answered that are likely to be more pressing and often acute. How should the anal lesions be handled? The surgeon is cautioned not to do fissurectomies and fistulectomies prior to attacking the primary regional enteritis, since poor healing and recurrence under such circumstances is the rule. For some as yet unexplained reason these lesions nearly all regress when the underlying small-bowel disease is medically abated or surgically corrected. Should the surgeon operate on gastric, duodenal and jejunal lesions? Only if they have failed to respond to thorough medical therapy and are causing obstructive symptoms. The upper reaches of the bowel have repeatedly shown a greater propensity to heal. It is known that gastric resections have been carried out with disastrous results, although the published reports are few. A patient reported by Heffernon and Kepkay18 died from postoperative complications, while studies by Martin and Carr21 clearly show the regressive nature of unmolested gastric lesions. Duodenal lesions have been thoroughly discussed by McGarity,22 who, in analyzing 25 cases, cautioned against resection and pointed to the favorable results following bypass gastrojejunostomy. In the jejunum one may encounter either very long segments of involvement or short, truncated, often multiple areas. In the former instance, as in the case described by Harris, Bell and Brunn,17 there may be difficulty in delineating the extent of the disease process at the operating table. The presence of "skip lesions" must be determined by careful complete abdominal exploration in every case. These short segments, usually associated with disease elsewhere in the ileum, tend to recur at various points throughout the small and occasionally the large bowel, particularly following previous resection. What is the treatment of acute regional enteritis? The surgeon who finds acute regional enteritis in exploring the acute surgical abdomen
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should recognize the extent and severity of the disease process and do no further surgery. The symptoms in 25 per cent of such patients subside on medical therapy with no recurrence of the disease. Should the appendix be removed? Eleven per cent of Marshall and Fechner's2o series of 114 patients who had appendectomies developed abdominal wall fistulas. Cattell 8 states that this was historically true in one-third of such patients seen at the Lahey Clinic. Crohn,6 on the other hand, in analyzing 700 cases, has found a similar incidence of fistula formation whether or not the appendix was removed, and therefore favors its removal. Perhaps the approach of Ferguson,11 who reports that no fistulas have ever developed in his patients, is best. He states that the appendix should not be removed if, in the surgeon's judgment, neither it nor the cecum is grossly involved in the disease process. In any event, regional enteritis may be the only situation in surgery in which the surgeon is operating through a McBurney incision and does not remove the appendix. What is the treatment of obstruction, bleeding, perforation and tender fluctuant abdominal abscess? These four complications, each having an incidence of less than 5 per cent, necessitate emergency surgical intervention. Obstruction is usually heralded by a long, progressive disease. Acute obstruction is not of the strangulating type unless it is caused by adhesions occurring after previous surgery. As stated previously, preoperative long-tube decompression is desirable. The procedure of choice is bypass rather than resection for the obstructed terminal ileum. Bleeding, on the other hand, requires resection. If the extent of involvement of the bowel is questionable, a division at its apparently affected midportion, as advised by Cattell,8 may help localize the pathologic process and the bleeding site with the hope of sparing some length of small bowel. The treatment of perforation has been reviewed by Neely.27 Only six cases of this ominous complication have been reported; each was treated differently, so we have no satisfactory therapeutic criteria. Abscesses, of course, should be drained. No special concern is necessary about iatrogenic fistula formation if the incision is carried out over the maximum area of fluctuation. With abscess, enteric fistulas may already be present, and further treatment will be required after the infection is controlled. What is the cause of recurrent regional enteritis following operation and what are the indications for further operation? Van Patter et al. 35 have studied the effects of various factors on recurrence rates following resection. Those which have been shown to have no bearing include the patient's sex, type of procedure previously carried out, the presence of tubercles at the resection margins, the location of the lesion, the length of the lesion up to 50 cm. and the amount of grossly normal small bowel proximal to the lesion. But the duration of the disease before the initial operation and the age of the patient at the onset of symptoms seem to
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have a direct bearing. Thus, in the event of equivocal medical control of a postoperative recurrence, the surgeon should be aware of the probable necessity for re-resecting those patients whose initial symptoms were of longer than five years' duration or in whom the onset of the disease occurred during the first four decades of life. There seems to be an arithmetical progression of recurrence following re-resection, so again caution is emphasized. The procedure chosen in such cases will obviously depend largely on the nature of the first procedure and the location of the recurrence, but most surgeons agree that bypass is seldom chosen as a secondary procedure, except in extremely poor-risk patients, and that a judicious limited resection is the operation of choice. Finally, what is the best elective surgical procedure in terminal ileitis? This unresolved dispute turns on the rate of recurrence of the disease symtomatology following bypass ileocolostomy versus resectional procedures, and is independent of the operative mortality rate, which now approaches 2 per cent in all major series. Most recurrences may be expected within the first six months. The major proponent of bypass is Garlock et al. 14 who claim a 46 per cent recurrence rate following resection, and less than half that with bypass. The Garlock procedure involves exclusion by complete division of the small bowel above its diseased segment and an end-to-side ileotransverse colostomy with closure of the blind loop end. The statistics of Van Patter et al.,a5 however, show no appreciable difference in the rate of recurrence between this procedure and a simple side-to-side ileocolic anastomosis. Crohn 6 puts forth the following data in favor of bypass: Primary resection-116 cases
Results good Recurrence Death
57.8% 37.7% 9.5%
Bypass-232 cases
Results good Recurrence Death
67.7% 29.0% 3.4%
It should be noted that only a few of these deaths were operative, mostly in the early years of treatment when the operative mortality approached 10 per cent. Marshall and Fechner20 reject the bypass procedure and, on the basis of a 15 per cent recurrence rate in 223 primary resections, advocate resectional surgery whenever possible. In the 600 cases reported by Van Patter et al.3 5 from the Mayo Clinic the recurrence rate was 67 per cent after resection and 71 per cent after bypass. Colp and Dreiling,2 in an exhaustive study in 1952, analyzed the reports from 16 separate series on bypass procedures and from 28 separate series on resection and compared the weighted averages of the incidence of recurrence. For bypass the recurrence rate was 28.9 per cent and for resection, 21.9 per cent. We prefer resection to exclusion except in the presence of obstruction, poor surgical risk, or if the nature or extent of
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the pathologic findings would make resection hazardous. Our follow-up results have indicated a more rapid recovery and lower incidence of recurrence. While the statistics point irrefutably to the difficulties encountered in a smoldering disease, the over-all survival rates are high, probably greater than 95 per cent. Some observers feel that recurrence eventually may be expected in all cases. Age of onset seems to be very important in this regard, since the recurrence rate in patients who develop the disease after the age of 50 is less than 10 per cent; physiological alterations in youth, such as pregnancy,5 have been shown to exacerbate the disease. A compilation of ten different authors puts the over-all recurrence rate at about 30 per cent, with a high of 60 per cent and a low of 20 per cent in a one to 20 year follow-up. Fortunately, however, unlike ulcerative colitis, the incidence of carcinomatous degeneration is small, as pointed out by Ginzburg et al.,15 and only three such cases have been reported. REFERENCES 1. Chess, S., Chess, D., Olander, G., Benner, W. and Cole, W. H.: Production of Chronic Enteritis and Other Systemic Lesions by Ingestion of Finely Divided Foreign Materials. Surgery 27: 221-234, 1950. 2. Colp, R. and Dreiling, D. A.: Peristent or Recurrent Proximal Ileitis Following Surgery. A.M.A. Arch. Surg. 64: 28-46, 1952. 3. Cooke, W. T., Fowler, D. 1., Cox, E. V., Gaddie, R. and Meynell, M. J.: The Clinical Significance of Seromucoids in Regional Ileitis and Ulcerative Colitis. Gastroenterology 34: 910--919, 1958. 4. Crohn, B. B., Ginzburg, L. and Oppenheimer, G. D.: Regional Ileitis; A Pathologic and Clinical Entity. J.A.M.A. 99: 1323-1328, 1932. 5. Crohn, B. B., Yarnis, H. and Korelitz, B. 1.: Regional Enteritis Complicating Pregnancy. Gastroenterology 31: 615-624, 1957. 6. Crohn, B. B.: Current Status of Therapy in Regional Ileitis. J.A.M.A. 166: 14791480,1958. 7. Crohn, B. B.: Life Cycle of Regional Ileitis. Gastroenterology 34: 300--306,1958. 8. Crohn, B. B., Bargen, J. A., Brooke, B. N., Cattell, R. B., Kirsner, J. B. and Templeton, F. E.: Panel Discussion: Regional Enteritis. Gastroenterology 36: 398--408, 1959. 9. Eggers, C.: Transactions of the New York Surgical Society: Discussion on Nonspecific Granuloma of Ileum. Ann. Surg. 97: 132, 1933. 10. Emsbo, P.: Terminal or Regional Ileitis in Swine. Nord. Vet. Med. 3: 1-23,1951. 11. Ferguson, L. K.: Surgical Viewpoint in Regional Ileitis. J.A.M.A. 165: 20482052,1957. 12. Frazer, A. C.: A New Mechanism of Vitamin Deprivation with Special Reference to the Sprue Syndrome. Brit. Med. J. 2: 731-733, 1949. 13. Frazer, A. C.: Fat Metabolism and the Sprue Syndrome. Brit. M. J. 2: 769773,1949. 14. Garlock, J. H., Crohn, B. B., Klein, S. H. and Yarnis, H.: An Appraisal of the Long-Term Results of Surgical Treatment of Regional Ileitis. Gastroenterology 19: 414-423, 1951. 15. Ginzburg, L., Schneider, K. M., Dreizen, R. H. and Levinson, C.: Carcinoma of the Jejunum Occurring in a Case of Regional Enteritis. Surgery 39: 347351,1956. 16. Goldman, L. and Gardner, R. E.: Recent Advances in the Surgical Treatment
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of Diseases of the Gastrointestinal Tract and Abdomen. Arizona Med. 15: 257-262, 1958. Harris, F. 1., Bell, G. H. and Brunn, H.: Chronic Cicatrizing Enteritis. Surg. Gynec. & Obst. 57: 637-645, 1933. Heffernon, E. W. and Kepkay, P. H.: Segmental Esophagitis, Gastritis, and Enteritis. Gastroenterology 26: 83-88, 1954. Kantor, J. L.: Regional (Terminal) Ileitis: Its Roentgen Diagnosis. J.A.M.A.103: 2016-2021, 1934. Marshall, S. F. and Fechner, M. B.: Chronic Regional Ileitis: Surgical Treatment and Complications. Am. Surgeon 20: 337-347, 1954. Martin, F. R. R. and Carr, R. J.: Crohn's Disease Involving the Stomach; A Report on 2 Cases. Brit. M. J. 1: 70G-702, 1953. McGarity, W. C.: Regional Enteritis of the Duodenum. Surg. Gynec. & Obst. 105: 203-209, 1957. Meyer, P. C.: Pathogenesis of Segmental Enteritis. Brit. J. Surg. 47: 375-381, 1960. Mock, H. E.: Infective Granuloma: Nonspecific Chronic Tumor-like Productive Inflammations of the Gastro-intestinal Tract. Surg. Gynec. & Obst. 52: 672-689, 1931. Morson, B. C. and Lockhart-Mummery, H. E.: Anal Lesions in Crohn's Disease. Lancet 2: 1122-1123, 1959. Moschcowitz, E. and Wilensky, A.: Non-specific Granulomata on the Intestine. Am. J. M. Sc. 166: 48-66,1923. Neely, J. C.: Perforation in Regional Enteritis. J.A.M.A. 174: 168G-1682, 1960. Neely, J. C.: A Ten Year Analysis of Primary Small Bowel Pathology Causing Acute Small Bowel Obstruction in Adults. Am. J. Surg. (in press). Priestley, J. T. and Judd, E. S.: The Duodenum, Jejunum, Ileum and Appendix. In Christopher's Textbook of Surgery, 6th ed. Philadelphia, W. B. Saunders Co., 1956, p. 644. Reichert, F. L. and Mathes, M. E.: Experimental Lymphedema of the Intestinal Tract and Its Relation to Regional Cicatrizing Enteritis. Ann. Surg. 104: 601-616, 1936. Refvem, 0.: Enteric Mycosis (Regional Enteritis). Gastroenterology 35: 321325,1959. . Strande, A., Sommers, S. C. and Petrak, M.: Regional Enterocolitis in Cocker Spaniel Dogs. A.M.A. Arch. Path. 57: 357-362, 1954. Tallarigo, A. and Cacudi, G.: Istamina e Linfostasi nella Patogenesi della Enterite Regionale Sperimentale. Gior. Clin. Med. 39: 1925-1943, 1958. Tietze, A.: tJber entziindliche DickdarmgeschwUlste. Ergebun. d. Chir. u. Orthop. 12: 211-273, 1920. Van Patter, W. N., Bargen, J. A., Dockerty, M. B., Feldman, W. H., Mayo, C. W. and Waugh, J. M.: Regional Enteritis. Gastroenterology 26: 347450,1954. Warren, S. and Sommers, S. C.: Cicatrizing Enteritis (Regional Ileitis) as a Pathologic Entity. Am. J. Path. 24: 475-501, 1948. Yarnis, H., Marshak, R. H. and Crohn, B. B.: Ileocolitis. J.A.M.A. 164: 7-13, 1957.
University of California Medical Center San Francisco 22, California