Crohn and Ginzburg and Oppenheimer (CGO) and Beyond
David Cohen, M.D.·Published 26 August 2015·10 min read
Key points
To understand the historical evolution of the disease, a review of its initial definition is critical.
Lastly, the ultimate presentation was that of intestinal obstruction noted to be occasionally "visible through the emaciated abdominal wall.
An important contribution to the definition of the disease was published in JAMA by Kantor in 1934, which created a more formal roentgenographic description of disease .
Throughout the remainder of the 1930s into the early 1940s, numerous case reports and small case series began to emerge, confirming and expanding upon the findings of Crohn et al.
To understand the historical evolution of the disease, a review of its initial definition is critical. In 1932, Crohn, Ginzburg, and Oppenheimer identified 14 cases of inflammatory disease of the terminal ileum which they believed to be a newly defined entity called "regional ileitis." The key diagnostic findings outlined by the authors included - 1) a mass in the right iliac region, 2) evidence of fistula formation, 3) emaciation and anemia, 4) the scar of previous appendectomy, and 5) evidence of intestinal obstruction". The mass in the right iliac region was inflamed, thickened ileum. Fistula was near universal finding and was noted to form readily to adjacent bowel, often sigmoid, or ascending colon. In at least half of the cases, the appendix had been removed at a prior operation indicating likely previous diagnostic confusion, but not definitively ruled out as a potential causative factor in pathogenesis.
Lastly, the ultimate presentation was that of intestinal obstruction noted to be occasionally "visible through the emaciated abdominal wall." In his comments, Crohn noted the great lengths to which Dr. Paul Klemperer, the pathologist, had gone to painstakingly exhaust alternative diagnoses such as tuberculosis, symphilis, actinomycosis, Hodgkin's disease, and lymphosarcoma.
An important contribution to the definition of the disease was published in JAMA by Kantor in 1934, which created a more formal roentgenographic description of disease . Dr. Kantor endowed the term "string sign" to the stricture often seen roentgenographically in the terminal ileum of advanced cases. Additional "chief changes" as described by Kantor included filling defect just proximal to the cecum, abnormality in contour of the last filled loop of ileum, and dilation of ileum proximal to the lesion.
Throughout the remainder of the 1930s into the early 1940s, numerous case reports and small case series began to emerge, confirming and expanding upon the findings of Crohn et al. The early experience was clouded by uncertainty as to the correct operation and high mortality associated with the stage of presentation. In 1935, Mixter published 11 operative cases from the Beth Israel Hospital in Boston. Six patients were treated with a single stage ileocecal resection, while five required staged resection all of which were complicated by fistula or abscesses postoperatively. In 1937, Pemberton et al. published the Mayo Clinic series of 39 cases (36 operative) with 47 major surgical procedures and an associated mortality rate of 4.2 % .
Amongst these early reports, operations commonly performed included bypass procedures (ileo-ileostomy, ileocolostomy, ileosigmoidostomy), resection and ileo-colonic anastomosis, or drainage alone without resection. These early series included patients with proximal small bowel lesions in addition to the terminal ileum, beginning the expansion of the clinical definition. With additional cases being brought to the literature, the clinical spectrum and epidemiology became elucidated. These early case reports were encouraging for the success of surgical management as gross recurrence was rarely encountered in the early experience and surgery was believed to be curative.
Written and revised by
David Cohen, M.D.
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Despite the initial description that the pathology was limited to the distal ileum, early series of Crohn's disease soon revealed more widespread gastrointestinal tract disease. Dr. Ralph Colp at The Mount Sinai Hospital is credited with the first description implicating Crohn's colitis as an associated entity in 1934 . Two years later Crohn reported being "loath to accept the fact that ileitis of any type could involve the colon in an analogous inflammatory process" however did ultimately accept this association later in his career . In a 1954 publication, Crohn described the finding of both ileitis and colitis as a "bewildering combination of two disease processes" . Associated colonic inflammation was believed to be either an innocent bystander from disease "spread," or a separate synchronous illness such as ulcerative colitis. It was not until the late 1950s and early 1960s that there was acceptance of Crohn's (granulomatous) colitis as a distinct entity . In 1952, Wells was the first to definitively use the description "Crohn's disease of the colon" .
Differentiation between alternative forms of colitis was challenging. In 1960, Lockhart-Mummery described 25 cases of regional enteritis of the large intestine with criteria to differentiate it from ulcerative colitis . By the 1970s, Crohn's colitis was a well-established entity .
Descriptions of involvement of other portions of the intestinal tract followed in parallel, including that of perianal disease, and gastroduodenal disease. Bissell, in 1934, reported an association between regional ileitis and perianal disease. Penner and Crohn in 1938 expanded upon this significantly with a series of patients with regional ileitis who also had perianal and rectovaginal fistula. While no etiology was suggested, they astutely recognized that in a series of 56 patients, 14 % were diagnosed with fistula in ano. This was a rate which far exceeded any known association with routine diarrheal illnesses. In 1950, Comfort et al. reported the first accounts of gastroduodenal granulomatous inflammation and its relationship with regional ileitis . In the early 1950s, extraintestinal manifestations of the disease were noted, specifically the association with arthritis which was later expanded upon in larger retrospective reviews in the 1970s.
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Likely impeding a wider recognition of the disease process earlier was the inability to precisely define the pathophysiology or epidemiology. Leading opinions of the 1930s were a yet undetermined microbiologic pathogen (bacterial, toxin-mediated, viral, protozoa), fecal stagnation due to the ileocecal valve, foreign body reaction, lymphangitis, vascular insult, or hereditary. Early case series speculated that there was a link to Jewish ancestry as hospitals with large Jewish populations were amongst the first to report cases. Genetic associations were first sug-gested by noting familial clustering as early as the 1930s and were confirmed decades later by identifying common polymorphisms (i.e., NOD2, ATG16L1) that affect host- microbe interactions in the intestinal tract and autophagy, respectively. Many more genetic associations have been since described.
The early surgical treatment of Crohn's disease was surrounded by controversy given the difficulty in diagnosis and the unknown prognosis. Initial case series reported that patients frequently underwent appendectomy when in retrospect the clinical picture and gross operative findings were more consistent with acute ileitis. With improved recognition of the disease, controversy existed as to the best operative strategy.
Resection was mandated by some groups, while others advocated for surgical bypass of the affected bowel. In groups advocating resection, further debate existed as to the merits of a single or multi-stage operations which included a first stage bypass followed by delayed resection of abnormal bowel. At the Mount Sinai Hospital, Dr. Berg initially advocated for right colectomy as performed for cancer but later changed his preference to bypass owing to lower surgical mortality rates. The bypass procedure was adopted as the procedure of choice at The Mount Sinai Hospital and was initially planned as a part of a staged operation and not definitive therapy . However, clinical improvement following bypass alone resulted in its being adopted as sole surgical therapy.
Principles touted by Ginzburg, in a 1942 review of cases at The Mount Sinai Hospital, included the need to evaluate the entire small bowel for skip lesions and that ileotransverse colostomy with exclusion should be the definitive surgical procedure, as he found a 0 % mortality rate when this procedure was performed . Diffuse involvement of the small bowel was widely considered to be a contraindication to surgery because of the significant risk of short bowel syndrome. Improvement in surgical mortality in successive decades likely had more to do with improvements in anesthesia and perioperative care rather than choice of procedure.
One particularly historic case of Crohn's disease involved the 34th President of the United States, Dwight David Eisenhower. His illness and treatment were subsequently reported in detail by Lt. Gen. Leonard Heaton et al.. In 1956, at 65 years of age, President Eisenhower presented with vague lower abdominal discomfort. Symptoms progressed to include obstipation, abdominal distention, and bilious emesis. After initial fluid resuscitation, he was brought to Walter Reed Army Hospital. He had a history of prior appendectomy and was known to have suffered from bouts of recurrent abdominal pain (Fig. 1.5 ).
On June 9th, he underwent laparotomy via a right paramedian incision. Gross description of the findings depicted a long strictured segment of terminal ileum with "claw-like" projections of mesenteric fat towards the antimesenteric border and no identifiable skip lesions. Ileotransverse colostomy was performed. His post-operative course was notable for passage of flatus on POD#5 and full resumption of administrative duties. He was ultimately discharged on post-operative day 21. There was significant criticism of the choice of operation at the time, since it did not involve resection. The surgeons concluded that a bypass was the most expeditious conservative operation given the President's preoperative state and his recent myocardial infarction.
During the 1950s, increasing experience lead clinicians to recognize that despite surgery, the disease process resulted in high recurrence rates. Large retrospective series from the major teaching institutions in the 1950s became available, and further scrutiny of the optimal operative strategy developed . These series allowed direct comparisons of patients who underwent the two predominating operations of the time: resection versus bypass.
Endpoints such as disease persistence and clinical recurrence were compared directly and were shown to favor resection with primary anastomosis (Fig. 1.6 ). Soon, additional concerns about the bypass procedure developed. Greenstein et al. from The Mount Sinai Hospital in the 1970s, published reports of carcinoma in the excluded bowel segment.
With high rates of surgical recurrence prevalent, even when all macroscopic disease was resected, there was significant controversy over the necessity of disease free margins. The effect of residual microscopic disease at the resection margins was evaluated for both recurrence risk and its potential for post-operative complication (e.g., anastomotic dehiscence). Retrospective reviews showed positive microscopic margins in up to 50 % of resections; however, no statistically significant effect was found on the rate of anastomotic complications . Early retrospective reviews suggested that the risk of recurrence was unaffected by presence of microscopic disease at the surgical margin. A randomized trial by Fazio et al., at the Cleveland Clinic, in 1996 concluded that recurrence rates did not differ when extended resection was performed even when microscopic disease was present at the margin. This provided further support to the practice of limiting extent of bowel resection in order to preserve as much intestinal length and absorptive surface as possible.
The presence of proximal small bowel lesions was considerably troublesome, and was widely considered a contraindication to surgery, as reiterated by Crohn in the 1950s . Common practice, when small bowel strictures were symptomatic, was either to avoid surgery with supportive care alone, perform limited resections or to bypass involved proximal segments of bowel.
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Surgical conservatism led to the principles of management still held today which involve treating specific complications (i.e., refractory obstruction, perforation) of the disease, and conserving as much bowel as possible. Stricturoplasty as a technique to relieve stricture was reportedly first employed in 1961 by Bryan Brooke and has subsequently been shown to be a useful adjunct to surgical management. The first case of Crohn's disease treated with stricturoplasty was published by Lee and Papaioannou in 1982.
They noted that many others were already describing this technique at meetings, but were reticent to publish their results due to fears that this technique would not provide long-term benefit, and would result in high morbidity due to the risks of leak and fistula. Their data, however, confirmed its safety.
The reduction of surgical morbidity has continued with the advent and dissemination of minimally invasive techniques. Contained perforation resulting in abscess formation is now readily managed with image-guided drainage. More recent advances in surgery have brought about the era of laparoscopic surgery for Crohn's disease. Laparoscopic ileocecal resection is now a well-validated option without any significant disease specific outcome disadvantages.
Major advances in the medical treatment of Crohn's disease have paralleled improved understanding of its pathophysiology. The initial treatment was believed to be surgical with therapeutic nihilism being the standard of care between relapses and supportive care for chronic symptoms. High rates of recurrence, need for reoperation, and medical consequences of wide resection (i.e., B12 deficiency, bile salt deficiency, chronic malnutrition, anemia) were frequently reported. Furthermore, because of the morbidity associated with extensive small bowel resections, patients with "jejunoileitis" were largely considered non-operative cases.
In the 1950s and 1960s, groups reported the first cases of remission with use of ACTH and corticosteroids . The side effects of chronic steroid use, however, provided the impetus for study of non-steroid agents to induce and maintain remission, and also led to the development of steroid medication with low systemic absorption such as budesonide, which was evaluated with a double-blind randomized trial in the early 1990s. Immunomodulatory agents including methotrexate, cyclosporine, azathioprine, and 6-mercaptopurine were tested throughout the 1980s and 1990s. With design and scaled production of monoclonal antibodies, development of anti-TNF- α antibodies has had significant success at inducing remission in steroid resistant patients with severe active disease.
Despite over 80 years of familiarity with the many facets of Crohn's disease, medical and surgical decision making remains challenging. Our current ability to provide a precise treatment to those affiicted with this disease mirrors our ability to define the precise mechanisms of disease.
Acknowledgments The authors wish to acknowledge the invaluable contributions made by Arthur H. Aufses, Jr., M.D., who was kind enough to critically review the manuscript, and who provided us with access to his personal photographs, and by Barbara J. Niss, Archivist of the Mount Sinai Medical Center, who provided us with access to the Mount Sinai Levy Library Archives.
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