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Capsule endoscopy in the diagnosis and management of inflammatory bowel disease
Gastrointest Endoscopy Clin N Am 14 (2004) 179 – 193
Capsule endoscopy in the diagnosis and management of inflammatory bowel disease Simon K. Lo, MD Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, 8635 West 3rd Street, Suite 876W, Los Angeles, CA 90048, USA
Crohn’s disease is suspected clinically by chronic or relapsing abdominal pain, diarrhea, gastrointestinal bleeding, or weight loss. The diagnosis is usually established by findings on intestinal radiography, endoscopy, or during surgery. Typical Crohn’s histopathology is preferred but not mandated to support the diagnosis.
Current modalities in diagnosing small intestinal Crohn’s disease Conventional radiology Because small intestinal Crohn’s disease has been traditionally difficult to visualize; contrast small bowel radiography remains the main diagnostic imaging modality [1]. There is not a single pathognomonic radiographic feature that defines Crohn’s disease. Rather, the radiologic diagnosis is based on subjective interpretations that takes into consideration a range of findings such as aphthous ulcers, deep ulcerations, mucosal cobblestoning, skip lesions, fissures, fistulas, strictures, and pseudopolyps [2]. A single contrast small bowel series is the most commonly ordered luminal radiographic study, although enteroclysis is considered the diagnostic test of choice because of the ability to distend the intestinal lumen for a detailed double contrast examination [2,3]. Conventional endoscopy The limited lengths of traditional endoscopes leave a significant segment of the small bowel without endoscopic examination for Crohn’s disease. Upper endoscopic examinations may identify Crohn’s lesions as erythema, aphthous ulcers, nodules, deep ulcers, and strictures in the gastric antrum or duodenum
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[4]. Endoscopic features of Crohn’s disease in the terminal ileum are less well described, but the mere identification of ileal ulcers is considered diagnostic. Histologic examination of ileal tissue obtained during endoscopy provides additional confirmation of the diagnosis and disease activity when the endoscopy alone is inconclusive. In the colon, the characteristics of Crohn’s disease include skip lesions, aphthous ulcers, cobblestoning, linear ulcers, serpiginous ulcers, and fistula formation [4]. Enteroscopy The dedicated push enteroscopy, with the length of roughly two to three times that of a regular upper endoscope, was designed with the hope that it would enter deep inside the small intestine. However, it can rarely reach 100 cm beyond the ligament of Trietz [5]. A push enteroscope has the same functions as a standard endoscope, and it allows biopsy to be performed for tissue confirmation of Crohn’s disease. However, the literature is lacking in the application of push enteroscopy for Crohn’s disease and it is probably not commonly practiced in the general community. Sonde enteroscopy has been reported to reach the ileum in roughly 75% of the time, although it rarely passes into the terminal ileum in practice [5]. It is a time-consuming process with significant patient discomfort and is now rarely used [4]. Push enteroscopy can be performed in a laparotomy setting in which the endoscopy is assisted down the tortuous intestine through surgeon’s manipulations. When performed in this manner, the scope can reach the entire length of the small intestine quite reliably [6]. Yamamoto [7] recently introduced a special version of a push enteroscopy that could reach the distal small intestine in a fraction of the patients. However, it is also a labor intensive procedure that may take more than 2 hours to perform. In addition, potentially serious complications that are seen with intra-operative enteroscopy, such as serosal tears, avulsion of mesenteric vasculature, and prolonged ileus will probably be encountered in this procedure [6]. Although the prospect of a total small bowel examination with the possibility to perform therapy or biopsy is exciting, it is unlikely to become a routine test used in the examination of the distal small intestine. Special enterography It is now possible to examine the small intestine using a multiplanar spiral computed tomography (CT) scanner and an oral contrast agent. In a recent study, this new CT enterography technique and barium contrast upper GI series produced similar findings in Crohn’s disease [8]. Therefore, this new application of CT is unlikely to add much to the existing radiologic imaging modalities. Instead, the role of CT is primarily restricted to the detection of complications of Crohn’s disease. It is very useful in identifying abscesses, fistulas, bowel wall thickening, and extra-intestinal inflammation [2]. Likewise, magnetic resonance (MR) enterography can be performed by modifying conventional MRI examina-
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tions and by intestinal infusion of methylcellulose. Although MR enteroclysis is capable of detecting lesions of Crohn’s disease such as thickening and distortion of small bowel folds, the resolution is insufficient for depiction of more subtle lesions such as aphthous ulcers [9].
Serologic diagnosis of Crohn’s disease Two of the principle symptoms of Crohn’s disease are chronic abdominal pain and diarrhea, which are also commonly seen in irritable bowel syndrome [10]. The number of individuals afflicted with these symptoms make it impractical to work up every potential patient with small bowel series, upper endoscopy, and colonoscopy. It is even more difficult to investigate patients without any upper gastrointestinal or colonic lesions because of the technical difficulty in accessing the mid- and distal small bowel. These limitations would invariably lead to mistakes in under-diagnosing the condition and hence treating it inappropriately for functional symptoms. It would be highly desirable to have a non-invasive blood test to triage symptomatic individuals for more intensive investigations of inflammatory bowel disease (IBD). This serologic test could be more valuable in further differentiating Crohn’s disease from ulcerative colitis. Indeed, a blood panel that can detect antineutrophil cytoplasmic antibodies (ANCA) and Saccharomyces cerevisiae antibodies (ASCA) has been shown to be positive in many patients with Crohn’s disease [11,12].
Are conventional studies adequate in evaluating small bowel Crohn’s disease? In spite of the large arrays of imaging and serologic studies for small bowel Crohn’s disease, there are still many case scenarios in which a more sensitive imaging modality is needed. Patients who have well controlled ulcerative colitis but experience significant symptoms should be screened for small bowel Crohn’s disease. These symptoms include unexplained hematochezia or melena, abdominal pain, diarrhea, or B12 deficiency. Likewise, patients with quiescent Crohn’s colitis who continue to have abdominal symptoms deserve to be worked up more thoroughly even if the conventional imaging tests are negative. It is common to encounter symptomatic Crohn’s disease patients who have a normal barium radiography and retrograde ileoscopy. In the past, these patients were frequently labeled as having functional problems. However, it is entirely possible that they may have subtle active small bowel disease that escapes detection because of insensitive imaging tests. Finally, patients with genuine chronic abdominal symptoms suggestive of Crohn’s enteritis, but without definite proof of disease, also deserve to be investigated further. Capsule endoscopy carries great promise in taking on the imaging role vacated by all existing modalities. The combination of total intestinal examination and visualization of fine mucosal details provide
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capsule endoscopy with unprecedented theoretical advantage in diagnosing intestinal Crohn’s disease [4].
Concerns about performing capsule endoscopy on Crohn’s patients Capsule endoscopy was approved by the Food and Drug Administration to study the small intestine in the United States in August of 2001. One of its contraindications is intestinal obstruction, which is obviously a major concern for Crohn’s disease. It has been reported that intestinal obstruction occurs in 35% to 54% of Crohn’s disease. [13]. If a capsule is stuck within the stricture of a Crohn’s lesion, it could lead to acute intestinal obstruction. Even if there is no obstructive symptoms, a retained capsule has to be removed before leakage of the capsule’s contents result in intestinal injuries. Indeed, capsule retention caused by obstructive lesions is the most common complication of capsule endoscopy, and it has been reported to be around 0.75% [14].
Case examples Patient 1 The author’s experience with capsule endoscopy for Crohn’s disease related issues began with a young woman with a known history of ulcerative colitis and persistent abdominal pain in spite of quiescent colitis. Her capsule study was negative and she was subsequently reassured and managed for other functional abdominal pain without further problems. Patient 2 A woman with Crohn’s disease was studied for severe mid abdominal pain despite negative upper endoscopy, colonoscopy, and small bowel series. It was previously believed that she had chronic pain syndrome with possible secondary gain, but her capsule endoscopy revealed extensive Crohn’s ulcers throughout the small intestine; she has since been treated accordingly. These early anecdotal experiences provided the authors with the rationale to proceed with further capsule endoscopy investigations, with slight trepidation for potential intestinal obstruction. Patient 3 The author’s first case of capsule endoscopy for an obstructive Crohn’s disease was incidentally done on a woman with long standing right lower abdominal pain, recurrent nausea, and abdominal bloating. Multiple endoscopic CT and small bowel imaging studies were unrevealing. Being a registered nurse and a medical researcher herself, this woman suspected that she had an obstructive disease that
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could not be proven by all conventional means. When warned of potential capsule retention in the setting of an obstructive lesion, she said that she would be delighted because she would readily accept surgical intervention. Indeed the capsule was arrested in the distal ileum, but the cause could not be identified because of a large amount of food debris in the same area. The patient underwent an ileal resection and the tissue specimen confirmed stenosing Crohn’s ileitis. She remained asymptomatic more than 12 months after her surgery. This case exemplifies the possibility of intestinal obstruction despite multiple negative gastrointestinal studies. In addition, her long standing symptoms might have eventually led her to surgical resection even if Crohn’s disease had been diagnosed and the capsule study had never been performed. Nonetheless, the author’s current policy is to look for possible obstructive symptoms before proceeding with any capsule study. All patients with suggestive symptoms must have a prior small bowel barium study with non-obstructive results.
Current clinical experience There are perhaps 20 preliminary studies on capsule endoscopy for Crohn’s disease that have been presented at the various international meetings. Virtually all of these studies reported on less than 50 patients but all showed some evidence that capsule endoscopy could become useful in the diagnosis and management of small bowel Crohn’s disease. The first report on the usefulness of capsule endoscopy for Crohn’s disease was published recently. Fireman et al [15] performed the study on 17 subjects suspected of the condition but without positive findings on conventional diagnostic tests of small bowel radiography and upper and lower endoscopies. All patients had some combination of complaints or findings that included iron deficiency anemia (59%), abdominal pain (71%), diarrhea (35%), and weight loss (18%). A surprisingly large number of patients (71%) in this small study were found to have intestinal lesions compatible with Crohn’s disease by capsule endoscopy. This small study provided the insight into the inadequacy of conventional imaging tests in diagnosing Crohn’s disease. Care must be taken, however, not to assume this to be a widespread problem because this patient population was probably selected. The author has studied over 200 patients with issues related to Crohn’s disease at his center. These patients include those with known history of Crohn’s disease, indeterminate colitis, suspected Crohn’s disease, and those with incidentally found Crohn’s enteritis. In the following paragraphs the author presents the available literature and his unpublished data on the use of capsule endoscopy in the diagnosis and management of Crohn’s disease [16 –19].
Appearance of Crohn’s lesions on capsule endoscopy Using capsule endoscopy to diagnose small intestinal Crohn’s disease can be challenging, because the small bowel lining has never been visualized in this
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Fig. 1. Sample of endoscopic pictures of intestinal Crohn’s lesions, in patients with established Crohn’s disease, captured with the Given capsule. (A – C) Focal and extensive loss of intestinal villi. (D, E) Solitary and multiple aphthous lesions. (F, G) Solitary erosion or shallow ulcers. (H, I) Linear ulcerations. (J – L) Extensive, coalescing ulcers with cobblestone appearance of intestinal mucosa. (M, N) Deep, fissuring ulcers. (O – Q) Ulcers with strictures. (See also Color Plates 60 and 61).
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Fig. 1 (continued).
manner. The natural assumption is that the typical ulcers, erosions, and inflammation seen in the terminal ileum and duodenum by conventional endoscopy would appear the same in the small bowel on capsule endoscopy. However, this assumption cannot be taken for granted without corroborating evidence on conventional endoscopy and perhaps even histological confirmation. To satisfy this point of contention by potential doubters, the author retrospectively examined his case records and identified patients with known Crohn’s disease who had undergone upper endoscopy, push enteroscopy, or colonoscopy within 5 weeks of capsule endoscopy. Histology reports were also reviewed to provide additional supporting information. Of 51 cases completed to date, 20 had an upper endoscopy, a retrograde ileoscopy, push enteroscopy, or surgical specimen for correlations. Nine of the 20 capsule endoscopies were normal and were confirmed negative by conventional video endoscopy in the upper gastrointestinal tract or terminal ileum. Five of these nine patients had both upper endoscopy or push enteroscopy and retrograde ileoscopy performed; the rest only had retrograde ileoscopy done. Ten Crohn’s patients had active disease on capsule endoscopy and independently confirmed by upper endoscopy or push enteroscopy [3], upper endoscopy and retrograde ileoscopy [1], surgical resection of the distal small bowel [1], or retrograde ileoscopy [5]. One patient had a normal capsule study but was found to have minimal ileitis with few superficial aphthous ulcers in the terminal ileum on retrograde ileoscopy. The author’s preliminary findings in a small sample of patients show that capsule endoscopy can accurately identify normal and Crohn’s lesions within the
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two ends of the small intestine, with a 95% sensitivity and 100% specificity. Interestingly, even the appearance of lesions on capsule endoscopy closely resembled those captured with conventional endoscopy (Fig. 1). The lesions were reported as linear ulcerations, circumferential ulcers, stellate ulcers, aphthous ulcers, or erosions. It was obviously not possible to correlate mid-small bowel findings between capsule endoscopy and conventional endoscopy. However, there is no reason to believe that they would appear differently from those seen elsewhere in the small intestine. In summary, endoscopic lesions seen on capsule endoscopy are identical to those seen on routine endoscopy. One should be able to apply the standard endoscopic criteria to capsule endoscopy in identifying Crohn’s lesions.
Is capsule endoscopy better than barium small bowel series in diagnosing Crohn’s lesions? Fireman’s study [15] provided the initial insight that capsule endoscopy might be superior to the conventional imaging modalities in diagnosing Crohn’s enteritis. Costamagna et al [20] performed sequential barium small bowel follow through and capsule endoscopy on 22 patients suspected of having small bowel diseases. Capsule endoscopy was found to be superior to small bowel radiographs in identifying mucosal pathologies. In this study, only 20% of the radiographic studies was positive, whereas the capsule produced diagnostic findings in 45% and suspicious findings in another 40%. The capsule study revealed lesions that were suggestive of Crohn’s disease in 3 patients, whereas the radiograph studies were positive in only one patient. The author retrospectively examined 27 patients with known Crohn’s [14], indeterminate colitis [9], or suspected Crohn’s disease [4] that had undergone capsule endoscopy and small bowel follow through within 45 days of each other (Table 1). All capsule studies were reviewed by an experienced endoscopist without prior knowledge of the radiograph results. Capsule endoscopy superior to small bowel studies in detecting Crohn’s like lesions (Fisher’s Exact Test P < 0.0001). More importantly, all the positive findings seen on small bowel series were also identified by capsule endoscopy. If one assumes that capsule endoscopy were the new ‘‘gold standard’’ for diagnosing intestinal Crohn’s disease, then the yield of radiography is only 24%. The low sensitivity of small bowel series and lack of additional information to findings on capsule endoscopy raises serious doubt about the value of radiographic studies. However, it must
Table 1 Comparison between capsule endoscopy and small bowel series in the detection of Crohn’s disease
Small bowel series Capsule endoscopy
Crohn’s like lesions
No Crohn’s lesions
5 (19%) 21 (78%)
22 (81%) 6 (22%)
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emphasized that there was a selection bias because of exclusion of patients with advanced, stricturing Crohn’s disease. Despite the imperfection of the author’s study, he is now ordering small bowel series as a screening procedure for obvious small bowel lesions and exclusion of obstructive disease in patients with suggestive symptoms. Symptomatic patients with negative radiograph examinations and without small bowel obstructions would routinely undergo investigations by capsule endoscopy.
Is capsule endoscopy better than push enteroscopy in diagnosing Crohn’s disease? Crohn’s disease is traditionally a distal small bowel disease and therefore places push enteroscopy at a disadvantage. There is no published report comparing push enteroscopy and capsule enteroscopy for this condition. However, Ell et al [21] performed enteroclysis, mesenteric angiography, bleeding scintigraphy, push enteroscopy, and capsule endoscopy on 32 patients referred for chronic obscure gastrointestinal bleeding. Two of the patients had chronic IBD causing the bleeding, whereas these lesions were missed by push enteroscopy. It has been reported that push enteroscopy could identify Crohn’s disease in 50% of suspected patients [4]. However, the original description was derived from a small sample and should not be regarded as the true experience without further confirmations [22].
Is capsule endoscopy better than serologic markers in diagnosing Crohn’s disease? Serologic markers are generally regarded as specific (> 90%) IBD but lacking the sensitivity (50 – 70%) to do large scale screening [23,24]. Therefore, they are primarily reserved to test individuals with significant and suspicious symptoms. When capsule endoscopy first became available, the author was uncertain if this test was sensitive in detecting small intestinal Crohn’s disease, clinically active Crohn’s disease, or not at all. One obvious question to the author was whether capsule endoscopy and serologies would merely identify Crohn’s disease on the same individuals or serve as complementary tests and hence increase the likelihood of detecting Crohn’s disease. Patients with established Crohn’s disease Perhaps the first step to assess the sensitivity of a diagnostic study is to apply the test on patients with known Crohn’s disease and that is what the author did with capsule endoscopy. In addition, the author measured it against the only available serologies for diagnosing Crohn’s disease. Of the author’s 51 patients who had been examined with capsule endoscopy, 27 had been tested with a commercially available serology panel (Prometheus Laboratories, San Diego, Cali-
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fornia) and only two thirds of these patients had positive results with either study. However, 81% of the patients had at least one positive test. Furthermore, neither test was superior to the other in the diagnosis of Crohn’s disease. Despite the suboptimal sensitivities of each test, the combined figure is reasonably acceptable. Patient with suggestive symptoms or physical findings Based on the author’s data on known Crohn’s disease, he hypothesized that IBD serology and capsule endoscopy were complementary to capsule endoscopy in making the diagnosis. In the author’s cohort of 79 patients suspected of Crohn’s disease and failed detection by conventional methods, 27 had IBD serologies examined. Only 19% of these patients were tested positive with both capsule endoscopy and serologies. Likewise, only 19% of these patients were tested negative with both tests. Furthermore, both studies seemed to have similar sensitivities. These results suggested that a symptomatic patient who does not have a prior history of Crohn’s disease should undergo a serology panel and capsule endoscopy. If both tests are normal, then it is unlikely that the patient is afflicted with Crohn’s disease. However, the results of this retrospective review of a small sample of patients should be confirmed with a large, prospective trial. Patients with indeterminate colitis Indeterminate colitis is defined here as established isolated colitis in which available endoscopic, pathologic, laboratory, and radiologic studies are inconclusive for ulcerative colitis or Crohn’s disease. As many as 10% of patients presenting with IBD are considered to have indeterminate colitis [1]. The diagnosis of colitis in these individuals would be re-classified as Crohn’s disease if small bowel lesions were identified. This may greatly impact on the prognosis and influence the choice of medical or surgical therapy [24]. Although serologic markers may help predict the patients who are more likely to have Crohn’s lesions, they are probably not sufficiently specific to be used to guide therapy. Endoscopic, radiographic, or surgical confirmation of intestinal disease activity is the only logical way to make this determination. Of these choices, capsule endoscopy holds the greatest promise because of high patient acceptance and the ability to visualize the entire small intestine [25]. To date, the author has examined 45 patients in this category with capsule endoscopy. Twenty-two (49%) had small bowel lesions suggestive of active Crohn’s disease and had therapeutic changes. There is no doubt that a positive capsule endoscopy study provides valuable information for this group of patients; the issue remains whether a negative examination can conclusively exclude small intestinal Crohn’s disease.
Incidental findings of small bowel ulcers suggestive of Crohn’s disease Crohn’s disease is usually thought of as a symptomatic condition with presenting symptoms consisting of abdominal pain, anemia, weight loss, or
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diarrhea. It is rarely considered the cause of obscure gastrointestinal bleeding without other clinical clues. Of 13 patients referred for obscure gastrointestinal bleeding, Costamagna [20] found 1 case of distal ileal ulcers that was suspicious for Crohn’s disease. Likewise, Ell [21] found 2 cases of inflammatory small bowel disease among 32 patients referred for obscure bleeding. In the author’s 305 patients referred for obscure or occult gastrointestinal bleeding, 28 (9.2%) had lesions compatible with Crohn’s disease. It is conceivable that some of these patients actually had NSAID induced enteropathy instead because of the difficulty in differentiating the two entities. In this group of patients, IBD serologies can play a role in confirming the diagnosis of Crohn’s disease. With increased usefulness of capsule endoscopy, it is quite likely that the author will find more ‘‘silent’’ Crohn’s disease.
Distribution of small bowel Crohn’s disease based on capsule endoscopy Limited by the inability to directly visualize most of the small intestine, the author’s current knowledge of disease distribution is mostly based on barium small bowel series and retrograde ileoscopy. These two procedures bias the author’s findings toward terminal ileal disease and obvious pathologies. Capsule endoscopy examinations are likely more objective and provide new insights into the true distribution of small bowel lesions. The author examined his patients who had complete small bowel examinations with capsule endoscopy. The findings confirmed the high prevalence of distal disease, with two thirds of the author’s Crohn’s patients having distal ileal ulcerations. However, the rest of the intestine seems to have an equal distribution of active disease, with one third of the cases occurring in both the proximal and mid-small bowel.
Capsule endoscopy may produce findings that alter disease management Using capsule endoscopy to make diagnosis and guide therapy of intestinal Crohn’s disease is a new concept. One’s enthusiasm toward this technology must rest on whether the findings would influence disease management and outcomes. In a preliminary, uncontrolled, retrospective study, the author reported his experience on the first 50 patients suspected of small bowel Crohn’s disease [16]. The capsule reader was unaware of the clinical and therapeutic information of these patients. Small bowel lesions were found in five patients with a history of isolated colitis, prompting a reclassification to Crohn’s disease after confirmatory ileoscopy and biopsy. Twenty cases were believed to be ‘‘diagnostic’’ and 10 cases were ‘‘suspicious’’ for Crohn’s disease, based on capsule endoscopy findings. Seventeen of 20 patients with ‘‘diagnostic’’ capsule findings improved with increased IBD-directed medical therapy, as did 7 of 10 patients with ‘‘suspicious’’ studies. In the remaining 20 patients the wireless capsule enteroscopy revealed nonspecific findings or were normal. Although these findings
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are promising, larger controlled studies are needed to confirm the true value of capsule endoscopy in the management of Crohn’s disease.
Future issues regarding capsule endoscopy for Crohn’s disease The author’s preliminary data suggest that capsule endoscopy will play an important role in the diagnosis and management of Crohn’s disease. Besides having to confirm this data with larger and controlled studies, many issues remain to be addressed. Until now, Crohn’s disease has been diagnosed somewhat subjectively after combining positive findings along with exclusion of other etiologies. Unless capsule endoscopy can identify pathognomonic features of Crohn’s disease, it may become just another supportive study among the array of other imaging examinations. Some future efforts will have to be devoted to differentiate Crohn’s lesions seen on capsule endoscopy from NSAID enteropathy, celiac disease, tuberculous ileitis, radiation enteritis, eosinophilic enteritis, and so forth. The author’s anecdotal experience with a large number of Crohn’s disease patients seems to show that the capsules tend to stop short of the terminal ileum before image recording ends. The main reason is perhaps delayed motility caused by thickened bowel wall or partial distal small bowel obstruction. This incomplete examination may lead to a false negative study or an under-estimation of the extent of disease. Perhaps a longer battery life and recording time would minimize the problem. Increased accumulation of debris from distal ileal disease is also an obstacle to a detailed capsule examination. The author favors the use of an oral purging solution immediately before a capsule study in an attempt to optimize the examination. After confirming the diagnosis of Crohn’s disease, one needs to understand the clinical significance of aphthous ulcers, superficial erosions, and stellate lesions. Do they indicate active disease or merely represent the footprints of the condition without pertaining to any clinical significance? Do they correlate with clinical symptoms and does healing represent remission of the disease? If the answer to the last question is yes, then capsule endoscopy may become a critically important tool in the management of Crohn’s disease. It has been accepted that mucosal healing does not accompany improvement of disease activity of Crohn’s disease [26,27]. However, D’Haens et al [28] observed complete or partial healing of colonic lesions in 95% of their 20 patients in clinical remission induced by azathioprine therapy. A similar finding was noted in the terminal ileum of these patients. It is conceivable that capsule endoscopy may be used in the future to objectively document clinical improvement and remission. Finally, capsule retention needs to be addressed more fully if the procedure were to be used more routinely for evaluation of Crohn’s disease. The author has not performed a systematic examination of the problem on his patient group. However, four patients with this problem have been brought to the author’s attention and all four underwent surgical resection of the obstructing segments and surgical removal of their capsules. Although this does not represent a higher
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incident of capsule retention relative to the author’s non-Crohn’s cases, the author has also made significant efforts to avoid problematic cases. The manufacturer of the endoscopic capsule is currently evaluating a ‘‘patency’’ capsule that would disintegrate after a certain number of days. The idea for this test capsule, with the same dimensions as the real one, is to prove that a dummy capsule can pass through the gastrointestinal tract in a patient suspected of partial small bowel obstruction. If capsule retention does not take place, then the non-dissolvable imaging capsule can be safely administered to the patient.
Integration of capsule endoscopy for Crohn’s disease in the clinical setting Capsule endoscopy has enormous potential in shaping the future management algorithm related to Crohn’s disease. Its potential impact in the diagnosis and management of IBD may be even more significant than for evaluation of gastrointestinal bleeding. The role of capsule endoscopy in Crohn’s disease may involve the entire spectrum of disease management, ranging from diagnosing to monitoring of disease activity and, hypothetically, surveying for cancer development. Although many potential applications in IBD remain to be explored, its value in diagnosing Crohn’s disease is quite evident. Based on the author’s current
Fig. 2. Proposed algorithm for use of capsule endoscopy in the diagnosis of Crohn’s disease.
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experience, he proposes a possible algorithm in the utility of capsule endoscopy for diagnosis of small bowel Crohn’s disease (Fig. 2).
Summary Capsule endoscopy was originally developed to detect small bowel sources of gastrointestinal bleeding. Barely 18 months old, this technology has now found a new and potentially more important indication in the diagnosis and management of small bowel Crohn’s disease. Early experiences suggest that it is superior to currently available imaging modalities and therefore an ideal test to diagnose Crohn’s disease. In the author’s experience, capsule endoscopy has already helped elucidate new diagnosis of Crohn’s disease, revise diagnosis from indeterminate colitis to Crohn’s disease, and identify active small bowel disease despite prior negative imaging studies. In Crohn’s disease the key limitation of performing capsule endoscopy is the possibility of capsule retention proximal to an occult stricture. With proper screening for obstructive symptoms, capsule retention has only occurred in less than 2% of the author’s patients. The inability to sample tissue during capsule endoscopy requires either conventional endoscopy with biopsy or IBD serologic studies to support the diagnosis.
Acknowledgments The author thanks Dr. Waleed Shindy and Jan Daniels for offering their assistance in the preparation of this manuscript.
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[9] Umschaden HW, Gasser J. MR enteroclysis. Radiol Clin N Am 2003;41(2):231 – 48. [10] Thompson WG, Longstreth G, Drossman DA, Heaton K, Irvine EJ, Muller-Lissner S. Functional bowel disorders and functional abdominal pain. In: Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead WE, editors. Rome II: the functional gastrointestinal disorders. Lawrence: Allen Press Inc.; 2000. p. 360. [11] Vasiliauskas EA, Kam LY, Karp LC, Gaiennie J, Yang H, Targan SR. Marker antibody expression stratifies Crohn’s disease into immunologically homogeneous subgroups with distinct clinical characteristics. Gut 2000;47:487 – 96. [12] Su C, Lichtenstein GR. Recent developments in inflammatory bowel disease. Med Clin N Am 2002;86(6):1497 – 523. [13] Berg DF. Acute surgical emergencies in inflammatory bowel disease. Am J Surg 2002;184: 45 – 51. [14] Barkin J, Friedman S. Wireless capsule endoscopy requiring surgical intervention: the world’s experience. Am J Gastroenterol 2002;97:S298. [15] Fireman Z, Mahajna E, Broide E, Shapiro M, Fich L, Sternberg A, et al. Diagnosing small bowel Crohn’s disease with wireless capsule endoscopy. Gut 2003;52:390 – 2. [16] Mow WS, Lo SK, Abreu MT, Targan SR, Papadakis KA, Vasiliauska EA. Video capsule enteroscopy can be useful in the diagnosis and management of inflammatory bowel disease. Gastroenterology 2002;122(Suppl 1):A218. [17] Lo SK, Zaidel O, Tabibzadeh S, Papadakis K, Treyzon L, Kimble J, et al. Utility of wireless capsule enteroscopy and IBD serology in re-classifying indeterminate colitis. Gastroenterology 2003;124(Suppl 1):A-192. [18] Tabibzadeh S, Kimble J, Zaidel O, Papadakis K, Vasiliauskas E, Treyzon L, et al. Distribution of small bowel erosions or ulcerations in patients presenting for wireless capsule enteroscopy. Gastrointest Endosc 2003;57:M1890. [19] Tabibzadeh S, Zaidel O, Papadakis K, Vasiliauskas E, Kimble J, Treyzon L, et al. Utility of wireless capsule enteroscopy versus serology in the evaluation of small bowel Crohn’s disease. Gastrointest Endosc 2003;57:M1889. [20] Costamagna G, Shah SK, Riccioni ME, Foschia F, Mutignani M, Perri V, et al. A prospective trial comparing small bowel radiographs and video capsule endoscopy for suspected small bowel disease. Gastroenterology 2002;123:999 – 1005. [21] Ell C, Remke S, May A, Helou L, Henrich R, Mayer G. The first prospective controlled trial comparing wireless capsule endoscopy with push enteroscopy in chronic gastrointestinal bleeding. Endoscopy 2002;34:685 – 9. [22] Perez-Cuadrado E, Macenlle R, Iglesias J, Fabra R, Lamas D. Usefulness of oral video push enteroscopy in Crohn’s disease. Endoscopy 1997;29:745 – 7. [23] Hoffenberg EJ, Fidanza S, Sauaia A. Serologic testing for inflammatory bowel disease. Journal of Pediatrics 1999;134:447 – 52. [24] Papadakis KA, Tabibzadeh S. Diagnosis and misdiagnosis of inflammatory bowel disease. Gastrointest Endosc Clin N Am 2002;12:433 – 49. [25] Lewis BS, Swain P. Capsule endoscopy in the evaluation of patients with suspected small intestinal bleeding: Results of a pilot study. Gastrointest Endosc 2002;56:349 – 53. [26] Modigliani R, Mary JY, Simon JF, Cortot A, Soule JC, Gendre R, et al. Clinical, biological and endoscopic picture of attacks of Crohn’s disease. Evolution on prednisolone. Gastroenterology 1990;98:811 – 8. [27] Olaison B, Sjodahl R, Tagesson C. Glucocorticoid treatment in ileal Crohn’s disease: relief of symptoms but not of endoscopically viewed inflammation. Gut 1990;31:325 – 8. [28] D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s ileo-colitis with azathioprine. Gastrointest Endosc 1999;50:667 – 71.
Capsule endoscopy in the diagnosis and management of inflammatory bowel disease Simon K. Lo, MD Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, 8635 West 3rd Street, Suite 876W, Los Angeles, CA 90048, USA
Crohn’s disease is suspected clinically by chronic or relapsing abdominal pain, diarrhea, gastrointestinal bleeding, or weight loss. The diagnosis is usually established by findings on intestinal radiography, endoscopy, or during surgery. Typical Crohn’s histopathology is preferred but not mandated to support the diagnosis.
Current modalities in diagnosing small intestinal Crohn’s disease Conventional radiology Because small intestinal Crohn’s disease has been traditionally difficult to visualize; contrast small bowel radiography remains the main diagnostic imaging modality [1]. There is not a single pathognomonic radiographic feature that defines Crohn’s disease. Rather, the radiologic diagnosis is based on subjective interpretations that takes into consideration a range of findings such as aphthous ulcers, deep ulcerations, mucosal cobblestoning, skip lesions, fissures, fistulas, strictures, and pseudopolyps [2]. A single contrast small bowel series is the most commonly ordered luminal radiographic study, although enteroclysis is considered the diagnostic test of choice because of the ability to distend the intestinal lumen for a detailed double contrast examination [2,3]. Conventional endoscopy The limited lengths of traditional endoscopes leave a significant segment of the small bowel without endoscopic examination for Crohn’s disease. Upper endoscopic examinations may identify Crohn’s lesions as erythema, aphthous ulcers, nodules, deep ulcers, and strictures in the gastric antrum or duodenum
E-mail address: [email protected] 1052-5157/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.giec.2003.10.010
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[4]. Endoscopic features of Crohn’s disease in the terminal ileum are less well described, but the mere identification of ileal ulcers is considered diagnostic. Histologic examination of ileal tissue obtained during endoscopy provides additional confirmation of the diagnosis and disease activity when the endoscopy alone is inconclusive. In the colon, the characteristics of Crohn’s disease include skip lesions, aphthous ulcers, cobblestoning, linear ulcers, serpiginous ulcers, and fistula formation [4]. Enteroscopy The dedicated push enteroscopy, with the length of roughly two to three times that of a regular upper endoscope, was designed with the hope that it would enter deep inside the small intestine. However, it can rarely reach 100 cm beyond the ligament of Trietz [5]. A push enteroscope has the same functions as a standard endoscope, and it allows biopsy to be performed for tissue confirmation of Crohn’s disease. However, the literature is lacking in the application of push enteroscopy for Crohn’s disease and it is probably not commonly practiced in the general community. Sonde enteroscopy has been reported to reach the ileum in roughly 75% of the time, although it rarely passes into the terminal ileum in practice [5]. It is a time-consuming process with significant patient discomfort and is now rarely used [4]. Push enteroscopy can be performed in a laparotomy setting in which the endoscopy is assisted down the tortuous intestine through surgeon’s manipulations. When performed in this manner, the scope can reach the entire length of the small intestine quite reliably [6]. Yamamoto [7] recently introduced a special version of a push enteroscopy that could reach the distal small intestine in a fraction of the patients. However, it is also a labor intensive procedure that may take more than 2 hours to perform. In addition, potentially serious complications that are seen with intra-operative enteroscopy, such as serosal tears, avulsion of mesenteric vasculature, and prolonged ileus will probably be encountered in this procedure [6]. Although the prospect of a total small bowel examination with the possibility to perform therapy or biopsy is exciting, it is unlikely to become a routine test used in the examination of the distal small intestine. Special enterography It is now possible to examine the small intestine using a multiplanar spiral computed tomography (CT) scanner and an oral contrast agent. In a recent study, this new CT enterography technique and barium contrast upper GI series produced similar findings in Crohn’s disease [8]. Therefore, this new application of CT is unlikely to add much to the existing radiologic imaging modalities. Instead, the role of CT is primarily restricted to the detection of complications of Crohn’s disease. It is very useful in identifying abscesses, fistulas, bowel wall thickening, and extra-intestinal inflammation [2]. Likewise, magnetic resonance (MR) enterography can be performed by modifying conventional MRI examina-
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tions and by intestinal infusion of methylcellulose. Although MR enteroclysis is capable of detecting lesions of Crohn’s disease such as thickening and distortion of small bowel folds, the resolution is insufficient for depiction of more subtle lesions such as aphthous ulcers [9].
Serologic diagnosis of Crohn’s disease Two of the principle symptoms of Crohn’s disease are chronic abdominal pain and diarrhea, which are also commonly seen in irritable bowel syndrome [10]. The number of individuals afflicted with these symptoms make it impractical to work up every potential patient with small bowel series, upper endoscopy, and colonoscopy. It is even more difficult to investigate patients without any upper gastrointestinal or colonic lesions because of the technical difficulty in accessing the mid- and distal small bowel. These limitations would invariably lead to mistakes in under-diagnosing the condition and hence treating it inappropriately for functional symptoms. It would be highly desirable to have a non-invasive blood test to triage symptomatic individuals for more intensive investigations of inflammatory bowel disease (IBD). This serologic test could be more valuable in further differentiating Crohn’s disease from ulcerative colitis. Indeed, a blood panel that can detect antineutrophil cytoplasmic antibodies (ANCA) and Saccharomyces cerevisiae antibodies (ASCA) has been shown to be positive in many patients with Crohn’s disease [11,12].
Are conventional studies adequate in evaluating small bowel Crohn’s disease? In spite of the large arrays of imaging and serologic studies for small bowel Crohn’s disease, there are still many case scenarios in which a more sensitive imaging modality is needed. Patients who have well controlled ulcerative colitis but experience significant symptoms should be screened for small bowel Crohn’s disease. These symptoms include unexplained hematochezia or melena, abdominal pain, diarrhea, or B12 deficiency. Likewise, patients with quiescent Crohn’s colitis who continue to have abdominal symptoms deserve to be worked up more thoroughly even if the conventional imaging tests are negative. It is common to encounter symptomatic Crohn’s disease patients who have a normal barium radiography and retrograde ileoscopy. In the past, these patients were frequently labeled as having functional problems. However, it is entirely possible that they may have subtle active small bowel disease that escapes detection because of insensitive imaging tests. Finally, patients with genuine chronic abdominal symptoms suggestive of Crohn’s enteritis, but without definite proof of disease, also deserve to be investigated further. Capsule endoscopy carries great promise in taking on the imaging role vacated by all existing modalities. The combination of total intestinal examination and visualization of fine mucosal details provide
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capsule endoscopy with unprecedented theoretical advantage in diagnosing intestinal Crohn’s disease [4].
Concerns about performing capsule endoscopy on Crohn’s patients Capsule endoscopy was approved by the Food and Drug Administration to study the small intestine in the United States in August of 2001. One of its contraindications is intestinal obstruction, which is obviously a major concern for Crohn’s disease. It has been reported that intestinal obstruction occurs in 35% to 54% of Crohn’s disease. [13]. If a capsule is stuck within the stricture of a Crohn’s lesion, it could lead to acute intestinal obstruction. Even if there is no obstructive symptoms, a retained capsule has to be removed before leakage of the capsule’s contents result in intestinal injuries. Indeed, capsule retention caused by obstructive lesions is the most common complication of capsule endoscopy, and it has been reported to be around 0.75% [14].
Case examples Patient 1 The author’s experience with capsule endoscopy for Crohn’s disease related issues began with a young woman with a known history of ulcerative colitis and persistent abdominal pain in spite of quiescent colitis. Her capsule study was negative and she was subsequently reassured and managed for other functional abdominal pain without further problems. Patient 2 A woman with Crohn’s disease was studied for severe mid abdominal pain despite negative upper endoscopy, colonoscopy, and small bowel series. It was previously believed that she had chronic pain syndrome with possible secondary gain, but her capsule endoscopy revealed extensive Crohn’s ulcers throughout the small intestine; she has since been treated accordingly. These early anecdotal experiences provided the authors with the rationale to proceed with further capsule endoscopy investigations, with slight trepidation for potential intestinal obstruction. Patient 3 The author’s first case of capsule endoscopy for an obstructive Crohn’s disease was incidentally done on a woman with long standing right lower abdominal pain, recurrent nausea, and abdominal bloating. Multiple endoscopic CT and small bowel imaging studies were unrevealing. Being a registered nurse and a medical researcher herself, this woman suspected that she had an obstructive disease that
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could not be proven by all conventional means. When warned of potential capsule retention in the setting of an obstructive lesion, she said that she would be delighted because she would readily accept surgical intervention. Indeed the capsule was arrested in the distal ileum, but the cause could not be identified because of a large amount of food debris in the same area. The patient underwent an ileal resection and the tissue specimen confirmed stenosing Crohn’s ileitis. She remained asymptomatic more than 12 months after her surgery. This case exemplifies the possibility of intestinal obstruction despite multiple negative gastrointestinal studies. In addition, her long standing symptoms might have eventually led her to surgical resection even if Crohn’s disease had been diagnosed and the capsule study had never been performed. Nonetheless, the author’s current policy is to look for possible obstructive symptoms before proceeding with any capsule study. All patients with suggestive symptoms must have a prior small bowel barium study with non-obstructive results.
Current clinical experience There are perhaps 20 preliminary studies on capsule endoscopy for Crohn’s disease that have been presented at the various international meetings. Virtually all of these studies reported on less than 50 patients but all showed some evidence that capsule endoscopy could become useful in the diagnosis and management of small bowel Crohn’s disease. The first report on the usefulness of capsule endoscopy for Crohn’s disease was published recently. Fireman et al [15] performed the study on 17 subjects suspected of the condition but without positive findings on conventional diagnostic tests of small bowel radiography and upper and lower endoscopies. All patients had some combination of complaints or findings that included iron deficiency anemia (59%), abdominal pain (71%), diarrhea (35%), and weight loss (18%). A surprisingly large number of patients (71%) in this small study were found to have intestinal lesions compatible with Crohn’s disease by capsule endoscopy. This small study provided the insight into the inadequacy of conventional imaging tests in diagnosing Crohn’s disease. Care must be taken, however, not to assume this to be a widespread problem because this patient population was probably selected. The author has studied over 200 patients with issues related to Crohn’s disease at his center. These patients include those with known history of Crohn’s disease, indeterminate colitis, suspected Crohn’s disease, and those with incidentally found Crohn’s enteritis. In the following paragraphs the author presents the available literature and his unpublished data on the use of capsule endoscopy in the diagnosis and management of Crohn’s disease [16 –19].
Appearance of Crohn’s lesions on capsule endoscopy Using capsule endoscopy to diagnose small intestinal Crohn’s disease can be challenging, because the small bowel lining has never been visualized in this
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Fig. 1. Sample of endoscopic pictures of intestinal Crohn’s lesions, in patients with established Crohn’s disease, captured with the Given capsule. (A – C) Focal and extensive loss of intestinal villi. (D, E) Solitary and multiple aphthous lesions. (F, G) Solitary erosion or shallow ulcers. (H, I) Linear ulcerations. (J – L) Extensive, coalescing ulcers with cobblestone appearance of intestinal mucosa. (M, N) Deep, fissuring ulcers. (O – Q) Ulcers with strictures. (See also Color Plates 60 and 61).
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Fig. 1 (continued).
manner. The natural assumption is that the typical ulcers, erosions, and inflammation seen in the terminal ileum and duodenum by conventional endoscopy would appear the same in the small bowel on capsule endoscopy. However, this assumption cannot be taken for granted without corroborating evidence on conventional endoscopy and perhaps even histological confirmation. To satisfy this point of contention by potential doubters, the author retrospectively examined his case records and identified patients with known Crohn’s disease who had undergone upper endoscopy, push enteroscopy, or colonoscopy within 5 weeks of capsule endoscopy. Histology reports were also reviewed to provide additional supporting information. Of 51 cases completed to date, 20 had an upper endoscopy, a retrograde ileoscopy, push enteroscopy, or surgical specimen for correlations. Nine of the 20 capsule endoscopies were normal and were confirmed negative by conventional video endoscopy in the upper gastrointestinal tract or terminal ileum. Five of these nine patients had both upper endoscopy or push enteroscopy and retrograde ileoscopy performed; the rest only had retrograde ileoscopy done. Ten Crohn’s patients had active disease on capsule endoscopy and independently confirmed by upper endoscopy or push enteroscopy [3], upper endoscopy and retrograde ileoscopy [1], surgical resection of the distal small bowel [1], or retrograde ileoscopy [5]. One patient had a normal capsule study but was found to have minimal ileitis with few superficial aphthous ulcers in the terminal ileum on retrograde ileoscopy. The author’s preliminary findings in a small sample of patients show that capsule endoscopy can accurately identify normal and Crohn’s lesions within the
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two ends of the small intestine, with a 95% sensitivity and 100% specificity. Interestingly, even the appearance of lesions on capsule endoscopy closely resembled those captured with conventional endoscopy (Fig. 1). The lesions were reported as linear ulcerations, circumferential ulcers, stellate ulcers, aphthous ulcers, or erosions. It was obviously not possible to correlate mid-small bowel findings between capsule endoscopy and conventional endoscopy. However, there is no reason to believe that they would appear differently from those seen elsewhere in the small intestine. In summary, endoscopic lesions seen on capsule endoscopy are identical to those seen on routine endoscopy. One should be able to apply the standard endoscopic criteria to capsule endoscopy in identifying Crohn’s lesions.
Is capsule endoscopy better than barium small bowel series in diagnosing Crohn’s lesions? Fireman’s study [15] provided the initial insight that capsule endoscopy might be superior to the conventional imaging modalities in diagnosing Crohn’s enteritis. Costamagna et al [20] performed sequential barium small bowel follow through and capsule endoscopy on 22 patients suspected of having small bowel diseases. Capsule endoscopy was found to be superior to small bowel radiographs in identifying mucosal pathologies. In this study, only 20% of the radiographic studies was positive, whereas the capsule produced diagnostic findings in 45% and suspicious findings in another 40%. The capsule study revealed lesions that were suggestive of Crohn’s disease in 3 patients, whereas the radiograph studies were positive in only one patient. The author retrospectively examined 27 patients with known Crohn’s [14], indeterminate colitis [9], or suspected Crohn’s disease [4] that had undergone capsule endoscopy and small bowel follow through within 45 days of each other (Table 1). All capsule studies were reviewed by an experienced endoscopist without prior knowledge of the radiograph results. Capsule endoscopy superior to small bowel studies in detecting Crohn’s like lesions (Fisher’s Exact Test P < 0.0001). More importantly, all the positive findings seen on small bowel series were also identified by capsule endoscopy. If one assumes that capsule endoscopy were the new ‘‘gold standard’’ for diagnosing intestinal Crohn’s disease, then the yield of radiography is only 24%. The low sensitivity of small bowel series and lack of additional information to findings on capsule endoscopy raises serious doubt about the value of radiographic studies. However, it must
Table 1 Comparison between capsule endoscopy and small bowel series in the detection of Crohn’s disease
Small bowel series Capsule endoscopy
Crohn’s like lesions
No Crohn’s lesions
5 (19%) 21 (78%)
22 (81%) 6 (22%)
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emphasized that there was a selection bias because of exclusion of patients with advanced, stricturing Crohn’s disease. Despite the imperfection of the author’s study, he is now ordering small bowel series as a screening procedure for obvious small bowel lesions and exclusion of obstructive disease in patients with suggestive symptoms. Symptomatic patients with negative radiograph examinations and without small bowel obstructions would routinely undergo investigations by capsule endoscopy.
Is capsule endoscopy better than push enteroscopy in diagnosing Crohn’s disease? Crohn’s disease is traditionally a distal small bowel disease and therefore places push enteroscopy at a disadvantage. There is no published report comparing push enteroscopy and capsule enteroscopy for this condition. However, Ell et al [21] performed enteroclysis, mesenteric angiography, bleeding scintigraphy, push enteroscopy, and capsule endoscopy on 32 patients referred for chronic obscure gastrointestinal bleeding. Two of the patients had chronic IBD causing the bleeding, whereas these lesions were missed by push enteroscopy. It has been reported that push enteroscopy could identify Crohn’s disease in 50% of suspected patients [4]. However, the original description was derived from a small sample and should not be regarded as the true experience without further confirmations [22].
Is capsule endoscopy better than serologic markers in diagnosing Crohn’s disease? Serologic markers are generally regarded as specific (> 90%) IBD but lacking the sensitivity (50 – 70%) to do large scale screening [23,24]. Therefore, they are primarily reserved to test individuals with significant and suspicious symptoms. When capsule endoscopy first became available, the author was uncertain if this test was sensitive in detecting small intestinal Crohn’s disease, clinically active Crohn’s disease, or not at all. One obvious question to the author was whether capsule endoscopy and serologies would merely identify Crohn’s disease on the same individuals or serve as complementary tests and hence increase the likelihood of detecting Crohn’s disease. Patients with established Crohn’s disease Perhaps the first step to assess the sensitivity of a diagnostic study is to apply the test on patients with known Crohn’s disease and that is what the author did with capsule endoscopy. In addition, the author measured it against the only available serologies for diagnosing Crohn’s disease. Of the author’s 51 patients who had been examined with capsule endoscopy, 27 had been tested with a commercially available serology panel (Prometheus Laboratories, San Diego, Cali-
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fornia) and only two thirds of these patients had positive results with either study. However, 81% of the patients had at least one positive test. Furthermore, neither test was superior to the other in the diagnosis of Crohn’s disease. Despite the suboptimal sensitivities of each test, the combined figure is reasonably acceptable. Patient with suggestive symptoms or physical findings Based on the author’s data on known Crohn’s disease, he hypothesized that IBD serology and capsule endoscopy were complementary to capsule endoscopy in making the diagnosis. In the author’s cohort of 79 patients suspected of Crohn’s disease and failed detection by conventional methods, 27 had IBD serologies examined. Only 19% of these patients were tested positive with both capsule endoscopy and serologies. Likewise, only 19% of these patients were tested negative with both tests. Furthermore, both studies seemed to have similar sensitivities. These results suggested that a symptomatic patient who does not have a prior history of Crohn’s disease should undergo a serology panel and capsule endoscopy. If both tests are normal, then it is unlikely that the patient is afflicted with Crohn’s disease. However, the results of this retrospective review of a small sample of patients should be confirmed with a large, prospective trial. Patients with indeterminate colitis Indeterminate colitis is defined here as established isolated colitis in which available endoscopic, pathologic, laboratory, and radiologic studies are inconclusive for ulcerative colitis or Crohn’s disease. As many as 10% of patients presenting with IBD are considered to have indeterminate colitis [1]. The diagnosis of colitis in these individuals would be re-classified as Crohn’s disease if small bowel lesions were identified. This may greatly impact on the prognosis and influence the choice of medical or surgical therapy [24]. Although serologic markers may help predict the patients who are more likely to have Crohn’s lesions, they are probably not sufficiently specific to be used to guide therapy. Endoscopic, radiographic, or surgical confirmation of intestinal disease activity is the only logical way to make this determination. Of these choices, capsule endoscopy holds the greatest promise because of high patient acceptance and the ability to visualize the entire small intestine [25]. To date, the author has examined 45 patients in this category with capsule endoscopy. Twenty-two (49%) had small bowel lesions suggestive of active Crohn’s disease and had therapeutic changes. There is no doubt that a positive capsule endoscopy study provides valuable information for this group of patients; the issue remains whether a negative examination can conclusively exclude small intestinal Crohn’s disease.
Incidental findings of small bowel ulcers suggestive of Crohn’s disease Crohn’s disease is usually thought of as a symptomatic condition with presenting symptoms consisting of abdominal pain, anemia, weight loss, or
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diarrhea. It is rarely considered the cause of obscure gastrointestinal bleeding without other clinical clues. Of 13 patients referred for obscure gastrointestinal bleeding, Costamagna [20] found 1 case of distal ileal ulcers that was suspicious for Crohn’s disease. Likewise, Ell [21] found 2 cases of inflammatory small bowel disease among 32 patients referred for obscure bleeding. In the author’s 305 patients referred for obscure or occult gastrointestinal bleeding, 28 (9.2%) had lesions compatible with Crohn’s disease. It is conceivable that some of these patients actually had NSAID induced enteropathy instead because of the difficulty in differentiating the two entities. In this group of patients, IBD serologies can play a role in confirming the diagnosis of Crohn’s disease. With increased usefulness of capsule endoscopy, it is quite likely that the author will find more ‘‘silent’’ Crohn’s disease.
Distribution of small bowel Crohn’s disease based on capsule endoscopy Limited by the inability to directly visualize most of the small intestine, the author’s current knowledge of disease distribution is mostly based on barium small bowel series and retrograde ileoscopy. These two procedures bias the author’s findings toward terminal ileal disease and obvious pathologies. Capsule endoscopy examinations are likely more objective and provide new insights into the true distribution of small bowel lesions. The author examined his patients who had complete small bowel examinations with capsule endoscopy. The findings confirmed the high prevalence of distal disease, with two thirds of the author’s Crohn’s patients having distal ileal ulcerations. However, the rest of the intestine seems to have an equal distribution of active disease, with one third of the cases occurring in both the proximal and mid-small bowel.
Capsule endoscopy may produce findings that alter disease management Using capsule endoscopy to make diagnosis and guide therapy of intestinal Crohn’s disease is a new concept. One’s enthusiasm toward this technology must rest on whether the findings would influence disease management and outcomes. In a preliminary, uncontrolled, retrospective study, the author reported his experience on the first 50 patients suspected of small bowel Crohn’s disease [16]. The capsule reader was unaware of the clinical and therapeutic information of these patients. Small bowel lesions were found in five patients with a history of isolated colitis, prompting a reclassification to Crohn’s disease after confirmatory ileoscopy and biopsy. Twenty cases were believed to be ‘‘diagnostic’’ and 10 cases were ‘‘suspicious’’ for Crohn’s disease, based on capsule endoscopy findings. Seventeen of 20 patients with ‘‘diagnostic’’ capsule findings improved with increased IBD-directed medical therapy, as did 7 of 10 patients with ‘‘suspicious’’ studies. In the remaining 20 patients the wireless capsule enteroscopy revealed nonspecific findings or were normal. Although these findings
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are promising, larger controlled studies are needed to confirm the true value of capsule endoscopy in the management of Crohn’s disease.
Future issues regarding capsule endoscopy for Crohn’s disease The author’s preliminary data suggest that capsule endoscopy will play an important role in the diagnosis and management of Crohn’s disease. Besides having to confirm this data with larger and controlled studies, many issues remain to be addressed. Until now, Crohn’s disease has been diagnosed somewhat subjectively after combining positive findings along with exclusion of other etiologies. Unless capsule endoscopy can identify pathognomonic features of Crohn’s disease, it may become just another supportive study among the array of other imaging examinations. Some future efforts will have to be devoted to differentiate Crohn’s lesions seen on capsule endoscopy from NSAID enteropathy, celiac disease, tuberculous ileitis, radiation enteritis, eosinophilic enteritis, and so forth. The author’s anecdotal experience with a large number of Crohn’s disease patients seems to show that the capsules tend to stop short of the terminal ileum before image recording ends. The main reason is perhaps delayed motility caused by thickened bowel wall or partial distal small bowel obstruction. This incomplete examination may lead to a false negative study or an under-estimation of the extent of disease. Perhaps a longer battery life and recording time would minimize the problem. Increased accumulation of debris from distal ileal disease is also an obstacle to a detailed capsule examination. The author favors the use of an oral purging solution immediately before a capsule study in an attempt to optimize the examination. After confirming the diagnosis of Crohn’s disease, one needs to understand the clinical significance of aphthous ulcers, superficial erosions, and stellate lesions. Do they indicate active disease or merely represent the footprints of the condition without pertaining to any clinical significance? Do they correlate with clinical symptoms and does healing represent remission of the disease? If the answer to the last question is yes, then capsule endoscopy may become a critically important tool in the management of Crohn’s disease. It has been accepted that mucosal healing does not accompany improvement of disease activity of Crohn’s disease [26,27]. However, D’Haens et al [28] observed complete or partial healing of colonic lesions in 95% of their 20 patients in clinical remission induced by azathioprine therapy. A similar finding was noted in the terminal ileum of these patients. It is conceivable that capsule endoscopy may be used in the future to objectively document clinical improvement and remission. Finally, capsule retention needs to be addressed more fully if the procedure were to be used more routinely for evaluation of Crohn’s disease. The author has not performed a systematic examination of the problem on his patient group. However, four patients with this problem have been brought to the author’s attention and all four underwent surgical resection of the obstructing segments and surgical removal of their capsules. Although this does not represent a higher
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incident of capsule retention relative to the author’s non-Crohn’s cases, the author has also made significant efforts to avoid problematic cases. The manufacturer of the endoscopic capsule is currently evaluating a ‘‘patency’’ capsule that would disintegrate after a certain number of days. The idea for this test capsule, with the same dimensions as the real one, is to prove that a dummy capsule can pass through the gastrointestinal tract in a patient suspected of partial small bowel obstruction. If capsule retention does not take place, then the non-dissolvable imaging capsule can be safely administered to the patient.
Integration of capsule endoscopy for Crohn’s disease in the clinical setting Capsule endoscopy has enormous potential in shaping the future management algorithm related to Crohn’s disease. Its potential impact in the diagnosis and management of IBD may be even more significant than for evaluation of gastrointestinal bleeding. The role of capsule endoscopy in Crohn’s disease may involve the entire spectrum of disease management, ranging from diagnosing to monitoring of disease activity and, hypothetically, surveying for cancer development. Although many potential applications in IBD remain to be explored, its value in diagnosing Crohn’s disease is quite evident. Based on the author’s current
Fig. 2. Proposed algorithm for use of capsule endoscopy in the diagnosis of Crohn’s disease.
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experience, he proposes a possible algorithm in the utility of capsule endoscopy for diagnosis of small bowel Crohn’s disease (Fig. 2).
Summary Capsule endoscopy was originally developed to detect small bowel sources of gastrointestinal bleeding. Barely 18 months old, this technology has now found a new and potentially more important indication in the diagnosis and management of small bowel Crohn’s disease. Early experiences suggest that it is superior to currently available imaging modalities and therefore an ideal test to diagnose Crohn’s disease. In the author’s experience, capsule endoscopy has already helped elucidate new diagnosis of Crohn’s disease, revise diagnosis from indeterminate colitis to Crohn’s disease, and identify active small bowel disease despite prior negative imaging studies. In Crohn’s disease the key limitation of performing capsule endoscopy is the possibility of capsule retention proximal to an occult stricture. With proper screening for obstructive symptoms, capsule retention has only occurred in less than 2% of the author’s patients. The inability to sample tissue during capsule endoscopy requires either conventional endoscopy with biopsy or IBD serologic studies to support the diagnosis.
Acknowledgments The author thanks Dr. Waleed Shindy and Jan Daniels for offering their assistance in the preparation of this manuscript.
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