RadioGraphics. Invited Commentary. From: Dean D. T. Maglinte, MD Department of Radiology, Indiana University Hospital Indianapolis, Indiana

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1 RG f Volume 25 Number 3 Hara et al 711 Invited Commentary From: Dean D. T. Maglinte, MD Department of Radiology, Indiana University Hospital Indianapolis, Indiana The concept of combining miniaturization of electronic components with advanced telemetry to overcome the limitations of push enteroscopy and retrograde ileoscopy became reality with the FDA approval of the wireless capsule endoscope (M2A capsule, Given Imaging) in August 2001 (1 3). The last bastion of the superiority of indirect imaging of the mucosa of mesenteric small bowel segments has technically now been overcome. The preceding article by Hara et al correlating abnormalities seen at wireless capsule endoscopy and radiologic examination is an update of their

2 712 May-June 2005 RG f Volume 25 Number 3 initial abstract presented at the 2002 RSNA Scientific Assembly (4,5). Their results also reflect findings of other studies comparing wireless capsule endoscopy with radiologic methods (6 11). The limitations of indirect imaging of the small bowel mucosa are starting to become apparent as more studies comparing wireless capsule endoscopy with radiologic investigation are reported (11). In the noteworthy article by Hara et al, some of the limitations of wireless capsule endoscopy are mentioned. Notwithstanding selection bias and the difficulty in evaluating the false-positive and false-negative rates of wireless capsule endoscopy, it appears that, based on the current literature, capsule imaging allows detection of more lesions in the mesenteric small intestine than does any other method of investigation of this segment of the alimentary canal (5,6,8,11). These reports predate the introduction of the obstruction pill (M2A patency capsule) (Fig 1). The conclusions of these reports suggested the need for radiologic investigation to exclude potentially obstructing small bowel abnormalities, a major risk of wireless capsule endoscopy. As experience has accumulated, it has become apparent that the most commonly used radiologic method of investigation, the small bowel follow-through study, has a poor sensitivity in the diagnosis of lower grades of partial mechanical small bowel obstruction and in the demonstration of small mucosal or submucosal lesions. The limitations in evaluating a long, nondistended, overlapping and tortuous organ such as the small bowel have long been recognized by proponents of enteral volume challenged (intubation infusion) small bowel examinations (barium enteroclysis and its current modifications, CT and MR enteroclysis) (12 16). The patency capsule was conceived because of the shortcomings of conventional radiologic examinations. Early experience with this biodegradable capsule, whose dimensions are similar to those of the wireless endoscopic capsule, indicates that it allows accurate and objective evaluation of potentially obstructing small bowel lesions prior to wireless capsule endoscopy (17 19). In fact, one report suggests that the patency capsule should be used in the early investigation of small bowel obstruction (18), a procedure that may obviate radiologic evaluation in the future. The patency capsule has just been introduced in the United States and is undergoing clinical trials. The current clinical indications for wireless capsule endoscopy have been expanded to include almost any symptom of small bowel disease. The Figure 1. Photograph shows the M2A patency capsule from Given Imaging. This obstruction pill is made of lactose and contains 100 mg of barium sulfate. It has dimensions similar to those of the wireless capsule and is biodegradable (100 hours). results described in the article by Hara et al and in other reports published prior to the introduction of the patency capsule beg the question, What will be the future role of radiologic examination in the elective clinical investigation of small bowel diseases given the results of wireless capsule endoscopy and the introduction of the patency capsule? To help answer this question, three common indications for small bowel investigation are analyzed: unexplained gastrointestinal bleeding, Crohn disease, and small bowel tumors. Unexplained Gastrointestinal Bleeding Initial trials of wireless capsule endoscopy were performed for unexplained gastrointestinal bleeding in patients with negative optical endoscopy of the upper and lower gastrointestinal tract (11). Some reports included the results of small bowel follow-through studies and conventional abdominopelvic CT for example, the reports by Hara et al (4,5). Notwithstanding questions on the scientific validity of these many reports, it is apparent that wireless capsule endoscopy will show more abnormalities in obscure gastrointestinal bleeding, since angiectasia is the most commonly seen abnormality with this clinical indication. In spite of isolated imaging reports showing vascular malformation of the small intestine, our experience with dual-phase (arterial and portal venous phase) CT enteroclysis with neutral enteral and intravenous contrast enhancement suggests that indirect methods of investigation will not demonstrate angiectasia. Perhaps dual-phase abdominopelvic CT with neutral oral-enteral and intravenous contrast enhancement in the emergent setting may demonstrate these abnormalities when the patient is actively bleeding. In this clinical scenario, non enteral volume challenged examination with intravenous contrast enhance-

3 RG f Volume 25 Number 3 Hara et al 713 Figure 2. Early Crohn disease in a 35-year-old woman with unexplained abdominal pain and anemia who was referred for wireless capsule endoscopy. Results from a small bowel followthrough study, abdominal CT, and endoscopic examination of the upper and lower gastrointestinal tract were unremarkable. (a) Wireless capsule endoscopic image shows mucosal ulceration (arrows) partly encircling the lumen of the jejunum. (b) Double-contrast barium enteroclysis image of the proximal and middle jejunum obtained with methylcellulose shows neither evidence of ulceration nor fold thickening. The rest of the small bowel was also normal. The patient responded to medical treatment. ment will suffice as long as neutral oral-enteral contrast material (water, methylcellulose) (Volumen; E-Z-EM, Westbury, NY) is used (20). The small bowel follow-through study will likely become an examination of the past for this specific clinical indication. In the elective assessment of patients with obscure gastrointestinal bleeding who have (a) a prior history of intake of NSAIDs or other medications that may produce mucosal damage, (b) a prior history of alimentary canal surgery, or (c) symptoms of partial obstruction, radiologic investigation will remain important as long as accurate methods of investigation are used. Of the modifications of enteral volume challenged small bowel examinations used, double-contrast air (CO 2 ) barium enteroclysis can best demonstrate the superficial mucosal scratches caused by NSAIDs and characterize the submucosal fibrosis of diaphragm disease (21 24). Elective radiologic investigation can otherwise be performed using CT enteroclysis with neutral enteral and intravenous contrast enhancement, which is technically simpler to perform than double-contrast air enteroclysis for the evaluation of potentially obstructing small bowel abnormalities (23). Crohn Disease The aphthoid lesion, the earliest and perhaps even the only mucosal abnormality of early small bowel Crohn disease, is now diagnosed with increasing frequency at wireless capsule endoscopy (11). In these reports, the small bowel followthrough study and abdominal CT have shown false-negative results. In fact, in our early experience at Indiana University Hospital, patients with unexplained gastrointestinal bleeding who had prior negative small bowel follow-through and abdominal CT examinations underwent wireless capsule endoscopy. The initial group of patients who had abnormal wireless capsule endoscopic findings compatible with early Crohn disease also underwent technically optimal double-contrast barium enteroclysis with methylcellulose. In these patients, the wireless capsule endoscopic findings and their possible location were revealed to the radiologist prior to his or her performing the examination (9). To our surprise, even with the technically optimal enteroclysis, the aphthae of early Crohn disease were difficult to demonstrate unless submucosal manifestations were present in addition to the superficial mucosal lesions (Fig 2). These subtle mucosal manifestations of early Crohn disease were seen at wireless capsule endoscopy but not at enteroclysis in the initial three patients. Our further experience shows that methylcellulose washes out superficial mucosal features (23). The more methylcellulose is infused to achieve a good double-contrast effect, the more subtle surface features are effaced, thereby diminishing lesion conspicuity. We have also observed

4 714 May-June 2005 RG f Volume 25 Number 3 Figure 3. Early Crohn disease in a 54-year-old woman with unexplained abdominal pain, nausea, and vomiting and occasional diarrhea. Results from a small bowel follow-through study were unremarkable. Colonoscopy showed inflammatory changes at the transverse colon, and biopsy revealed lymphocytic colitis. (a) Axial CT enteroclysis image obtained at the level of the kidneys with water and intravenous contrast material shows thickening and increased mural enhancement of a segment of the transverse colon (arrow). Note the normal middle and distal ileal loops. C ascending colon. (b) Coronal CT enteroclysis image shows increased paracolic vascular flow (hyperemia) in addition to the mural inflammatory findings. The small bowel appears normal. (c) Double-contrast air-barium enteroclysis image obtained 1 week after wireless capsule endoscopy shows scattered punctate and linear mucosal ulcerations (arrow) involving a long segment of the midileum, findings that are consistent with aphthae in early Crohn disease. The distal and terminal ileum are uninvolved. C cecum. this washout effect on small submucosal masses: The submucosal lesions become inconspicuous when the desired double-contrast visual effect is produced. A review of the Japanese and European radiology literature has shown that the aphthae of early Crohn disease can be reliably demonstrated only with double-contrast air enteroclysis (21,22, 24). Because of this initial experience, I have abandoned the use of biphasic enteroclysis with methylcellulose in the work-up of patients with a clinical background of possible early Crohn disease. My preferred method of enteroclysis examination is air-barium examination, a modification of the Japanese technique (23,24). However, in a patient with a history of known Crohn disease, CT enteroclysis performed with neutral enteral and intravenous contrast enhancement can provide answers to all questions relevant to management. This method of examination has the advantages of being easier to perform and well tolerated by patients; furthermore, it allows evaluation, not only of the mesenteric small bowel, but of the duodenum and colon as well. However, this method will not demonstrate the aphthae of early Crohn disease if they are the only manifestation of the disease (Fig 3). In reports in which images from capsule studies and small bowel followthrough studies are shown, the abnormalities shown on the barium examination are either moderately severe or severe active inflammatory and even stenosing subtypes of Crohn disease. As stated by Hara et al in their article, the false-nega-

5 RG f Volume 25 Number 3 Hara et al 715 Figure 4. Diaphragm disease in a 69-year-old man who was referred for wireless capsule endoscopy because of unexplained gastrointestinal bleeding, negative barium and CT examinations, and unremarkable endoscopic findings in the upper and lower gastrointestinal tract. (a) Wireless capsule endoscopic image obtained at the level of the distal small bowel show a circumferential linear ulcer (arrow) and mild luminal narrowing. Double-contrast air-barium enteroclysis was requested to characterize ulcerations and the extent of possible stenosing Crohn disease obstructing the wireless capsule. (b) Double-contrast air-barium enteroclysis image shows focal circumferential fold thickening (arrow) obstructing the capsule. Multiple areas of proximal narrowing that did not obstruct the capsule were also seen in the midileum. Findings at surgery confirmed the radiologic diagnosis of diaphragm disease from long-term use of baby aspirin (81 mg of acetylsalicylic acid). tive results are more than simply perceptual errors. Prior reports have shown that these errors are combined perceptual-technical pitfalls secondary to inherent limitations of the method of examination (12,13). Small Bowel Tumors As previously reported, enteroclysis is the most reliable radiologic method of investigation in the diagnosis of small bowel neoplasms (25). Small mucosal and submucosal masses are increasingly being diagnosed with wireless capsule endoscopy in patients with negative small bowel followthrough and abdominal CT examinations. This trend has been shown by many investigators, including Hara et al. However, the diagnosis of small submucosal masses may not be straightforward with wireless capsule endoscopy. Experience in a large number of patients suggests that CT enteroclysis with neutral enteral and intravenous contrast enhancement is a technically simple and reliable method of radiologic investigation where the possibility of a small bowel neoplasm exists (26). Early reports of false-negative findings at CT enteroclysis involved a very small number of patients, and the CT enteroclysis was performed prior to state-of-the-art multichannel technology. In some reports, there is no discussion or illustration of the CT enteroclysis procedure, making it hard to judge the quality of the procedure (27). False-Negative and False-Positive Findings at Wireless Capsule Endoscopy The expanded clinical indication for wireless capsule endoscopy includes almost all investigations for possible small bowel disease. Current reports on wireless capsule endoscopy emphasize its diagnostic yield compared with that of other methods of investigation. As more reports appear in the literature and the adoption of wireless capsule endoscopy becomes universal, additional limitations of this technique will become more apparent. Further experience will help determine the specificity and predictive values of wireless capsule endoscopy in the clinical setting. Missed lesions at wireless capsule endoscopy due to poor bowel preparation, rapid or delayed small bowel transit, orientation of the camera away from a lesion, and fistulas have been reported. A stricture that causes a downstream lesion to be missed may not be clinically relevant if the stricture requires surgery. Otherwise, accurate radiologic investigation will be required to characterize areas of narrowing seen at wireless capsule endoscopy (Fig 4). The role of the patency capsule in the diagnosis of potentially obstructing small bowel lesions will be better defined with further clinical experience.

6 716 May-June 2005 RG f Volume 25 Number 3 Role of Radiologic Investigation Radiologic Investigation Prior to Capsule Endoscopy Except for emergent clinical investigation for possible small bowel disease, in which abdominal CT will remain the primary method of investigation, the role of imaging is likely to undergo reassessment based on the results of wireless capsule endoscopy in the elective work-up of patients. In patients without a risk factor for a potentially obstructing small bowel lesion, radiologic evaluation may have a limited role. As stated earlier, when the indication raises the possibility of early Crohn disease or NSAID enteropathy, double-contrast air enteroclysis is the most reliable method of imaging (Fig 5). CT enteroclysis with neutral enteral and intravenous contrast enhancement should otherwise suffice for all precapsule radiologic investigations when there is a possibility of a potentially obstructing small bowel abnormality. How the introduction of the patency capsule will impact the use of radiologic investigation remains to be seen. Radiologic Investigation Following Capsule Endoscopy As with all examinations in which the human factor is involved, perceptual errors are inevitable. Already, the clinical significance of the small arteriovenous malformations without positive evidence of bleeding and the superficial mucosal scratches seen at wireless capsule endoscopy are increasingly being questioned. A mucosal scratch is a mucosal scratch and will need further characterization in many instances if a precise diagnosis is to be made. Unpublished data in our practice concerning double-contrast air-barium enteroclysis performed following wireless capsule endoscopy, the findings at which were interpreted by experienced endoscopists to characterize or assess the extent of Crohn disease, have shown the latter to have limitations in characterizing superficial ulcers and determining their precise location. In one instance, radiologic examination showed a giant Meckel diverticulum with ulcerations at the junction of the diverticulum and the ileum (Fig 6). In another patient, air enteroclysis demonstrated NSAID-induced ulcers and diaphragm disease that had been ascribed to Crohn disease with wireless capsule endoscopy (Fig 4). Patients Figure 5. Early Crohn disease in a 35-year-old woman with anemia and chronic diarrhea. Doublecontrast air-barium enteroclysis image obtained prior to capsule endoscopy shows scattered linear ulcerations in the midileum (arrow). There is no fold or bowel wall thickening. Results of wireless capsule endoscopy confirmed diffuse early Crohn disease. The patient responded to medical treatment. with persistent symptoms or bleeding and negative wireless capsule endoscopic findings will require accurate radiologic investigation. We have diagnosed a Meckel diverticulum with prior negative wireless capsule endoscopy. NSAID-induced ulcers were seen at double-contrast air-barium enteroclysis performed in a teenage patient with negative wireless capsule endoscopic findings who was suspected of having Crohn disease. The localization of lesions and the subtyping of different manifestations of Crohn disease necessary for the triage of patients for medical or surgical treatment will also require accurate radiologic investigation. Summary The article by Hara et al in this issue is representative of the results of many reports in the literature comparing radiologic investigation with wireless capsule endoscopy. The data in their article were obtained in patients who were examined prior to the clinical introduction of the patency capsule. The small bowel follow-through study was an essential part of precapsule protocol to exclude potentially obstructing small bowel lesions. Many patients also underwent abdominal CT with positive oral and intravenous contrast enhancement. False-negative results and the low sensitivity of these methods of investigation for

7 RG f Volume 25 Number 3 Hara et al 717 Figure 6. Giant Meckel diverticulum in a 21-year-old man who was referred for wireless capsule endoscopy because of chronic abdominal pain and anemia. Results of a small bowel follow-through study, radionuclide examination, and endoscopy of the upper and lower gastrointestinal tract were unremarkable. (a) Wireless capsule endoscopic image shows a shallow ulcer in one segment of the ileum (arrow). Other images showed ulcers in an adjacent segment and possibly in the colon. Double-contrast barium enteroclysis was requested to determine the extent of Crohn disease. (b) Double-contrast air-barium enteroclysis image shows a large saccular dilatation (arrowheads) in a pelvic segment of the ileum. Scattered ulcerations (arrow) are seen adjacent to the point of attachment of the dilatation to a normal-appearing loop of ileum. Results of surgery confirmed the presence of a giant Meckel diverticulum with ulcerations. There was no evidence of Crohn disease. potentially obstructing small bowel abnormalities led to the development of the patency capsule. Wireless capsule endoscopy reports emphasize diagnostic yield compared with that of push enteroscopy and retrograde ileoscopy (28,29). The length of small bowel examined with the wireless capsule endoscopic method would therefore favor wireless capsule endoscopy. The superiority of wireless capsule endoscopy over radiologic investigation has again exposed the limitations of non enteral volume challenged examinations known to radiologists but infrequently used because of inconvenience, high cost, and patient discomfort (16,30,31). As more experience with wireless capsule endoscopy and the recently introduced patency capsule is reported, the role of radiologic evaluation in the elective clinical investigation of small bowel disease will need to be reevaluated. In a marketdriven healthcare environment, given the current reported results of wireless capsule endoscopy (11), convenience and ease of performance will no longer justify the use of radiologic investigation, with its low sensitivity and poor negative predictive values. Only the use of accurate methods of radiologic investigation will justify its continued use and make it complementary to wireless capsule endoscopy in the optimal investigation of small bowel disease. References 1. Iddan GJ, Swain CP. History and development of capsule endoscopy. Gastrointest Endosc Clin N Am 2004; 14: Swain CP, Gong F, Mills TN. Wireless transmission of a colour television moving image from the stomach using a miniature CCD camera, light source and microwave transmitter (abstr). Gut 1996; 39:A Lightdale CJ. Foreword. Gastrointest Endosc Clin N Am 2004; 14:xvii xviii. 4. Hara AK, Leighton JA, Sharma VK, Fleisher DE. Small bowel: preliminary comparison of capsule endoscopy with barium study and CT. Radiology 2004; 230: Hara AK, Leighton JA, Sharma VK. Video capsule endoscopy: findings missed at barium SBFT and CT (abstr). Radiology 2002; 125(P): Friedman S. Comparison of capsule endoscopy to other modalities in small bowel. Gastrointest Endosc Clin N Am 2004; 14: Tang SJ, Haber GB. Capsule endoscopy in obscure gastrointestinal bleeding. Gastrointest Endosc Clin N Am 2004; 14: Costamagna G, Shah SK, Riccioni ME, et al. A prospective trial comparing small bowel radiographs and video capsule endoscopy for suspected small bowel disease. Gastroenterology 2002; 123: Liangpunsakul S, Chadalawada V, Rex DK, et al. Wireless capsule endoscopy detects small bowel

8 718 May-June 2005 RG f Volume 25 Number 3 ulcers in patients not seen with state of the art enteroclysis. Am J Gastroenterol 2003; 98: Eliakim R, Fischer D, Suissa A, et al. Wireless capsule video endoscopy is a superior diagnostic tool in comparison to barium follow-through and CT in patients with suspected Crohn s disease. Eur J Gastroenterol Hepatol 2003; 15: Liangpunsakul S, Maglinte D, Rex DK. Comparison of wireless capsule endoscopy and conventional radiologic methods in the diagnosis of small bowel disease. Gastrointest Endosc Clin N Am 2004; 14: Maglinte DD, Burney BT, Miller RE. Lesions missed on small bowel follow-through: analysis and recommendations. Radiology 1982; 144: Maglinte DD, Hall R, Miller RE, et al. Detection of surgical lesions of the small bowel by enteroclysis. Am J Surg 1984; 147: Herlinger H, Maglinte D. Clinical radiology of the small intestine. Philadelphia, Pa: Saunders, Maglinte DD, Lappas JC, Kelvin FM, Rex D, Chernish SM. Small bowel radiography: how, when, and why? Radiology 1987; 163: Maglinte DD, Kelvin FM, O Connor K, Lappas JC, Chernish SM. Review: current status of small bowel radiography. Abdom Imaging 1996; 21: Riccioni ME, Spada C, Spera G, et al. M2A patency capsule in the evaluation of patients with intestinal stricture: preliminary results (abstr). Endoscopy 2003; 35(suppl II):A Belvin ML, Voderholzer WA, Loch S. Diagnosing small intestinal strictures: first experience with the M2A patency capsule (abstr). Endoscopy 2003; 35(suppl II):A Cauendo A, Rodriquez-Teilez M, Hernandez- Duran M, et al. Evaluation of M2A patency capsule in the gastrointestinal tract: one-capsule preliminary data from a multicentre prospective trial (abstr). Endoscopy 2003; 35(suppl II):A Maglinte DD, Rhea JT, Ledbetter MS. The role of CT in acute abdominal disease: pitfalls and their lesions. In: Mann FA, ed. Syllabus: a categorical course in diagnostic radiology emergency radiology. Oak Brook, Ill: Radiological Society of North America, 2004; Tanaka K. Double contrast study of the minute lesions of Crohn s disease of the small intestine. Stom Intest 1982; 17: Ekberg O. Crohn s disease of the small bowel examined by double contrast technique: a comparison with oral technique. Gastrointest Radiol 1977; 1: Maglinte D, Lappas JC, Heitkamp D, et al. Technical refinements in enteroclysis: advances in intestinal imaging. Radiol Clin North Am 2003; 41: Yao T. Double contrast enteroclysis with air. In: Freeny P, Stevenson GA, eds. Alimentary tract radiology. 5th ed. St Louis, Mo: Mosby, 1995; Bessette J, Maglinte D, Kelvin F, Chernish S. Primary malignant tumors in the small bowel: a comparison of the small bowel enema and conventional follow-through examination. AJR Am J Roentgenol 1989; 153: Romano S, DeLutio E, Rollandi GA, et al. Multichannel CT enteroclysis with neutral enteral and IV contrast enhancement: experience in tumor detection. Eur Radiol 2005 (in press). 27. Voderholzer WA, Ortner M, Roggila P, et al. Diagnostic yield of wireless capsule enteroscopy in comparison with computed tomography enteroclysis. Endoscopy 2003; 35: Cave DR. Reading wireless capsule endoscopy. Gastrointest Endosc Clin N Am 2004; 14: Chong J, Tagle M, Barkin J, et al. Small bowel push-type enteroscopy for patients with occult gastrointestinal bleeding of suspect small bowel pathology. Am J Gastroenterol 1994; 89: Ha AS, Levine MS, Rubesin SE, et al. Radiographic examination of the small bowel: survey of practice patterns in the United States. Radiology 2004; 231: Barloon TJ, Lu CC, Franken EA, et al. Small bowel enteroclysis survey. Gastrointest Radiol 1988; 13: