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Perspective |
1 Department of Radiology, Indiana University School of Medicine and Indiana
University Hospital, 550 N University Blvd., UH 0279, Indianapolis, IN
46202-5253.
2 Division of Gastroenterology, Indiana University School of Medicine,
Indianapolis, IN.
Received December 5, 2006; accepted after revision March 28, 2007.
Address correspondence to D. D. T. Maglinte
(dmaglint{at}iupui.edu).
OBJECTIVE. The purpose of our study was to review how commonly performed radiologic examinations compare with capsule endoscopy in the investigation of small-bowel diseases, to analyze the limitations of capsule imaging, and to propose an algorithm for use of specific radiologic examinations to complement wireless capsule endoscopy.
CONCLUSION. The diagnostic yield of capsule endoscopy is superior to that of radiologic examinations except air double-contrast enteroclysis for mucosal details. Radiologic investigations find new applications in clinical practice by complementing capsule endoscopy to overcome its limitations.
Keywords: barium studies • capsule endoscopy • Crohn's disease • CT enteroclysis • CT enterography • small-bowel diseases
Indirect imaging of the mesenteric small intestine by radiologic methods of investigation has been dominant in clinical practice for decades because of the limitations of standard endoscopy. Innovations in imaging have been driven by a constant demand for clinical information necessary for appropriate patient management. Limitations of standard methods of small-bowel examination have provided the stimulus for alternative techniques [1, 2]. The undisputed supremacy of radiologic imaging of the small bowel has been overcome with the U.S. Food and Drug Administration (FDA) approval of the video capsule endoscope (Pill Cam Small Bowel, formerly called M2A Capsule, Given Imaging) in August 2001 [1, 2]. Segments of the small bowel that could not be reached by standard endoscopy can now be visualized with wireless capsule endoscopy.
A pooled analysis of prospective comparison studies of wireless capsule endoscopy with other techniques (push enteroscopy, colonoscopy, small-bowel follow-through, and barium enteroclysis with methylcellulose) to evaluate for suspected small-bowel disease showed that capsule endoscopy had a diagnostic yield of 87% compared with an average of 13% for the alternative method [3-50]. Although air (or carbon dioxide) double-contrast barium examination has been shown in the radiology literature to be more sensitive for mucosal abnormalities than any other radiologic method, it has never been compared with wireless capsule endoscopy [51, 52].
Wireless capsule endoscopy is now considered the state-of-the-art method to noninvasively examine the small bowel [3, 53]. However, as clinical experience with capsule endoscopy is accumulating, its limitations are also becoming apparent [11, 16, 54-57]. Modern radiologic investigations are finding a new clinical application by complementing capsule endoscopy in an attempt to overcome these limitations. This article will review how commonly performed radiologic investigations compare with capsule endoscopy in the investigation of small-bowel diseases and analyze the limitations of capsule imaging. On the basis of this review, recommendations are made on how radiologic investigations can complement capsule endoscopy. Future research venues for small-bowel imaging are suggested.
Limitations of Wireless Capsule Endoscopy
The pill camera advances through the gastrointestinal tract by virtue of peristaltic activity and transmits high-definition color views of the bowel at a frequency of two frames per second. This amounts to an average of 50,000-75,000 frames collected in 7-8 hours of study. The images are then reviewed on a computer station at variable frame speeds, thus compressing the recording. Wireless capsule endoscopy images are of low quality compared with standard endoscopy. An experienced endoscopist can interpret an average study in about 45 minutes. Not surprisingly, the yield of capsule endoscopy is quite remarkable. Yet it has become increasingly apparent that not all mucosal abnormalities seen on wireless capsule endoscopy are clinically relevant. Mucosal breaks or small-bowel erosions may be seen in as many as 14% of asymptomatic healthy subjects, and the rate of such abnormalities in users of nonsteroidal antiinflammatory drug (NSAID) agents is more than double [50]. Thus, differentiating Crohn's disease from NSAID ulcers and from normal background noise may be challenging. Differentiating NSAID-induced diaphragm disease from the stricture of Crohn's disease can be difficult at wireless capsule endoscopy. The need for a complementary radiologic examination is apparent. Because inflammation in Crohn's disease subsequently affects the entire thickness of the bowel wall, radiologic examinations that optimize mucosal and bowel wall detail will prove to be useful complementary methods [57].
Localization of various small-bowel abnormalities is another limitation of wireless capsule endoscopy [58]. The capsule location in the abdomen is estimated using triangulation of wireless signals. Despite software improvements, localization has not been reliable. Location software may display tracings of normal luminal progression even when the capsule is retained because of the high mobility of the small bowel inside the peritoneal cavity.
A rapid capsule transit, the presence of fluid in the small bowel, and the lack of luminal distention may produce equivocal endoscopic visualization. Because only one end of the small-bowel capsule is fitted with a camera, retrograde advancement of the wireless capsule may decrease visualization of strictures in particular. Radiologic studies may prove helpful under these circumstances.
Capsule retention remains a significant limitation and concern for wireless capsule endoscopy. Capsule retention is defined as the lack of elimination of the camera from the digestive tract within 14 days after ingestion. "Temporary retention" has been described in 0.7-14% of patients, depending on the indication for the study. Reported rates of capsule retention are 0.7-2% for obscure gastrointestinal bleeding and suspected Crohn's disease [54, 55], whereas the occurrence is higher (up to 8%) in patients with established Crohn's disease [54, 59]. There is a high incidence of asymptomatic strictures in Crohn's disease [59]. Almost all reported capsule retentions have followed negative small-bowel radiologic investigations [21, 24, 34, 55, 58-60]. In a study at Northwestern University [59], despite the high retention rate, the small-bowel follow-through (SBFT) compared well with capsule endoscopy in making the diagnosis of Crohn's disease. In the study by Voderholzer et al. [16], no capsules were retained because patients with stenosing Crohn's disease diagnosed on CT enteroclysis were excluded. Results similar to those of Voderholzer et al. were observed by the Mayo Clinic group on patients who underwent CT enterography followed by capsule endoscopy [37]. However, the Voderholzer study underestimated some strictures and the Mayo Clinic study had capsule retention. Thus, CT enteroclysis and CT enterography appear to be reliable radiologic examinations in screening for most strictures in patients with suspected small-bowel Crohn's disease. If either study shows findings of Crohn's disease, the need for capsule endoscopy should be questioned unless issues relevant to management are not fully answered. Prolonged capsule retention is generally due to a significant anatomic abnormality and may require endoscopic or surgical removal of the capsule.
Most retained capsules are asymptomatic. To date, a single case report has been described in the literature of a pill camera causing acute bowel obstruction, out of more than 750,000 studies performed worldwide [60]. Furthermore, the capsule is usually retained upstream from significant bowel abnormalities, and the ensuing surgical intervention will provide a definitive diagnosis and therapy for the condition that was responsible for the patient's symptoms. This argument for the use of capsule endoscopy is valid unless the retention is secondary to an inflamed segment of small bowel or an asymptomatic stricture for which surgery is unnecessary. Capsule retention should therefore be an indication for radiologic investigation [57]. This particular limitation of capsule endoscopy should be taken into account when interpreting the true accuracy of wireless capsule endoscopy because most reports do not include in their denominator the proportion of the study population that was screened out on the basis of contraindications to capsule endoscopy because of bowel strictures seen on previous radiologic studies.
Recently, a "patency" capsule (Agile, Given Imaging) has been approved by the FDA for screening patients with suspected small-bowel strictures. The capsule has identical size and shape to the pill camera and has a lactose content that surrounds a small rod-shaped radiofrequency detector. If the capsule is retained, the lactose core disintegrates rapidly in the small bowel, and the radiofrequency detector tag can either be identified with an extracorporeal manual scanner or visualized on conventional abdominal radiographs. Retention of patency capsules is considered a contraindication for wireless capsule endoscopy [56].
Finally, the capsule may not reach the cecum despite the lack of any visible anatomic obstacle. Failure to reach the cecum has been reported, on average, in 15% of studies and is thought to be due to either a motility problem (impaired gastric emptying, delayed small-bowel transit) or, rarely, to technical failure of the capsule (short battery life) [10, 16, 32, 35, 37]. The development of longer lasting batteries or means to control the advancement of the capsule inside the gastrointestinal tract will likely reduce the frequency of these occurrences.
Last, the pill camera cannot be used for either sampling or therapy, which is a significant shortcoming in comparison with traditional endoscopy. Until recently, tissue diagnosis or therapeutic interventions required surgical interventions or intraoperative enteroscopy. The advent of double-balloon endoscopy will likely obviate most of these invasive interventions [61]. Animal studies are ongoing for the development of an autonomous radio-controlled robotic capsule endoscope with movement function and the ability to perform fine-needle aspiration or brush cytology [62].
Limitations of Studies Comparing Capsule Endoscopy with Other Imaging Tests
The superior yield of capsule endoscopy to most radiologic investigations and to push enteroscopy has been shown by several studies (Table 1). However, many of these trials suffer from design biases that may have artificially inflated the yield of capsule endoscopy. In some studies, patients were recruited for the study if the barium small-bowel studies were reported as negative; these studies were reported routinely and were not reviewed for accuracy, whereas capsule studies were interpreted by experts [23, 26, 28]. In other studies using colonoscopy as the comparator, examination of the terminal ileum was not reported or not performed [7, 23, 25, 26, 28]. Arbitrary diagnostic criteria were often used because standard criteria for most of the diagnoses brought in question by wireless capsule endoscopy do not exist. Thus, a legitimate concern exists for possible circular thinking in these studies that used wireless capsule endoscopy both as the study investigation and as the gold standard. Except for obscure gastrointestinal bleeding, the impact of capsule endoscopy on outcome has been unclear [63]. As mentioned previously, patients with possible contraindications to capsule endoscopy were generally excluded from many studies, but the percentage of patients excluded was not considered in the denominator [2, 7, 16, 25, 26]. The time interval between the imaging study and capsule endoscopy was often not given [23, 28].
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Contraindications to Capsule Endoscopy
Most gastroenterologists consider capsule endoscopy to be contraindicated in patients with suspected small-bowel strictures (e.g., from Crohn's disease or prior bowel surgery), swallowing disorders, motility disorders, intestinal pseudoobstruction, and pregnancy. A relative contraindication may exist in patients with esophageal, small-bowel, or colonic diverticula, and in patients with implantable pacemakers, defibrillators, or other electronic devices, although reports have challenged many of these guidelines [64-66].
Status of Radiologic Imaging
Barium Radiography
The most accurate radiologic method in the diagnosis of small-bowel
obstruction, Crohn's disease, unexplained gastrointestinal bleeding, and
small-bowel neoplasms documented in the literature is enteroclysis
[67]. However, the SBFT has
remained the most commonly performed method for the investigation of
small-bowel diseases because of its ease of performance and the convenience to
radiologists; disadvantages of enteroclysis include the discomfort to patients
of intubation without the use of conscious sedation and the need for hands-on
involvement by the radiologists in performing the procedure. The SBFT has a
low diagnostic yield and negative predictive value. In a recent study, 8% of
patients with known Crohn's disease experienced capsule retention despite a
normal SBFT performed by an experienced gastrointestinal radiologist
[59]. The limitations of
nonintubation infusion small-bowel examinations that do not challenge the
distensibility of the bowel wall in the evaluation of partially obstructing
lesions and small polyps or masses have been well documented
[68].
Accumulating experience with wireless capsule endoscopy has uniformly shown poor performance of the SBFT compared with capsule imaging [3]. Ulcers, erosions, and polyps shown by capsule imaging were reported to be frequently missed by SBFT. SBFT was often ordered before wireless capsule endoscopy to exclude potential causes of small-bowel obstruction, a major contraindication to wireless capsule endoscopy before the introduction of the patency capsule. Although large diverticula and small-bowel dysmotility can be diagnosed by the SBFT, comparative study results have shown significant limitations of the SBFT for the evaluation of unexplained gastrointestinal bleeding and suspected Crohn's disease and in excluding potential obstructing lesions. The success of the redesigned patency capsule may potentially eliminate the need for the SBFT before capsule imaging. As wireless capsule endoscopy becomes increasingly widespread, the role of the SBFT in the investigation of unexplained anemia or gastrointestinal bleeding in a patient without a clinical background of possible small-bowel obstruction will decline [57].
The biphasic enteroclysis examination with methylcellulose as the double-contrast agent has been the most commonly performed enteroclysis method in many countries [68]. However, methylcellulose as a double-contrast agent has resulted in a washout effect on superficial mucosal features [29]. Subtle surface abnormalities have been shown to be effaced as more methylcellulose is infused to achieve a good double-contrast effect that diminishes lesion conspicuity. In an overview comparing double-contrast enteroclysis with air and methylcellulose small-bowel enemas, Amberg [51] has stated, "There is little argument over whether one can see mucosal lesions better with the air contrast technique...this is the best method for showing mucosal details of the small bowel." A report correlated double-contrast air enteroclysis findings with surgical and histologic specimens in patients with Crohn's disease who had surgery [52]. Barium enteroclysis with air showed good correlation in the visualization of aphthae and small scars. Air-barium double-contrast enteroclysis is the only radiologic method of examination that has not been formally compared with wireless capsule endoscopy.
CT
After negative upper and lower endoscopic examinations, abdominal and
pelvic CT may be recommended, especially for suspected bowel tumors. However,
CT has performed poorly compared with wireless capsule endoscopy for
small-bowel tumors such as polyps, erosions, or even ulcers
[3,
11,
35]. In many of these studies,
MDCT was not used, and the protocols were not optimized for small-bowel
examination. Positive oral contrast material was used, and the volumes were
usually inadequate for small-bowel opacification and distention.
A modification of enteroclysis first reported in 1992 was introduced to overcome the individual deficiencies of CT and barium enteroclysis and to combine the advantages of both into one technique [67, 69]. The ability of MDCT technology to increase anatomic coverage with fewer motion artifacts and to obtain thinner collimation with increased temporal and spatial resolutions has improved imaging of organs that are longer than wide, such as the mesenteric small intestine, using the CT enteroclysis method [70]. Clinical experience has shown that CT enteroclysis is a reliable method of diagnosing small-bowel diseases [69-72]. Initially described using positive enteral (water-soluble) contrast material, CT enteroclysis has been further refined by using neutral enteral and IV contrast enhancement to address the clinical indications of unexplained gastrointestinal bleeding, anemia, or Crohn's disease.
The small-bowel distention achieved by infusion of neutral enteral contrast material (water, VoLumen, E-Z-EM) and the depiction of the small-bowel wall by IV contrast material shows great promise in the differentiation of mucosal hyperemia and bowel wall edema in active inflammation of Crohn's from the soft-tissue increased attenuation of fibrostenosis. A recent report of a large group of patients has shown the reliability of this method in the diagnosis of small-bowel tumors [71, 72]. Experience with both methods of CT enteroclysis indicates that the use of neutral enteral and IV contrast media is technically a simpler method for the evaluation of small-bowel Crohn's disease and tumors than all the other modifications of enteroclysis and is better tolerated by patients except those with a history of vomiting. CT enteroclysis allows a more global look not only at the small bowel but also at the stomach, colon, and solid abdominal organs. However, in patients with a history of vomiting, the ability to adjust the infusion rate of fluoroscopy using positive enteral (water-soluble) contrast material allows a more accurate examination [70].
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Complementary Role of Radiology to Wireless Capsule Endoscopy
Wireless capsule endoscopy will have a significant impact on radiologic investigations in the 21st century. Current evidence suggests that the universal adoption of wireless capsule endoscopy will change the role of radiology in the elective investigation of small-bowel diseases [57]. Its superiority for obscure or occult small-bowel bleeding is unquestionable. The SBFT may become, for the most part, a historical vignette limited to institutions without expertise in more reliable methods of small-bowel imaging (Table 2). However, because capsule endoscopy provides information regarding the intestinal mucosa only, additional investigations will be required for a complete and accurate diagnosis in certain clinical scenarios such as Crohn's disease or staging of small-bowel tumors. Furthermore, sophisticated radiologic techniques will be able to overcome certain limitations of wireless capsule endoscopy such as the exploration of strictures, radiation injury, and luminal or extraluminal tumors (adenocarcinoma, carcinoids, mesenchymal tumors, and so forth). The relative convenience of conventional radiologic methods of investigation that have poor sensitivity will not be justified in a market-driven health care environment, given the reported results of wireless capsule endoscopy.
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The literature suggests that air (CO2) barium enteroclysis is the most sensitive radiologic method of revealing superficial small-bowel ulcers, but it is a technically more demanding examination and requires expertise [57]. Studies comparing air double-contrast barium enteroclysis and capsule endoscopy would be of interest. CT enteroclysis is the most accurate radiologic method for the diagnosis of small-bowel obstruction. The use of neutral enteral contrast material has been shown to be reliable in assessing the extent of Crohn's disease and its complications, but it may be insensitive for the aphthoid lesions that are the earliest manifestation of disease if they are the only abnormality and are readily identified by wireless capsule endoscopy [57]. CT enterography will likely replace the SBFT in most radiology practices [37, 73].
On the basis of this review, we propose the following algorithm for use in specific radiologic examinations to complement and add diagnostic information to wireless capsule endoscopy in the elective investigation of small-bowel disease.
Before Capsule Endoscopy
In the patient with obscure gastrointestinal bleeding, without risk factors
or symptoms suggestive of small-bowel obstruction, no radiologic
investigations are necessary before wireless capsule endoscopy. Furthermore,
no current radiologic method can reliably identify angiodysplasias, which are
the most common cause of obscure intestinal bleeding
[57]. In patients with
suspected early Crohn's disease or NSAID enteropathy, air double-contrast
enteroclysis is the most sensitive method for diagnosing the superficial
ulcers or erosions (Fig. 1)
(Maglinte DDT, presented at the 2006 meeting of the Society of
Gastrointestinal Radiologists/European Society of Gastrointestinal and
Abdominal Radiology).
In patients with a risk factor for possible obstruction, CT enteroclysis is the most reliable investigation that can determine bowel patency before performing capsule endoscopy. CT enteroclysis may be the only noninvasive imaging study needed and thus may have substantial benefit in patients diagnosed with significant bowel strictures. In patients with Crohn's disease, CT enterography is appropriate [37]. Recent reports indicate a good performance of CT enterography for different clinical indications, including obscure gastrointestinal bleeding, and particularly for screening out patients with stenosing Crohn's disease [73]. CT enterography will play a significant role in imaging of the small bowel but will have similar limitations to those of other nonenteral volume-challenged examinations, which hopefully can be diminished by the large volume of enteral contrast material and MDCT technology.
Under these circumstances, radiology serves not only as a preliminary study but also in establishing a diagnosis because of its ability to image the entire small-bowel wall and the surrounding tissues. Therefore, it is reasonable to expect that CT enterography and MR enterography will replace SBFT; and when additional questions relevant to management are not answered, CT enteroclysis or MR enteroclysis can be performed. Probably little role exists for the SBFT in present-day small-bowel imaging except for assessment in the immediate postoperative period. How the introduction of the patency capsule will affect the precapsule utilization of radiologic investigations remains to be seen. CT enteroclysis may also have a role in patients with suspected small-bowel neoplasms, in particular those with a significant submucosal component, such as mesenchymal tumors (gastrointestinal stromal tumors, leiomyomas) or carcinoids, and less in small-bowel polyposis (i.e., Peutz-Jeghers, FAP), where, again, wireless capsule endoscopy appears to be superior [71, 72].
After Capsule Endoscopy
The patient with persistent symptoms or bleeding after a negative capsule
examination may require further investigations. Patients with equivocal
findings, whether due to rapid or delayed transit, inadequate illumination, or
poor preparation, may benefit from additional investigations
[57]. Barium-air
(CO2) enteroclysis is the most accurate radiologic study for the
diagnosis of mucosal abnormalities such as erosions or superficial ulcerations
and may show the aphthae of early Crohn's disease. Submucosal or intraluminal
masses can be confirmed and further characterized on CT enterography, CT
enteroclysis, MR enterography, or MR enteroclysis, specifically in regard to
size, location, and extension. Similarly, establishing the extent, severity,
and presence of complications (fistulas or abscesses) in Crohn's disease will
likely benefit from these high-performance studies, particularly CT or MR
enteroclysis [57]. Although CT
enterography and MR enterography do not show mucosal details, other findings
of Crohn's disease, such as abnormal mural signal and wall thickness, are
shown. Further research is needed to correlate early mucosal findings with
these methods.
Summary
The superior diagnostic capabilities of capsule endoscopy compared with conventional radiologic methods of investigations of small-bowel disorders have exposed the limitations of these techniques, which, until now, were the dominant method in the investigation of the small bowel. The role of radiologic investigations in the elective clinical investigations of the small-intestine disease will likely require reevaluation. The current clinical indications of wireless capsule endoscopy have been expanded to include almost any symptom of small-bowel disease. The widespread dissemination of capsule imaging and double-balloon endoscopy will require more reliable and refined complementary radiologic methods of examination. Because of its apparent limitations, wireless capsule endoscopy is unlikely to be a universal stand-alone diagnostic test, except perhaps for obscure small-bowel bleeding. Over time, the accuracies of capsule endoscopy and radiologic methods are likely to become similar with the elimination of reference standard bias and technical improvements on the radiology side.
On the basis of this review, the appropriate use of air-barium (double-contrast) enteroclysis, CT enterography or MR enterography, and CT enteroclysis or MR enteroclysis appears rational in a market-driven health care environment and will complement capsule endoscopy for the foreseeable future. Outcome-based and nonbiased designed research studies comparing capsule endoscopy with present-day small-bowel imaging will further define the role of radiology in small-bowel investigations in the 21st century. Modern radiologic examinations more than complement capsule endoscopy. They provide diagnostic information that capsule endoscopy does not.
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