Current Opinion in Gastroenterology
Wireless Capsule Endoscopy of the Small
Intestine
A Review With Future Directions
Helmut Neumann, Lucía C. Fry, Andreas Nägel, Markus F. Neurath
Disclosures
Curr Opin Gastroenterol. 2014;30(5):463-471.
Abstract and Introduction
Abstract
Purpose of review Here, we review the clinical applications of small bowel capsule
endoscopy. Moreover, we provide an outlook on the exceptional future developments of
small bowel capsule endoscopy. We discuss clinical algorithms for diagnosis of small
bowel diseases. Multiple studies have shown the potential of capsule endoscopy for
identification of the bleeding source located in the small bowel and the increased
diagnostic yield over radiographic studies. Capsule endoscopy could detect villous
atrophy and severe complications in patients with nonresponsive celiac disease. In
addition, small bowel capsule endoscopy was proven as a valid tool to diagnose polyps
and tumors and Crohn's disease.
Summary Major current clinical indications of capsule endoscopy in the small bowel
include evaluation of obscure gastrointestinal bleeding, diagnosis and surveillance of
small bowel polyps and tumors, celiac disease and Crohn's disease. Recent
developments have also passed the way for small bowel capsule endoscopy to become a
therapeutic instrument.
Introduction
The small bowel has an average length of 7 m with a diameter of 2.5–3 cm and is
mainly responsible for digestion and absorption of food. Although the small bowel is
the largest portion of the luminal gastrointestinal tract, thorough examination of the
small bowel was for a long time restricted to radiological imaging techniques and
endoscopic approaches by using long endoscopes.[1,2]
Wireless, small bowel capsule endoscopy was invented by Gavriel Iddan, an electrooptical engineer who previously worked at the Israeli military manufacturer Rafael
Israel Armament Development Authority, developing guided-missile technology.
During a sabbatical year in Boston, Iddan was challenged by a neighbor, an Israeli
gastroenterologist who suffered from chronic abdominal pain of unknown cause, to
invent an endoscope that could make its way through the entire gastrointestinal tract.
After 20 years of development, Iddan was issued patent for capsule endoscopy in 1997.
Within recent years, the advent of capsule endoscopy has revolutionized our way of
how to examine the small bowel in a gentle and elegant fashion. Moreover, capsule
endoscopy provided new insights on the appearance and clinical relevance of small
bowel diseases in a noninvasive and painless fashion. It is of capricious fate that capsule
endoscopy, despite its beneficial use in multiple indications, was shown to be only of
limited effectiveness for evaluation of chronic abdominal pain.[3–5] General indications
of wireless capsule endoscopy according to different locations are as follows:
1. Esophagus
a. Gastroesophageal reflux disease
b. Barrett
c. Esophageal varices
2. Small bowel
a. Obscure gastrointestinal bleeding
b. Intestinal tumors
c. Crohn's disease
d. Celiac disease
e. Malabsorption
3. Colon
a. Polyps
b. Cancer
4. General
a. Diarrhea
b. Abdominal pain
Here, we review the clinical applications of small bowel capsule endoscopy, focusing
on gastrointestinal bleeding, celiac disease, intestinal tumors and small bowel Crohn's
disease. Moreover, we provide an outlook on the future developments of small bowel
capsule endoscopy. We discuss clinical algorithms for diagnosis of small bowel
diseases. The review is underlined by high-quality endoscopic images highlighting
findings of small bowel capsule endoscopy.
Technical Specifications
Multiple capsule systems are available worldwide of which two Food and Drug
Administration and capsule endoscopy-certified capsule devices are currently available
(Table 1).[6] Both are plastic capsules of disposable use. The Given (Given Imaging
Ltd., Yokneam, Israel) small bowel capsule measures 11 × 26 mm and has a weight of
less than 4 g. The field of view is 140° and the system can detect objects less than 0.1
mm. The SB2/4 capsule is capable of capturing four images per second. The operating
time is between 6–8 h. The Given capsule for esophageal diseases (PillCam Eso) has the
same size as the small bowel capsule but is capable to take up to 18 images per second
as it passes down the esophagus. The endocapsule system from Olympus (Olympus,
Tokyo, Japan) has a maximum field of view of 145°, a depth of field between 0–20 mm
and a sampling rate of two frames per second. The dimensions of the capsule are 11 mm
in diameter and 26 mm in length. The operating time of the device is about 8 h.[6,7]
Relative and Absolute Contraindications
Capsule endoscopy should only be used with caution in patients with known or
suspected gastrointestinal obstruction (e.g., Crohn's disease, long-term use of
nonsteroidal anti-inflammatory drugs, abdominal radiotherapy), fistulas or motility
disorders.[8,9] In those patients, nonexcretion of the capsule was reported to occur in up
to 5%.[10] Although capsule retention is usually clinically asymptomatic, it may require
either endoscopic or surgical removal to avoid further complications.[11,12] Of note, one
case of intestinal perforation of a capsule has been described after impactation for at
least 2 months without any clinical symptoms.[13] The patient presented to the
emergency service with sudden, intense, diffuse abdominal pain. Surgery was
performed and revealed a perforation in the distal ileum secondary to an impacted
endoscopic capsule in an area of severe postsurgical adhesions under a subcostal
cholecystectomy incision, which was performed 10 years ago. Another case of small
bowel perforation after capsule endoscopy was described for a patient with undiagnosed
Crohn's disease.[14]
If suspicion of impaired capsule excretion is present, use of the so-called patency
capsule (Agile capsule; Given Imaging Ltd., Yokneam, Israel) is recommended. The
patency capsule has the same size as the conventional capsule system and is composed
of lactose and 5% barium sulfate, dissolvable components, surrounding a tiny radio
frequency identification tag that can easily be detected on the accompanying hand-held
battery-operated radio frequency identification scanner. In addition, the patency capsule
has a radiopaque coating that permits its detection by using X-ray. After about 30–40 h
after ingestion, the patency capsule starts to dissolve so that it can pass naturally
through the gastrointestinal tract, even if strictures are obstructing the lumen
significantly.[8] Nevertheless, patients with suspected strictures need to be advised of
possible symptoms during the procedure because some cases of abdominal pain have
been reported.
In the past, concerns have been raised regarding the use of capsule endoscopy in
patients with cardiac diseases requiring defibrillators and pacemakers. Nevertheless,
evidence has shown that capsule endoscopy can be safely performed in those patients,
although intense monitoring of vital signs may be recommended. In this context it has
also been shown that capsule-induced electromagnetic interference remains a
possibility, but is unlikely to be clinically important. Cardiac pacemaker-induced
interference of capsule endoscopy is also possible, but is infrequent and does not result
in loss of images transmitted by the capsule.[8,15–17]
In patients requiring MRI after capsule endoscopy, one should first confirm capsule
excretion with plain radiographic imaging.
Patient Preparation
Patient preparation for capsule endoscopy of the esophagus is performed after the
patient has fasted for at least 2 h. For small bowel capsule endoscopy, there are several
accepted preparation methods, which include fasting since the day before, clear liquid
diet, the ingestion of 2–4 l of polyethylene glycol solution or the use of mannitol. In
addition, some experts recommend the use of simethicone before the ingestion of the
capsule to reduce intraluminal foam and bubbles.
Capsule endoscopy is a minimally invasive technique, and patient compliance is good in
most cases. Only a minority of patients have problems to swallow the capsule. For those
patients, or even small children, special delivery devices are available. The AdvanCE
(US Endoscopy, Ohio, USA) is a capsule-loading device which is preloaded through the
working channel of an endoscope and a special cup is screwed onto its leading end.[12]
Afterwards, the activated capsule endoscopy is loaded into the cup and the endoscope is
advanced into the small bowel before the capsule is released. When the delivery device
is not available, one could also use overtubes, polypectomy snares, nets or foreign body
graspers to deliver the capsule to the stomach or duodenum, although some mucosa
damage with some bleeding, which may interfere with the analysis, can be observed in
those cases.
Small Bowel Capsule Endoscopy: Clinical Indications
According to one recent systematic review, obscure gastrointestinal bleeding was the
main indication for capsule endoscopy, accounting for 66% of interventions.[18] In case
of obscure overt small bowel bleeding (i.e., visible bleeding), device-assisted
enteroscopy is recommended in hemodynamically stable patients to diagnose and
subsequently treat the bleeding source. In unstable patients, interventional radiology or
surgery should be taken into account. In case of obscure occult gastrointestinal
bleeding, capsule endoscopy should be performed after at least one normal upper and
lower endoscopy.[19]
Multiple studies have shown the potential of capsule endoscopy for identification of the
bleeding source located in the small bowel and the increased diagnostic yield over
radiographic studies, including barium follow-through and computed tomography (CT)
enterography, and push enteroscopy (Figs 1 and 2). One meta-analysis evaluated
diagnostic yields of capsule endoscopy to other diagnostic imaging modalities in
patients with obscure gastrointestinal bleeding.[20] A total of 14 studies comparing the
diagnostic yield of capsule endoscopy and push enteroscopy were analyzed. The
diagnostic yield for capsule endoscopy and push enteroscopy was 63 and 28%,
respectively and for clinically significant findings, 56 and 26%, respectively. Ten of the
14 trials classified the types of lesions found on examination. Capsule endoscopy had a
36% yield for vascular lesions versus 20% for push enteroscopy. Inflammatory lesions
were also significantly more frequently found in capsule endoscopy than in push
enteroscopy. Three studies were evaluated comparing the diagnostic yield of capsule
endoscopy to small bowel barium radiography. The yield for capsule endoscopy and
small bowel barium radiography for any finding was 67 and 8%, respectively, and for
clinically significant findings, 42 and 6%, respectively.[20] One recent meta-analysis
comparing diagnostic yields of double-balloon enteroscopy and capsule endoscopy for
obscure gastrointestinal bleeding reported on similar diagnostic yields.[21] Importantly,
the diagnostic yield of balloon-assisted enteroscopy was significantly higher when
performed in patients with a positive capsule endoscopy.
(Enlarge Image)
Figure 1.
Angiovascular malformation of the small bowel visualized by using capsule endoscopy.
(Enlarge Image)
Figure 2.
Angiovascular malformation of the small bowel in patient presenting with obscure
occult gastrointestinal bleeding.
In case of overt gastrointestinal bleeding, capsule endoscopy detected the bleeding
source in 92%, and in case of occult blood-positive stool and anemia in 44% of
patients.[22]
Figure 3 highlights the proposed Erlanger algorithm for the diagnosis of obscure
gastrointestinal bleeding.
(Enlarge Image)
Figure 3.
Proposed Erlanger algorithm for the diagnosis of obscure gastrointestinal bleeding. +'
='Yes'; '−'='No'. Adapted with permission [7].
Small Bowel Tumors
Small bowel tumors account for 5–7% of patients presenting with obscure
gastrointestinal bleeding and are the most common cause in patients under the age of 50
years.[23] The most common tumors in the small bowel are adenocarcinomas,
lymphomas, gastrointestinal stromal tumors (GISTs), neuroendocrine tumors and
metastasis.
Postgate et al. [24] aimed at evaluating significant small bowel lesions detected by
alternative diagnostic imaging modalities, including double-balloon enteroscopy, CT
enterography or magnetic resonance enterography, after negative capsule endoscopy. In
this retrospective case series, it was shown that capsule endoscopy may miss significant
small bowel pathologies. In four patients, the lesions were in the proximal small bowel
(adenocarcinoma, malignant melanoma, varices and stromal tumor) whereas the fifth
patient had a large Peutz-Jeghers syndrome polyp in the proximal ileum.[24] These
results were also confirmed by another recently introduced study by Zagorowicz et al..
[25]
The study included 145 consecutive patients in whom 150 capsule endoscopies were
performed. Results of double-balloon or single-balloon enteroscopy performed after
capsule endoscopy and the results of surgery in all patients operated were retrieved and
evaluated. Although the sensitivity of capsule endoscopy for tumor detection was 83%
and the negative predictive value was 98%, capsule endoscopy missed three small
bowel tumors (two GISTs and one mesenteric tumor of undefined nature).
One potential limitation of capsule endoscopy seems to be the examination of the
proximal duodenum and the periampullary region which could only be visualized in
about 10% of examinations in one recent study.[26] This is also highlighted by the fact
that in patients with familiar adenomatous polyposis, capsule endoscopy was superior to
conventional white-light endoscopy for the detection of small bowel polyps, but not for
duodenal neoplasia.[27] For hereditary polyposis syndromes, including Lynch syndrome
and Peutz-Jeghers syndrome, studies indicate capsule endoscopy as a well tolerated and
effective method for small bowel surveillance.[28–30]
Taken together, capsule endoscopy is a valid tool to diagnose small bowel lesions.
Nevertheless, one has to be aware that even capsule endoscopy may miss neoplasms,
especially in the proximal small bowel. Reasons may include that those lesions
predominantly grow in the submucosa and extraluminally rather than in the small bowel
lumen. Accordingly, complementary endoscopic and/or radiologic imaging tests are
recommended in patients with obscure small bowel gastrointestinal bleeding and a
negative capsule endoscopy examination.
Celiac Disease
Advanced celiac disease is characterized by villous atrophy which can be identified by
using capsule endoscopy (Fig. 4). Rokkas and Niv[31] performed a meta-analysis on the
role of capsule endoscopy for diagnosis of celiac disease. Out of 461 titles initially
generated by the literature searches, six studies met the inclusion criteria and were
finally eligible for the meta-analysis. The overall pooled sensitivity of capsule
endoscopy for diagnosis of celiac disease was calculated as 89% with a specificity of
95% and an area under the curve (AUC) under the weighted symmetric summary of
0.96. In addition, capsule endoscopy could detect severe complications in patients with
nonresponsive celiac disease, including ulcerative jejunitis and adenocarcinoma.[32] In
patients with complicated celiac disease (i.e., abdominal pain, cancer surveillance, overt
bleeding or persistent iron deficiency), capsule endoscopy was shown to detect
unexpected findings like ulcerations, cancer, polyps, strictures, submucosal masses,
ulcerated nodular mucosa and intussusception in 60% of patients (Fig. 5).[33] Very
recently, Kurien et al. [34] determined the role of capsule endoscopy in equivocal celiac
disease cases, compared with patients with biopsy-proven and serology-proven celiac
disease who had persisting symptoms. It was shown that the diagnostic yield of capsule
endoscopy in patients with antibody-negative villous atrophy is better than that of
capsule endoscopy in patients with celiac disease with persisting symptoms. The
authors advocated the use of capsule endoscopy in equivocal cases, particularly in
patients with antibody-negative villous atrophy.
(Enlarge Image)
Figure 4.
Capsule endoscopy in celiac disease reveals engorged and flattened intestinal villi.
(Enlarge Image)
Figure 5.
Severe ulcerative jejunitis as a very rare finding in severe celiac disease visualized by
small bowel capsule endoscopy.
Crohn's Disease
Crohn's disease is a heterogeneous disease which can affect the whole gastrointestinal
tract. In about 30% of Crohn's patients, disease is limited to the small bowel.[35–37] Small
bowel Crohn's disease can cover a large spectrum ranging from erythema to small
aphthoid lesions, erosions and ulcers. Therefore, differential diagnosis is wide and
includes infectious diseases, celiac disease, drug-induced enteropathy and the use of
nonsteroidal anti-inflammatory drugs. Therefore, it is of critical importance to read the
capsule results with extensive knowledge about the patient's history (Figs 6 and 7).
(Enlarge Image)
Figure 6.
White spot surrounded by erythematous mucosa as typical appearance of an aphthoid
lesion in small bowel Crohn's disease.
(Enlarge Image)
Figure 7.
Superficial ulcerous lesion in small bowel Crohn's disease.
Gal et al. [38] proposed a simple capsule endoscopy Crohn's disease activity index
(CECDAI) in order to grade the severity of small bowel capsule endoscopy findings.
The system involves dividing the small bowel into proximal and distal segments
according to transit time and then rating each segment on the basis of three parameters:
inflammation (A), extent of disease (B) and presence of strictures (C). The segmental
score is calculated by multiplying the inflammation subscore by the disease-subextent
score and adding the stricture subscore (A × B + C); the final score is calculated by
adding the two segmental scores: CECDAI = (A1 × B1 + C1) + (A2 × B2 + C2).[38]
Very recently, the score was additionally validated in a multicenter prospective
study.[39]
To date, three meta-analyses have analyzed the diagnostic yield of capsule endoscopy in
Crohn's disease.[40–42] The latest, published in 2010, reported on diagnostic yields in
patients with suspected and established small bowel Crohn's disease of capsule
endoscopy versus small bowel radiography of 52 versus 16%, respectively and capsule
endoscopy versus CT enterography of 68 versus 21%, respectively.[42] Diagnostic yield
of capsule endoscopy as compared to colonoscopy with ileoscopy was 47 versus 25%,
respectively. Statistically significant yields for capsule endoscopy versus an alternate
diagnostic modality in established Crohn's disease patients were seen in capsule
endoscopy versus push enteroscopy (66 versus 9%), capsule endoscopy versus small
bowel radiography (71 versus 36%) and in capsule endoscopy versus CT enterography
(71 versus 39%).[42]
Figure 8 highlights the proposed Erlanger algorithm for the diagnosis of small bowel
Crohn's disease.
(Enlarge Image)
Figure 8.
Proposed Erlanger algorithm for the diagnosis of suspected small-bowel Crohn's
disease. '+'='Yes'; '−'='No'. Adapted with permission [7].
Future Projections of Capsule Endoscopy
The inherent limitation of capsule endoscopy is that its movement is passively
controlled by the gut peristalsis. Various approaches have been studied allowing
steering or active locomotion of the capsule system.[43–46] Recently, Rey et al. [47]
introduced a novel magnetically navigated capsule which is steered by a low-level
magnetic field. The magnetically guided capsule endoscopy (MGCE) system was
recently prospectively evaluated in patients with routine indications for gastroscopy.[48]
One hundred eighty-nine symptomatic patients underwent capsule and conventional
gastroscopy. The gold standard was unblinded conventional gastroscopy with biopsy.
Accuracy of capsule endoscopy was 91% with a specificity of 94% and a sensitivity of
62%, respectively. Therefore, it was shown that MGCE is feasible in clinical practice.
MGCE was also clearly preferred by patients.
Capsule recordings are of extraordinary length, therefore, requiring significant time for
analysis of the examiner. Proceedings of software algorithms now allow for more timesparing approaches by automatically identifying gastric, duodenal and cecal landmarks
and by automatically scanning images for bleeding-suspicious or lesion-suspicious
images.[49,50]
Another potential limitation of capsule endoscopy is that no tissue analysis can be
performed once a suspicious lesion is found. Recent studies have shown the potential
benefit of virtual chromoendoscopy techniques (i.e., flexible spectral imaging color
enhancement; FICE, Fujifilm, Tokyo, Japan) for detection and diagnosis of small
intestinal lesions found by capsule endoscopy.[51,52]
In addition to software improvements and enhancements, novel capsule prototypes also
allow obtainment of mucosal biopsies and placement of clips for hemostasis.[53] The
Nano-based capsule-Endoscopy with Molecular Imaging and Optical biopsy project by
Given Imaging Ltd. and a global consortium [Zarlink Semiconductor (Sweden and
United Kingdom), Fraunhofer Institute for Biomedical Engineering, Israelitic Hospital
and Indivumed (Germany), Imperial College of Science, Technology and Medicine
(London, England), ITC-irst Research Institute (Italy), The Hebrew University of
Jerusalem, Novamed and Ernst & Young (Israel)] ultimately intends to develop a
capsule system that will combine optical and nano technologies in order to further
improve diagnostic and therapeutic possibilities.
At least, externally rechargeable batteries (using radio frequency, microwave,
ultrasound or electric induction) or even 'battery-free' capsule endoscopy systems are
under development to extend retention times and enable activities like capsule
movements or clip placements.[54]
Conclusion
Capsule endoscopy has proven its efficacy in multiple clinical trials since its invention
in the late 1990s. Current clinical indications in the small bowel include evaluation of
obscure gastrointestinal bleeding, diagnosis and surveillance of small bowel polyps and
tumors, celiac disease and Crohn's disease. Initially invented as a pure diagnostic test,
recent developments show the shift of capsule endoscopy from a diagnostic test to a
multimodal instrument allowing specific diagnosis and even therapy within the small
bowel. New computer-assisted algorithms will further allow improved and faster
readings of capsule recordings whereas steerable capsule devices will open new paths
for specific diagnosis and targeted therapies.