Dr. Vicente Lorenzo-Zúñiga García
Hospital Universitario Germans Trias i Pujol. Badalona
II.2.1.1. Capsule endoscopy
Capsule endoscopy (CE) is a minimally-invasive endoluminal examination technique that allows us to directly observe the mucosa of the digestive tract. To perform this technique, the patient must ingest a capsule, with an average size of 26 x 11 mm, equipped with a battery to allow the constant capture of images, which are transmitted wirelessly for an average of 8–10 hours and recorded in a storage device carried in a belt. The CE is moved through the digestive tract by intestinal motility.
Since CE was introduced in 20001, study of the small intestine has been revolutionised, with the corresponding diagnostic and therapeutic implications. There are currently several small bowel CE (SBCE) devices available on the market2, but only those produced by Given and Olympus have been approved for the North American and European markets.
• Pillcam SB®, Given Imaging, Yoqneam, Israel (http://www.givenimaging.com).
• EndoCapsule®, Olympus Europe GmbH, Hamburg, Germany
• CapsoVision®, Saratoga, CA, USA
• OMOM®, Choongqing Jinshan Science, Beijing, China (http://www.cqjs.net).
• MiroCam®, IntroMedic, Seoul, Korea
(http://www.intromedic.com) (Table I).
The Pillcam capsule uses the Complementary Metal-Oxide-Semiconductor (CMOS) system to capture images, while the other devices use the Charge-Coupled Device (CCD). The Pillcam and EndoCapsule capsules also allow real-time visualisation of the images obtained by the capsule using a coaxial cable connected to a portable screen.
BCE is the most sensitive technique for detecting mucosal lesions in the small intestine3-5, but suboptimal intestinal preparation limits its utility, as the diagnostic yield varies between 33.8% in unprepared patients and 48.8% in patients who were previously prepared (odds ratio 1,88)6. Despite the evident benefits of intestinal preparation, current guidelines still recommend an 8–12 hour fasting period before starting the test7. In the two meta-analyses conducted to date, not only the diagnostic capacity of CE but also the endoscopic imaging quality were found to be superior in those patients who were previously prepared compared to those who only received a liquid diet6,7. Both studies demonstrated the advantage of using products based on polyethylene glycol (PEG) solutions, and no benefits of the use of sodium phosphate were found. Regarding the dose of PEG, it is not known whether the volume of PEG can affect the outcome, as there were no differences based on the ingestion of 2 or 4 litres of PEG, but it has been suggested that the dose required is lower than that required for colonoscopy. Therefore, given the better tolerance and acceptance by patients, the use of a 2 litres PEG solution is recommended as the usual preparation for performing a CE examination.
CAPSULE ENDOSCOPY IN THE DIAGNOSIS AND FOLLOW-UP OF CROHN DISEASE
Acceptance of SBCE as a high-yield examination technique has increased very dramatically in recent years. Although its role in the study of occult gastrointestinal bleeding is very well established, the same is not true in the evaluation other intestinal diseases. Due to its great sensitivity for detecting superficial lesions, its specificity and its negative predictive value of over 90%, this is an ideal technique for studying Crohn disease (CD), either for suspected diagnosis or to monitor progress, as the small intestine is involved in over two thirds of these patients8-12. Conversely, it must be remembered that the main limitations of SBCE are the impossibility of taking biopsies or applying treatments, the difficulty of specifying the exact position of lesions, and steering control.
Retention of the capsule is one possible complication of this test, with an incidence varying between 1 and 2.5%, primarily due to intestinal stenosis either in the context of CD or due to enteropathy associated with non-steroidal, anti-inflammatory drugs (NSAIDs)13,14. In general, CE retention is defined as the capsule remaining in the digestive tract for a minimum of two weeks, requiring surgical or endoscopic extraction, although the capsule retention must be managed on an individual basis for each case. A recent multicentre study confirmed that the presence of CD was a predictive risk factor for retention (odds ratio 9.39; 95% CI 3.32–26.54)15. Due to the elevated risk of retention in these patients, a preceding radiological study is recommended to rule out the presence of intestinal stenosis that could obstruct the passage of the capsule. However, when there is a suspected stenosis, in order to avoid CE retention the use of a biodegradable capsule or Patency Capsule (AGILE Patency capsule®, Given) is recommended. This has the same size as the SBCE capsule and allows us to determine in which patients the use of a conventional rigid capsule is safe, as it is made from lactose and barium and degrades 32–72 hours after being ingested16.
CE is indicated for patients with suspected non-stenotic CD with previous negative ileocolonoscopy and biopsies, and for patients with a known diagnosis of non-stenotic CD, to assess the presence of post-surgical recurrence, the extent of the disease and the response to treatment.
Diagnosis of Crohn disease
We currently have no “gold standard” test available for the diagnosis of CD, so diagnosis of this disease requires a set of various clinical, analytical, radiological and endoscopic tests. Several studies have shown that over 30% of patients with CD have involvement of the small intestine alone17. Involvement of the terminal ileum in CD can be proven by ileoscopy, so we must perform an endoscopy before requesting a CE examination. In other patients for whom ileocaecal valve cannulation is not possible, CE is indicated, provided that there is no risk of intestinal stenosis.
The clinical applicability of CE for diagnosing CD is unknown18, as 13% of healthy, asymptomatic individuals have non-significant lesions in the intestinal tract, so it is difficult to establish a correlation between the CE findings and clinical symptomatology without a histological diagnosis. Nor should it be forgotten that the patient’s medical records are required when interpreting CE results, as 14% of healthy volunteers have non-specific mucosal lesions in the context of ingesting NSAIDS, which could be present in patients with suspected CD12. These data suggest that the use of CE should be reserved for cases where ileocolonoscopy and radiological examinations do not provide a diagnosis and there is a high likelihood of CD, as CE has the great advantage of allowing complete visualisation of the entire small intestine, although it does not reach the caecum in 8–40% of cases18. Real-time visualisation of CE images allows us to verify whether or not the capsule has reached the colon, as the examination time can be extended in such cases, provided that the battery does not run out.
Anormal CE examination has a high negative predictive value (96–100%) for active CD. The CDAP-Plus study, which included 50 patients with suspected CD and signs of inflammatory activity (elevated C-reactive protein and erythrocyte sedimentation rate, thrombocytosis or leukocytosis), showed that the presence of any of these increased the diagnostic yield of the CE with an odds ratio of 3.219. In another field study with 17 patients with abdominal pain, diarrhoea, anaemia and weight loss over a mean period of 6.3 years and with normal diagnostic tests (colonoscopy, upper digestive endoscopy, radiological study of the small intestine), CE diagnosed the presence of CD in 12 (70.5%) of these patients10. All this data suggests that screening criteria are required to correctly indicate this examination, as established at the first consensus conference on CE (ICCE)20, which proposed the use of CE to diagnose or rule out the presence of CD if patients presented clinical symptoms associated with extraintestinal manifestations, inflammatory activity parameters or pathological findings during imaging studies (Video 1).
When CE is used to diagnose CD, there is a risk of false positives because, despite the use of standardised diagnostic criteria, the positive predictive value is 50%21, so it is difficult to justify the use of CE as a first-line diagnostic technique for CD. The available scientific evidence shows that CE can identify early inflammatory changes in the mucosa of the small intestine, which can be used for earlier diagnosis of CD, although it is not clear whether this would benefit the patient (Video 2).
Follow-up of Crohn disease
Endoscopic examinations play an important role in the follow-up of CD patients. Most subjects with this disease have lesions in the terminal ileum, which can be accessed by flexible endoscopy, so these patients can be managed without the need for other endoscopic techniques. However, in those patients with an unexplainable clinical symptomology and/or non-specific findings from radiographic or endoscopic studies, CE allows mucosal lesions to be detected in the proximal small intestine, which could have therapeutic implications. An important limitation of this technique is that it only provides information on patients with non-stenotic CD and does not assess transmural or extraintestinal involvement (Video 3 and Video 4).
Lorenzo Zúñiga et al.22 found that the indications for a change in patient management were iron-deficiency anaemia and abdominal pain. This is an important piece of data, as the presence of an abnormal segment in the small intestine, which occurs in 93% of CD patients, provides no significant data unless it affects patient management.
Approximately 80% of CD patients will require surgical intervention during the course of their disease, due to the appearance of complications such as stenoses and fistulae or due to refractory activity to the treatments used. As is well known, surgery does not cure the disease and it recurs in the great majority of patients. Around 70–80% will have endoscopic recurrence within a year of surgery and up to 57% will require another surgery within 10 years of the first23. Endoscopic recurrence is evaluated by the Rutgeerts’ score (Fig. 1), which also shows a strong correlation between the severity of endoscopic lesions and the subsequent clinical course23. Given that post-surgical recurrence occurs in the terminal neo-ileum, CE is of great use in detecting these lesions (Video 5). In this regard, two available studies have evaluated the role of CE in detecting post-surgical recurrence, defined as the presence of a Rutgeerts’ score >1. In the first study, ileoscopy showed a sensitivity of 90% and a specificity of 100%, whereas CE had a sensitivity of 62–76% and a specificity of 100%; however, both techniques showed a statistically significant correlation in the staging of mucosal lesion severity24. In the other study, a prospective study of 24 CD patients, the presence of post-surgical recurrence (Rutgeerts’ score >2) was found by ileoscopy in 25% of cases, compared to 62% with CE, as this detected more proximal lesions that were out of the colonoscope’s range25.
Those CD patients who undergo clinical remission without reaching endoscopic remission have a worse prognosis, so the purpose of treatment is to achieve mucosal healing, thus evaluating the response to treatment and helping us make decisions.
ACTIVITY INDEX. IS IT OF PRACTICAL USE?
Diagnosis of CD that only involves the small intestine is a great diagnostic challenge, as the clinical symptoms and physical signs are typically non-specific and do not always correlate with the level of inflammatory activity. CE is a very useful tool for evaluating ulcerative diseases of the small intestine. It is very helpful for assessing the level of inflammatory activity, the extent of the disease and the existence of mucosal healing.
The lack of specificity of endoscopic findings from CE, the presence of interobserver variability and the lack of histological material increase the risk of an imprecise diagnosis, which emphasises the need to adopt common terminology for describing lesions and uniform criteria for stratifying their severity26 (Fig. 2).
There are currently several inflammatory activity indices available for CD patients, none of which have acquired a prominent role27-30, which are based on clinical symptoms, analytical parameters or endoscopic findings. These were all designed to provide clinical utility, by monitoring the response to treatment and helping in decision-making. In an attempt to quantify damage to the mucosa, an endoscopic activity index for CD (Crohn’s Disease Endoscopic Index of Severity [CDEIS]) and its simplified version (Simple Endoscopic Score for Crohn’s Disease, SES-CD)31 were designed and validated (Fig. 3). According to the SES-CD score, the level of CD activity is stratified into:
• ≤2 = inactive disease.
• 3–6 = mild activity outbreak.
• 7–15 = moderate activity outbreak.
• ≥16 = severe activity outbreak.
Furthermore, we have the Rutgeerts’ score, which evaluates mucosal activity or recurrence after ileocolic surgical intervention, based on the number of erosive lesions in the terminal neo-ileum32. The problem with these two indices is that they only allow for the assessment of areas accessible by colonoscopy, namely the colon or terminal ileum. With the introduction of CE, full visualisation of the small intestine has been achieved, demonstrating the need for an inflammatory activity index for the intestinal mucosa; thus, in 2005 the ICCE proposed the need to develop and validate an endoscopic activity index for CE. The studies by Fireman10 and Eliakim8, which defined the viability of CE in patients with suspected CD, did not specify the findings required to diagnose CD. Goldstein et al.12, who compared the effects of naproxen and ibuprofen vs celecoxib, only counted the number of mucosal tears to quantify the level of damage to the mucosa. Mow et al.9 established a cut-off of three or more ulcers to establish a diagnosis of CD for patients with no previous ingestion of NSAIDs. Finally, Fidder et al.33 defined the presence of four or more ulcers, erosions or areas with exudation, mucosal hyperaemia or oedema as positive findings for CD. Therefore, as an attempt to design appropriate indices for CE, in 2008, Gal et al. published a CD activity index with CE (Capsule Endoscopy Crohn’s Disease Activity Index [CECDAI], or Niv score)29, which was recently validated34. Subsequently, Gralnek et al. developed the Lewis score (LS) to rate inflammatory activity in the mucosa30.
The CECDAI evaluates three pivotal parameters of mucosal involvement in CD: inflammation (A), extent of the disease (B) and presence of stenosis (C) (Table II). Before calculating the index, the midpoint of transit through the small intestine must be identified; this is estimated using the bowel transit time, which differentiates a proximal from a distal segment. Inflammation (A) (Fig. 4) is rated from 0 to 5 points:
• 0 = no inflammation.
• 1 = mild oedema/hyperaemia.
• 2 = severe oedema/hyperaemia.
• 3 = small ulcers (<5 mm).
• 4 = moderate ulcers (5–20 mm).
• 5 = large ulcers (>20 mm).
Extent (B) (Fig. 5) is rated from 0 to 3 points:
• 0 = normal.
• 1 = focal involvement.
• 2 = patchy involvement.
• 3 = diffuse involvement.
Stenosis (C) (Fig. 6) is rated from 0 to 3 points:
• 0 = no stenosis.
• 1 = single non-obstructive stenosis.
• 2 = multiple non-obstructive stenosis.
• 3 = obstructive stenosis.
Three parameters are quantified for each segment, multiplying the degree of inflammation by the extent (A x B) and adding the stenosis score (C), so the final calculation is as follows: CECDAI = proximal
([A x B] + C) + distal ([A x B] + C). The purpose
of the CECDAI is to allow clinicians to estimate the mucosal inflammation of CD patients.
This index has a high rate of interobserver correlation (range 0.8–0.92; p <0.001) and agreement (0.865).
The Lewis score LS quantifies damage to the mucosa based on the appearance of the villi (oedema), the presence of ulcers and stenoses. The finding of erosions, erythema, nodules and villous atrophy are not included in the rating score due to their limited clinical significance and poor interobserver agreement. The LS, which is included in the reading programme of some capsules, can be calculated relatively easily. The score has been designed to evaluate inflammatory enteropathy, whether this is CD, NSAID-induced enteropathy, actinic enteritis or vasculitis, and it allows the level of involvement to be classified into three categories:
• Severe involvement (>790).
• Moderate (135–790).
• Normal (<135).
The LS shows excellent interobserver agreement for assessing the severity of mucosal involvement (84–86%).
Both indices, CECDAI and LS, can be used to objectively rate the level of inflammatory activity and assess mucosal healing. Although these indices constitute a qualitative improvement, they still have some limitations, including the fact that we need prospective clinical studies to evaluate their utility in clinical practice and that they do not distinguish between CD lesions and other pathologies, such as NSAID-induced enteropathy, coeliac disease or ischaemia.
Measurement of faecal calprotectin (FC), which is proportional to the level of granulocyte activation and mucosal inflammation35, is another non-invasive method for discovering the level of intestinal inflammation. Several studies have shown a correlation between FC and the CE activity indices36,37; as such, an FC <100 µg/g predicts a lack of CE findings, while an FC >200 µg/g is associated with the presence of mucosal lesions found by the CE, confirming the presence of CD in 50% of cases38. The correlation between CECDAI and LS and FC levels is maintained when the FC is normal, which is consistent with CE’s negative predictive value in these cases. Conversely, this association is not as strong when FC levels are high. There are various factors that could contribute to this disagreement, such as the presence of fibrotic stenoses, which have an elevated effect on the indices’ scores and are not associated with the release of FC. Therefore, the presence of high FC levels alerts the clinician to the presence of an inflammatory process, and CE is beneficial in such cases to rule out or confirm the presence of significant inflammation in the intestinal mucosa.
CORRELATION OF CAPSULE ENDOSCOPY WITH OTHER IMAGING TECHNIQUES
With the introduction of CE and enteroscopy, whether push enteroscopy or single- or double-balloon enteroscopy, endoscopic imaging of the small intestine has been revolutionised, resulting in diagnostic, therapeutic and prognostic implications for managing CD patients. Numerous articles have shown that SBCE is superior to barium studies and enteroscopy for detecting lesions in the small intestine. In patients with suspected CD, CE is clearly superior (22–47%) to barium swallow, abdominal computed tomography (CT) and colonoscopy with ileoscopy39. CE is also more efficient in patients with a previous diagnosis of CD compared to abdominal CT, enteroscopy and barium swallow. The great advantage of abdominal CT and magnetic resonance enterography (MR enterography) is their ability to assess transmural involvement, so these techniques can be used in addition to CE (Fig. 7).
Diagnosis of Crohn disease
A recent meta-analysis of 12 clinical studies with 428 enrolled patients compared the diagnostic viability of CE in CD patients40: eight studies (n = 236) compared CE with ileocolonoscopy, 4 studies (n = 119) compared CE with abdominal CT, 2 studies (n = 102) compared CE with enteroscopy and another 4 (n = 123) compared CE with MR enterography. The results of this meta-analysis showed that the diagnostic viability of CE was superior to that obtained by other imaging techniques in patients with suspected CD (Table III).
Enteroscopy and CE allow direct visualisation of the mucosa of the small intestine. CE has the advantage of being less invasive, but it also has the disadvantage of not allowing samples to be taken for histological study or the application of treatments. Another study compared the diagnostic viability of both techniques39, finding that both are comparable in detecting lesions, so they should be considered complementary.
Follow-up of Crohn disease
In patients with established CD, the diagnostic viability of CE was 71%, compared to 36% for barium study of the small intestine (p <0,0001) and 39% for abdominal CT (p <0,0001)40.
Another four clinical studies compared CE and MR enterography41-44, with diagnostic viabilities of 70 and 79% (p = 0,065), respectively, finding no clear correlation with clinical symptoms or the prognosis. The last meta-analysis showed SBCE to have a superior diagnostic viability compared to CT and ileocolonoscopy in patients with non-stenotic ileal CD18,45, with the use of CE allowing for an earlier diagnosis.
Radiological studies, abdominal CT and MR enterography allow for the assessment of transmural and extraintestinal involvement, so the comparison of their viability against CE is very useful. Two studies have been conducted that compared CE and abdominal CT in assessing the small intestine in CD patients46,47. Compared to an abdominal CT, CE detected more lesions in the proximal intestine, with no differences found in the distal intestine. However, the lesions detected by CE only led to a change in management in 24% of patients. CE has been compared to MR enterography in 4 studies41-44. Although CE had higher sensitivity for detecting mucosal lesions, MR enterography allowed the level of transmural inflammation and the presence of extraintestinal abnormalities, such as abscesses or fistulae, to be assessed, so CE is not superior to a MR enterography study.
1. CE is a minimally-invasive technique for evaluating the small intestine, with high diagnostic viability and high sensitivity for detecting mucosal lesions.
2. When CE is used to diagnose CD, there is a risk for false positives; despite the use of standardised diagnostic criteria, the positive predictive value is 50%, so it is difficult to justify the use of CE as a first-line diagnostic technique for CD.
3. CE is most useful in evaluating patients with a previous diagnosis of CD, as it allows the disease’s extent and activity to be monitored. However, it must be used in combination with other techniques that allow for the transmural assessment of the intestine, such as abdominal CT and, more preferably, MR enterography, as these provide relevant data on the presence of abscesses, stenoses or fistulae, which significantly affect the management of these patients.
4. Given the risk of capsule retention and the potential need for surgical intervention, radiological examinations must always be performed before requesting CE to rule out the presence of stenoses that could obstruct the passage of the capsule.
5. CE can play a prominent role in the assessment of post-surgical recurrence, particularly in cases of anastomosis that are not accessible by endoscopy, in studies of persistent iron-deficiency anaemia or in digestive bleeding in CD patients. However, positive findings by CE must be interpreted with caution since a mucosal lesion does not necessarily have clinical repercussions, and the patient must always be reminded to stop taking NSAIDs before undergoing a CE examination.
6. To avoid the overdiagnosis of CD and the resulting overtreatment with immune suppressants or other biological therapies, the use of common terminology is fundamental, as is the use of endoscopic activity indices specifically designed for CE, such as CECDAI and the LS.
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