Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterised by mucocutaneous pigmentation and the presence of hamartomatous polyps throughout the gastrointestinal tract. Polyps are most commonly found in the jejunum and may cause bleeding and anaemia or intussusception and obstruction from an early age. In a retrospective review, 68% of children had undergone a laparotomy for bowel obstruction by the age of 18 years and many of these proceeded to a second laparotomy within 5 years (1).
Prophylactic polypectomy of larger small bowel polyps (>1.5 cm) by intraoperative or double balloon enteroscopy is performed to reduce the incidence of subsequent complications and the requirement for emergency laparotomies (1–4). Accordingly, it has been recommended that endoscopic evaluation of the upper and lower gastrointestinal tract and imaging of the small bowel should be performed from the age of 8 years or earlier if symptoms are present (1,5,6). Barium enterography (BE) has been the standard radiological technique for small bowel surveillance in children with PJS. However, the test is potentially limited by poor sensitivity, patient discomfort, and concerns over the lifetime accumulated radiation exposure from repeated studies (7–9).
Capsule endoscopy (CE) was introduced into clinical practice in 2001 and has revolutionized many aspects of small bowel imaging (10). Consisting of a tablet-sized video camera, which is propelled passively through the small bowel by peristalsis, CE is a safe, noninvasive, radiation-free modality and has proven superior to BE for polyposis surveillance in the adult population (7,8,11–13). There are limited data on the use of CE in the paediatric population and there are only a handful of case reports or series describing its application in PJS or other polyposis syndromes (14–20). We aimed to prospectively assess the feasibility and performance of CE compared with BE in a paediatric population with PJS.
MATERIALS AND METHODS
This study was a single-blinded prospective trial and was approved by regional ethical and institutional review boards. Children with PJS who were registered on the St Mark's Hospital Polyposis Registry and were between the ages of 6 and 16.5 years were eligible for recruitment. Children were excluded from the study if they had symptoms of bowel obstruction or had undergone small bowel surgery within the preceding 12 months.
The primary endpoint was comparison of the total number of small bowel polyps of 10 mm in maximal diameter or greater, which were identified by each modality. The secondary endpoints were comparison of the number of children with significant polyps identified by each modality; comparison of number of polyps of any size identified by each modality; and comparison of children's scores for test comfort and convenience and their future test preference. Accurate sample size calculation was limited by the absence of literature in the paediatric population and by the limited number of children with PJS on the polyposis registry. However, the limited published data available from the adult population and our own experience suggested that 5 significant small bowel polyps may be detected per patient using CE compared with 1 significant polyp by BE, a difference of 4. Using 5% significance and a power of 80%, a sample size of around 9 patients would be required, whereas a power of 90% would require a sample size of around 12 patients (12,13).
The CE and BE examinations were performed at St Mark's Hospital and were reported by experienced investigators who were blinded to the results of the alternative modality. The 2 examinations were performed on separate visits to the hospital with the barium examination taking place before CE. BE was performed according to standard unit protocol after an overnight fast. Ten milligrams of metoclopramide were taken before ingestion of 100 mL of barium sulphate (baritop 100, 100% w/v, EZEM) mixed with 100 mL of water. The small bowel was examined fluoroscopically at intervals using graded abdominal compression by 1 of 3 experienced radiologists. Additional volumes of barium were administered at the discretion of the supervising radiologist to ensure adequate luminal distension. Once barium had reached the terminal ileum 10 to 20 mg of hysocine butylbromide was given intravenously (according to patient weight) to achieve small bowel paresis before final fluoroscopic examination. CE was performed after an overnight fast. Surveillance gastroscopy and colonoscopy were routinely performed on the same day as the CE procedure: for older children, the capsule (PillCam SB, Given Imgaing Ltd, Yoqneam, Israel) was swallowed at 9 AM with 20 mL of water and 0.5 mL of simethicone, and gastroscopy and colonoscopy would then take place the same morning under sedation; for younger children undergoing endoscopic surveillance under general anaesthesia the capsule was placed endoscopically into the duodenum before completing the endoscopic examinations.
Because of potential inaccuracy of size assessment using either modality, polyps of 10 mm in diameter or greater were regarded as “significant” because this allowed a margin of error for the underestimation of larger polyps and minimised the number of false-negative assessments. Evidence from an animal model study from our own institution has suggested that polyp size may be underestimated at CE by up to 50% even in experienced hands and, therefore, polyps initially estimated at around 10 mm may still be clinically relevant (21). Polyps of <10 mm in diameter were also recorded as in other publications (22). Although of less clinical relevance, conversation with Polyposis Registry clinicians (A. Latchford, MBBS, MRCP, MD, personal communication, April 2008) suggests that the presence of multiple <10 mm polyps that have rapidly enlarged since the previous assessment may require a reduction in the surveillance interval, and in this setting the detection of small polyps can influence future clinical management. The decision to proceed with intraoperative (IOE) or double balloon enteroscopy (DBE) was made by the Polyposis Registry clinicians on the basis of test findings and clinical symptoms. IOE or DBE findings, when performed, were regarded as the “reference standard” against which the accuracy of CE or BE findings could be compared. Finally, each child's opinion regarding procedure comfort, convenience, and future test preference was assessed using a 100-mm visual-analogue scale questionnaire, which for the younger children was completed with the help of their parents.
All statistical data were analysed by a consultant medical statistician (P.B.). Due to small sample size, the paired exact test and the Wilcoxon matched-pairs test were used to compare significant polyp detection for the 2 modalites. Test comfort and convenience were compared using the Wilcoxon matched-pairs test, and future test preference was analysed using the 1-sample test of proportion.
Eleven children were recruited between January 2004 and February 2008 (2 male and 9 female) (Table 1). The mean age was 11.2 years (range 6.0–16.1 years). Two children had undergone previous IOEs and polyp resections (Table 1). An additional child had previously sustained a duodenal perforation following enteroscopic polypectomy, and had required surgical repair (Table 1). Five children were symptomatic with abdominal pain at the time of examination.
All 11 children underwent BE before CE at a median interval of 5 months: 10 underwent BE at St Mark's Hospital, 1 at the referring institution (child 4, Table 1). CE was swallowed without difficulty in 5 children (age range 9.3–16.1 years) and placed endoscopically under anaesthesia in 6 children (age range 6.0–15.0 years). Complete small bowel transit was achieved in 9 children (82%) with a mean small bowel transit time of 226 minutes. No complications occurred in any of the children and the capsule was excreted naturally in all of the cases.
Significant (≥10 mm) Small Bowel Polyps
Overall, 3 of 11 children (27.3%) were found to have significant (≥10 mm) small bowel polyps: CE identified 3 polyps in 2 children and BE identified 3 polyps in 1 child (Table 2). There was no significant difference in either the number of children in whom significant polyps were detected by either modality (P = 1.0) or in the number of significant polyps detected overall by either modality (P = 1.0). Ongoing clinical symptoms and unblinding of the barium results in 1 child led to re-review of the capsule video at a later date by a different study investigator. On this occasion 3 significant small bowel polyps of 10 to 25 mm in diameter were identified from the ligament of Trietz distally (Table 2).
Nonsignificant (<10 mm) Small Bowel Polyps
Nine of 11 children (81.2%) were found to have nonsignificant (<10 mm) small bowel polyps: CE identified 61 polyps in 9 children and BE identified 6 polyps in 2 children (Table 2). CE identified small polyps in significantly more children than BE (9 children vs 2 children, P = 0.02) and identified significantly more small polyps overall (median 4 polyps per child vs median 0 polyps for BE, P = 0.01).
Confirmation of “Significant” Findings
Although BE in child 4 identified 3 jejunal polyps (20 mm), examination of the small bowel at laparotomy at the referring institution found only a solitary 30 × 35 mm jejunal polyp that was resected (Table 3, Fig. 1). In comparison, CE in the same child did not identify any significant polyps on the initial reading, although re-reporting of the capsule study by a different investigator at a later date identified 3 significant polyps (see Significant (≥10 mm) Small Bowel Polyps) that had been missed. CE identified 2 polyps (10–15 mm) in child 5, but surgical intervention was declined. A repeat surveillance CE was performed 3 years later in the same patient (at age 19 years) at which 3 significant polyps up to 20 mm in diameter were identified. The patient has been referred for double balloon enteroscopy. A 10- to 15-mm polyp was identified in the proximal jejunum in child 10 and a push enteroscopy is planned.
Test Preference Questionnaire
Ten out of the 11 children completed the VAS questionnaire (see Appendix). CE was rated as being significantly more comfortable than BE (median score CE 76 [interquartile range 69–87] vs BE 37 [interquartile range 31–68], P = 0.03) (Fig. 2). CE was rated as more convenient than BE but this did not reach statistical significance (median score CE 72 [interquartile range 43–83] vs BFT 53 [interquartile range 25–59], P = 0.24) (Fig. 2). CE was the preferred test in 9 of the 10 children (90%, P = 0.02).
Complications resulting from small bowel polyps in PJS may occur from a young age, and historically the majority of children are likely to have undergone at least 1 laparotomy for polyp-related complications by the age of 18 years (1). Regular small bowel screening during childhood to identify and prophylactically remove large polyps may help reduce the emergency laparotomy rate and the associated complications (1–6). BE has traditionally been used for small bowel polyp surveillance in both adults and children with PJS, but the development of newer, potentially more sensitive imaging techniques such as CE has placed the usefulness of this older technique in doubt (7,8). Furthermore, in the paediatric population the procedure discomfort associated with BE combined with the potential lifetime risk from the cumulative radiation exposure is increasingly difficult to justify when alternative modalities are now available (9).
CE has demonstrated greater sensitivity than traditional BE for small bowel polyp surveillance in adults with PJS and is now well established in the surveillance algorithm (7,8,11–13). The worldwide experience of CE in children is predominantly limited to case reports and small case series investigating occult gastrointestinal bleeding or chronic abdominal pain (14,15,17,23–25). To date there are only a handful of reports in the literature of CE in children with PJS (14–20). We report the first prospective blinded study examining the performance of CE compared with BE in a paediatric population with PJS. In our series CE proved to be both feasible and well tolerated. Although older children were generally able to swallow the capsule unaided, younger children (aged 6–10 years) who were undergoing bidirectional endoscopic surveillance under general anaesthesia had the capsule placed endoscopically at the same time. In our series, the youngest child to swallow the capsule was 9 years and 4 months of age; however, the literature reports much younger children successfully swallowing the video capsule unassisted (14,26). Both modalities identified the same number of significant polyps at first reading and CE identified significantly more small polyps (P = 0.01) than BE. However, it was clear following careful review of 1 capsule video by a different study investigator at a later date that large polyps had been missed in 1 child at the initial reading. This not only highlights the significant learning curve associated with reporting CE studies but also suggests that CE may detect more significant polyps than BE as has been demonstrated in the adult PJS population (7,8,11–13). “Significant” polyps were identified by CE in 2 children at the initial reading compared with only 1 child at BE. This led to a change in subsequent management in 1 child who was subsequently referred for double balloon enteroscopy. Procedure comfort and test preference is of particular relevance in the paediatric population, especially for screening tests that are repeated on a regular basis. CE was rated as being significantly more comfortable than BE (P = 0.03) and all but 1 child expressed a preference for CE to be performed on the next occasion (P = 0.02).
Although the present study is the largest study to date investigating children with PJS undergoing capsule endoscopy, it is nevertheless limited by small numbers of patients and significant findings. The study power calculation was derived from the adult literature. However, the smaller number of significant polyps detected in our paediatric series resulted in the study being underpowered for identifying a difference between modalities for significant polyp detection. Examination of the small bowel intraoperatively or using the new technique of double balloon enteroscopy (3,4) remain the gold standard methods for verification of radiological and CE findings, but to date has only been performed in 1 child in our series. Interestingly only 1 significant polyp was detected at laparotomy in this child despite 3 polyps being reported by BE and CE (after re-review). It is recognized that intraoperative palpation of the small bowel, as performed by the referring institution in this case, is less reliable than intraoperative enteroscopy for small bowel polyp clearance and that polyps can be missed using this technique (2).
The procedural cost of CE remains several-fold that of BE. Nevertheless the additional cost may be offset by the potential for greater accuracy, superior test comfort, and most important, the absence of radiation. Capsule retention within a postsurgical stricture, adhesion, or by a large polyp occluding the small bowel lumen is a potential risk of capsule endoscopy. The overall risk of capsule retention is low, at around 0.75% of CE studies (27), and to date there have been no reported cases occurring in patients undergoing CE for PJS surveillance. Careful selection of patients for CE will help reduce the risk of retention, whereas in those in whom a concern remains (because of recent small bowel surgery or obstructive-type abdominal symptoms) a “patency capsule” can now be used before CE to confirm luminal patency. The patency capsule is a dummy pill of identical proportions to the video capsule that slowly dissolves if retained in the small bowel. An assessment of patency capsule position is made after 30 hours using a handheld patency scanner or abdominal radiograph, and if the capsule is not identified, then capsule endoscopy can be performed safely. However, retention of the patency capsule is highly predictive of underlying pathology and further evaluation by an alternative imaging modality is advised (28). Finally, there has been a general decline in BE examinations following the introduction of newer imaging modalities, and consequently BE should be considered a highly specialised test in this patient group that is most appropriately performed in a specialist centre, as is the case with CE. It is not yet clear how new imaging modalities such as small bowel magnetic resonance enterography will affect the paediatric PJS population, but there is evidence in adult studies that magnetic resonance imaging may be comparable with CE for the detection of large polyps (22,29).
We conclude that CE is a feasible and safe procedure for small bowel polyp surveillance in children with PJS. Children rate the test as being significantly more comfortable than BE and prefer it for future surveillance in the majority of cases. It appears more accurate than BE and has now replaced this technique in the small bowel surveillance algorithm at our institution. However, reporting capsule studies in PJS is difficult and is associated with a significant learning curve and appropriate experience and training is essential.
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