Introduction
The wireless motility capsule (WMC) (SmartPill® ; Given Imaging Corp., Yoqneam, Israel) is a single-use, ingestible device [1 ]
[2 ]. With dimensions 26.8 × 11.7 mm, it is slightly bulkier than its imaging counterpart (PillCam® SB Medtronic, Minnesota, USA). SmartPill® records intraluminal pH, pressure and temperature as it is propelled through the gastrointestinal tract. Hence, the WMC is capable of providing gut motility parameters (i. e. gastric transit time [GTT], small-bowel transit time [SBTT], colonic transit time [CTT] and whole gut transit time [WGTT]) noninvasively. The American and European Neurogastroenterology & Motility Societies recommend the use of WMC to assess suspected gastroparesis, suspected small-bowel (SB) dysmotility and/or CTT in chronic constipation [3 ].
Data are scarce on the motility patterns in patients with known or suspected Crohn’s disease (CD). Furthermore, the use and clinical validity of the WMC has not been evaluated in this patient group. It is envisaged that future wireless investigation platforms for the digestive tract will be multimodal and versatile, and therefore able to incorporate imaging information with physiological or biochemistry data such as fecal calprotectin (FC), hemoglobin and gas constituents of the gastrointestinal tract. Such combination data could be useful in the investigation and management of patients with CD. For instance, orocecal transit time has been found to be prolonged in CD patients for various reasons including SB bacterial overgrowth (SBBO) whereas SBTT may conversely be shortened in CD patients following ileocecal resection; this would affect absorption of medications and should ideally be taken into account during drug design [4 ]. Therefore, we designed a pilot study to investigate whether WMC examination is feasible and safe in the assessment of gut motility in patients with known or suspected CD, and its utility compared to conventional video capsule endoscopy.
Patients and methods
Patient recruitment and study protocol
Consecutive patients with known or suspected CD (FC > 200 μg/g), referred for SB evaluation with small-bowel capsule endoscopy (SBCE), were invited to participate in this study. The inclusion & exclusion criteria of the study are summarized in [Table 1 ]. Patients who accepted the invitation and consented to participate were invited for a lactulose hydrogen breath test for exclusion of SB bacterial overgrowth (SBBO) and were provided with a kit for stool sample collection and FC measurement (CALPROLAB™ ELISA (ALP), Calpro AS, Lysaker, Norway; reference range < 50 μg/g). Those with a positive breath test, indicating SBBO, were excluded. Patients with negative SBBO breath test were invited to return a stool specimen and attend for a SB patency check with the AGILE® capsule (Given Imaging Corp., Yoqneam, Israel).
Table 1
Inclusion and Exclusion Criteria.
Inclusion criteria
Exclusion criteria
Age > 18 years
Known diagnosis of CD, being referred for (re-) assessment of extent & severity of SB inflammation
Suspected CD with FC > 200 µg/g
Pregnancy or lactation
Swallowing difficulties or frailty
Known SB strictures
Pacemaker/ICD in situ
Psychiatric history
Prior upper gastrointestinal tract surgery (other than end-to-end anastomosis)
Known DM or other cause of metabolic gastroparesis
Pts on codeine/morphinoids unable or unwilling to stop them prior to the study
Lactose intolerance or egg allergy (for PC)
Positive hydrogen breath test
History of functional symptoms e. g. cyclical vomiting, irritable bowel syndrome
Abbreviations : CD, Crohn’s disease; DM, diabetes mellitus; FC, fecal calprotectin; ICD, implantable cardioverter defibrillator; PC, patency capsule; SB, small-bowel; pts, patients
The detailed flowchart of the study design is presented in [Fig. 1 ]. Patients ingested the PillCam® SB, followed 4 hours later, by the SmartPill® . The technical characteristics of the two capsules used (PillCam® SB and SmartPill® ) are detailed in [Table 2 ].
Fig. 1 Summary of study protocol.
Table 2
Comparison between specifications of PillCam® SB2 and SmartPill® .
Specifications
PillCam® SB2
SmartPill®
Length (mm)
26
26
Diameter (mm)
11
13
Battery life
8 h
5 days
Mode of data transmission
Ultra-high frequency band radio telemetry
Radiofrequency-based
Data collection
Data were downloaded from the recorders to the relevant workstations and analyzed using proprietary software (RAPID
® for PillCam® SB and semi-automated pressure analysis software, MotiliGI
®
[Given® Imaging Corp] for SmartPill® ). For the latter, results are presented in both graphical and statistical forms. PillCam® data include gut transit times and SB findings. Inflammation levels were quantified using the Lewis score (LS), which has been devised to objectively report SB inflammation in SBCE. SmartPill® data examined in this study were pH, transit times (GTT, SBTT, CTT and WGTT) and motility index (MI) per segment, where MI = Ln (sum of pressure amplitudes × number of contractions + 1). The data acquired from the study group were compared to historical controls (healthy individuals with no known pathology obtained from unpublished data), used to establish the normal range for segmental and total gut transit times.
Statistical analysis
Microsoft Excel (© 2015 Microsoft) and StatsDirect (StatsDirect Ltd, Altrincham, UK) software were used for statistical analysis. A two-tailed Mann-Whitney U test was used for comparison of the study and control groups. Linear regression was used to establish any correlation between motility indices and FC or LS. P values < 0.05 were considered statistically significant.
The study was supported by a defined grant by Given® Imaging Ltd (ESGE- Given® Imaging Research grant 2011) and approved by the local ethics committee (ref. 12/SS/0013).
Results
Over a 12-month period (2012), 19 patients were recruited. Three patients were excluded because their previous history included a known strong functional component to their symptoms that could affect gut motility independently of CD, including irritable bowel syndrome, chronic idiopathic intestinal pseudo-obstruction and cyclic vomiting. Another four patients, referred for SBCE on suspicion of CD, were also excluded because their FC levels were < 200 μg/g. Twelve patients completed the study (7 female/5 male; mean age 44.2 ± 16.6 years). [Fig. 2 ] shows the number of patients recruited, dropouts, and complete/incomplete data sets obtained. Clinical characteristics and per patient study results are tabulated in detail in [Table 3 ]. The differences in the motility of the study group vs. the control group are depicted in [Table 4 ]. Patients in our study had longer transit times and significantly lower gut motility when compared to the control group, [Fig. 3 ] and [Fig. 4 ].
Fig. 2 Recruitment process for this study.
Table 3
Summary of clinical characteristics and findings of patients in our study.
No.
Age (years)
Gender
Indication
MS (if known CD)
FC (μg/g)
SBCE findingsFindings
LS
MotilGI® report
TT (min)
pH
MI (segmental)
1
49
M
Known CD
A2
60
546; 125; 205
135
Signal loss, long GTT of SBCE but not WMCs
1667; 226; 141
n/a
n/a
2
37
M
Known CD
A1 /2
–
516; 36; 242
0
Generally prolonged transit times, poor motility
6620; 2577; 288
Gastric 1.4
Gastric 16.75
3
58
F
Known CD
A3
590
683; 28; 552
3810
Prolonged transit time
7161; 1096; 638
n/a
Gastric –
4
34
F
Known CD
A2
Insuff
n/a
n/a
High gastric pH, ?pt on PPI
2686; 867; 240
Gastric 5.4
Gastric 16.3
5
72
F
Known CD
A?
Insuff
857; 77; 252
5160
Generally low motility
1956; 798; 447
Gastric 1.1
Gastric 14.65
6
51
M
Known CD
A2
80
436; 65; 342
450
Signal loss
1609; n/a; n/a
n/a
n/a
7
37
F
Known CD
A2
290
384; 19; n/a
0
WMC not done – dropout
n/a
n/a
n/a
8
40
F
Known CD
A2
–
410; 10; 254
0
Signal loss, rapid transit time
808[* ]; 233; n/a
n/a
n/a
9
66
F
?CD
NA
970
369; n/a; n/a
n/a
Data loss, CR
n/a
n/a
n/a
10
58
M
?CD
–
320
517; 31; 169
280
Low motility, acidic SB
1312; 167; 192
Gastric 1.2
Gastric 11.58
11
36
M
?CD
–
110
234; 33; 188
450
Signal loss but normal transit of WMC
n/a
n/a
n/a
12
23
F
?CD
–
300
439; 14; 327
450
High gastric pH, very long colon transit
6650; 142; 252
Gastric 3.7
Gastric 10.26
Abbreviations: CD, Crohn’s Disease; CR, capsule retention; Duo, duodenum; FC, fecal calprotectin; GTT, gastric transit time; LS, Lewis score; MI, motility index; MS, Montreal score; PPI, proton pump inhibitor; SB, small bowel; SBCE, small-bowel capsule endoscopy; SBTT, small-bowel transit time; TT, transit times; WBTT, whole-bowel transit time; WMC, wireless motility capsule
* In the case of patient 8, WBTT was taken as time to excretion of capsule in ileostomy.
Table 4
Comparison of results from our patients vs controls.
Patients
Controls
P values
Number
12
33
Gender
7 F, 5 M
15 F, 18 M
Average Age ±SD
44.25 ±16.66 years
40.85 ±16.28 years
FC (μg/g)
340 ±307.71 (n = 8)
n/a
LS
1073.5 ±1835.5 (n = 10)
n/a
GTT (min)
763.25 ±821.47 (n = 8)
249.61 ±167.47
0.09
SBTT (min)
314 ±171.99 (n = 7)
288.81 ±107.74
0.89
WBTT (min)
3385.44 ±2621.03 (n = 9)
1988.67 ±972.99
0.82
Gastric pH
2.56 ±1.92 (n = 5)
1.64 ±0.89
0.35
SB pH
6.9 ±0.37 (n = 5)
7.16 ±0.45
0.17
Gastric MI
13.91 ±2.88 (n = 5)
52.00 ±32.68
0.002
Duodenal MI
10.99 ±1.22 (n = 6)
90.27 ±76.50
0.0001
SB MI
14.55 ±1.92 (n = 5)
122.48 ±65.90
0.0004
Cecal MI
13.28 ±1.35 (n = 6)
108.58 ±121.10
0.0006
Abbreviations: FC, fecal calprotectin; GTT, gastric transit time; LS, Lewis score; MI, motility index; SB, small bowel; SBTT, small-bowel transit time; WBTT, whole-bowel transit time
Fig. 3 Comparison of transit times between study group and controls.Abbreviations: Ctrl, controls; GTT, gastric transit time; SBTT, small-bowel transit time; WBTT, whole bowel transit time
Fig. 4 Comparison of motility index between study group and controls.Abbreviations: Ctrl, controls; duo, duodenum; MI, motility index; SB, small bowel
The motility index (MI) in the stomach, SB and colon was significantly lower in patients with CD, as compared with controls, and this was statistically significant (P < 0.05) for all motility indices measured throughout the gut. The total transit time for the WMC was longer compared with the SBCE, which could be attributed to the differences in the capsules’ specifications as detailed in [Table 2 ] [1 ]
[5 ]
[6 ] and the difference in capsule density, [Fig. 5 ] [7 ]
[8 ]. The distribution of WGTT, FC and LS for those study subjects for whom the data were available is presented in [Fig. 6a ]. [Figs. 6b and 6c ] show the linear regression between MI/FC and MI/LS, respectively.
Fig. 5 Floating characteristics of Pillcam SB2 (left) and Smartpill (right) submerged in 400 mL sterile water for irrigation.
Fig. 6a (see above) Distribution of WBTT, FC and LS for patients in our study for whom the relevant data sets were available. Each plot point represents a patient in our study with the numbers corresponding to patient numbers in [Table 3 ].Abbreviations: FC, fecal calprotectin; LS, Lewis score; WBTT, whole bowel transit timeb Linear regression of FC against motility indices for patients in our study for whom the relevant data sets were available.c Linear regression of LS against motility indices for patients in our study for whom the relevant data sets were available.
Discussion
This pilot study is the first to attempt dual use of SBCE and WMC in assessment of patients with known or suspected CD. Currently, diagnosing CD requires a clinical evaluation and a combination of endoscopic, histological, radiological, and/or biochemical investigations [9 ]. To date, the value of SBCE in the investigation of CD has already been established [10 ]. A previous study [11 ], in which cine magnetic resonance enterography (MRE) was employed in addition to the regular MRI protocol, found that imaging areas of altered gut motility helped to detect more CD-specific findings. Other studies have shown that CD is associated with delayed gastric emptying, possibly due to inflammation [12 ].
Therefore, addition of motility data in this setting could be of use [2 ]
[13 ], especially when first-line investigations are inconclusive. Compared to the traditional method of assessing gastrointestinal motility with scintigraphy/radio-opaque markers, WMC is not associated with any radiation exposure. Concurrent use of SBCE and WMC shows how multimodal information can provide information not only on the mucosal appearances of patients with CD but also physiological motility data. However, that needs to be balanced against the risk of capsule retention, a feared complication in patients with CD. In our study, there was one case of stomach retention of the capsule, which occurred despite patency check with follow-up plain abdominal x-ray where the patency capsule had been reported to be in the large bowel. Limited CT scanning post-patency may be more useful in these patients [14 ].
Our patients had significantly longer transit times compared to the controls (P < 0.05 for all parameters measured) ([Table 4 ]). However, statistical significance should be interpreted with caution given the small sample size. Other limitations of this pilot study include potential selection bias, as patients with significant SB inflammation were excluded due to fear of capsule retention, and the SmartPill® signal loss (resulting in incomplete data sets in 5 /10 completed WMC examinations). It is not clear if this is due to technological limitations or whether the concurrent use (4 hours apart) of two capsules caused some radiofrequency interference [1 ]
[5 ]
[6 ]. Furthermore, the complexity of the WMC data did not allow meaningful correlation with other parameters such as FC and LS. This can be seen in other studies that have tried to explore the relationship between LS and FC in patients with SB CD [15 ].
Take home messages
Physiological data obtained from the use of the SmartPill® could be of value in conjunction with ‘conventional’ SBCE to shed more light in the pathophysiology of CD and perhaps assist in patient management. However, to better help clinicians to understand and maximize use of the motility information, the development of a simplified interpretation system is necessary.
Despite concerns about capsule retention in patients with CD, our study suggests that the SmartPill® seems generally safe for use in these patients, although use of a patency capsule is recommended beforehand.
