Wireless motility capsule compared with scintigraphy in the assessment of diabetic gastroparesis

Gastroparesis is a potentially severe late complication of diabetes mellitus. Today, delayed gastric emptying (GE) is mandatory for establishing the diagnosis. In this study, we compared wireless motility capsule (WMC) with gastric emptying scintigraphy (GES).


| INTRODUC TI ON
Diabetic gastroparesis is a condition characterized by upper gastrointestinal (GI) symptoms and delayed gastric emptying (GE) without gastric outlet obstruction. 1 In addition to potentially debilitating symptoms of nausea, vomiting and upper abdominal pain, the condition may have profound implications for the patients' ability to regulate their blood glucose levels. 2,3 Delayed GE is associated with both short-and long-term hyperglycemia. 4 Gastroparesis may also influence the absorption of oral medications, emphasizing the need for reliable, inexpensive, and accessible tests for measuring GE. 5 Gastric emptying scintigraphy (GES) has long been considered gold standard for evaluating GE in both research and clinical practice. 6 By radiolabeling a liquid or solid meal and tracking it by a gamma camera, the method gives a physiological, quantitative measurement of GE. 7 Unfortunately, a number of local variants of the test exist, both in terms of meal composition, and duration and frequency of imaging. 6,8 The radiation dosage also limits its applicability in certain patient groups. 9 Moreover, the availability of gamma cameras is reduced, in part due to high acquisition costs.
The wireless motility capsule (WMC; SmartPill, Medtronic) measures pH, pressure, and temperature throughout the GI tract, thereby providing the means for calculating GE. 10

WMC has since 2009 been approved by The United States Food and Drug
Administration for the investigation of suspected gastroparesis and has in previous studies shown good agreement with scintigraphy. 8,11 However, there are few studies validating WMC against GES, highlighting the need for further research. To our knowledge, this is the first European study comparing the two methods in a cohort of diabetes patients with suspected gastroparesis.
The primary aim of this study was to assess the diagnostic reliability of WMC compared to GES for the measurement of GE. We also wanted to determine the WMC test's inter-rater reliability and identify the optimal cutoff value for delayed GE by WMC. A secondary aim was to identify proportions with rapid, normal, and delayed gastric emptying by the two methods. We also aimed to illuminate why some patients presented inconsistent test results (one positive/ one negative), by comparing with those showing delayed emptying on both tests. Finally, we wanted to compare symptom severity between patients with rapid, normal, and delayed gastric emptying.

| Study population
Seventy-two patients (49 women) with diabetes mellitus (DM) and symptoms consistent with gastroparesis were prospectively included between 2014 and 2018 (Table 1). Patients were recruited from all over Norway after being referred to Haukeland University Hospital for diagnostic evaluation. They were previously examined with upper endoscopy to rule out obstructing lesions or other pathology explaining their symptoms. Patients under 18 years of age and pregnant or breastfeeding women were not included in the study. During examinations, all patients were admitted to the hospital where they, in addition to tests and questionnaires, gave blood samples and were interviewed and examined by a physician.

| Gastric emptying tests
After an overnight fast of minimum 8 hours, GES and WMC testing were initiated simultaneously at 09:00 AM. Patients first consumed a standardized 260 kilocalorie (kcal; 66% carbohydrate, 17% protein, 2% fat, 3% fiber) nutrient bar (SmartBar, Medtronic), and a boiled egg (90 kcal; 1.1% carbohydrate, 13% protein, 11% fat, 0% fiber) radiolabeled with Tc-99m-nanocolloid. 12 Then, the WMC was swallowed, and scintigraphic imaging commenced immediately afterward. During the meal, patients could drink 120 mL of water. After swallowing the WMC, they fasted for another six hours, but were allowed to drink an additional 100 mL of water. During the fasting and examination period, all patients were on intravenous glucose-insulin infusion with frequent blood glucose measurements by finger-prick.
Target levels were 4-10 mmol/L, and patients received intravenous glucose if they fell below 4 mmol/L.

| Gastric emptying scintigraphy
Simultaneous anterior and posterior planar scintigraphy of the upper abdomen (1 minute per view) were performed on a doubleheaded camera system (Siemens e.cam; Siemens Healthineers).
Pictures were taken at 0, 30 minutes, 1, 2, 3, and 4 hours in accordance with current guidelines. 13 Images were quantified using Segami Oasis 1.9.4.9 (Segami Corp., Inc) by drawing a region of interest around the outline of the stomach at 0 minutes, which was

Key Points
• Gastroparesis is an important complication of diabetes mellitus, and detecting delayed gastric emptying is currently mandatory for establishing the diagnosis.
• Examining gastric emptying in a cohort of symptomatic diabetes patients, wireless motility capsule showed substantial agreement with scintigraphy.
• We found no differences in symptom severity between patients with normal and delayed gastric emptying by any of the tests. then copied onto images taken at other time-points ( Figure 1).
Gastric retention was quantified as the root mean square of the counts in the anterior and posterior regions of interest relative to the acquisition at 0 minutes. 13 Normal retention value for GES at 4 hours is <10%. 6 Retention at 4-hour GES can be graded into mild (10%-15%), moderate (15%-35%), and severe (>35%). 14 Normative retention values for other time-points are given in Table 2.

| Wireless motility capsule
WMC is a 26.8 × 11.7 mm, non-digestible, single-use capsule, containing sensors for pH, temperature and pressure, a battery and a transmitter. 10,15 After activation, it transmits data to a portable receiver, which the patient carries close to the body during the entire examination. 15 Our patients were instructed to return the receiver after 5 days, whereupon data were downloaded to a personal computer using a USB docking device.
WMC transit times were calculated using MotiliGI software (Medtronic). WMC gastric emptying time (WMC GET) was defined as the time between capsule ingestion and passage through the pylorus, as marked by a rapid rise of >3 pH units ( Figure 1). Delayed WMC GET is defined as >300 minutes (5 hours), severely delayed WMC GET >720 minutes (12 hours). 10,16,17 In cases of uncertainty, results were based on a consensus of two or more examiners. To calculate inter-rater reliability, all tests were re-analyzed by a different examiner, blinded for previous results. We also compared with automatically generated results by the MotiliGI software.

| Autonomic function tests
Cardiac autonomic function was assessed by a simple five-minute supine heart rate variability (HRV) recording, using the Heart Rhythm Scanner PE (Biocom Technologies). The system investigates both time and frequency domain parameters, and has been described and validated in detail elsewhere. 18 All recordings were performed in a fasting state by the same trained technician. The HRV recordings were reviewed offline by the second author, and minor editing (missing or misplaced beats) was performed. Recordings with persistent ectopic activities or frank arrhythmias were excluded from subsequent analyses.

| Statistical analysis
Results are stated as median (interquartile range, IQR

TA B L E 2 Gastric emptying by GES and WMC
index. P ≤ .05 was defined as the level of statistical significance.

| Ethical considerations
The study was approved by The Western Norway Regional Medical Ethics Committee (2015/58) and was conducted in accordance with the Declaration of Helsinki. Participants received oral and written information, and signed an informed consent prior to any study-related procedures.

| RE SULTS
The study flowchart is shown in Figure 2. Detailed clinical characteristics are given in Table 1
We identified 385 minutes as the optimal cutoff value for delayed WMC GET (Youden's J = .75). Detailed measures of accuracy for both WMC GET cutoff values are presented in Table 3.
Inter-rater correlation for identifying WMC GET between the two examiners was r = .996, while agreement was Cohen's kappa

| Gastric emptying test results
Median GE values and proportions with rapid, normal, and delayed GE are presented in  Table 5 contains results for GCSI, PAGI-SYM, and all subsets, in-

| D ISCUSS I ON
In this prospective study, we aimed to validate WMC against GES in a patient cohort with DM and symptoms compatible with gastroparesis. We found a strong correlation between WMC and 4-hour GES,  8,11 However, in the latter study overall agreement was only moderate when also including patients without DM. In comparison with other methods for determining gastric emptying, WMC has a similar diagnostic accuracy to 13 carbon-labeled gastric emptying breath tests for solids (GEBT) and is far superior to gastric emptying of radiopaque markers (ROMs). 21,22 Other methods have not gained widespread usage outside research settings. 16 We also found a near perfect inter-rater correlation (r = .996, P < .001) and Cohen's kappa (κ = .97, P < .001) for identifying WMC GET. For the evaluation of delayed GE, our findings indicate a high diagnostic accuracy of WMC, with interpretation of results being examiner independent. Interestingly, the correlations between each examiner and the MotiliGI software for estimating GET were also very strong. However, in as many as 25% of tests the software did not manage to calculate GET, compared to the one patient where manual analysis failed to make an estimation. Until further refinement of the software, manual test analysis is therefore essential. Indeed, passage of the WMC does not occur before >90% of the meal has emptied. 8 As underlined by Kloetzer et al, WMC is therefore able to provide information about both gastric fasting and fedstate. 17 Interestingly, doing subgroup analyses, Lee et al found the same proportions with delayed emptying by both tests in diabetes patients. 11 The overall difference in their study was thus driven by the higher proportion with delayed emptying by WMC in the non-diabetic group. 11 To better understand the discrepancies in test results between the two methods, we compared patients with false-positive (normal GES and delayed WMC GET) and true-positive (both delayed) test results (Table 4). While glucose levels, HRV parameters, symptom scores, and clinical characteristics except for age were similar in both groups, the median WMC GET was more than 35 hours longer in the true positive group. This finding further bolsters the argument for increasing the cutoff value for delayed emptying in diabetes patients.
Wireless motility capsule also identified a higher proportion of patients with severe retention than GES. In this respect, we only found a fair agreement between the two methods (κ = .34, P < .001), similar to previous studies. 11 The most likely explanation is that definite cutoff values for severely delayed GET are not clearly established. WMC failed to identify any patients with rapid gastric emptying, while GES found three (4.2%) and seven (10.0%) at the 60 and 30 minutes time-points, respectively. Previous studies also found a higher share with rapid GE using GES. 11 Still, given that 20% of symptomatic diabetes patients may have rapid GE, it was surprising that we did not identify any cases using WMC. 23 Interestingly, the prevalence with delayed GE increased at each GES time point.
This underlines the importance of following the recommended protocol of taking pictures until four hours to avoid false-negative tests. 6,14 Previous studies comparing the symptom severity between patients with normal and delayed GE have shown inconsistent results. [24][25][26] In this study, we found no difference in PAGI-SYM, GCSI or any of their subsets between patients with normal and delayed GE. Neither did we find any differences comparing patients with normal and rapid emptying. This lack of association between GE and patient-reported symptoms is one of the main challenges in the field of gastroparesis research. The explanation is likely multifactorial. Firstly, patients with suspected diabetic gastroparesis often present a diversity of unspecific symptoms, not only limited to cardinal symptoms of nausea, vomiting, early satiety, fullness, and bloating, but often also abdominal pain, reflux, diarrhea, constipation, and fecal incontinence. [27][28][29][30] Adding to the confusion, delayed GE is present in 30%-50% with longstanding diabetes regardless of symptoms, probably as a consequence of autonomic neuropathy.  controlled for in studies, the influence of medication side-effects and other comorbidities on gastrointestinal symptoms, can also be a confounder. Finally, more than a quarter of patients with functional dyspepsia, a highly prevalent condition with symptoms mimicking gastroparesis also present with delayed GE. 24 An important goal for future gastroparesis studies must therefore be to identify other biomarkers better correlated to patient-reported symptoms.
By expanding focus beyond the pylorus, recent studies have indeed uncovered a possible link between small bowel dysmotility and symptoms suggestive of gastroparesis. [37][38][39] Here, the WMC may play an important role in further research, providing pH and pressure profiles from gut segments otherwise largely unavailable for examination. 5,40,41 Nevertheless, as the rate of GE is pivotal in determining postprandial glycaemia, its measurement will still be of great importance in diabetes patients, especially those presenting with unexplained fluctuations in blood glucose levels. 3  we thank all participating patients.

CO N FLI C T O F I NTE R E S T
The authors have no competing interests.  How missing data on the index test and reference standard were handled 5 and Figure 2 17

R E FE R E N C E S
Any analyses of variability in diagnostic accuracy, distinguishing prespecified from exploratory -

18
Intended sample size and how it was determined 2, 5 and Figure 2 Results

19
Flow of participants, using a diagram Figure 2 20 Baseline demographic and clinical characteristics of participants Table 1 21a Distribution of severity of disease in those with the target condition -21b Distribution of alternative diagnoses in those without the target condition -

Time interval and any clinical interventions between index test and reference standard 2
Test results 23 Cross-tabulation of the index test results (or their distribution) by the results of the reference standard 5

24
Estimates of diagnostic accuracy and their precision (such as 95% confidence intervals) 5, Table 3 and Figure 3 25 Any adverse events from performing the index test or the reference standard 5

26
Study limitations, including sources of potential bias, statistical uncertainty, and generalizability 8 27 Implications for practice, including the intended use and clinical role of the index test 6-8 Other information 28 Registration number and name of registry 4 29 Where the full study protocol can be accessed 9 30 Sources of funding and other support; role of funders 1