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Original Articles: Gastroenterology

Rumination Syndrome in Children Presenting With Refractory Gastroesophageal Reflux Symptoms

Nikaki, Kornilia∗,‡; Rybak, Anna; Nakagawa, Kenichiro; Rawat, David; Yazaki, Etsuro; Woodland, Philip; Borrelli, Osvaldo; Sifrim, Daniel

Author Information
Journal of Pediatric Gastroenterology and Nutrition: March 2020 - Volume 70 - Issue 3 - p 330-335
doi: 10.1097/MPG.0000000000002569
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Abstract

What Is Known/What Is New

What Is Known

  • Up to 40% of children with gastroesophageal reflux symptoms do not respond to standard medical treatment.
  • Rumination syndrome has been recently recognized as a frequent cause (20%) of nonresponse to proton pump inhibitors in adults.

What Is New

  • Rumination syndrome is present in 44% of children with refractory reflux-like symptoms.
  • Rumination syndrome can be positively identified with an impedance-pH study. This improves the chances of an early diagnosis and initiation of appropriate treatment.

The response rate to proton pump inhibitors (PPIs) in children with symptoms compatible with gastroesophageal reflux disease (GERD) is reported as 70% (1,2). Only 66% of children over the age of 5, with typical reflux symptoms, fulfil the diagnostic criteria of Rome IV for non-erosive reflux disease (NERD) and reflux hypersensitivity (3). Similarly, up to 40% of adults clinically diagnosed with GERD may be refractory to PPI treatment (4). Rumination syndrome has recently been recognized as a frequent cause (20%) of nonresponse to proton pump inhibitors in adults (5).

The prevalence of rumination syndrome amongst children with PPI-refractory GERD is unknown. Rumination in children, as defined by the Rome IV criteria, is a clinical diagnosis, made in the presence of repeated regurgitation and rechewing or expulsion of food that is postprandial, does not occur during sleep, and is not preceded by retching; where an appropriate evaluation has excluded other reasons, including an eating disorder. The history of the symptoms need to be 2 months or longer (6). Abdominal pain and weight loss appear to be the most commonly associated symptoms (7,8). Most importantly, there is a significant delay in the diagnosis of pediatric rumination (8,9) and a high number of investigations per patient are performed before clinical management and treatment (10). In the past, gastroduodenal manometry was employed for diagnosis but this was only positive in 40% of the clinically diagnosed cases (8). More recently, high-resolution esophageal manometry with impedance (HRM/Z) is the preferred method for diagnosis of rumination syndrome (11,12). The diagnosis of rumination syndrome in children with refractory reflux symptoms is highly relevant as management is completely different from GERD, including a multi-professional approach to provide cognitive behavioral therapy and medications, such as Baclofen (13,14).

The aim of our study was to identify rumination syndrome in children with clinically diagnosed refractory GERD undergoing ambulatory impedance-pH monitoring.

METHODS

Study 1: Identification of Rumination Pattern Using Impedance-pH

We identified children (0–18 years) who had an initial impedance-pH study because of suspicion of GERD, and were subsequently diagnosed with rumination syndrome based on a positive HRM/Z test that included a meal and postprandial monitoring (max 30 minutes of postprandial recording); minimum of 2 postprandial episodes of liquid retrograde flow with high proximal extent associated with abdominal straining (a rapid increase in gastric pressure of >30 mmHg) (12).

We then compared impedance-pH tracings from rumination patients versus 3 groups: children who tested negative for rumination on HRM/Z and underwent an impedance-pH study; children diagnosed with GERD (esophageal acid exposure of >6%); and children with a negative impedance-pH study (esophageal acid exposure <4%) and an alternative final diagnosis (non-GERD). All patients included were studied OFF PPIs. All tests were performed based on clinical grounds, and therefore, patients with GERD and non-GERD did not have a HRM/Z test performed. All data were retrieved from the electronic database at the GI Physiology Unit in Royal London Hospital; patients studied between July 2012 and November 2018.

The HRM/Z traces were recorded with either a Sandhill Scientific catheter (HRM/Z SD High Resolution Impedance Manometry Catheter, 32 directional pressure/16 impedance channels, 8 FR) or MMS catheter (HRM/Z 35 unidirectional pressure/13 impedance channels, 8FR) and presence of rumination episodes in the postprandial period was re-ascertained.

All impedance-pH traces (recorded with the Sandhill Scientific equipment setting and catheter-sized appropriate for age and height) were re-assessed; applying the automated analysis as a first step and then manually analysing each trace page by page (excluding meal periods from the analysis). For the 24-hour trace analysis, the relevant parameters were divided by the actual total study duration and multiplied by 24, in order to have comparable data over a 24-hour period. A 60-min postprandial period for each main meal (meals lasting less than 5 minutes were excluded from the analysis) was automatically calculated and the data for the total of the postprandial period analysis were included in the system's report. The Symptom Index (SI) (15) and Symptom Association Probability (SAP) (16) were recorded for the symptoms of regurgitation and/or reflux and/or vomiting. The Mean Nocturnal Baseline Impedance (MNBI) was calculated as a mean over the recumbent period using an integrated analysis tool for Channel 5 and 6 of impedance. MNBI is considered as a method of in vivo measurement of esophageal mucosa integrity and is directly linked to the total esophageal acid exposure (17–19).

Development of Rumination Score on Impedance-pH Monitoring

One-way analysis of variance (ANOVA) was used for impedance-pH data comparison amongst the 4 groups of Interest. We then compared all MII-pH parameters between patients with confirmed rumination (positive HRM/Z—gold standard) versus all control groups combined (Rumination negative, GERD and non-GERD), as the parameters for the rumination score would need to be able to distinguish rumination against all patients presenting with reflux type symptoms. Continuous variables following a normal distribution were compared between groups using the unpaired t-test. Only statistically significant variables were considered for the ROC curve analysis to determine the cut off values of the variables that best discriminated children with rumination from children presenting with reflux symptoms. From the ROC curve, we identified parameters with a high area under the curve (AUC), closest to 1, and designed a scoring point system for rumination syndrome using impedance-pH.

Study 2: Diagnosis of Rumination Syndrome in Patients With Refractory Gastroesophageal Reflux Disease

We identified, at the Department of Pediatric Gastroenterology at Great Ormond Street Hospital, London, UK, a separate group of patients who underwent both a HRM/Z with a meal and postprandial monitoring and an impedance-pH study OFF PPIs, as a part of the diagnostic pathway for persistent vomiting and regurgitation.

After de-identification and anonymization, two assessors blindly analyzed the impedance-pH traces in a similar fashion as for study 1 (i.e. applying the automated analysis tool and then assessing each trace page by page). The newly developed Rumination score was then applied. The HRM/Z traces were reviewed and using the HRM/Z as “gold standard” for the diagnosis of rumination syndrome, the sensitivity and specificity of the scoring system was calculated. The prevalence of rumination syndrome amongst these children with refractory GERD symptoms was recorded.

Our study adhered to the principles outlined in the Declaration of Helsinki (20) and as this was a retrospective data analysis and all clinical interventions performed were based on clinical indications, formal medical research approval from the local Ethics committee was not required.

RESULTS

Study 1: Identification of Rumination Pattern Using Impedance-pH

We identified 27 children with refractory GERD who underwent an impedance-pH study and HRM/Z as part of their diagnostic work-up. Out of the 27, 12 children (44%) were diagnosed with rumination syndrome confirmed on HRM/Z (rumination-positive group). Their median age was 13.9 years (range: 8.5–17.7 years) and there was an equal gender distribution (6 boys : 6 girls). Regurgitation was the main complaint for all patients. Three patients had a history of Ehlers Danlos syndrome, 1 had ulcerative colitis in remission and 1 had a history of hydronephrosis. None of the children had a major esophageal motility disorder based on the Chicago classification 3.0 nor did they have a manometrically identified hiatus hernia. A median number of 4.5 episodes of rumination during HRM/Z were observed (Fig. 1). The rest of the children, who were negative for rumination syndrome based on HRM/Z, served as a control group (rumination negative). Out of these 15 children, 1 was still treated for rumination with Baclofen with good response, and therefore, has been excluded from further analysis. Their median age was 14.8 years (range: 10.9–16 years) and there were 8 girls. Regurgitation was a major complaint for all patients. Three patients had mild delay in gastric emptying, 3 had a history of Ehlers Danlos syndrome and 1 had type 1 diabetes and adrenal insufficiency. There were neither major esophageal motility disorders identified nor presence of hiatus hernia.

F1
FIGURE 1:
Example of an episode of rumination noted during high-resolution manometry impedance. There is an increase in the intra-abdominal pressure (black arrow) transmitted through the esophagus leading to retrograde bolus movement to the proximal esophagus (white arrow) that is followed by swallowing. The patients are concurrently reporting regurgitation and swallowing back down the bolus.

We then identified a cohort of 18 children with GERD and a cohort of 12 children in the non-GERD group. The median age of the GERD group was 8.1 years (range: 0.5–17.7 years) with a slight female predominance (8 boys : 10 girls). The median age of the non-GERD group was 12.4 years (range: 4.8–16.5 years) with an equal gender distribution (6 boys : 6 girls). Out of the 18 patients with GERD, 11 presented with regurgitation as a major complaint and 9 out of 12 patients had regurgitation in the non-GERD group. The final diagnosis of the non-GERD group included: functional dyspepsia (n = 1), functional nausea (n = 2), functional abdominal pain (n = 3), Crohn disease (n = 1), Helicobacter pylori (n = 2), eosinophilic esophagitis (n = 2), postgastroenteritis syndrome (n = 1).

Twenty-four Hours’ Trace Analysis

The total acid exposure was not significantly increased in the rumination-positive group (median: 3.6%) and it was not statistically significantly different between the rumination group and all control groups (median: 2.1%), P = 0.126 (Fig. 2). The total number of reflux events (RE) per 24 hours was significantly higher in the rumination-positive group (median: 124.2) versus the control groups (median: 45.1), P < 0.0001. Similarly, the total number of proximal RE per 24 hours was significantly higher in the rumination group (median: 97.1) versus the control groups (median: 17.4), P < 0.0001. The percentage of proximal to total (distal) RE per 24 hours was significantly higher in the rumination group (median: 81.6) versus the control groups (median: 23.3), P < 0.0001. The percentage of non-acid RE per 24 hours over the total number of RE per 24 hours was not significantly higher in the rumination group compared with the control groups, P = 0.315. The bolus exposure time was significantly higher in the rumination group (median: 4.5%) compared with the control groups (median: 1.6%), P = 0.0002. The MNBI values in impedance distal channels were similar between the rumination group (median: 2308 Ω) and the control groups (median: 2055 Ω), P = 0.865. The SI for regurgitation/reflux or vomiting was significantly higher in the rumination group (median: 91) compared with the control groups (median: 0), P < 0.0001. The SAP was significantly higher in the rumination group (median: 100) compared with the control groups (median: 0), P < 0.0001. The results of the comparison of all variables between each separate group and the rumination-positive group are presented in detail in Table 1.

F2
FIGURE 2:
Example of impedance-pH trace of a patient positive for rumination syndrome. Note the large number of reflux events, the aggregation of episodes of regurgitation postprandially that correlate with the reflux events and the paucity of symptoms during the recumbent period.
T1
TABLE 1:
The median values for the main impedance-pH parameters examined amongst the group of children diagnosed with rumination syndrome based on high-resolution manometry impedance, children negative for rumination based on high-resolution manometry impedance, children with gastroesophageal reflux disease and children presenting with reflux symptoms but an alternative final diagnosis

Postprandial Period Analysis

The postprandial acid exposure in the rumination group (median: 3.8%) was higher compared with the control groups (median: 1.75%). The total number of reflux events in the postprandial period (expressed as number of RE per hour) were significantly higher in the rumination group (median: 14.2) versus the control groups (median: 4.0), P < 0.0001. The number of non-acid RE in the postprandial period (expressed as non-acid RE per hour) was significantly higher in the rumination group (median: 3.2) versus the control groups (median: 1.2), P = 0.0001. The postprandial bolus exposure time was significantly higher in the rumination group (median: 6.1%) versus the control groups (median: 2.1%), P = 0.0002. All subgroup comparisons are presented in detail in Table 1.

We also performed a subgroup analysis comparing only patients presenting with regurgitation as the main complaint and observed the same differences between rumination-positive patients and all other groups as described above, with similar statistical significance.

For the development of the impedance-pH scoring system, we used the results of the ROC curve analysis and took into account the effect of collinearity. Collinearity is exhibited between the different parameters for reflux events, reflux events and bolus exposure time, SI and SAP. As rumination is characterized by proximal RE and episodes of non-acid refluxate in the postprandial period, the total proximal RE per 24 hours and the non-acid RE per hour from the postprandial analysis were taken forward alongside the SAP, which was a more robust parameter compared with SI. The cut-off levels of each parameter are total proximal RE per 24 hours greater than 57.5 episodes, area under the curve (AUC): 0.97 [0.94–1.0], likelihood ratio (LR): 11.2; postprandial nonacid RE per hour >2, AUC: 0.74 [0.56–0.93], LR: 2.8, SAP index for regurgitation/reflux/vomiting ≥95%, AUC: 0.94 [0.87–1.0], LR: 8.78. Each parameter scores 1 and rumination syndrome is diagnosed if the score is ≥2 (Table 2).

T2
TABLE 2:
Paediatric impedance-pH rumination score

Study 2: Diagnosis of Rumination Syndrome in Patients With Refractory Gastroesophageal Reflux Disease

We applied the rumination score in the analysis of impedance-pH tracings from 18 children with refractory GERD, 6 boys : 12 girls, median age 10.2 years (range: 2.3–16.8). Main reported symptoms included vomiting, persistent regurgitations, dysphagia, and nausea. None of the patients were diagnosed with a major motility disorder, based on Chicago classification (21). Eight patients had rumination syndrome (44%) confirmed on HRM/Z.

Application of the Impedance-pH Rumination Score

Out of the 8 children with rumination syndrome, 6 had a positive score (≥2), scoring system sensitivity 75%. Out of the 10 patients investigated for possible rumination syndrome but with a negative HRM/Z, 8 had a negative score (<2), scoring system specificity 80%. Notably, the variability of the impedance-pH measurements recorded by the two assessors (K.N. and A.R.) was <10% and did not have any effect on the final scoring of the studies. Furthermore, we tested the performance of the adult scoring system in the paediatric population, which performed suboptimally, sensitivity 87.5% and specificity 60%.

DISCUSSION

Rumination syndrome is increasingly being recognized as a major contributor to refractory GERD symptoms in adults (5). Our study aimed at improving our diagnostic ability to distinguish rumination from clinically persistent GERD in children undergoing impedance-pH monitoring. We identified that 44% of children with refractory reflux-like symptoms present with rumination syndrome confirmed on HRM/Z. Children with rumination syndrome have a large number of reflux episodes and the majority of these reach the proximal esophagus; present with a high frequency of reflux events in the postprandial period; can positively identify the episodes of regurgitation leading to highly positive symptom-reflux association analysis; and do not appear to have esophageal mucosal impairment despite the large number of reflux events.

The epidemiological data on the incidence and prevalence of rumination syndrome in children are sparse. One study from the United States surveyed 949 mothers of children 4 to 18 years old and none of them reported rumination (22). Another study from Sri Lanka surveyed 2163 children ages 10 to 16 years and reported a 5% prevalence rate in school-aged children and adolescents (55.5% boys, mean age: 13.4 years) (7). In our highly selective pediatric population (children with PPI refractory GERD, referred to tertiary care), we noted that 44% of the children with refractory GERD were diagnosed with rumination syndrome based on HRM/Z in both centers. If one was to use our impedance-pH rumination score, 75% of these children would be correctly identified at an earlier stage, as impedance-pH is instigated as a first-line investigation of refractory GERD.

In our study, children with rumination have a very high number of RE per 24 hours and the majority are to the proximal esophagus. The number of proximal RE per 24 hours has been included in the scoring system not only based on its statistical significance but also due to its importance in the pathogenesis of rumination, as for rumination to occur the retrograde fluid movement needs to reach the mouth before being swallowed back down (6,23,24).

Children with rumination presented with a ratio of more than 80% of proximal to total RE, also accounting for the prolonged bolus exposure time. Patients with rumination strain the abdominal muscles and generate an increase in the intragastric pressure that is transmitted to the esophagus and leads to retrograde refluxate movement (23). In contrast, in GERD, the refluxate reaches the esophagus most commonly during transient lower esophageal sphincter relaxations (25,26) that are most commonly triggered during gastric distention (27). These differences in the pathophysiology of retrograde bolus movement are most likely responsible for the difference observed in the proximal extend of RE between rumination-positive patients and GERD patients. Interestingly, patients with rumination show no evidence of esophageal mucosa impairment, as assessed in vivo by means of MNBI.

During the postprandial period, children with rumination have a higher number of RE per hour compared with controls. The number of nonacid RE in the postprandial period were included in the scoring system as these are the commonest occurring episodes (23).

Our finding that the SI and SAP for regurgitation/reflux/vomiting are strongly positive in the rumination group suggest that ruminators perceive or know when the events occur. The SI and SAP are related to the ability of the patient or carer to mark the symptoms during the study. The rumination groups included in both study 1 and study 2 had a median age above 8 years, and therefore would be more likely to self-report and press the marker button in a timely fashion. Equally though, parents of younger children should be able to recognize accurately an episode of regurgitation that reaches the mouth, and therefore, the scoring system could be applicable to younger children as well. Overall, our findings in children are in accordance to our recently published findings in adults (28), although the adult scoring system performed suboptimally in the paediatric population.

We believe that impedance-pH can assist us in achieving an early, reliable diagnosis of rumination, as it is more widely used compared with HRM/Z and offers prolonged recording time (24 hours), including usually more than 1 meal. Impedance-pH monitoring is less invasive and sedation is not usually required as the catheter is thinner and softer, compared with the solid-state catheter used in esophageal manometry (29). This is, therefore, a promising diagnostic tool.

As an immediate clinical application, the scoring system could be used as a screening tool amongst children with persistent GERD and guide physicians as to whether they should proceed with HRM/Z testing for children with a positive score. In the long-term, impedance-pH could replace HRM/Z but larger studies are needed to confirm this. Most importantly, the clinical implication of our study is mainly conferred by the different management strategies that should be considered in rumination syndrome treatment compared with GERD. Diaphragmatic breathing and cognitive behavioral therapy are the current mainstay of treatment in rumination syndrome (30) whilst lifestyle changes, pharmacotherapy—mainly with PPIs—and antireflux surgery are the main approaches for the treatment of GERD (31).

Our study has some limitations that need to be taken into consideration. The number of patients included in each group/part of the study is relatively limited. Although the groups appear small, the differences identified between the groups are large and performing both HRM/Z and impedance-pH for all children was only based on clinical indications. Moreover, other published studies on rumination syndrome in children include similar sized groups (12,32,33). Secondly, in study 1, the rumination group includes mainly adolescents whereas the GERD group includes slightly younger children; yet the differences in the impedance-pH parameters are significant. This is a pragmatic limitation of the study that can only be addressed with future studies evaluating the clinical application of the scoring system, especially for younger children, benchmarking it against response to rumination-specific management with pharmacotherapy and cognitive behavioral therapy. Finally, we acknowledge that the children in the GERD and non-GERD group did not undergo HRM/Z testing, as this would not be ethically appropriate if clinically not indicated. Therefore, we tested all impedance-pH parameters amongst only children who presented with regurgitation as a main symptom (therefore, more likely to have rumination) and the results of our study remain the same.

In conclusion, 44% of children with persistent reflux symptoms, referred to a tertiary setting, are diagnosed with rumination syndrome based on HRM/Z. Children with rumination syndrome have a distinct pattern of impedance-pH monitoring, which can be distinguished amongst children presenting with PPI refractory GERD. Applying a simple scoring system during the analysis of impedance-pH studies could raise the suspicion of rumination syndrome and lead to an early diagnosis and management of the condition.

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Keywords:

gastroesophageal reflux disease; impedance-pH monitoring; rumination syndrome

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