Manometric Subtypes of Ineffective Esophageal Motility

Ineffective esophageal motility (IEM) is identified by a well-defined set of manometric criteria1 but its etiology is poorly understood. It was initially defined in 1997 by Leite et al.,2 its definition and nomenclature were standardized by Spechler and Castell,3 and subsequently revised.4 IEM is the most common abnormal manometric finding in our esophageal laboratory (20–30%).5 Current guidelines of diagnosis require low amplitude pressures (distal contractile integral (DCI)<450 mm Hg/s/cm on high-resolution manometry (HRM)) in ≥50% of test swallows.1, 5, 6 Defective bolus transit (DBT), as noted on impedance measurement (>20% of liquid swallows and/or >30% of viscous swallows), is used to attach the adjectives “mild” (normal BT for liquid & viscous swallows), “moderate” (DBT for either liquid or viscous swallows), or “severe” (DBT for both liquid & viscous swallows) to the diagnosis.4 Its pathophysiology and clinical significance are still being debated. There is much suggestion in the literature that IEM is associated with coexisting gastroesophageal reflux disease (GERD), but causality or interaction of the two conditions still remains unknown.2, 7, 8, 9, 10, 11, 12, 13, 14 On the other hand, there are studies that show different results even though their data do not disprove some association between GERD and IEM, but rather declare that IEM is not standing alone as a cause of GERD.15, 16, 17 Other hypotheses suggest an association with rapid food intake,18, 19 Vagal hyper-reactivity,20 advanced age,21, 22 or damage to the enteric nervous system or smooth muscle16 as possible etiologies. Furthermore, patient demographics such as age, sex, and race of afflicted patients are subjects of debate.21, 22, 23 While the manometric diagnosis of IEM is made when ≥50% of test swallows are noted to be weak, variation exists within the diagnosis. Within the 10 usually analyzed liquid test swallows, some patients will show exactly five low amplitude swallows, but also exhibit some normal swallows in between—this is known locally within our laboratory as “IEM Alternans” or IEM-A (Figure 1). Other patients reveal consistently low amplitude swallows with no single normal swallow seen; this subtype is named “IEM Persistens” or IEM-P in our laboratory (Figure 2). The goal of this study was to more closely investigate these two different subtypes concerning patients’ demographics, presenting symptoms, manometric, and impedance metrics and association with pathological GERD. We proposed that either “IEM Persistens” is a more advanced manifestation of “IEM Alternans” with the same underlying etiology or that the two are different disorders with heterogeneous pathophysiology.15, 16 The multichannel intraluminal impedance-pH (MII-pH) catheter is a 2.1-mm-diameter polyurethane catheter incorporating 6 impedance segments and two pH-measuring antimony electrodes located 5 cm above the LES and at 10 cm below the LES in the gastric fundus25 (Sandhill Scientific). Subjects underwent HRIM testing with 10 liquid (5 ml normal saline) swallows performed 30 seconds apart, and patients refrained from swallowing in between test swallows. This was followed by 10 viscous (5 ml of applesauce-like substance) swallows. Subsequently, the data were analyzed with the Sandhill BioVIEW Analysis Suite 64 software (Sandhill Scientific Inc.).24 After completion of the combined HRIM study, patients underwent ambulatory combined MII-pH testing, if they presented with symptoms concerning for pathological GERD (146/231 patients). Testing was done while patients were on treatment with proton pump inhibitor (PPI) in 84% of the patients, and off PPI in 16%. All events during testing, including meals, medications, symptoms, and body position (upright/recumbent), were entered by the patient directly into the monitor. The patient was also asked to keep a diary of activities during testing. Participants had ambulatory monitoring done for a minimum of 16 h. Approval for performing this study and publishing information was obtained from the Institutional Review Board (IRB) of the Medical University of South Carolina (MUSC). Bolus transit for liquid and viscous swallows, and mean resting LES pressure were compared between the two groups. Subgroup analysis of IEM-A and IEM-P patients who presented with dysphagia included distal contractile integral (DCI), integrated relaxation pressure (IRP), mean resting LES pressure, and bolus transit data for liquid and viscous swallows. Parameters calculated from the combined MII-pH monitoring included: Gastric acid control on PPI; distal esophageal acid exposure (that is, time with esophageal pH<4 in upright and recumbent positions); total number of reflux episodes, and symptom index for the three most prominent symptoms.19, 26, 27 The level of gastric acid control for each impedance-pH study was performed by a direct visual inspection of the 24-h gastric pH study using the following score: As published by our group in 2012, there was a strong correlation (r=0.9) between the qualitative scale of acid control and the numerical value for percentage of time that the gastric pH was >4.28 Pathological GERD was defined on MII-pH study by the following criteria: Excess total number of reflux episodes (≥48 episodes/24 h on or off PPI); abnormal esophageal acid exposure (≥6.3% in upright position and/or ≥1.2% in recumbent position off PPI, or ≥1.5% in upright position and/or ≥0.5% on PPI); or positive symptom association (symptom index ≥50%).29 A total of 195 (84%) patients with IEM-A and 36 (16%) with IEM-P were identified. There was a striking gender difference with 128 (66%) females and 67 (34%) males having IEM-A vs. 17 (47%) females and 19 (53%) males with IEM-P (P=0.035). The mean age of IEM-P patients (59.6 years+/−13.1) was significantly higher than that of IEM-A (55.5 years+/−13.6) (P=0.04). There was no significant difference in race: 139 (71%) whites, 52 (27%) blacks in IEM-A vs. 27 (75%) whites and 9 (25%) blacks in IEM-P (P=0.84). There was no significant difference between the two groups in the following variables: body mass index (BMI), diabetes mellitus, tobacco use, alcohol use, connective tissue disease, or neurologic disease (Table 1). Symptom distribution of the main presenting symptom at time of manometry study in all IEM patients is depicted in Figure 3. Dysphagia was the main presenting symptom in 18%, followed by cough (15%), chest pain (13%), regurgitation (12%) and heartburn (12%). Although dysphagia and chest pain were more prevalent in IEM-P and heartburn, regurgitation, cough and throat clearing were more prevalent in IEM-A patients, that did not reach significance level (Table 2). In 226 out of 231 patients, the LES was interpretable. The mean resting pressure was significantly lower in IEM-P (20.8+/−1.4 mm Hg), compared to IEM-A (29+/−1.2 mm Hg) (P=0.002). There was no significant difference in LES-integrated relaxation pressure (IRP), or manometric presence of hiatal hernia between the two groups. Defective bolus transit (DBT) for both liquid and viscous swallows was present in 21/36 (58%) of IEM-P vs. 120/195 (62%) of IEM-A, (P=0.71). In subgroup analysis (Table 3), 41 patients had dysphagia as main presenting complaint, of which 33 had IEM-A (17% of IEM-A patients) and 8 had IEM-P (22% of IEM-P patients) (P=0.27). Mean DCI for liquid swallows was significantly lower in IEM-P (111+/−142 mm Hg/s/cm) compared to IEM-A (421+/−502 mm Hg/s/cm) (P=0.047). Mean LES resting pressure among dysphagia patients was significantly lower in IEM-P (16.6+/−9 mm Hg) compared to IEM-A (31.7+/−18 mm Hg) (P=0.01). Out of 231, 146 patients had an ambulatory reflux study done as ordered by the referring physician for evaluation of clinical symptoms suspected to be secondary to pathologic reflux disease. 84% of reflux studies were done on PPI. Out of 146, 89 reflux studies (61%) were abnormal. Of the 89 abnormal reflux studies, 76 were IEM-A (85%) and 13 IEM-P (15%) (P=0.13). The average percentage of esophageal acid exposure in the upright position was significantly higher in IEM-P than IEM-A (3.5 vs. 1.7%, P=0.04). Poor gastric acid control (pH<4 most of the 24 h of the pH study (looks similar to patient not taking medications)) was significantly more prevalent in IEM-P (58%) than in IEM-A (27%) (P=0.007). There was no significant difference in symptom association with reflux disease (Symptom Index (SI) ≥50%) between IEM-A and IEM-P groups (SI=47% for IEM-A and 41% for IEM-P) (P=0.80). Detailed analysis of reflux studies for IEM-P and IEM-A patients is summarized in Table 4. Ineffective esophageal motility (IEM) is the most common motility abnormality found in our esophageal function laboratory. Characterized by low amplitude peristalsis in the distal esophagus,1, 3, 6 it is often associated with impaired bolus transit.30, 31 Nevertheless, the clinical significance and pathophysiology of this disorder is still open to debate. Using the Chicago Classification criteria1, 6, 32 as a model, the aim of this study was to more closely investigate two manometric patterns of IEM; “IEM Persistens” (IEM-P) without any single normal swallow seen vs. “IEM Alternans” (IEM-A) with normal swallows seen in between the five or more weak ones. Our results show an older male predominance of IEM-P with more acid exposure in upright position, weaker LES and poor response to acid suppression, which seems consistent with more advanced reflux disease. To date, the majority of studies in this field suggest an important role of IEM in increased esophageal acid exposure. Several studies have repeatedly shown that esophageal hypomotility is increasingly prevalent with increasing severity of GERD.2, 13, 33, 34 Additionally, a functional defect in the esophagus with impaired acid clearance has been suggested to be related to IEM.30, 35 Inspite of that, it has not been shown whether IEM is a primary motor abnormality or a secondary motility disorder due to chronic inflammation. There are experimental studies that report reversibility of esophageal hypomotility after healing of inflammation.36, 37, 38 Fornari and colleagues reported a transient reversibility of over 50% in 11 patients with severe IEM after adequate cholinergic stimulation of the esophagus.34 However, other studies show that patients with chronic erosive GERD did not recover from esophageal dysmotility after pharmacological or surgical treatment of their reflux disease.39, 40, 41 This controversy could be explained possibly by a dysfunctional neuromuscular control due to inflammatory mediators in acute GERD-related esophagitis vs. fibrosis in chronic inflammation. To date, there is evidence in the literature for both neurological and myopathic pathologies underlying IEM. Kim and colleagues had a closer look at the histopathologic abnormalities of esophageal neuromuscular structures in esophageal tissues of patients with total gastrectomy due to gastric cancer. They reported that esophageal smooth muscle of patients with IEM frequently exhibited fibrosis, myolysis and widened intercellular spaces, suggesting the possibility of a myopathic process. In addition, more neuronal nitric oxide synthase (nNOS) immunoreactivity was seen in the circular muscle layer of patients with IEM, thus excess nitric oxide (NO) production with consecutive diminished amplitude of esophageal peristalsis is one plausible mechanism for IEM. The esophageal tissues revealed histopathologic changes of myopathy, whereas the myenteric plexus appeared morphologically normal, another indication that the myopathic process may contribute more to pathogenesis of IEM.16 In contrast to the myopathic etiology of IEM, there are several studies that suggest a relationship between esophageal dysfunction and neuropathy like in some patients with diabetes mellitus,42, 43, 44 where acute hyperglycemia is believed to be an unlikely contributing factor.45, 46 However, there is evidence that neurologic factors play a role in the pathophysiology of esophageal dysmotility. Stewart and colleagues documented that 31 diabetic patients with autonomic neuropathy revealed diminished peristaltic amplitudes and esophageal emptying as well as a reduced LES pressure.47 Because the patients were suffering from diabetic neuropathy, the degeneration of the ganglion cells of the esophageal myenteric plexus was assumed to be associated with hypersensitivity of the esophageal smooth muscle to cholinergic agents. In fact, bethanechol, a cholinergic drug with muscarinic actions, accelerated esophageal emptying and increased the LES resting pressure.48 The group concluded that, in diabetic autonomic neuropathy, the predominant lesion is in the preganglionic fibers of the vagus rather than in the myenteric plexus of the esophageal wall. In addition, Hollis and colleagues stimulated the esophagus of 50 patients with diabetes mellitus and healthy subjects with edrophonium, an effective acetyl-cholinesterase inhibitor. There was a significant decrease in peristaltic velocity in diabetics with peripheral neuropathy when compared to diabetics without neuropathy and controls. It was concluded that abnormal motility in diabetes mellitus was associated with peripheral neuropathy and was characterized by a dysfunction of esophageal innervation with intact smooth muscle function.49 Although our study showed a profoundly weaker LES and pronounced reflux in IEM-P compared to IEM-A patients, diabetes mellitus was not significantly different between our two groups. A possible explanation of such finding could be related to the high prevalence of diabetes in the patient population as a whole (18%), same as BMI (average 29.3 kg/m2). Dysphagia was the most prevalent symptom among patients with IEM (18%). Subgroup analysis of IEM patients with dysphagia, as a severe symptom of esophageal dysmotility, showed a drastically weaker LES and much lower DCI for liquid swallows in IEM-P compared to IEM-A, affirming our hypothesis of a manometric gradient between the two groups. Bolus transit (BT), a measure of esophageal function depicted non-invasively by impedance measurement, was very defective in both IEM-P (85% of liquid and 95% of viscous swallows) and IEM-A (89% of liquid & 83% viscous swallows) patients who presented with dysphagia, without significant difference between the two groups. BT was also noticeably defective for both liquid and viscous swallows in the whole group of IEM patients (58% for IEM-P and 62% for IEM-A). These important findings of severely defective bolus transit (DBT) in IEM patients, although not significantly different between the two groups, indicate that IEM carries an important functional defect that manifests in different array of symptoms and could have an adverse implication on the patient. There are limitations in our present study. The retrospective nature of the analysis involves lack of detailed medical data of all included patients as the operator could only rely on the available documented data. As many patients get referred to our open-access esophageal motility laboratory for the manometric and reflux-monitoring studies while they receive medical care by the referring physician, concluding outcome data would be a challenging task. A more prospective analysis of IEM subtypes could elaborate more on this important aspect. Furthermore, our study has not been blinded. However, it is extremely difficult to incorporate bias in the data analysis of the measured metrics that has already been analyzed and interpreted. In summary, our results support the concept of two manometric subtypes of IEM and suggest an association between IEM and GERD, with IEM-P showing a significantly higher esophageal acid exposure in upright position along with worse response to acid suppression therapy than IEM-A. Furthermore, IEM-P shows an older male predominance, which might be indicative of chronic reflux disease. In addition, LES tone was weaker in IEM-P. However, we doubt that GERD is standing alone in the etiology of IEM, although an association with diabetes, connective tissue disease or neurological disorder could not be shown in our study. Further studies are needed to shed more light on this controversial complex issue. Guarantor of the article: Donald O. Castell, MD, MACG. Specific author contributions: Hiestand: collected the initial data, performed initial analysis, and drafted initial manuscript. Abdel Jalil: Further data collection and critical data analysis, drafted the manuscript and its subsequent revisions. Submitted manuscript to the journal. Castell: concept/design of the study. Critical revision and approval of manuscript, and subsequent revisions. All authors have approved the final draft submitted. Financial support: None. Potential competing interests: None.