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ARTICLE: FUNCTIONAL GI DISORDERS

Clinical Characteristics and Associated Psychosocial Dysfunction in Patients With Functional Dysphagia: A Study Based on High-Resolution Impedance Manometry and Rome IV Criteria

Lu, Po-Wen MD1,2; Chen, Chien-Chuan MD3; Wu, Jia-Feng MD, PhD4; Lee, Hui-Chuan BS4; Lee, Yi-Chia MD, PhD3; Wang, Hsiu-Po MD3; Wu, Ming-Shiang MD, PhD3; Tseng, Ping-Huei MD, PhD3

Author Information
Clinical and Translational Gastroenterology: July 2022 - Volume 13 - Issue 7 - p e00511
doi: 10.14309/ctg.0000000000000511
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Abstract

INTRODUCTION

Esophageal dysphagia is a common complaint encountered in the daily clinical practice of physicians (1). Some patients may suffer from dysphagia as a result of luminal obstruction. This could be due to benign or malignant tumors from the upper digestive tract or secondary to reflux esophagitis or foreign body impaction (2). However, some patients may suffer from dysphagia without any structural evidence of mechanical obstruction in the esophagus after serial endoscopic and radiological examinations; this is known as nonobstructive dysphagia (NOD) (3). Esophageal motility disorders, including achalasia and other hypercontractile or hypocontractile disorders as defined by manometry, are the major causes of NOD.

Functional dysphagia is 1 of the 5 esophageal functional disorders based on the updated Rome IV criteria. After a comprehensive set of examinations, it is defined as an abnormal sensation of solid or liquid food impaction when swallowing without any structural or esophageal mucosal lesions (4). According to the Rome IV definition, both gastroesophageal reflux disease and eosinophilic esophagitis (EoE) must be excluded before a diagnosis of functional dysphagia can be made. Furthermore, other major esophageal motility disorders diagnosed using high-resolution manometry or high-resolution impedance manometry (HRIM) under the Chicago Classification, such as achalasia and distal esophageal spasm, should also be excluded. Nevertheless, the presence of minor esophageal motor disorders, such as ineffective esophageal motility (IEM) and fragmented peristalsis, does not exclude the diagnosis of functional dysphagia (4).

The pathophysiology of functional dysphagia is complex and mostly unknown. It is challenging to obtain a definitive diagnosis and adequate treatment of the condition quickly, leading to high health care utilization and unnecessary financial burden (5,6). Despite the introduction of functional dysphagia in the Rome IV criteria, related studies on the clinical features of functional dysphagia remain scarce. In addition, we hypothesized that psychosocial dysfunction and minor esophageal dysmotility might contribute to the pathophysiology of functional dysphagia. Our secondary aim was to investigate the role of psychiatric comorbidities and minor esophageal motility abnormalities on the clinical manifestations of functional dysphagia.

MATERIAL AND METHODS

Study design

We retrospectively identified consecutive patients who had the chief complaint of esophageal dysphagia, namely the sensation of food stuck in the esophagus or chest, and were evaluated in our motility laboratory from 2014 to 2020 in our prospectively established electronic database. Patients were included if they were older than 20 years and had dysphagia with a frequency of at least once a week and a duration of at least 3 months, with onset more than 6 months before the visit. After taking a detailed history, all patients underwent a standardized diagnostic work-up, including (i) validated symptom questionnaires to evaluate the dysphagia severity and reflux status, as well as questionnaires for psychiatric comorbidities and sleep problems, and (ii) an upper endoscopy and biopsy to exclude obstructive and mucosal lesions, which was only required if the patients had not received an upper endoscopy within the past 6 months. Proton pump inhibitor therapy was prescribed for at least 8 weeks to observe for symptom resolution in patients with negative endoscopic findings. Patients with persistent dysphagia despite proton pump inhibitor treatment would receive further HRIM examination (7). Patients were excluded if they had acid reflux-related causes evidenced by ambulatory pH or pH-impedance monitoring before the referral. Patients were also excluded if they had (i) previous esophageal, gastric, or thoracic operation history, (ii) endoscopic erosive esophagitis, Barrett's esophagus, EoE, hiatal hernia, stricture or mass lesions in the esophagus, or (iii) major esophageal motility disorders as diagnosed by the Chicago Classification v3.0 (8). Finally, patients who fulfilled the Rome IV criteria for functional dysphagia were included in the final analysis. For comparison purposes, we further identified the age- and sex-adjusted, healthy volunteers from our previous healthy cohort to clarify the possible pathophysiology of functional dysphagia (9). This study was approved by the Research Ethics Committee of the National Taiwan University Hospital (No. 201505131RIND), and all patients provided written informed consent.

Endoscopic examination

After an overnight fast, an upper endoscopy was performed by experienced endoscopists to exclude visible obstructive lesions. We carefully checked the appearance of the esophageal mucosa and whether the presence of any food or fluid retention inside the esophageal lumen. The distal esophagus and esophagogastric junction were carefully evaluated for the existence of hiatal hernias and erosions. Hiatal hernia was defined as a gap of at least 2 cm between the top of the gastric folds and the diaphragmatic hiatus. Each patient received an endoscopic biopsy to exclude the presence of EoE (10).

Esophageal HRIM

After an overnight fast, all patients underwent an esophageal HRIM performed by an experienced gastroenterologist (P.H.T.). The examination was served with a water-perfused catheter (4.2 mm in diameter, with 22 closely spaced pressure sensors at 1 cm intervals and 12 impedance channels at 2 cm intervals) (Medical Measurements Systems, Enschede, The Netherlands). The manometric signals were recorded at a frequency of 20 Hz and stored. The data were analyzed by the same gastroenterologist (P.H.T.) using the package analysis software from Medical Measurements Systems and confirmed by another experienced pediatric gastroenterologist (J.F.W.). The diagnoses of major motility disorders were made according to the criteria stipulated by the Chicago Classification v3.0 (8). However, for the diagnosis of IEM, we used the more stringent criteria of Chicago Classification v4.0 (e.g., normal median integrated relaxation pressure, with >70% ineffective swallows or ≥50% failed peristalsis”) (11).

Symptom questionnaire

All patients completed standardized symptom questionnaires to evaluate dysphagia severity, gastroesophageal reflux disease, and other associated functional gastrointestinal (GI) symptoms, as well as psychosocial comorbidities, including the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM), the 5-item Brief Symptom Rating Scale (BSRS-5), and the Pittsburgh Sleep Quality Index (PSQI). The severity of dysphagia was assessed based on the Eckardt symptom score, which consists of 4 items: dysphagia, regurgitation, retrosternal pain, and weight loss in kilograms (12).

The BSRS-5 is a 5-item, self-administered questionnaire derived from the 50-item BSRS and has good reliability and validity in screening for psychological comorbidities (13). It measures the severity of anxiety (feeling tense or high-strung), depression (feeling depressed or in a low mood), hostility (feeling easily annoyed or irritated), interpersonal sensitivity (feeling inferior to others), and additional symptoms (having trouble falling asleep in the past week) (14). The score for each item ranges from 0 to 4 (0, not at all; 1, a little bit; 2, moderately; 3, quite a bit; and 4, extremely). A total score equal to or above 6 indicated psychiatric comorbidity.

The PSQI is also a self-rated questionnaire designed to evaluate sleep quality and disturbances in the past month (15). This questionnaire comprises 7 different items: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction. Each item ranges from 0 to 3. A total score equal to or above 6 implied poor sleep quality.

The PAGI-SYM is a self-report instrument containing 20 items for evaluating the severity of common GI symptoms in the previous 2 weeks. It can be categorized into 6 subscales: heartburn/regurgitation, fullness/early satiety, nausea/vomiting, bloating, upper abdominal pain, and lower abdominal pain (16). The scores for all items range from 0 to 5 (0, none; 1, very mild; 2, mild; 3, moderate; 4, severe; and 5, very severe).

Statistical analysis

We applied Kolmogorov-Smirnov tests to test for the normal distribution of variables. The continuous data were expressed as the mean and SD and were compared using Student t tests. The proportional distribution of binary variables (e.g., male vs female) or among multiple groups (e.g., BSRS-5 score over or equal to 6) was examined with χ2 tests, and the Anderson-Darling test was used to test for normality. The scores from symptom questionnaires (continuous variables) for different patient subgroups were compared using Kruskal-Wallis tests. All statistical analysis was performed using SPSS 25.0 (SPSS, Chicago, IL). Statistical significance was defined as a P value less than 0.05.

RESULTS

Demographics and clinical characteristics of functional dysphagia

As shown in Figure 1, data from a total of 96 patients who were ultimately diagnosed with functional dysphagia based on the Rome IV criteria were analyzed (Figure 1). Among them, 53 had a previous negative endoscopy within the past 6 months, and therefore, the endoscopy was not repeated. Twenty-four patients were referred from other hospital for HRIM evaluation after inconclusive endoscopic findings. The prevalence of functional dysphagia was 21.9% among those evaluated for esophageal dysphagia (n = 460) and as high as 30.5% among those dysphagia patients excluded for obstructive or acid reflux-related causes (n = 315). The incidence of functional dysphagia in our dysphagia subjects peaked at middle age (40–60 years, 47.9%), and functional dysphagia was more predominant in women (67%) (Table 1). More than half of the patients (59.3%) suffered from dysphagia more than daily frequency, but only 6.3% of the dysphagia patients experiencing a weight loss of more than 10 kg.

F1
Figure 1.:
Flow chart of the study.
Table 1. - Demographics and clinical characteristics of patients with functional dysphagia
All patients characters Total (n = 96)
Age, yr 51.7 ± 15.5
 20–40 25 (26.0)
 40–60 46 (47.9)
 >60 25 (26.0)
Male sex 32 (33.0)
BMI, kg/m2 22.0 ± 4.1
Waist, cm 76.8 ± 14.4
 Male 80.5 ± 19.2
 Female 75.1 ± 11.1
Social habits
 Smoking 6 (6.25)
 Drinking 13 (13.5)
Symptom profile
 Dysphagia
  Weekly 39 (40.6)
  Daily 25 (26.0)
  Each meal 32 (33.3)
 Regurgitation
  None 43 (44.8)
  Weekly 30 (31.3)
  Daily 19 (19.8)
  Each meal 4 (4.2)
 Retrosternal pain
  None 63 (65.6)
  Weekly 27 (28.1)
  Daily 5 (5.2)
  Each meal 1 (1.0)
 Weight loss, kg
  None 43 (44.8)
  <5 39 (40.6)
  5–10 8 (8.3)
  >10 6 (6.3)
Data are presented as mean ± SD, or number (percentage).
BH, body height; BMI, body mass index; BW, body weight.

Comparison of psychiatric, sleep, and gastrointestinal symptom profiles between male and female patients with functional dysphagia

As shown in Table 2, 44 patients (45.8%) had psychiatric comorbidities based on the BSRS-5, whereas 80 patients (83.3%) experienced poor sleep quality according to the PSQI. Because female patients were predominant among our dysphagia subjects, we compared the psychiatric, sleep, and GI symptoms profiles between male and female patients. On the BSRS-5, female patients with functional dysphagia experienced more trouble falling asleep (1.83 ± 1.45 vs 1.09 ± 1.25, P = 0.017). On the PSQI, female patients had significantly shorter sleep duration than male patients (1.48 ± 1.01 vs 0.94 ± 0.91, P = 0.011). A marginally increased number of patients using sleeping medications among women (1.14 ± 1.4 vs 0.63 ± 1.13, P = 0.056), suggesting more severe sleep dysfunction in women. On the PAGI-SYM, female patients had more severe bloating than male patients (3.42 ± 2.42 vs 1.44 ± 1.92, P < 0.001), and also had higher total scores (25.95 ± 17.11 vs 18.19 ± 11.35, P = 0.01), suggesting a greater burden of troublesome GI symptoms.

Table 2. - Psychological features, sleep characteristics, and common gastrointestinal symptoms in functional dysphagia patients, based on the 5-item Brief Symptom Rating Scale, Pittsburgh Sleep Quality Index, and Patient Assessment of Gastrointestinal Disorders Symptom Severity Index further stratified by sex
All (n = 96) Male (n = 32) Female (n = 64) P value
BSRS-5
 Trouble falling asleep 1.58 ± 1.43 1.09 ± 1.25 1.83 ± 1.45 0.017 c
 Feeling tense 1.39 ± 1.21 1.03 ± 1.13 1.55 ± 1.22 0.064
 Feeling easily annoyed or irritated 1.31 ± 1.069 1.25 ± 1.11 1.34 ± 1.06 0.688
 Feeling depressed 1.18 ± 1.20 1.09 ± 1.15 1.22 ± 1.23 0.632
 Feeling inferior to others 0.49 ± 0.94 0.38 ± 0.83 0.55 ± 1.00 0.401
 Total score 5.95 ± 4.41 4.88 ± 4.25 6.48 ± 4.43 0.092
 Total score ≥ 6 a , n (%) 44 (45.8) 12 (37.5) 32 (50.0) 0.247
PSQI
 Sleep duration 1.30 ± 1.01 0.94 ± 0.91 1.48 ± 1.01 0.011 c
 Sleep latency 1.23 ± 1.03 1.09 ± 0.93 1.30 ± 1.08 0.366
 Habitual sleep efficiency 1.23 ± 1.05 1.09 ± 1.00 1.30 ± 1.08 0.375
 Sleep disturbances 2.28 ± 1.09 2.47 ± 0.88 2.19 ± 1.18 0.193
 Subjective sleep quality 1.74 ± 0.77 1.66 ± 0.83 1.78 ± 0.75 0.457
 Use of sleeping medication 1.33 ± 0.10 0.63 ± 1.13 1.14 ± 1.40 0.056
 Daytime dysfunction 1.11 ± 1.26 1.19 ± 1.23 1.08 ± 1.28 0.690
 Total score 9.86 ± 4.59 9.06 ± 4.35 10.27 ± 4.69 0.228
 Total score ≥ 6 b , n (%) 80 (83.3%) 27 (84.4%) 53 (82.8%) 0.846
PAGI-SYM
 Heartburn/regurgitation 7.94 ± 6.61 6.63 ± 5.57 8.59 ± 7.02 0.17
 Nausea/vomiting 2.95 ± 3.08 2.69 ± 2.98 3.08 ± 3.14 0.56
 Postprandial fullness 5.76 ± 4.71 5.00 ± 4.41 6.14 ± 4.84 0.266
 Bloating 2.76 ± 2.44 1.44 ± 1.92 3.42 ± 2.42 <0.001 c
 Upper abdominal pain 2.40 ± 2.62 1.72 ± 2.64 2.73 ± 2.56 0.073
 Lower abdominal pain 1.04 ± 2.03 0.59 ± 1.32 1.27 ± 2.28 0.071
 Total score 23.36 ± 15.81 18.19 ± 11.35 25.95 ± 17.11 0.010 c
Data are presented as mean ± SD or number (percentage).
BSRS-5, 5-item Brief Symptom Rating Scale; PAGI-SYM, Patient Assessment of Upper Gastrointestinal Symptom Severity Index; PSQI, Pittsburgh Sleep Quality Index.
aBSRS-5 score ≥ 6 indicates psychological comorbidity.
bPSQI score ≥ 6 indicates poor sleep quality.
cIndicates statistical significance (P < 0.05).

Impact of psychiatric comorbidity on symptom profiles and sleep quality in patients with functional dysphagia

Up to 45.8% of patients with functional dysphagia were found to have psychiatric problems; thus, we compared the symptom profiles and sleep quality between those with and without psychiatric comorbidities (Table 3). Among patients with functional dysphagia, those with psychiatric comorbidities frequently reported daily regurgitation (29.5% vs 11.5%, P = 0.027). There were no significant differences in other associated symptoms, such as dysphagia, retrosternal pain, and weight loss. However, patients with psychiatric comorbidities reported more severe sleep dysfunction in most sleep parameters. Similarly, patients with psychiatric comorbidities had more severe functional GI symptoms based on the PAGI-SYM, including the parameters of heartburn/regurgitation, postprandial fullness, and bloating, and the total score (27.23 ± 14.96 vs 20.1 ± 15.90, P = 0.0027). Therefore, we further explored the correlation between psychiatric comorbidity and various functional GI symptoms. The severity of psychiatric distress (BSRS-5 scores) was positively correlated with the severity of most functional GI symptom domains on the PAGI-SYM, except for nausea/vomiting (Figure 2).

Table 3. - Subgroup analysis of functional dysphagia stratified by psychological distress as per the 5-item Brief Symptom Rating Scale
BSRS-5 ≥ 6 (n = 44) BSRS-5 < 6 (n = 52) P value
Dysphagia
 Weekly, n (%) 14 (31.8) 25 (48.1) 0.106
 Daily, n (%) 15 (34.1) 10 (19.2) 0.098
 Each meal, n (%) 15 (34.1) 17 (32.7) 0.885
Regurgitation
 None, n (%) 17 (38.6) 26 (50.0) 0.265
 Weekly, n (%) 12 (27.3) 18 (34.6) 0.439
 Daily, n (%) 13 (29.5) 6 (11.5) 0.027 b
 Each meal, n (%) 2 (4.5) 2 (3.8) 0.864
Retrosternal pain
 None, n (%) 27 (61.4) 36 (69.2) 0.419
 Weekly, n (%) 14 (31.8) 13 (25.0) 0.459
 Daily, n (%) 3 (6.8) 2 (3.8) 0.514
 Each meal, n (%) 0 (0.0) 1 (1.9) 0.355
Body weight loss
 None, n (%) 20 (45.5) 23 (44.2) 0.904
 <5 kg, n (%) 17 (38.6) 22 (42.3) 0.715
 5–10 kg, n (%) 4 (9.1) 4 (7.7) 0.805
 >10 kg, n (%) 3 (6.8) 3 (5.8) 0.832
PSQI
 Sleep duration 1.70 ± 0.98 0.96 ± 0.91 <0.001 b
 Sleep latency 1.50 ± 1.11 1.00 ± 0.91 0.019 b
 Habitual sleep efficiency 1.41 ± 1.09 1.08 ± 1.01 0.123
 Sleep disturbances 2.57 ± 0.85 2.04 ± 1.22 0.014 b
 Subjective sleep quality 2.05 ± 0.68 1.48 ± 0.75 <0.001 b
 Use of sleeping medication 1.36 ± 1.43 0.63 ± 1.16 0.008 b
 Daytime dysfunction 1.50 ± 1.28 0.78 ± 1.14 0.005 b
 Total score 12.09 ± 3.84 7.98 ± 4.35 <0.001 b
 Total score ≥ 6 a , n (%) 43 (97.7) 37 (71.2) <0.001 b
PAGI-SYM
 Heartburn/regurgitation 9.73 ± 6.32 6.42 ± 6.57 0.014 b
 Nausea/vomiting 2.73 ± 2.78 3.13 ± 3.33 0.521
 Postprandial fullness 6.80 ± 4.55 4.88 ± 4.71 0.047 b
 Bloating 3.30 ± 2.51 2.31 ± 2.31 0.048 b
 Upper abdominal pain 2.80 ± 2.45 2.06 ± 2.73 0.170
 Lower abdominal pain 1.43 ± 2.13 0.71 ± 1.89 0.086
 Total score 27.23 ± 14.96 20.1 ± 15.90 0.027 b
Data are presented as mean ± SD or number (percentage).
BSRS-5, 5-item Brief Symptom Rating Scale; PAGI-SYM, Patient Assessment of Upper Gastrointestinal Symptom Severity Index; PSQI, Pittsburgh Sleep Quality Index.
aPSQI score ≥ 6 indicates poor sleep quality.
bIndicates statistical significance (P < 0.05).

F2
Figure 2.:
Correlation between psychiatric distress (5-item Brief Symptom Rating Scale [BSRS-5]) and respective symptom domains of Patient Assessment of Upper Gastrointestinal Symptom Severity Index.

Comparison of symptom profiles and esophageal motility between patients with functional dysphagia and healthy volunteers

To further clarify the pathophysiology of functional dysphagia, we compared the symptom profiles and esophageal motility parameters of patients with functional dysphagia to age- and sex-adjusted healthy volunteers (Table 4). Patients with functional dysphagia had significantly higher total scores on the BSRS-5 and PSQI when compared with the healthy volunteers (5.34 ± 3.91 vs 1.84 ± 2.61, 9.64 ± 4.13 vs 4.77 ± 3.60, both P < 0.001). However, there were no significant differences between the 2 groups in the various HRIM metrics, including contractile vigor, lower esophageal sphincter resting pressure and relaxation pressure, and percentage of IEM.

Table 4. - Comparison of demographics, psychological and sleep characteristics, and esophageal motility based on high-resolution manometry between patients with functional dysphagia and health volunteer adjusted by age and sexa
Functional dysphagia b Healthy volunteer c P value
(n = 44) (n = 44)
BW, kg 60.76 ± 13.24 62.36 ± 11.38 0.546
BH, m 1.65 ± 0.08 1.63 ± 0.09 0.475
BMI, kg/m2 22.27 ± 4.44 23.13 ± 3.02 0.295
Waist, cm 76.01 ± 16.84 79.22 ± 9.89 0.281
Questionnaire
 BSRS-5, total scores 5.34 ± 3.91 1.84 ± 2.61 <0.001*
  BSRS-5 ≥ 6 17 (38.64) 3 (6.82) <0.001*
 PSQI, total scores 9.64 ± 4.13 4.77 ± 3.60 <0.001*
  PSQI ≥ 6 39 (90.9) 20 (54.55) <0.001*
HRIM parameters
 LES resting pressure, mm Hg 20.46 ± 9.80 22.59 ± 10.97 0.342
 LES IRP-4s, mm Hg 7.59 ± 4.93 6.71 ± 5.74 0.444
 DCI, mm Hg*cm*s 1,291.5 ± 1,135.3 1,019.1 ± 818.6 0.219
 Break size, cm 2.95 ± 3.34 3.23 ± 3.65 0.685
 Intact peristalsis, % 70.23 ± 33.34 68.41 ± 34.44 0.803
 Weak peristalsis, % 16.19 ± 19.99 15.23 ± 20.29 0.825
 Failed peristalsis, % 10.71 ± 20.88 16.36 ± 30.20 0.314
 Distal latency, s 8.02 ± 1.51 8.01 ± 1.85 0.874
 IEM 4 (9.1%) 0 (0%) 0.116
Data are presented as mean ± SD or number (percentage).
DCI, distal contractile integral; HRIM, high-resolution impedance manometry; IEM, ineffective esophageal motility, IRP-4s, 4-seconds integrated relaxation pressure; LES, lower esophageal sphincter.
*Indicates statistical significance (p < 0.05).
aPropensity score matching method was applied and adjusted for age and sex.
bFunctional dysphagia group mean age is 45.96 ± 15.29 years; sex (male 52%).
cHealthy volunteer group mean age is 44.34 ± 12.02 years; sex (male 45%).

Comparison between functional dysphagia patients with normal esophageal motility and with IEM

Sixteen patients (16.7%) with functional dysphagia were found to have IEM on HRIM, so we further explored the impact of IEM on the clinical manifestations of functional dysphagia (see Supplementary Table 1, https://links.lww.com/CTG/A830). Among patients with functional dysphagia, patients with IEM experienced poorer sleep efficiency than those with normal esophageal motility (1.75 ± 1.13 vs 1.13 ± 1.01, P = 0.029). However, there were no significant differences between these 2 groups in other aspects of clinical demographics, dysphagia frequency, GI symptoms, psychiatric comorbidities, and sleep quality.

DISCUSSION

Functional dysphagia is an under-recognized cause of dysphagia because its diagnosis requires comprehensive evaluation to exclude various organic lesions and major motility disorders (4). Furthermore, much remains unclear about the epidemiology, pathophysiology, and predisposing factors of functional dysphagia, making the definitive diagnosis and treatment of functional dysphagia a significant challenge to clinicians (17). Our study revealed that functional dysphagia was predominant in women (67%) and was associated with a higher rate of sleep disturbance (83.3%). Moreover, almost half of the patients with functional dysphagia had psychiatric comorbidities (45.8%), and most functional GI symptoms were correlated with psychiatric distress. Esophageal motility in terms of the various parameters on HRIM was similar between patients with functional dysphagia and healthy volunteers.

One significant finding of this study was that patients with functional dysphagia are primarily female, which is compatible with previous studies on various functional GI diseases (18). In a 2005–2008 nationwide survey in Taiwan using the Rome III criteria, the overall prevalence of functional GI disorders was 27.7% and was higher in female subjects (33.2% vs 22.4%). Nevertheless, functional dysphagia was not included in that survey, and thus, its actual demographics were not available. Several other studies also reveal a similar phenomenon of female predominance in functional dyspepsia, which may be attributed to complex biopsychosocial integrations, including involvement of the central nervous system, gut microbiota, and sex hormones (19,20). Nevertheless, as a single-center retrospective study, our findings may have been affected by referral bias and may not be generalized to other study populations. Among the 460 patients for evaluation of dysphagia in this study, 270 (59%) were female. Further prospective studies including more medical centers may help to clarify the exact role of sex in functional dysphagia.

In this study, up to 45% of patients with functional dysphagia had psychiatric comorbidities, commonly observed in patients with other functional GI disorders. Patients with functional dysphagia have significantly higher scores in the BSRS-5 and the PSQI when compared with healthy volunteers. The pathophysiology of functional dysphagia and other functional GI disorders has not been thoroughly investigated and remains elusive. The most troublesome symptoms among functional GI disorders (including functional dysphagia) stem from complex interactions between esophageal contractility, mucosal hypersensitivity, and psychological problems. Galmiche et al. pointed out that patients with NOD have higher rates of anxiety, depression, and somatization disorders. Acute stress experiments implied that the central nervous system might impact the esophageal dysmotility responsible for the manifestation of dysphagia (21). Barofsky and Fontaine (22) found that patients with psychogenic dysphagia scored significantly higher on the interpersonal sensitivity, depression, anxiety, and general severity index than patients in the dysphagia comparison group, suggesting that psychological distress affects the pathophysiology of functional dysphagia. Epidemiological research has shown that nearly half of the clinical manifestations of various functional GI disorders were initiated from psychological distress followed by GI tract symptoms. By contrast, the other half suffered from the GI disorders first and then presented with subsequent psychological distress (23,24).

Sleep disturbance is also frequently observed in patients with various functional GI disorders and is closely related to emotional stress in these patients (25,26). Several cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor, may influence the circadian sleep cycle. At the same time, sleep deprivation would also activate the release of IL-1 and tumor necrosis factor (27,28). In this study, more than 80% of patients with functional dysphagia had a PSQI of 6 or higher, suggesting poor sleep quality, which could further aggravate the vicious cycle of psychological comorbidity-related stress in the pathophysiology of functional dysphagia. In this study, however, we did not use the validated questionnaires, such as Berlin Questionnaire and STOP-Bang Questionnaire, to screen obstructive sleep apnea (OSA) in patients with esophageal dysphagia. Previous studies have shown an association between OSA and swallowing dysfunction or oropharyngeal dysphagia (29,30). However, there have not been reports focusing on the relationship of OSA and function dysphagia to date. Further prospective studies incorporating the OSA questionnaires in the evaluation of patients with suspected functional dysphagia may help to answer this important question.

Although the definition of functional dysphagia under the Rome IV criteria excludes major esophageal motor disorders according to the Chicago Classification, minor motility disorders, such as IEM and fragmented peristalsis, do not exclude patients from being diagnosed with functional dysphagia. Ravi et al. (31) demonstrated that patients with normal and minor esophageal motor abnormalities reported minimal symptoms and had few medical interventions for esophageal dysfunction during a mean follow-up of 6.4 years. In addition, the prevalence of dysphagia symptoms in patients with minor manometric abnormalities was similar to those with normal esophageal manometry. This was consistent with our findings that most symptom scores on dysphagia (i.e., PAGI-SYM, BSRS-5, and PSQI) were similar between patients with IEM as defined by the updated Chicago Classification v4.0 and those with normal motility.

To the best of our knowledge, this is the first comprehensive report on functional dysphagia's clinical, psychosocial, and motility characteristics as defined by the Rome IV criteria. Nevertheless, there are several limitations to our study. First, the relatively small sample size in our study may hamper the strength and generalizability. In addition, some patients had a previous endoscopy within the past 6 months, and therefore, the endoscopy was not repeated, whereas some patients were referred from other hospitals, and the actual esophageal histology was not available in our electronic database. Therefore, we could not exclude the possibility of undiagnosed EoE in those who might not receive an esophageal biopsy and thus contributed to the low prevalence of EoE in our screening patient population (2/460, 0.4%). However, EoE is rarely seen in Taiwan, and only very few case reports were found in the literature (32). In addition, the prevalence of EoE is also reported to be low in the Chinese and Asian populations (approximately 1 of 5,000 endoscopy examinations, 0.02%) (33,34). Future prospective study adopting standardized esophageal biopsy protocol for evaluation of patients presenting with esophageal dysphagia is warranted. Second, provocative tests, such as multiple rapid swallows or positional changes, were not routinely used during high-resolution manometry in this study, and the diagnosis of major motility disorders was based on Chicago Classification v3.0. However, we have diagnosed the IEM patients with the more stringent criteria on Chicago Classification v4.0, which may have a higher clinical utility. Further studies incorporating provocative tests as standardized by the updated Chicago Classification v4.0 may help uncover obscure esophageal dysmotility in patients with functional dysphagia (11). Third, some newly developed diagnostic modalities, such as high-frequency ultrasound and endoluminal functional lumen imaging probe, which can detect the incoordination between circular and longitudinal esophageal muscle contraction and abnormal esophageal distensibility, are not yet available in Taiwan (35,36). Future investigations involving these novel diagnostic modalities may help recognize slight structural or functional defects in patients with functional dysphagia. Finally, although our study has demonstrated an association between psychiatric stress, sleep disturbance, and functional dysphagia, the causal-effect relationship could not be established. Future studies adopting treatment strategies directed at these psychosocial and sleep problems in patients with functional dysphagia and close monitor for improvement in dysphagia symptoms are warranted.

In conclusion, functional dysphagia is an easily ignored entity with a complex pathophysiology and clinical manifestations in patients with unexplained dysphagia symptoms. Middle-aged women are the most vulnerable group for functional dysphagia. Our findings have shown an association between functional dysphagia and questionnaire-based psychiatric abnormality and sleep disturbance and with no significant difference in manometry findings compared with normal volunteers. Although HRIM is used to exclude major motility abnormalities, the addition of a psychological evaluation may help to identify the possible underlying psychiatric comorbidities in patients with functional dysphagia and tailor further treatment plans.

CONFLICTS OF INTEREST

Guarantor of the article: Ping-Huei Tseng, MD, PhD

Specific author contributions: P.W.L., C.C.C., J.F.W., H.C.L., Y.C.L., and P.H.T.: contributed to case enrollment. P.W.L., C.C.C., J.F.W., and P.H.T.: contributed to data analysis, manuscript draft, and discussion. M.S.W., H.P.W., and P.H.T.: conceived and designed the study and reviewed the manuscript. P.H.T.: takes responsibility for the manuscript content.

Financial support: This study was supported by research grants from the National Taiwan University Hospital (NTUH 110-005025; NTUH 111-S0174) and the Ministry of Science and Technology (MOST 108-2628-B-002-019, 109-2628-B-002-036, and 110-2628-B-002-048).

Potential competing interests: None to report.

IRB approval statement: This study was approved by the Research Ethics Committee of the National Taiwan University Hospital (No. 201505131RIND), and all patients provided their written informed consent.

Study Highlights

WHAT IS KNOWN

  • ✓ Functional dysphagia is 1 of the 5 esophageal functional disorders based on the updated Rome IV criteria.
  • ✓ Functional dysphagia is defined as an abnormal sensation of solid or liquid food impaction when swallowing without any structural, mucosal, or major motility disorders of the esophagus.
  • ✓ The pathophysiology of functional dysphagia is complex and mostly unknown.

WHAT IS NEW HERE

  • ✓ Patients with functional dysphagia are predominantly middle-aged women.
  • ✓ There is high prevalence of psychiatric comorbidities and sleep disturbance in patients with functional dysphagia.
  • ✓ Patients with functional dysphagia display higher psychiatric distress and sleep disturbance, but similar esophageal motility as the healthy volunteers do.

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