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Abstract

Background:

Nonobstructive esophageal dysphagia (NOD) is a common benign condition that significantly impacts quality of life. Management requires a motility-focused approach and consideration for concomitant comorbidities such as gastroesophageal reflux, visceral hypersensitivity, and psychological factors. Currently, esophagogastric junction (EGJ) outflow disorders have the most studied and effective treatments. Data on patient-reported dysphagia and quality of life in this population, and their evolution over time and treatment, are scarce.

Objective:

This study aims to evaluate the real-world management and behavior of NOD, focusing on motility profiles and the implementation of specific treatments.

Design:

This is a multicenter prospective observational study that follows the management and evolution of NOD in a Portuguese cohort for 6 months, focusing on dysphagia and quality of life, to evaluate its clinical behavior.

Methods:

Dysphagia and quality of life were assessed in 195 patients using validated patient-reported questionnaires at baseline and follow-up.

Results:

From 195 patients, 61% (n = 119) were female, with a mean age of 61 (SD 15) years. According to Chicago classification 4.0, 32.3% (n = 63) had EGJ outflow disorders, 12.8% (n = 25) spastic disorders, 16.4% (n = 32) hypomotile disorders, 35.9% (n = 70) normal motility, and 2.6% (n = 5) were inconclusive. At baseline, the mean PROMIS Gastrointestinal Disrupted Swallowing (PDS) T-score, EQ-5D-3L, and Visual Analog Scale (VAS) scores were 61.7 (SD 7.4), 0.61 (SD 0.26), and 69 (SD 18), respectively. Overall, at 6 months, there were significant improvements in the Eckardt, PDS, and EQ-5D-3L scores, with no difference in VAS. In EGJ disorders, myotomy significantly improved all measurements. In the remaining subgroups, a favorable evolution of dysphagia was observed, without differences between treated and untreated patients.

Conclusion:

NOD tends to follow a benign course. Apart from achalasia, which has the most defined treatments with documented benefits, decisions for the remaining motility profiles should follow a comprehensive and personalized approach.

Keywords

dysphagia esophageal motility disorders patient-reported outcomes

Background

Esophageal nonobstructive dysphagia (NOD) is a benign condition defined as the subjective sensation of food getting stuck in the esophagus, following the exclusion of any mechanical obstruction.¹ It is commonly encountered in clinical practice, with well-known impacts on patients’ nutrition, quality of life, survival, and healthcare consumption.^2
–5

Regarding etiologies and associations, NOD has been linked to esophageal motility disorders, functional syndromes, gastroesophageal reflux disorder (GERD), and psychological factors.^6
–8 In fact, achalasia and ineffective esophageal motility (IEM) have been documented in 55.0% and 38.6% of NOD patients, respectively.^1,6,9,10 GERD-related symptoms have been reported in 17.2%–55.8% of patients and are associated with IEM.^1,6,9 In addition, 45.8% of functional dysphagic patients have been diagnosed with psychological conditions, which significantly correlated with their symptoms, with an expected reverse causality.¹¹

Overall, a correlation between dysphagic symptoms, manometric findings, and disease severity is inconsistent, and holistic management is mandatory.¹² Indeed, clinical evaluation and treatment monitoring based solely on objective dysphagia scores may be insufficient, as they fail to capture the full patient experience. This limitation can be overcome by incorporating quality of life measures and patient-reported outcomes (PROs).¹³

Regarding therapeutics, the esophagogastric junction (EGJ) outflow disorders have the most efficient and validated options. For achalasia type I and II, pneumatic dilation (PD), peroral endoscopic myotomy (POEM), and laparoscopic Heller myotomy (LHM) have shown similar success rates, around 90%, with type II better responding to all.^14,15 For achalasia type III, POEM has been the preferred method due to the possibility of a more precise, tailored, and longer myotomy, with a 93% response rate.¹⁶ Compared to surgery, POEM comprises fewer serious adverse events; however, with a higher rate of reflux esophagitis, around 44% after 2 years.¹⁷ In addition, PD is known to lose its effect over time, decreasing clinical response to 44% at 6 years.¹⁵ In nonsurgical candidates, botulinum toxin (BT) might be an option; however, with poor outcomes, as 18%–59% response rate and need for reintervention.¹⁸

Regarding idiopathic EGJ outflow obstruction (EGJOO), conservative treatment has been advocated for mild symptoms, with response rates of 63.6%. For more symptomatic EGJOO, BT and PD have shown acceptable responses of 63.6% and 66.7%, respectively, and POEM looks promising with a high success rate of 93.3%.^15,19,20 In addition, medical treatments such as smooth muscle relaxants are generally ineffective, with a response rate of approximately 30%.^14,19

Spastic disorders, such as distal esophageal spasm (DES) and hypercontractile esophagus (HE), may be first addressed with medical treatments such as smooth muscle relaxants; however, BT and PD are possible options, with responses around 30% at 1 year and 70%, respectively.^21,22 POEM and surgical myotomy have also been suggested for highly selected patients, with response rates around 72%–88%.²³ In addition, similarly to every subgroup, effective control of GERD with acid suppression is essential.

Management of hypomotile disorders, such as IEM and absent contractility (AC), is challenging, as currently there is no effective pharmacotherapy. It should focus on symptomatology, diet, and lifestyle modifications. In noncardiac chest pain, esophageal hypersensitivity should be addressed with neuromodulators, cognitive, and behavioral therapies.^14,15,24

Lastly, in patients with normal motility, after considering medication revision (such as opioid, anticholinergic, and antimuscarinic drugs), GERD and visceral hypersensitivity, empirical esophageal dilation has been suggested, however, with conflicting data.^24,25 In addition, studies have reported the long-term improvement or disappearance of dysphagia in patients with minor motor abnormalities or normal motility without any intervention.^24,26

With this study, the authors aim to describe the real-world management and clinical behavior of distinct NOD subgroups within a national multicenter cohort over a 6-month period. In addition, we intend to complement previous literature on NOD clinical assessment and treatment monitoring with more robust and patient-centered data.

Methods

Study population

From September 2021 to April 2024, consecutive adult patients who complained of nonobstructive esophageal dysphagia were prospectively evaluated over a 6-month period in seven Portuguese centers. Patients were included if they (1) were older than 18 years old, (2) had a previous upper endoscopy excluding obstructive, mechanical obstruction, and eosinophilic esophagitis (through biopsies), (3) had a valid high-resolution manometry (HRM) study, (4) answered three PRO measures (EuroQol EQ-5D-3L descriptive, Visual Analog Scale (VAS), and PROMIS Gastrointestinal Disrupted Swallowing (PDS) scale), and (5) were clinically reevaluated 6 months after study inclusion or intervention. Exclusion criteria included (1) obstructive or mechanical dysphagic etiology on upper endoscopy, (2) previous esophageal surgery or fundoplication, (3) oropharyngeal dysphagia, (4) inability to comprehend the proposed questionnaires, and (5) missed 6-month reevaluation.

All patients underwent a comprehensive workup for esophageal dysphagia following each center’s protocol and clinical relevance, including upper endoscopy, HRM, timed barium esophagram (if relevant), and pH-impedance monitoring (if relevant). The study protocol and its multicentric nature were approved by local and Lisbon Academic Medical Center ethical committees. All patients provided written informed consent to participate in the study. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology statement.²⁷

Epidemiological and clinical data

Epidemiological and clinical data were collected through the patients’ electronic data registry, in-person or telephonic interviews, and written questionnaires. Dysphagia severity was objectively characterized and reevaluated through the validated Eckardt score. GERD-related symptoms were evaluated through the Gastroesophageal Reflux Disease Questionnaire (GerdQ). All data were registered and codified on paper and electronic case report forms.

Patient-reported outcomes

Patients were asked to complete three validated and translated to Portuguese PRO evaluating their overall and specific quality of life: PDS T-score, EuroQol EQ-5D-3L, and VAS.

The PDS T-score is a 7-item measure designed to assess the frequency of swallowing-related symptoms over the past 7 days. Each item is scored on a scale from 0 to 5, and the total score is calibrated against the median of the United States general population.⁴

The EuroQol EQ-5D-3L is a descriptive system containing five 3-level dimensions of a patient’s health: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. The result takes into consideration the relative importance of each item and can be converted into a value from 0 (dead) to 1 (full health).²⁸

The EuroQol VAS score records the patient’s health on a VAS where its endpoints are “the best health you can imagine” and “the worst health you can imagine.”²⁸

HRM protocol and analysis

After a minimum of 6-h fasting, HRM was obtained with Diversatek^®, Medtronic^®, or Laborie^® solid-state or water-perfusion catheters and software, depending on the center. The HRM assembly was placed transnasally and positioned to record from the hypopharynx to the stomach. After a 2-min baseline, protocol was performed and evaluated by highly trained doctors, according to the Chicago classification 4.0 (CC v4.0). Integrated relaxation pressure (IRP) threshold values varied among systems. Nonconforming elevated IRP between primary and secondary positions or with unsurpassable EGJ were integrated with the remaining patient’s clinical data for a final diagnosis. EGJOO diagnosis implied a non-manometric confirmation, such as a timed barium esophagram. No patient was submitted to endoluminal functional lumen imaging probe (FLIP) due to its unavailability in the centers. Due to software diversity, after HRM evaluation and interpretation in each center, HRM data (such as IRP, esophageal body activity, and the result of provocative tests) were collected and discriminated through the REDCap electronic platform hosted at the Portuguese Society of Gastroenterology – CEREGA, for central validation by the principal investigators. Nevertheless, the final manometric diagnosis was primarily determined by investigators with manometry expertise at each local center.

Population subgroups

According to HRM results, patients were divided into four manometric groups: EGJ outflow disorders (achalasia and EGJOO), spastic disorders (DES and HE), hypomotile disorders (IEM and AC), and normal motility. Patients with elevated IRP values in both HRM positions, who were not submitted to a non-manometric confirmatory test, were considered inconclusive. As they could not be integrated into the CC v4.0 criteria, they were excluded from further subgroup analyses to minimize heterogeneity and prevent confusion.

Treatments and follow-up

Patients were evaluated on the day HRM was performed, and questionnaires were administered on that same day (baseline). Participants were reassessed 6 months later. If no intervention was initiated during this period, the questionnaires were administered again at that time (month 6). If an intervention was introduced within the six-month period, a follow-up evaluation was scheduled for 6 months after the start of the intervention (month 6 from that point). The study design is clarified in Figure 1.

Figure 1.

Study design indicating exclusion of missing data, baseline, and 6-month period.

Patients were managed according to current practice guidelines, clinical judgment, disease severity, impact on quality of life, surgical risk, and shared decisions with the patient. Since this was an observational study reflecting real-world experience with dysphagic patients, management followed each clinician and center’s protocol. All surgically and endoscopically intervened patients signed informed consents regarding the technique.

Endoscopic treatments included POEM, PD, and BT, all performed by highly trained physicians. POEM was executed under anesthesia and included anterior or posterior mucosotomy, submucosal tunnel creation, and selective myotomy of the circular muscle layer of the distal esophagus, EGJ, and cardia. Myotomy length depended on the physician’s judgment, but standard protocol included extension from 3 to 5 cm of the mucosotomy until 2–3 cm distal to the EGJ. In type III achalasia and spastic disorders, myotomy was guided by HRM results and the endoscopist’s judgment. After the procedure, patients stayed under clinical surveillance for 1–2 days and were discharged after tolerating a soft diet. Empirical antibiotics (e.g., third-generation cephalosporin) were administered according to each center’s protocol, and patients were discharged home on high-dose proton pump inhibitors (PPI).

PD and BT were performed as outpatient procedures, under conscious sedation or anesthesia. BT technique generally involved four-quadrant injections (25 U each), into the lower esophageal sphincter in achalasia; 2 cm above the EGJ and 5 cm proximal to this in spastic disorders. PD was generally done under fluoroscopic guidance, with a sequentially dilated Rigiflex balloon (Boston Scientific^®, Massachusetts, United States) positioned at the EGJ, according to standard protocol and immediate response. Patients were discharged on PPI therapy.

LHM was done by each center’s highly trained surgical team, according to standard protocol, and under general anesthesia. After the division of the phrenoesophageal ligament, the distal esophagus was mobilized on its lateral and anterior side, and a myotomy was performed from at least 6 cm above the EGJ to at least 1 cm over the stomach, with fundoplication.

Medical treatments included smooth muscle relaxants such as the calcium-channel blockers (CCB) diltiazem 60–90 mg and nifedipine 10 mg; neuromodulators such as the tricyclic antidepressant amitriptyline 10–25 mg; and PPI introduction or optimization.

For every intervention, treatment success was defined as the reduction of the Eckardt score to an absolute value of 3 or lower and freedom from reintervention in the 6-month period.

Statistical analysis

Descriptive and inferential analyses were performed in Microsoft^® Excel (version 16.83, Washington, United States) and IBM^® SPSS (version 29, New York, United States). Continuous variables were characterized by median (interval), and categorical variables were reported as frequency (percentage). Patients with missing data or follow-up were excluded from the analysis. The Central Limit Theorem was considered applicable for a sample size greater than 30, provided the underlying distribution was not excessively skewed. Smaller samples were assessed for normality using the Shapiro–Wilk test and for homogeneity of variances using the Levene test. Categorical data were compared using the chi-square test or Fisher’s exact test, depending on the sample size or whether the expected frequencies were low. Continuous data were analyzed using ANOVA and paired samples t tests when normality and homogeneity of variances were met. The Kruskal-Wallis and Wilcoxon signed-rank tests were used for nonparametric data. Corrections for multiple comparisons were applied when deemed appropriate, and this has been clarified in the text. Effect sizes were calculated for all paired comparisons between subgroups, using Cohen’s d or r, depending on sample size and the normality of the data.

Results

Study population

From a total of 250 individuals recruited from 7 Portuguese centers, 195 were included in the study due to missing or incoherent data. Of these, 61% (n = 119) were female, with a mean age of 61 (SD 15) years old. The majority (94.9%, n = 185) were Caucasian, and 41.5% (n = 81) attended secondary school or higher. Regarding concomitant clinical data, 62 (31.8%) patients had a previously established rheumatological or metabolic disease, mainly systemic sclerosis and diabetes mellitus. In addition, 106 (54.4%) patients reported moderate to extreme depressive and/or anxious symptoms in the EQ-5D-3L questionnaire. Regarding dysphagia, mean disease duration was 7 (SD 8) years, with an Eckardt score of 4 (SD 2) and 102 (52.3%) patients were refractory to at least one relevant medical or endoscopic treatment, accordingly: 86 PPI, 6 neuromodulators, 5 smooth muscle relaxants, 3 BT, and 3 PD. Epidemiological and clinical data, according to the manometric group, are in Table 1. Most baseline characteristics were significantly different between motility groups, as seen in Table 1.

Table 1.

Epidemiological and clinical data at baseline by manometric group.

Variables, N (%)	EGJ outflow, 63 (32.6)	Spastic, 25 (13.0)	Hypomotile, 32 (16.6)	Normal, 70 (35.9)	p Value
Female, n (%)	30 (47.6)	12 (48)	20 (62.5)	54 (77.1)	0.002
Age, years, mean (IQR)	58 (25)	71 (10)	56 (23)	62 (14)	<0.001
Only primary education, n (%)	27 (42.9)	12 (48.0)	16 (50.0)	42 (60)	0.125
Concomitant disorder, n (%)*	9 (14.3)	10 (40)	19 (59.4)	21 (30)	<0.001
Symptom duration, years, mean (SD)	6 (9)	7 (7)	10 (13)	6 (6)	0.235
Previous treatment, n (%)	24 (38.1)	17 (73.9)	18 (56.3)	40 (57.1)	0.01
Eckardt score, mean (SD)	5 (3)	3 (2)	4 (2)	3 (2)	<0.001
PDS raw score, mean (SD)	20 (5)	17 (5)	17 (7)	17 (5)	<0.001
PDS T-score, mean (SD)	65 (6)	61 (6)	60 (10)	60 (7)	<0.001
GerdQ, mean (SD)	9 (2)	8 (3)	8 (3)	7 (2)	<0.001
EQ-5D-3L, mean (SD)	0.67 (0.22)	0.61 (0.28)	0.61 (0.26)	0.57 (0.28)	0.185
EuroQol VAS, mean (SD)	68 (17)	72 (20)	75 (16)	68 (19)	0.163
Depressed or anxious, n (%)^$	33 (52.4)	15 (60)	16 (50.0)	39 (55.7)	0.907

Disorders that were considered relevant for gastrointestinal motility were rheumatological (e.g., systemic sclerosis and systemic lupus erythematosus) and metabolic (e.g., diabetes mellitus).

Patients were considered anxious or depressed if they reported moderate to extreme symptoms in the EuroQol questionnaire.

EGJ, esophagogastric junction; GerdQ, Gastroesophageal Reflux Disease Questionnaire; PDS, PROMIS Gastrointestinal Disrupted Swallowing; VAS, Visual Analog Scale.

Esophageal data

According to CC v4.0, 32.3% (n = 63) of patients were diagnosed with EGJ outflow disorders, 11 achalasia type I, 38 achalasia type II, 11 achalasia type III, and 3 EGJOO. Twenty-five (12.8%) patients were diagnosed with spastic disorders, 14 HE and 11 DES. Thirty-two (16.4%) patients had hypomotility disorders, 8 AC, and 24 IEM; and 70 (35.9%) patients had normal motility on HRM, suggesting a functional diagnosis. Five patients (2.6%) received an inconclusive diagnosis. The EGJ was classified as type III in 14.9% (n = 29) of patients. In addition, 64 (32.8%) patients had a positive GerdQ questionnaire; however, only 10 (5.1%) had available pH-impedance monitoring studies. Indeed, an objective diagnosis of GERD was only made in 6 (3%) patients.

Patient-reported outcomes

At baseline, the mean PDS T-score was 61.7 (SD 7.4), meaning moderate severity, with significantly higher values in the EGJ outflow subgroup, with a mean of 65.0 (SD 6.0) in this group compared to values lower than 62.0 in the remaining (p < 0.001). Regarding overall quality of life, mean EQ-5D-3L and VAS scores were 0.61 (SD 0.26) and 69 (SD 18), with no significant differences between subgroups.

Overall follow-up

In our whole sample, a 6-month evaluation (including both treated and untreated patients) demonstrated a global reduction in dysphagia severity, with the mean Eckardt score significantly decreasing from 4 (SD 2) to 2 (SD 2; p < 0.001, Cohen’s d 0.6) and the mean PDS T-score significantly decreasing from 61.7 (SD 7.4) to 53.1 (SD 10.0; p < 0.001, Cohen’s d 0.8). A smaller significant improvement was also observed in the EQ-5D-3L (p = 0.032, Cohen’s d 0.1); however, no significant change was noted in the VAS score (p = 0.214). In multivariate analysis, baseline factors as male gender (p = 0.035), higher Eckardt (p = 0.039), higher PDS T-score (p = 0.043), and the presence of EGJ outflow disorders (p < 0.001) were all positively associated with the decision to initiate treatment. Below is the evaluation of outcomes across different motility disorder subgroups.

EGJ outflow disorders

At baseline, EGJ outflow disorders were associated with the most severe dysphagia compared to other motility subgroups, as reflected by higher Eckardt and PDS scores. Over a 6-month period, 36 patients (57.1%) underwent POEM, 1 (1.6%) underwent LHM, 5 (7.9%) received BT, and 2 (3.2%) underwent PD. The remaining 19 patients (30.2%) remained under clinical surveillance, although most were awaiting a treatment intervention.

At 6 months, there were overall large significant reductions in Eckardt scores (p < 0.001, Cohen’s d 1.1) and PDS T-score (p < 0.001, Cohen’s d 1.2). Quality of life, as measured by the EQ-5D-3L score, also showed moderate improvement (p < 0.001, Cohen’s d 0.5), as did the VAS score (p < 0.001, Cohen’s d 0.6). Table 2 presents the clinical evolution across the different treatment modalities (myotomy, BT, and PD) and CC v4.0 categories.

Table 2.

Evolution of Eckardt, EQ-5D-3L, VAS, and PDS scores after a 6-month follow-up period, in the EGJ outflow disorders group, according to treatment subgroups.

Treatment	Eckardt baseline	Eckardt 6m	EQ-5D-3L baseline	EQ-5D-3L 6m	VAS baseline	VAS 6m	T-PDS baseline	T-PDS 6m
Myotomy (n = 37)	6 (2)	1 (1)*	0.7 (0.2)	0.8 (0.2)*	69 (17)	86 (12)*	67 (5)	44 (5)*
8 achalasia I	6 (2)	1 (2)*	0.7 (0.3)	0.8 (0.3)	70 (20)	86 (12)*	64 (5)	45 (8)*
21 achalasia II	6 (2)	1 (1)*	0.7 (0.2)	0.9 (0.2)*	70 (18)	89 (9)*	68 (6)	45 (5)*
8 achalasia III	7 (2)	1 (1)*	0.6 (0.3)	0.7 (0.2)	67 (14)	76 (15)	68 (3)	42 (3)*
BT (n = 5)	5 (3)	3 (1)	0.7 (0.2)	0.7 (0.1)	76 (13)	64 (19)	63 (7)	59 (7)
2 achalasia I	6 (2)	3 (1)	0.8 (0.2)	0.8 (0.2)	80 (15)	73 (25)	67 (7)	56 (3)
2 achalasia II	6 (6)	4 (1)	0.6 (0.1)	0.7 (0.0)	68 (11)	50 (14)	61 (10)	59 (10)
1 EGJOO	2 (na)	3 (na)	0.8 (na)	0.7 (na)	90 (na)	75 (na)	62 (na)	67 (na)
PD (n = 2) 2 achalasia II	4 (0)	3 (1)	0.4 (0.5)	0.7 (0.1)	50 (42)	93 (4)	63 (1)	60 (9)
No treatment (n = 19)	4 (3)	3 (2)	0.6 (0.2)	0.7 (0.2)	64 (14)	71 (13)	62 (5)	58 (10)
1 achalasia I	2 (na)	2 (na)	0.7 (na)	1 (na)	70 (na)	75 (na)	49 (na)	52 (na)
13 achalasia II	5 (3)	4 (2)	0.6 (0.2)	0.7 (0.2)	60 (15)	73 (12)*	62 (5)	59 (9)
3 achalasia III	3 (1)	2 (2)	0.7 (0.1)	0.8 (0.2)	73 (12)	78 (8)	62 (3)	54 (12)
2 EGJOO	2 (0)	3 (3)	0.5 (0.3)	0.5 (0.4)	70 (0)	50 (0)	66 (1)	54 (19)

Values are shown in mean (SD).

p Value <0.05 within the different groups.

BT, botulinum toxin; EGJ, esophagogastric junction; EGJOO, EGJ outflow obstruction; na, not applicable; PD, pneumatic dilation; PDS, PROMIS Gastrointestinal Disrupted Swallowing; VAS, Visual Analog Scale; 6m, 6 months.

At 6 months, myotomy was the only treatment to elicit a statistically significant change in both dysphagia severity, general and GI specific quality of life (p < 0.001), with large effect sizes in the Eckardt (Cohen’s d 2.2), PDS (Cohen’s d 3.7), and VAS (Cohen’s d 0.9) scores; and moderate effect in the EQ-5D-3L (Cohen’s d 0.6). Furthermore, BT, PD, and “no treatment” were not associated with any significant positive or negative change in Eckardt, EQ-5D-3L, VAS, and PDS scores at 6 months. When EGJOO patients were excluded from the cohort, the results remained the same. Overall, in our cohort, POEM, BT, and PD success rates, as defined by Eckardt absolute reduction, were 97.2%, 60.0%, and 100.0% at 6 months, respectively.

Spastic disorders

Over 6 months, two patients (8.0%) were treated with smooth muscle relaxants, while another 2 (8.0%) had their PPI therapy optimized. Four patients (16.0%) underwent intraesophageal injection of BT. The remaining 17 patients (68.0%) were maintained on clinical surveillance, with opioids detected and discontinued in two of these cases.

At the 6-month evaluation, there was a significant overall moderate reduction in Eckardt score (p = 0.028, r = 0.4) and a large reduction in PDS T-score (p < 0.001, r = 0.8). However, quality of life, assessed by EQ-5D-3L and VAS scores, showed no significant changes (p = 0.456 and p = 0.228, respectively). Table 3 shows the clinical evolution among different treatments and by CC v4.0 subgroup.

Table 3.

Evolution of Eckardt, EQ-5D-3L, VAS, and PDS scores after 6 months, in the spastic disorders group, according to treatment subgroups.

Treatment	Eckardt baseline	Eckardt 6m	EQ-5D-3L baseline	EQ-5D-3L 6m	VAS baseline	VAS 6m	T-PDS baseline	T-PDS 6m
BT (n = 4)	4 (1)	2 (1)	0.6 (0.1)	0.6 (0.3)	65 (16)	74 (11)	65 (4)	57 (6)
2 HE	3 (0)	2 (0)	0.6 (0.1)	0.6 (0.5)	70 (21)	80 (14)	65 (4)	53 (5)
2 DES	4 (1)	3 (1)	0.6 (0.1)	0.5 (0.3)	60 (14)	68 (4)	66 (6)	61 (2)
SM relaxant (n = 2) 2 HE	5 (0)	6 (4)	0.5 (0.3)	0.2 (0.4)	75 (21)	40 (28)	63 (5)	60 (12)
PPI (n = 2) 2 HE	5 (1)	3 (0)	0.3 (0.4)	0.5 (0.2)	70 (14)	70 (28)	67 (6)	64 (3)
No treatment (n = 17)	3 (1)	2 (2)	0.7 (0.3)	0.6 (0.3)	75 (23)	66 (26)	59 (6)	49 (9)*
8 HE	3 (1)	2 (2)	0.6 (0.3)	0.7 (0.3)	78 (19)	74 (23)	60 (5)	51 (10)*
9 DES	3 (2)	2 (2)	0.7 (0.3)	0.5 (0.4)*	72 (26)	58 (27)	58 (6)	47 (8)*

Values are shown in mean (SD).

p value <0.05 within the different groups.

BT, botulinum toxin; DES, distal esophageal spam; HE, hypercontractile esophagus; PD, pneumatic dilation; PDS, PROMIS Gastrointestinal Disrupted Swallowing; PPI, proton pump inhibitors; SM, smooth muscle; VAS, Visual Analog Scale; 6m, 6 months.

At 6 months, neither BT nor any medical treatment significantly changes (positively or negatively) any evaluated dysphagia or quality of life score. Overall, BT and CCB achieved success rates at 6 months of 100% and 50%, respectively. In addition, the “no treatment” subgroup showed an isolated significant improvement with a large effect size in PDS T-score at 6 months (p = 0.003, r = 0.8) in both HE and DES subgroups.

Hypomotile disorders

Over a 6-month period, eight patients (25.0%) had their PPI optimized, while 24 (75.0%) remained under clinical surveillance. Overall, there was a significant moderate improvement in the Eckardt score (p = 0.02, Cohen’s d 0.6) and a small improvement in VAS score (p = 0.045, Cohen’s d 0.4). However, no significant changes were observed in the EQ-5D-3L and PDS scores (p = 0.197 and p = 0.147, respectively). Table 4 presents the clinical evolution at 6 months in both treated and untreated patients, according to CC v4.0 categories.

Table 4.

Evolution of Eckardt, EQ-5D-3L, VAS, and PDS scores after 6 months, in the hypomotile disorders group, according to treatment subgroups.

Treatment	Eckardt baseline	Eckardt 6m	EQ-5D-3L baseline	EQ-5D-3L 6m	VAS baseline	VAS 6m	T-PDS baseline	T-PDS 6m
PPI (n = 8)	4 (2)	2 (2)*	0.6 (0.2)	0.7 (0.2)	79 (11)	71 (18)	61 (7)	57 (4)
6 IEM	5 (2)	3 (2)	0.6 (0.2)	0.7 (0.2)	78 (12)	65 (16)	63 (7)	57 (5)*
2 AC	3 (1)	2 (0)	0.7 (0.1)	0.7 (0)	85 (7)	90 (0)	56 (3)	57 (3)
No treatment (n = 24)	4 (3)	3 (2)*	0.6 (0.3)	0.6 (0.3)	74 (17)	65 (22)	59 (10)	57 (11)
18 IEM	4 (2)	3 (2)	0.6 (0.3)	0.6 (0.2)	77 (16)	68 (23)	58 (10)	56 (11)
6 AC	6 (3)	5 (2)	0.5 (0.3)	0.6 (0.3)	65 (18)	58 (20)	63 (12)	62 (11)

Values are shown in mean (SD).

p Value <0.05 within the different groups.

AC, absent contractility; IEM, ineffective esophageal motility; PDS, PROMIS Gastrointestinal Disrupted Swallowing; PPI, proton pump inhibitors; VAS, Visual Analog Scale; 6m, 6 months.

When evaluating the entire group, a moderate decrease in the Eckardt score was observed in both treated (p = 0.048, r = 0.7) and untreated patients (p = 0.024, r = 0.5). However, no significant changes were found in quality-of-life scores (EQ-5D-3L or VAS). When analyzing individual CC v4.0 categories, patients with IEM treated with PPI had a significant improvement in PDS T-score (p = 0.043, r = 0.8).

Normal motility group

Over 6 months, 6 (8.6%) patients had their PPI optimized and 2 (2.9%) were medicated with amitriptyline. The remaining 62 were kept on lifestyle education and clinical surveillance. There was a significant moderate overall reduction in PDS T-score (p < 0.001, Cohen’s d 0.6), with no significant change in the Eckardt score (p = 0.054). Quality of life, assessed by EQ-5D-3L and VAS scores, also showed no significant changes (p = 0.735 and p = 0.667, respectively). Table 5 presents the clinical evolution among different treatments.

Table 5.

Evolution of Eckardt, EQ-5D-3L, VAS, and PDS scores after 6 months, in the normal motility group, according to treatment subgroups.

Treatment	Eckardt baseline	Eckardt 6m	EQ-5D-3L baseline	EQ-5D-3L 6m	VAS baseline	VAS 6m	T-PDS baseline	T-PDS 6m
PPI (n = 6)	3 (2)	3 (2)	0.6 (0.3)	0.6 (0.3)	74 (18)	75 (17)	65 (8)	62 (5)
Neuromodulator (n = 2)	5 (0)	4 (3)	0.5 (0.2)	0.4 (0.4)	65 (21)	63 (18)	64 (4)	58 (0)
No treatment (n = 62)	3 (2)	3 (2)	0.6 (0.3)	0.6 (0.3)	67 (19)	67 (21)	60 (7)	54 (10)*

Values are shown in mean (SD).

p Value <0.05 within the different groups.

PDS, PROMIS Gastrointestinal Disrupted Swallowing; PPI, proton pump inhibitors; VAS, Visual Analog Scale.

At 6 months, the “no treatment” group showed a similarly moderate and significant isolated decrease in PDS T-scores (p < 0.001, Cohen’s d 0.6). No other significant differences were noticed between subgroups.

Treatment modality across disease subgroups

Analyzing clinical strategies applied across more than one motility disorder subgroup, intraesophageal BT injection showed a similar nonsignificant tendency of improvement in Eckardt and PDS scores in both EGJ outflow and spastic disorders. However, minimal changes were observed in the EQ-5D-3L score, as illustrated in Figure 2.

Figure 2.

Evolution of Eckardt, PDS, and EQ-5D-3L scores after 6 months, in patients submitted to botulin toxin injection, according to disorder subgroups.

Regarding PPI therapy, it resulted in a significant improvement in the Eckardt score among patients with hypomotile disorders (p = 0.048), while no significant changes were observed in patients with normal motility. The PDS T-score had a nonsignificant tendency to improve in both groups, and the EQ-5D-3L showed nonsignificant differences. Figure 3 depicts the progression of the calculated scores in both groups following PPI treatment.

Figure 3.

Evolution of Eckardt, PDS, and EQ-5D-3L scores after 6 months, in patients treated with PPI, according to disorder subgroups.

In the “no treatment” group, a significant decrease in the Eckardt score was only observed in patients with hypomotile disorders (p = 0.024). In addition, a significant improvement in the PDS T-score was also observed in patients with spastic disorders (p = 0.003) and normal motility (p < 0.001). Figure 4 illustrates the progression of the calculated scores across different disorders in patients who did not receive any treatment in the 6-month follow-up period.

Figure 4.

Evolution of Eckardt, PDS, and EQ-5D-3L scores after 6 months, in patients without treatment, according to disorder subgroups.

Other treatment modalities, such as myotomy, PD, SM relaxants, and neuromodulators, were either applied exclusively to a single type of esophageal disorder or involved only a very limited number of patients, making their comparison among different motility subgroups unfeasible.

Discussion

The present prospective study illustrates the real-life approach to nonobstructive esophageal dysphagia across different regions of Portugal. Although all data were collected from motility centers, investigators did not interfere with clinical decisions unless they were also the treating physicians. This approach helped to avoid selection bias and ensured a more accurate representation of real-world practice, with a focus on clinical outcomes.

Overall, both therapeutic choices and clinical results align with those reported in previous literature. As expected, treated patients had more severe baseline dysphagia, as assessed by the Eckardt and PDS scores, and EGJ outflow disorders were the motility group with a higher percentage of treated patients. Indeed, achalasia, which is the most studied esophageal motility disorder, has the most studied and efficient treatment options.

Regarding EGJ outflow disorders, myotomy (endoscopic and surgical, n = 37) achieved a success rate of 97.2% at 6 months, like previous reported results.^14,15 To note that, in our cohort, most patients referred to myotomy were submitted to POEM (and not LHM) since at least one recruiting center is a national reference center with high expertise in this area. In addition, BT (n = 5) was associated with a 60.0% treatment success rate, which is compatible with previous literature, showing a symptomatic relief of 53.3% at 6 months.²⁹ This may be explained by BT only interrupting the neurogenic component of the lower esophageal sphincter, without affecting the myogenic influence.³⁰ Since a small sample of patients were submitted to BT or PD, a careful interpretation of their efficacy should be done.

Regarding spastic disorders (HE and DES), at 6 months, there was a significant overall improvement in dysphagia, as assessed by the Eckardt and PDS scores. When treatment was decided, BT (n = 4) demonstrated an interesting clinical outcome, with higher improvements in the Eckardt score compared to published results (100% vs 50%–71% at 6 months).^21,31 However, the small sample size and the absence of significant statistical differences in quality-of-life PROs should be taken into consideration. CCB led to an improvement in the Eckardt score in one out of two treated patients, which is consistent with previous Japanese data (61.1%).³² In addition, 62.5% (n = 10) of the “no treatment” subgroup had improvements in their Eckardt score, and there was a significant improvement in the PDS T-score. This is in line with Hosaka et al. observations, where 77% of HE patients not receiving any treatment showed clinical improvements, possibly highlighting confounding factors such as the benign and fluctuating nature of these conditions and the unmeasured effects of supportive care.³²

The management of hypomotility disorders is challenging, and no pharmacological treatment has been demonstrated to improve esophageal contractility.³³ Lifestyle, diet modifications, and GERD management remain the cornerstone.³⁴ Our study showed that both PPI (n = 8) and “no treatment” (n = 24) were correlated with significant decreases in the Eckardt score. This is concordant with the known association with GERD and suggests empirical PPI as a reasonable approach, particularly in the presence of typical GERD symptoms. However, objective pH-monitoring might be important in selected cases, as IEM with normal acid exposure seems more refractory to therapy.³⁵ The symptomatic long-term improvement has also been previously demonstrated, reassuring of the benignity of this diagnosis.²⁶

Lastly, management of dysphagia with normal motility studies is also challenging and mostly based on GERD and visceral hypersensitivity treatment.²⁴ However, in our cohort, patients did not significantly respond to either PPI or amitriptyline, which may be partially explained by a baseline GerdQ lower than 9 and the absence of significant chest pain complaints in the baseline Eckardt of most medicated patients. Once again, treatments were initiated in a small number of patients, which prevents drawing definitive conclusions. As in IEM, its benignity and clinical improvement over time have already been postulated.²⁶

Overall, the clinician’s evaluation using the Eckardt score broadly aligned with PRO measurement PDS score. However, there is a degree of inconsistency between both scores and their evolution over time and with different treatments, raising questions about their reliability for monitoring patients and treatment effectiveness. Previous studies have reported fair reliability of the Eckardt score in assessing dysphagia.³⁶ Incorporating PROs, including measures of holistic quality of life and psychological factors, appears to enhance this evaluation.³⁷ This may explain why improvements in the Eckardt score are not always accompanied by significant changes in patients’ experiences, as observed in our hypomotile cohort. Conversely, when myotomy was performed in patients with achalasia, a well-established treatment, improvements were observed across all evaluated scores, suggesting, in this context, a stronger alignment between clinician judgment and patient experiences.

Moreover, in general, no significant negative change was detected in the whole cohort during the 6-month follow-up, despite being managed or not, which reinforces the stability and benign nature of NOD diagnosis, enabling a balanced, comprehensive, and holistic approach.

To the best of our knowledge, this is the first prospective study aimed at evaluating real-world clinical practice in the management of patients with NOD, as well as the effectiveness of the chosen therapeutic options. Its multicentric nature provides a comprehensive and realistic perspective on community-based practice.

There are some limitations to this study, including its observational nature, small number of patients in several therapeutic options, heterogeneity between centers and subgroups, absence of a complete GERD workup, and small follow-up period. Moreover, 55 patients were excluded due to missing or inconsistent data at the 6-month evaluation. However, baseline characteristics between included and excluded patients were comparable, suggesting that this exclusion is unlikely to have significantly affected the results. To further address the potential impact of missing data, a sensitivity analysis was conducted in which missing values were imputed using mean substitution; the results remained materially unchanged. Although all efforts were made to minimize bias, the authors acknowledge the possibility of selection bias and limited generalizability to real-world clinical populations, where missing data and greater heterogeneity are more frequent. Nonetheless, the consistency of findings across approaches reinforces the robustness of the conclusions. Randomized control trials are thus needed for the study and standardization of spastic, hypomotile, and functional disorders management.

Conclusion

Nonobstructive esophageal dysphagia is a benign condition that may significantly impact the quality of life of affected patients. Apart from achalasia, which has the most effective treatment options, the management of other motility profiles should follow a comprehensive and holistic approach. PRO measurements may be used to better evaluate and guide clinical decision-making.

Supplemental Material

sj-pdf-1-tag-10.1177_17562848251345340 – Supplemental material for Real-life management of nonobstructive esophageal dysphagia: analysis of a prospective multicentric Portuguese cohort

Supplemental material, sj-pdf-1-tag-10.1177_17562848251345340 for Real-life management of nonobstructive esophageal dysphagia: analysis of a prospective multicentric Portuguese cohort by Raquel R. Mendes, José Pedro Rodrigues, Inês Simão, Helena Lima, Tiago Guedes, Sílvia Barrias, Mara Sarmento Costa, Paulo Souto, João Carlos Silva, João Correia, Bárbara Morão, Joana Revés, Carina Leal, José Dias Curto, Rui Tato Marinho and Miguel Mascarenhas Saraiva in Therapeutic Advances in Gastroenterology

Footnotes

Acknowledgements

The authors would like to thank all the colleagues and patients that made this study possible.

Declarations

ORCID iD

José Pedro Rodrigues

Supplemental material

Supplemental material for this article is available online.

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