A narrative review of functional dysphagia—what we know so far

Introduction

Background

Functional dysphagia (FD) is a condition characterized by a sensation of food sticking in the esophagus, without the presence of obstructive, mucosal, motor, or acid-related abnormalities (1). It is a disorder of gut-brain interaction (DGBI) and is estimated to be the least prevalent of all functional gastrointestinal disorders (2-4). Nonetheless, the associated symptoms can be debilitating and severely impact quality of life, putting a substantial burden on the health care system (3,5,6).

Dysphagia is defined as the subjective sensation of abnormalities in swallowing, typically characterized by the feeling of food or liquids getting stuck during the oropharyngeal or esophageal phase of deglutition. Dysphagia is prevalent in the general population, estimated to affect over 50% of people over 60 years of age (7). It is the tenth leading cause of ambulatory care visits in the U.S. for gastrointestinal symptoms and has a reported international prevalence of 2% to 20% (8-10). Besides organic pathologies that can lead to dysphagia, a small subset of patients have no identifiable abnormality and are thus classified as having FD. While the pathophysiology of FD is not well understood, multiple mechanisms have been proposed, including localized hormonal dysregulation, subtle and undetectable motility abnormalities, and peripheral neuronal over-activation and central sensitization (11-23).

Rationale and knowledge gap

FD is likely underdiagnosed, likely in part due to lack of sufficient provider awareness. Even when properly diagnosed, management strategies are based on data extrapolated from the management of other DGBI. To our knowledge, there are no published review articles specifically summarizing our current understanding of FD, and there are no robust trials examining the efficacy of our currently utilized treatment strategies for this patient population.

Objective

The objective of this narrative review is to provide a comprehensive overview of the clinical presentation, diagnostic approaches, and therapeutic strategies currently employed in the management of FD. We hope that doing so will highlight the need for further research specific to FD. We present this article in accordance with the Narrative Review reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-40/rc).

Methods

We performed a literature search using PubMed, Google Scholar, and Medline databases. The keywords used were “functional dysphagia”, “functional esophageal dysphagia”, “functional oesophageal dysphagia”, “disorders of gut brain interaction”, and “functional gastrointestinal disorders”. Studies published in English were included. No date range filters were utilized (Table 1). Studies from reputable centers, guidelines, and studies published in prominent journals were prioritized.

Main body

Epidemiology

The prevalence of FD is largely unknown, likely due to the relative lack of studies on the topic and resource-intensive diagnostic algorithms. However, a large multinational internet and householder survey study completed by the Rome Foundation estimated the prevalence to be 1% to 3% (3). In another US population study, the prevalence was estimated to be 5% (24). However, the true prevalence of FD may be underestimated, as some evidence suggests that more than 50% of cases go unreported and undiagnosed (4). The prevalence of all functional esophageal disorders, including FD, seems to be higher among women, which is consistent with previous reports of female predominance in other DGBIs (25,26). Prevalence seems to peak in middle age. Similar to other DGBIs, patients with FD seem to have a higher rate of psychiatric comorbidities and sleep disturbances than the general population, particularly women (25). Patients with DGBIs (including FD) tend to have more gastrointestinal-related health care visits, surgical interventions, medication use, and nonsurgical interventions, resulting in decreased overall quality of life (27).

Presentation and diagnosis

FD is defined as a sensation of abnormal bolus transit through the esophageal body in the absence of structural, mucosal, or motor abnormalities to explain the symptom. Diagnosis of FD requires exclusion of oropharyngeal abnormalities, structural lesions, gastroesophageal reflux disease (GERD), eosinophilic esophagitis (EoE), and major motor disorders. Diagnosing FD can be challenging due to nonspecific symptoms and unfamiliarity among physicians. While invasive testing and imaging studies are required for diagnosis, we propose an algorithm with a cost-effective approach (Figure 1).

Figure 1 Diagnostic algorithm for functional dysphagia. VFSS positive causes are not a comprehensive list. These instead represent the most common causes of VFSS positive oropharyngeal dysphagia. VFSS, videofluoroscopic swallow study; EGD, esophagogastroduodenoscopy; ALS, amyotrophic lateral sclerosis; EndoFLIP, endoluminal functional lumen imaging probe; PPI, proton pump inhibitor; GERD, gastroesophageal reflux disease.

The first step is a careful history with the specific goal of ruling out drug-induced dysphagia (Table 2) and oropharyngeal dysphagia, which is often characterized by nasal regurgitation, coughing or choking on swallow initiation, and aspiration (28). Four questions have been shown to discriminate between oropharyngeal and esophageal dysphagia with 80% sensitivity: (I) Is there a delay in initiating the swallow? (II) Is there deglutitive postnasal regurgitation? (III) Is there deglutitive coughing? (IV) Is repetitive swallowing needed to achieve satisfactory clearance (29)? An affirmative answer to any of these questions is indicative of oropharyngeal dysphagia (29). In contrast, esophageal dysphagia is characterized by a sensation of food sticking in the middle chest or chest discomfort shortly after swallowing. When esophageal dysphagia is suspected, an upper endoscopy with biopsies of the middle and lower esophagus should be obtained to rule out GERD and EoE. Barium esophagram should be performed to rule out structural lesions (e.g., strictures, rings, webs) and preliminarily evaluate for esophageal motility disorders (e.g., achalasia, esophageal spasm, esophagogastric junction outflow obstruction). Finally, high-resolution esophageal manometry (HRM) should be obtained to evaluate for more subtle motility disorders. If all testing is negative, and the Rome IV criteria are met (Table 3) (1), a diagnosis of FD can be made.

Although this generally accepted diagnostic algorithm has improved the reliable identification of esophageal motility disorders, which must be ruled out prior to the diagnosis of FD, it is important to mention its limitations. For example, standard barium esophagram and HRM protocols typically utilize liquid swallows only (30,31). There is much debate in the literature on whether the addition of solid bolus assessment to current liquid-only protocols may aid in the detection of subtle motility disorders which are otherwise being overlooked, resulting in a larger proportion of patients being characterized as having functional spectrum disorders (32,33). Unfortunately, solid bolus swallows create complex pressure patterns on HRM making interpretation difficult; there is also no universally accepted normative data available for solid swallows on HRM or for the solid component of timed barium swallows, hindering clinical application (31,34). Development of ambulatory HRM equipment or catheter-free technologies may 1 day result in improved symptom-association measures or normative data sets but for now, solid bolus swallows are not utilized in every day practice (35).

Newer modalities such as endoscopic functional luminal imaging probe and high-frequency ultrasound can also demonstrate subtle motility abnormalities, such as abnormal esophageal distensibility and lack of coordination between circular and longitudinal muscle contraction. However, these technologies are not currently used in the routine evaluation of dysphagia at the moment (7,36,37).

Pathophysiology

While the pathophysiology of FD is not well understood, multiple theories have been proposed. Much of the existing evidence is derived from studies on GERD and extrapolated to FD.

Central sensitization and hypervigilance

The past five decades have brought considerable advancements in the conceptualization of DGBIs, including FD. Central sensitization is a concept first introduced in the early 2000s in the context of irritable bowel syndrome, but has been proposed as a unifying theory among all DGBIs (38). Likely due to the complex neurophysiology involved in the swallowing reflex, this mechanism has not been further investigated in the specific context of FD but has been alluded to as a likely cause (39). As stated above, much of the data on this population are extrapolated from studies on GERD.

Wong et al. (40) observed that the experience of reflux symptoms in patients with GERD is inconsistently correlated with reflux events. Both peripheral and central mechanisms, such as psychological comorbidities and neurotransmitter systems, contribute to the patient’s experience of symptom severity (41,42). Furthermore, while symptoms in the esophagus can be related to underlying inflammatory states or motor dysfunction, there is often a discrepancy between experienced symptom severity and degree of measurable abnormality, suggesting the involvement of other processes in symptom experience, such as neuronal input and processing abnormalities (40).

Sensation in the esophagus is a complex process mediated by both peripheral and central neurologic mechanisms. Peripheral sensory inputs can sensitize the esophagus to noxious stimuli, while factors such as enhanced synaptic transmission can lead to central sensitization (43). Negative mood or increased emotional arousal can further exacerbate symptom severity and lead to fear-based responses to less severe symptoms. Patients with DGBIs, including FD, report histories of psychological trauma more often than patients with organic gastrointestinal diseases (44). Traumatic events, ranging from previous choking episodes to post-traumatic stress disorder, can trigger the onset of psychiatric conditions known to increase sensitivity to pain as well as directly affect the corticolimbic pain system (45). The current belief is that the up-regulation of peripheral sensory inputs and loss of the ability to centrally down-regulate these inputs (aka, central sensitization) leads to maladjusted sensation and the interpretation of normal inputs as painful (46). This can result in selective attention to future esophageal sensations, increased anxiety related to the expectation of painful episodes, and catastrophic thinking about the consequences, which collectively define esophageal hypervigilance (12,22). Other stressful situations, such as sleep disturbances and anxiety-provoking situations may cause similar changes. Studies on patients with other pain syndromes, such as functional chest pain, have shown that this patient population has increased sensitivity (i.e., higher degrees of discomfort) to balloon dilation of the esophagus (47). In other words, these patients experience the same degree of physiologic or pathologic alteration to a higher degree than their functional disorder-negative counterparts, therefore interpreting normal mechanical alterations of the esophagus as pain. The specific neurons and brain areas involved have not yet been elucidated.

Hormones

The function of the gastrointestinal tract is regulated by both intrinsic and extrinsic neural pathways. Intrinsic neural plexuses provide a certain level of autonomy over gastrointestinal functions, while the central nervous system provides extrinsic inputs that modulate and control these functions. The intestines can function largely without extrinsic input, but the esophagus and stomach are more reliant on input from sympathetic and parasympathetic pathways.

Sympathetic pathways primarily inhibit muscle and mucosal secretion while causing neurally mediated vasoconstriction (11,48). On the other hand, the peripheral nervous system exerts both excitatory and inhibitory control over gastric and intestinal tone and motility (11). Although the autonomic nervous system was previously thought to be solely responsible for regulating gastrointestinal functions, recent research has shown that higher central nervous system centers can also influence homeostatic control and cognitive and behavioral functions (11).

Furthermore, specific hormones including norepinephrine, epinephrine, dopamine, and serotonin exert regulatory influence over blood flow, motility, nutrient absorption, the innate immune system of the gastrointestinal tract, and the composition of the microbiome (13). In conditions such as inflammatory bowel disease and Parkinson disease, dysregulation of these hormones can result in a variety of gastrointestinal symptoms. Exogenous modulation of catecholamine serum concentrations has demonstrated potential for reducing symptoms or mitigating disease progression in these conditions. Although no studies to date have specifically examined hormonal abnormalities in patients with FD, it is plausible that they play an important role in the development of sensitization and hypervigilance in both the central and peripheral nervous systems.

Motility

Swallowing induces a peristaltic wave involving sequential inhibition and distension followed by contraction of the esophageal muscles that travels from the superior to inferior portion of the esophagus, pushing the food bolus into the stomach. High-resolution manometry and the Chicago classification only assess the contraction phase. Mittal et al. compared the distension-contraction profile of patients with FD and control individuals using high-resolution manometry impedance recordings, finding that although there was no difference in high-resolution manometry between a healthy individual and a patient with FD, the amplitude of luminal distension was smaller, peak distension occurred earlier, and the distension waveform was irregular and fragmented in patients with FD (14). Other studies have demonstrated similar results; there seems to be a higher nadir impedance value (i.e., lower luminal cross-sectional area) and alteration in the temporal relationship between distension and contraction (15-21). A lower luminal cross-sectional area during bolus transport implies that the esophagus is narrower during swallowing. This contraction wave through a narrow esophagus suggests reduced distensibility of the esophageal lumen. It is speculated that although the contraction wave (as measured by HRM) is normal in FD patients, it is the contraction wave pushing bolus through a narrow and less distensible lumen that causes the symptoms of dysphagia in this patient population (17). However, controversy exists related to this conclusion as multiple studies have shown limited correlation between esophageal distensibility scores and symptoms of dysphagia (14-16,23,49,50).

Management

There is currently no curative treatment for FD, and no randomized controlled trials have been completed in this patient population. Management is mainly supportive and involves a multifaceted approach with a multidisciplinary team of providers. While some recent advancements have been achieved, the fundamental principles in managing FD involve minimizing extraneous factors that contribute to central nervous system overactivation, providing reassurance, implementing lifestyle modifications, and using neuromodulators. Typically, an optimal approach entails a stepwise progression with regular follow-up under the guidance of the patient’s primary healthcare provider.

Cognitive behavioral therapy (CBT)

The rationale for the use of CBT in patients with FD is based on numerous retrospective studies demonstrating an association between stressful life events and DGBIs, an increased frequency of comorbid psychiatric conditions in patients with DGBIs, and randomized controlled trials showing symptom improvement following psychological treatments (51-53). Over 30 randomized controlled trials have assessed CBT in DGBIs, although the vast majority are in patients with irritable bowel syndrome, and none have been completed in patients with FD (53). Case reports and case series do exist, which mirror the beneficial effects seen in randomized controlled trials in other DGBIs (54,55). A full CBT treatment typically involves 6 to 12 sessions consisting of psychoeducation, relaxation skills training, diaphragmatic breathing, and behavior modification (56). The overarching theme is providing reassurance by explaining to patients that there is no structural abnormality or pathologic processes to cause harm to their esophagus, and redirecting their care to focus on development of protective habits to minimize negative thoughts, stressors, and irrational beliefs. To be truly beneficial, CBT courses should be flexible to meet the needs of each individual patient (49,56,57).

Pharmacotherapy

No pharmacologic therapies have been specifically evaluated for use in FD. In general, clinicians have extrapolated from studies examining the use of medications in other DGBIs, particularly irritable bowel syndrome. Tricyclic antidepressants, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, trazodone, and gabapentin have been utilized in practice due to their ability to modulate peripheral and central hyperalgesia (58). In a large, double-blind, multicenter randomized controlled trial, desipramine was found to have approximately 20% symptom reduction when compared to placebo in patients with severe functional gastrointestinal disorder, although the study had concerns for selection bias due to a high rate of loss to follow-up (59). A recent systematic review and meta-analysis demonstrated that both tricyclic antidepressants and serotonin reuptake inhibitors have positive impacts on pain reduction, with favorable numbers needed to treat (58,60). The use of serotonin noradrenergic reuptake inhibitors is based on studies of their analgesic properties in neuropathic pain disorders, particularly fibromyalgia and diabetes (61). A small but well-designed double-blind, placebo-controlled trial showed that trazodone helped abate symptoms in patients with esophageal contraction abnormalities (62). Gabapentin has been shown to reduce symptom severity scores in patients with refractory functional dyspepsia (63). Although utilized in the clinical management of FD, further research is needed to validate efficacy of these medications in this population.

Empiric dilation and noninvasive neuromodulation

In a prospective randomized trial, patients with nonobstructive dysphagia were empirically dilated with either a 50- or 26-Fr Maloney dilator (64). The study showed that symptom severity scores were similar in dilated vs. nondilated patients, but those who had dilation had significant improvement in diet scores (greater variety of foods were tolerated without dysphagia). At 2-year follow-up, 80% of patients who underwent the larger dilation had sustained improvement. A large drawback of this study, however, is that patients had not undergone esophageal endoscopy with biopsies to rule out EoE prior to enrollment (64).

Another retrospective review of 107 patients with nonobstructive dysphagia who underwent empirical esophageal dilation found no statistical difference in symptom outcomes between those who received polyvinyl bougie dilation with adjunctive medical treatment vs. those who received medical treatment alone (65). By expert opinion, some patients may benefit from empiric dilation due to presence of subtle anatomic abnormalities, such as strictures, that are not identified during work-up (65). More recently, noninvasive brain modulation using repetitive transcranial magnetic stimulation (rTMS) has been evaluated in a single patient with postintervention symptom improvement; however, this result did not reach statistical significance (66). While this may represent an area of future exploration, given lack of statistical significance and small study size, this cannot yet be generalized to FD patients. It is important to note that trials involving empiric dilation have not been completed specifically in the FD population, and nonobstructive dysphagia may or may not overlap with FD. More research is needed to assess the efficacy of these potential treatment modalities.

Summary

This narrative review of the literature provides a much needed overview of the current state of the field with regards to FD. We reviewed the literature on diagnostic strategies, current theories with regards to pathophysiologic underpinnings of the disease, current management paradigms, and possible future directions. Through our review, we hope it is apparent that there is a great need for high-quality, well-powered studies specific to the FD population.

Conclusions

FD is an underdiagnosed and difficult-to-treat condition that negatively impacts the lives of those affected. Its pathophysiology is not fully understood but is thought to involve peripheral sensory overstimulation, central sensory under-modulation, and potential motor dysfunction, contributing to the complex clinical presentation. FD is a diagnosis of exclusion, requiring clinicians to rule out organic abnormalities, such as oropharyngeal dysphagia, GERD, EoE, esophageal obstruction, and motility disorders. Management involves the establishment of a strong patient-provider relationship and a multifaceted approach including psychological therapies and medications directed at modulation of hyperalgesia. Research specific to this patient population is limited, and much of what directs clinical practice is extrapolated from similar DGBIs.

Acknowledgments

The Scientific Publications staff at Mayo Clinic provided copyediting, proofreading, administrative, and clerical support.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-40/rc

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-40/prf

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