Dramatic progress has been made over the past decade in the sophistication and availability of equipment to test esophageal motility and sensation. High-resolution esophageal manometry and impedance have moved from the research clinic into clinical practice. Some of the testing is costly and time consuming, and requires extensive experience to perform the testing and properly interpret the results. These sensory studies are valuable in the interpretation of clinical problems, and provide important research information. Clinicians should evaluate the research studies to advance their understanding of the pathophysiology of the esophagus.
Key points
- •
Dramatic progress has been made over the past decade in the sophistication and availability of equipment to test esophageal motility and sensation.
- •
High-resolution esophageal manometry and impedance have moved from the research clinic into clinical practice.
- •
Some of the testing is costly, time consuming, and requires extensive experience to perform the testing and properly interpret the results.
- •
The sensory studies are valuable in the interpretation of clinical problems, and provide important research information.
- •
Clinicians should evaluate the research studies to advance their understanding of the pathophysiology of the esophagus.
Introduction
Hippocrates noted in patients with “nausea, heartburn and salivation, there will be vomiting,” setting the stage for exploring the relationship of esophageal sensory phenomena with pathophysiology of esophageal disease. These 8 words capture the concepts of esophageal pain as an important clinical symptom, the bidirectional relationship of peripheral sensation and central nervous system response with nausea and vomiting, the complex gastrointestinal neurologic relationship of the esophagus and the stomach also causing vomiting, the relationship of esophageal sensation and sialorrhea, and the spectrum of gastroesophageal reflux from heartburn to vomiting. Rigorous clinical tests of esophageal sensation began nearly 6 decades ago with balloon distension, an exploration of referred pain locations associated with well-localized balloon placement throughout the gastrointestinal tract. The esophageal findings were simple. The location of discomfort with balloon distension is always at or proximal to the anatomic location of the balloon distension. This simple experiment provided the explanation for the clinical observation that an obstructive bolus at the gastroesophageal junction may present as discomfort from near the suprasternal notch to the gastroesophageal junction. Awareness of the importance of gastric acid as a cause of esophageal discomfort opened new vistas in drug development. To evaluate the role of acid in inducing esophageal symptoms, hydrochloric acid was infused into the esophagus to test the sensitivity of the esophagus to acid (Bernstein test). Measurement of endogenous esophageal acid exposure associated with gastroesophageal reflux with continuous esophageal pH measurements began with a bedside pH monitoring platform and evolved into ambulatory 24-hour pH recordings documenting gastric and esophageal pH with concurrent symptom recording. The amazing resolution of symptoms and esophageal erosions associated with control of gastric acid secretion and esophageal acid exposure gave birth to the hypothesis that all heartburn could be explained by acid secretion, with nonerosive esophageal reflux disease simply exposure to acid at a lower level than the acid exposure associated with erosive esophagitis. This hypothesis began to flounder with the recognition that excellent acid secretory control did not improve symptoms in many patients with nonerosive gastroesophageal reflux disease. As the drugs used to control acid secretion have achieved generic status, a new era in understanding esophageal pathophysiology has emerged with the proposal of alternative hypotheses to explain esophageal symptoms. Many of the hypotheses are based on the physiology and pathophysiology of sensation. Contemporary research in esophageal physiology and pathophysiology carries more interest, innovation, and importance than ever before. Evaluation of esophageal sensation plays an essential role in these research efforts.
Introduction
Hippocrates noted in patients with “nausea, heartburn and salivation, there will be vomiting,” setting the stage for exploring the relationship of esophageal sensory phenomena with pathophysiology of esophageal disease. These 8 words capture the concepts of esophageal pain as an important clinical symptom, the bidirectional relationship of peripheral sensation and central nervous system response with nausea and vomiting, the complex gastrointestinal neurologic relationship of the esophagus and the stomach also causing vomiting, the relationship of esophageal sensation and sialorrhea, and the spectrum of gastroesophageal reflux from heartburn to vomiting. Rigorous clinical tests of esophageal sensation began nearly 6 decades ago with balloon distension, an exploration of referred pain locations associated with well-localized balloon placement throughout the gastrointestinal tract. The esophageal findings were simple. The location of discomfort with balloon distension is always at or proximal to the anatomic location of the balloon distension. This simple experiment provided the explanation for the clinical observation that an obstructive bolus at the gastroesophageal junction may present as discomfort from near the suprasternal notch to the gastroesophageal junction. Awareness of the importance of gastric acid as a cause of esophageal discomfort opened new vistas in drug development. To evaluate the role of acid in inducing esophageal symptoms, hydrochloric acid was infused into the esophagus to test the sensitivity of the esophagus to acid (Bernstein test). Measurement of endogenous esophageal acid exposure associated with gastroesophageal reflux with continuous esophageal pH measurements began with a bedside pH monitoring platform and evolved into ambulatory 24-hour pH recordings documenting gastric and esophageal pH with concurrent symptom recording. The amazing resolution of symptoms and esophageal erosions associated with control of gastric acid secretion and esophageal acid exposure gave birth to the hypothesis that all heartburn could be explained by acid secretion, with nonerosive esophageal reflux disease simply exposure to acid at a lower level than the acid exposure associated with erosive esophagitis. This hypothesis began to flounder with the recognition that excellent acid secretory control did not improve symptoms in many patients with nonerosive gastroesophageal reflux disease. As the drugs used to control acid secretion have achieved generic status, a new era in understanding esophageal pathophysiology has emerged with the proposal of alternative hypotheses to explain esophageal symptoms. Many of the hypotheses are based on the physiology and pathophysiology of sensation. Contemporary research in esophageal physiology and pathophysiology carries more interest, innovation, and importance than ever before. Evaluation of esophageal sensation plays an essential role in these research efforts.
Neurophysiology of the esophagus
Normal and aberrant sensory function are critical neurophysiologic components of esophageal function and pathophysiology. A simple inventory of common symptoms including the discomfort from a spoonful of peanut butter that doesn’t seem to move, chest pain with a frozen drink, sialorrhea after the first sip of hot tea, the cough associated with vomiting, and symptoms of regurgitation or heartburn attests to the complexity of esophageal neurophysiology.
The required anatomic and physiologic transition from skeletal muscles controlled by somatic nerves to the smooth muscles innervated by the autonomic nervous system further emphasizes the complexity of neurophysiologic control of the esophagus.
In addition, sensory discrimination is perplexing, as intraesophageal balloon inflation occurs as either chest pain or heartburn irrespective of balloon volume or location. The quality of symptom perception may be independent of stimulus.
Esophageal sensory testing focuses on understanding the differences in sensory perception in the proximal and distal esophagus, the role of the enteric nervous system in sensory perception, the role of the physiologic stress-response system in stimulus perception, the importance of the neuroimmune axis with the associated subset of inflammatory and immunologically induced pain pathways, and the relative importance of pain amplification pathways and central processing of abnormal esophageal sensation.
Efforts to understand the important details of these concepts have generated the development of the techniques described in this section on sensory testing of the esophagus. A recent article summarizes the state of the art of neurophysiologic research in esophageal physiology.
Gastrointestinal sensitivity and gastroesophageal reflux disease
Prompt improvement of heartburn with antacid treatment suggests a direct relationship between acid in the esophagus and esophageal discomfort. Early clinical studies supported the importance of esophageal acid exposure and esophageal pain. In 1958, Bernstein and Baker perfused 0.1 N HCl into the esophagus to identify patients with acid-induced esophagitis. The provocation of heartburn with the perfusion of the esophagus with acid became the first easily available test of esophageal sensitivity. The ability to monitor esophageal pH for 24 hours while signaling a symptomatic event onto the electronic pH record was an important advancement in the testing of esophageal sensitivity. Although the percent time of esophageal acid exposure to gastric fluid with a pH lower than 4.0 helps identify patients with symptomatic heartburn amenable to inhibition of gastric acid, the lack of association between symptoms and discrete acid reflux events failed to provide a convincing relationship between symptoms to a specific reflux event. One explanation for the failure to correlate reflux events with symptoms is the observation that the more proximal the reflux event travels, the more likely a sensory stimulus will occur.
As an important corollary to the discordant pH recording and symptomatic events, the dissociation of the controlled perfusion of acid into the esophagus and the identification of abnormal esophageal acid exposure in patients with noncardiac chest pain (NCCP) challenges the paradigm that sensory perception of esophageal acid exposure is an easily interpretable event. Jung and colleagues failed to find an association between symptoms induced by spontaneous reflux during prolonged esophageal pH monitoring and symptoms as a result of esophageal acid perfusion in patients with symptomatic heartburn, suggesting that the pathways of sensitivity in spontaneous esophageal acid exposure and provocative testing arise from different stimulatory pathways.
Prolonged monitoring of reflux events with impedance monitoring provides additional insight into the movement of fluid in the esophagus. The simultaneous measurement of esophageal pH and impedance support a role for pH and volume clearance time in symptomatic reflux events. Perception of volume plays an important role in esophageal sensation in normal subjects and in disease. Unfortunately, although impedance studies can determine the proximal extent of a reflux event, the technology is not yet able to provide information about the volume of refluxant into the esophagus, making it necessary to use the proximal location of refluxant as a surrogate marker for volume.
Although there is a clear clinical relationship between esophageal acid exposure and symptoms of heartburn, the temporal association of symptoms with a reflux event is perplexing. Addressing the difficulty of the poor symptom index with documented acid reflux has led to the numerous tests of esophageal sensitivity available today, in addition to sound paradigms for multiple sensory pathways, changes in permeability of the esophageal mucosa, and models of visceral hypersensitivity associated with molecular and inflammatory pathways. The discussion of esophageal sensitivity always begins with gastroesophageal reflux disease (GERD).
Independent of the evaluation of reflux events, extensive research focusing on molecular aspects of pain-induction pathways (the acid receptor TRPV1 and adenosine triphosphate, and the purine and pyrimidine receptor subfamilies P1, P2X, and P2Y) provides new information about esophageal sensitivity, and should lead to the development of new drugs for the management of esophageal pain.
Esophageal sensitivity testing
Esophageal Manometry and 24-Hour Esophageal pH/Impedance
The important details of esophageal manometry and 24-hour pH/impedance are presented elsewhere in this issue. The assessment of esophageal sensitivity depends on these tests to provide important information about esophageal motor function and the exposure of the esophageal lumen to gastric contents.
Provocative Esophageal Perfusion Testing
The Bernstein esophageal acid perfusion test has a long history, recently fraught with controversy. The authors use a modified Bernstein test with a 5-minute saline infusion followed by 10 minutes of acid infusion. The initial sensation, discomfort, and pain thresholds are identified separately, and descriptors of the sensation are recorded in the patient’s words. For a test to be positive, “typical symptoms” (symptoms for which the patient is being evaluated) need to be voiced, and the intensity of discomfort is recorded. The initial placebo control infusion period may be positive for typical symptoms, which may be due to sensitivity of the slightly acidic pH of unbuffered saline or sensitivity to fluid at room temperature. When the acid is perfused, the 3 thresholds of sensation are identified and the accompanying symptoms recorded. The authors use acid perfusion as an index of chemical sensitivity. As expected, most of the reported symptoms revolve around a description related to acid heartburn; however, approximately 16% of subjects report the symptom associated with acid infusion as “pressure,” the symptom associated with balloon distension with testing or esophageal motor dysfunction by clinical history. Although the clinical value of provocative clinical testing may be an issue in the clinical assessment of GERD, chemical testing is a necessary part of the sensory assessment of esophageal function.
Of all of the esophageal perfusion provocative tests the authors have explored, the comparison of chenodeoxycholic acid and ursodeoxycholic acid has been the most interesting. Using a complex infusion protocol, asymptomatic controls and patients with functional heartburn were given provocative esophageal sensory testing with 0.1 N HCl, 2 mM solutions of both ultrapure chenodeoxycholic and ursodeoxycholic acid (provided by Axcan Pharmaceuticals, Montreal, QC, Canada). If there was no reported pain after 15 minutes of esophageal perfusion of the bile acid (10 mL/min), the concentration of bile acid was increased to 5 mM for a maximum of 15 more minutes. Relative sensitivity to pain was greater with 0.1 N hydrochloric acid than with chenodeoxycholic acid, which was greater than with ursodeoxycholic acid. The difficulty in obtaining ultrapure bile acids prohibits utilization of esophageal perfusion of bile acids as a routine clinical test. This provocative sensory testing contributes the following to the understanding of esophageal sensation: (1) perfusion of the esophagus with the most prevalent bile acid (chenodeoxycholic acid) in lower concentration (2 mM) than is often found in the stomach of patients with enterogastric reflux (4 mM) causes heartburn symptoms; (2) different bile acids have different thresholds for provoking pain, with chenodeoxycholic acid more potent than ursodeoxycholic acid; and (3) using ursodeoxycholic acid to decrease chenodeoxycholic acid concentration in the bile acid pool may provide a therapeutic pathway for patients with bile reflux esophageal symptoms. The use of esophageal perfusion with specific chemical substances to test chemically activated sensory pathways should be considered in investigative studies exploring the pathophysiology of pain, and there may be limited value for specific clinical problems.
As a variant of provocative esophageal perfusion testing, the authors administered capsules containing capsaicin to patients with heartburn to test esophageal sensitivity to capsaicin before a standard reflux-inducing meal. Directed delivery of capsaicin to the stomach assured that any symptoms induced by capsaicin would be related to gastroesophageal reflux and not oropharyngeal or esophageal symptoms arising from contact with capsaicin during swallowing. No change in the intensity of the symptoms occurred, but there was a dramatic shift in the time to heartburn, suggesting a sensitizing effect of the capsaicin. This clinical study was conducted around the time that transient receptor vanilloid potential (TRVP1) was recognized as a receptor for capsaicin, providing clinical relevance for the observation in animal studies that TRPV1 induced sensitization of the esophagus to gastroesophageal reflux of acid.
The provocative chemical sensory testing discussed thus far has focused on sensory stimulatory pathways to classes of compounds. Specific food stimulation may also be used for exploring changes in esophageal physiology in individual patients. The authors evaluated a patient with pheasant-induced dysphagia who presented with severe chest pain and dysphagia every autumn for several years. Esophageal biopsies demonstrated high numbers of eosinophils. The history suggested that the symptoms were related to a pheasant rice casserole. Esophageal motility and barium swallow studies were performed with the casserole prepared with and without the pheasant, documenting the occurrence of clinical symptoms and motility changes related to the pheasant component of the casserole. At the time of this provocative testing, eosinophilic esophagitis had not emerged as an important esophageal disease. As eosinophilic esophagitis has become better understood, there is no need for specific food testing in the presence of increased esophageal eosinophils. This innovative provocative test demonstrates the feasibility of specific testing for dietary sensory or immune-associated symptoms.
Noncardiac Chest Pain Provocative Testing
NCCP refers to symptomatic chest pain, which has been evaluated and for which a cardiac cause has been excluded. The second tier of evaluation explores esophageal pain as the cause of the chest pain. In a recent large multicenter study, 70% of the patients with NCCP had normal esophageal manometry. Richter and colleagues compared the acid perfusion test with 24-hour esophageal pH monitoring, and found pH monitoring to be a superior diagnostic test for identification of an acid-sensitive esophagus in NCCP patients.
Some patients with chest pain of esophageal origin may be identified only by provocative testing during esophageal manometry. Edrophonium is an anticholinesterase with a short half-life and onset of action within 60 seconds. London and colleagues showed that the administration of ergonovine or edrophonium provoked typical chest pain in association with high amplitude, long duration, and repetitive esophageal contractions in all patients. However, none of the controls in their study reported chest pain in response to ergonovine or edrophonium. The test can be performed by injecting either 80 mg/kg or 10 mg/kg followed by 5 to 10 swallows of 5 to 10 mL of water over 5 to 10 minutes. The routine use of provocative testing for chest pain in clinical practice is limited by the fact that these drugs can induce coronary spasms, and are associated with other side effects related to excessive cholinergic stimulation such as increased salivation and abdominal cramps.
Techniques such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), magnetoencephalography, and electroencephalography have led to the identification of a network of brain areas that processes visceral sensation. These studies have improved understanding of the pathophysiology of NCCP, and are discussed in more detail later.
Provocative Barostat Balloon Testing
Balloon distension testing of sensation in the gastrointestinal tract has been used for decades to investigate the physiology and pathophysiology of the gastrointestinal tract. Latex balloons and hand-held syringes were used until the advent of the electronic barostat. Latex balloons were chosen because of the low profile when deflated, the low cost (condoms), and the tolerance of latex to very large volumes of distension. When intraballoon pressure became an important experimental end point of esophageal balloon distension, the hysteresis and nonlinear elasticity of the latex became a disadvantage as the intrinsic pressure of the inflated latex balloon at each distension volume needed to be subtracted from the measured pressure, and pressure profiles of the balloon could change with each inflation, making accurate pressure readings impossible. Because the pressure curves of pressure against volume (compliance) are not linear, calculations and interpretations of data acquired with latex balloon distension were difficult. This difficulty led to the inflation of an infinitely compliant balloon with no intrinsic wall pressure using an electronically controlled barostat. The barostat controls balloon pressure and simultaneously measures balloon volume. Although the barostat has become the instrument of choice for luminal pressure and distension studies, diagnostic protocols and standard values are not widely available. Another serious issue unique to esophageal balloon placement concerns keeping the esophageal balloon in a designated location in the esophagus. The ellipsoid latex balloon is pulled toward the stomach with strong longitudinal force, often entering into the stomach, which complicates interpretation of the data. Approximately 10 years ago the authors developed a cylindrical, infinitely compliant balloon with a slippery synthetic surface ( Fig. 1 ) that allows the balloon to stay in place in the esophagus with little longitudinal force. The current research trend is to use intraballoon pressure (mm Hg), rather than balloon volume (milliliters of air), as the quantitative measure to assess sensitivity. Barlow and colleagues investigated esophageal distension with manometry and impedance planimetry to demonstrate that stretch and not tension activated the sense of distension in normal subjects. In the assessment of patients with visceral hypersensitivity, the authors can demonstrate sensitivity to both pressure and volume, often independently, suggesting multiple sensory distortion pathways for abnormalities of visceral sensation. Because the authors have postulated that stretch (volume in milliliters) and pressure (mm Hg) receptors may have variable sensitivity, their data are reported with both volume and pressure. Three symptom end points are assessed: first sensation, discomfort, and pain. In the authors’ clinical practice and research studies, the balloon is placed above the lower esophageal sphincter and below the upper esophageal sphincter for 2 separate inflation studies to assess the differences in proximal and distal sensory function.
