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Clinical and Translational Aspects of Normal and Abnormal Motility in the Esophagus, Small Intestine and Colon
22.1
Introduction
Motility is the process of moving luminal contents through the gastrointestinal (GI) tract. However, motility encompasses many complex processes and is influenced by many internal and external factors. While there is intrinsic or enteric nervous system, motility is also influenced by the central nervous system and the sympathetic and parasympathetic nervous systems, by the hormonal milieu by receptors throughout the GI tract, by luminal contents and by the microbiome of the GI tract. In health, this complex integrated system works seamlessly to transport liquid, solid, and gaseous contents through the GI tract sampling the contents and adjusting transport accordingly by speeding, slowing or stopping the flow and by increasing or decreasing pressure within the sphincters. However, these complex integrated systems are subject to acute and chronic pathophysiologic changes that can lead to short- and/or long-term dysfunction.
Various aspects of the physiology and pathophysiology of motility within the luminal GI tract can be investigated. At a molecular level, one can look at the receptors and the GI hormones on the muscles and nerves within the luminal GI tract. At a cellular level, one can look at the smooth and skeletal muscle cells and the neural cells and ganglia within the GI tract. At a histological level, one can evaluate the muscle that makes up the circular, longitudinal smooth muscle (LSM) and the muscularis propria (MP) within the wall of the GI tract. At an organ level, one can look at the coordination of the muscle layers as they contract to propel luminal contents through the GI tract and at the innervation of each of the organs by the sympathetic and parasympathetic nervous system. Finally, at a systems level, one can determine how each organ “talks” with the other organs within and outside of the GI tract, through hormones, nerves, and the passage of luminal contents. This chapter delves into the clinical methods and techniques that are used to interrogate the luminal GI tract to investigate the normal physiology and the pathophysiology of functional motility disorders.
Rapid advances in technology have allowed the development of cutting edge diagnostic methods that can be applied to patients with functional motility disorders of the GI tract. These technologies and methods allow the clinician to investigate various aspects of motility. For example, manometry allows for luminal pressure measurements, endoluminal ultrasound and endoscopy allows for investigation of anatomy related to motility, the smart pill and nuclear tracers allow for the measurement of movement of luminal contents while breath tests and cultures tell us about the microbiome within the lumen. pH probes allow us to measure acidity within the lumen. Biopsies give us insight into the histology and pathophysiology at a histologic level. Similarly, with the advances in our understanding of the physiology and pathophysiology of motility and the rapid progress in technology, we have been able to develop and tailor therapies directed at the underlying pathophysiologic abnormalities. In this chapter, we will discuss recent diagnostic tests and cutting edge therapeutic advances aimed at diagnosing and treating functional motility disorders within the luminal GI tract of the esophagus, small intestine, and colon. The stomach will be discussed in another section.
22.2
Esophageal Motility
22.2.1
Normal Anatomy and Physiology of the Distal Esophageal High-Pressure Zone
22.2.1.1
Introduction
Considering the simple task of transporting food and liquid from the mouth to the stomach, the anatomy and physiology of the esophagus may seem overly complicated. However, the esophagus actually performs a number of different tasks simultaneously: the regulation of esophageal emptying into the stomach, permitting air venting and wanted regurgitation from the stomach, and the protection against unwanted reflux of gastric content. These tasks must be carried out in a coordinated and efficient manner to prevent dysphagia, regurgitation, chest pain, gastroesophageal reflux disease (GERD), and odynophagia. The tonic contributions of the muscles within the gastroesophageal high-pressure zone (HPZ) protect the esophagus from reflux of gastric contents, while the relative loss of tone during transient sphincteric relaxations can lead to reflux of gastric contents into the esophagus.
The coordination of the circular and longitudinal skeletal and smooth muscle within the esophagus and the neural coordination of muscle contraction and relaxation underlie esophageal peristalsis. Recent studies have demonstrated a coordination and complexity to both the peristaltic contraction and the gastroesophageal junction HPZ that was previously unrecognized. This information, which will be examined in this chapter, has been obtained using new technologies to study the anatomy and physiology of the esophagus including high-resolution manometry (HRM), high-resolution ultrasound (HRU), artificial HPZs created by balloons, functional luminal imaging probe (FLIP), and a combination of HRM and HRU used simultaneously.
22.2.1.2
The High-Pressure Zone of the Distal Esophagus (The Muscular Components of the Distal Esophageal High-Pressure Zone Antireflux Barrier)
The HPZ, antireflux barrier, is classically thought of as consisting of circular muscle within the lower esophagus, which was termed the lower esophageal sphincter (LES). However, for the HPZ to carry out its many functions it takes coordination between various muscle groups, enteric neurons, and receptors within the HPZ and stomach, and coordination with the esophagus orad to the HPZ. Code et al. were the first to report an intraluminal HPZ in the segment separating the esophageal body from the gastric cardia and suggested that intrinsic smooth muscles of the distal esophagus were responsible for maintaining a high-pressure barrier to reflux. Soon thereafter Ingelfinger argued that crural diaphragmatic contraction was also important to the antireflux barrier. There is now general agreement on an extrinsic sphincter component arising from the skeletal muscles of the right crus of the diaphragm that wraps around the abdominal esophagus and which is attached to the inferior surface of the costal diaphragm above, and to the vertebral column below Liebermann-Meffert et al. measured a thickened wall of smooth muscle at the junction that coincides with the gastric sling-clasp muscle groups. “Sling” fibers surround the junction of the esophagus on the greater curvature side of the gastric cardia. Opposing these are “clasp” circular muscle fibers on the lesser curvature junction. Stein et al. argued for an anatomical smooth-muscle sphincter defined by the sling-clasp muscle groups at the locally thickened esophago-cardiac junction.
Brasseur et al. were able to separate and quantify the skeletal and smooth muscle HPZ components and clarify the description of the HPZ antireflux barrier in vivo using pharmacologic manipulation combined with simultaneous endoluminal ultrasound and manometry. The smooth muscle pressures had well-defined upper and lower peaks. The upper peak overlapped and moved rigidly with the crural sling during respiration, while the distal peak separated from the crus/upper-peak by 1.1 cm between full inspiration and full expiration. These results suggest the existence of separate upper and lower intrinsic smooth-muscle components innervated by muscarinic receptors. The upper component, the lower esophageal circular sphincter (LECS) overlaps and moves with the crural diaphragm. The distal smooth-muscle pressure peak reflects the gastric sling/clasp muscle fibers within the cardia of the stomach (the upper gastric sphincter). The distinct anatomy and physiology of these three components underlie aspects of normal sphincter function (see Fig. 22.1 ).
22.2.1.3
Mucosal Contraction During Swallowing as an Antireflux Barrier
There are four separate muscles within the HPZ antireflux barrier (LECS, Clasp, Sling, Crural Diaphragm). Vegesna et al. demonstrated a fifth previously unrecognized muscular component that contributes to the antireflux barrier, the muscularis mucosa. The movement of the MMS at the gastroesophageal junction was evaluated during swallowing in non-GERD subjects. It was found that the gastric MMS moved rostrally into the distal esophagus during swallowing significantly earlier and to a greater distance than MP. The muscularis mucosa was seen to pull the mucosa and submucosa from the gastric cardia up into the distal esophagus, forming a mucosal plug that temporarily blocked the distal esophagus during swallowing and prevented reflux of gastric contents. This is exactly the period of time during the swallow in which the sphincter components of the distal esophagus relax and there is no HPZ antireflux barrier. Given the fact that the pressure within the chest cavity may be negative when compared to the pressure within the abdominal cavity during swallowing, there would be free reflux of gastric contents into the esophagus if there were no barrier formed by this mucosal plug.
22.2.1.4
Contraction of the Muscular Components of the Gastroesophageal High-Pressure Zone in Normal Humans
The sphincter muscles are under very fine tuned regulatory control. Considering the importance of these muscles in controlling passage of food and in gas venting it is very important that contraction and relaxation be well coordinated. Contraction of the muscular components of the gastroesophageal high-pressure zone (GEJHPZ) is controlled mostly through the stimulation of muscarinic receptors on the smooth muscle. Contraction through muscarinic stimulation is greater in the gastric sling and the LECS fibers than in the gastric clasp fibers. M 2 receptor density is greatest in the gastric sling followed by gastric clasp and LECS. M 3 receptor density is greatest in the LECS followed by gastric sling and then gastric clasp. Despite the dominant role of muscarinic stimulation in the contraction of the GEJHPZ, there are numerous other receptors and chemical mediators involved. CCK8 and gastrin-17 also cause contraction of the smooth muscle with gastric sling contracting more than gastric clasp. CCK-A receptors are more important for the generation of contraction in gastric sling muscle whereas both CCK-A and CCK-B receptors are involved in the functional regulation of the gastric clasp muscle. Dopamine at high concentrations, through D 1 , D 2 , and D 5 receptors, causes contraction of the gastric sling muscle. Dopamine at low concentration causes no contraction of the clasp fibers but cause a slow contraction with an increase in concentration through the D 1 , D 2 , and D 5 receptors. Tachykinins contract the LECS. Substance P, neurokinin A, and neurokinin B produced a concentration-dependent contractile response. The contractile effects of the tachykinins are mediated by NK2 receptor stimulation. A phosphoramidon-sensitive mechanism plays a role in the regulation of the response to substance P.
22.2.1.5
Relaxation of the Muscular Components of the GEJHPZ in Normal Humans
Relaxation of the muscular components of the GEJHPZ is more complex than contraction. Nicotine causes relaxation of gastric clasp, gastric sling, and LECS muscle indirectly, by activation of nicotinic receptors on enteric nerves that induces release of multiple relaxing substances. These relaxing substances include NO in gastric clasp, gastric sling, and LECS fibers, norepinephrine acting on β-adrenoceptors in gastric clasp fibers, and GABA acting on GABA A receptors in gastric sling fibers. In gastric sling fibers, activation of both β-adrenoceptors and GABA A receptors is required to relax bethanechol precontracted muscle, whereas in gastric clasp fibers, activation of β-adrenoceptors alone causes relaxation but activation of GABA A receptors alone does not. The location of the nicotinic receptors on the enteric nerves mediating the relaxations in gastric sling and LECS fibers is likely at or near the neuromuscular junction. In gastric clasp fiber enteric nerves, the nicotinic receptors are most likely located on the soma or along the axons but not near the neuromuscular junction because TTX sensitive, sodium channel-mediated action potentials are required for relaxation. VIP mediates relaxation in the gastric clasp and purines also mediate relaxation through the P2Y1 receptors in gastric clasp. In general, the sling fibers appear to have a major role with contraction, while the clasp fibers appear to have a major role with relaxation.
22.2.2
Peristaltic Contraction
With swallowing, the peristaltic wave produces a lumen-occluding contraction of the esophageal circular muscle. With respect to peristaltic contraction, nitric oxide is the predominant inhibitory neurotransmitter, whereas acetylcholine, acting on muscarinic receptors, is the predominant excitatory neurotransmitter. Sifrim et al. demonstrated that a wave of inhibition precedes primary peristaltic contractions in the human esophagus. To study deglutitive inhibition in humans, an artificial HPZ was created by inflating an intraesophageal balloon to a critical level. The pressure changes at the interface between the balloon and the esophageal wall at various levels along the esophagus were measured. In this artificial HPZ, deglutition induced a relaxation beginning simultaneously at various levels of the esophagus but lasted progressively longer in progressively more distal segments.
22.2.2.1
The Role of the Longitudinal Smooth Muscle
The role of the circular smooth muscle (CSM) seems clear in that the circular muscle tone generates radial closure pressure to create a local peristaltic closure wave. However, the role of the LSM is less obvious. Nicosia et al. analyzed local longitudinal shortening (LLS) by combining concurrent ultrasonography and manometry with basic principles of muscle mechanics. Two clear phases of LLS were observed during bolus transport. During luminal filling by bolus fluid, the muscle layer distends and the muscle thickness decreases in the absence of circular or longitudinal muscle contraction. This is followed by local contraction, first in longitudinal muscle, then in circular muscle. Maximal longitudinal shortening occurs nearly coincidently with peak intraluminal pressure. Longitudinal muscle contraction begins before and ends after circular muscle contraction. Larger longitudinal shortening is correlated with higher-pressure amplitude, suggesting that circumferential contractile forces are enhanced by longitudinal muscle shortening. The peristaltic wave of longitudinal muscle contraction envelops the wave of circular muscle contraction as the peristaltic contraction wave moves down the esophagus, with peak longitudinal contraction aligned with peak circular muscular contraction. Physiologically, LLS concentrates circular muscle fibers where closure pressure is highest. The mechanical function of LLS is to reduce the level of pressure required to maintain closure. The combined physiological and mechanical consequences of LLS are to reduce circular muscle fiber tension and power, by as much as 1/10 that would be required for peristalsis without the longitudinal muscle layer.
22.2.2.2
The Distal Esophagus Shortens More Than the Proximal Esophagus
Dai et al. evaluated LLS using simultaneous high-resolution endoluminal ultrasound (HREUS) and manometry at different levels of the esophagus. Normal subjects underwent simultaneous HREUS/manometry at 4 levels (5, 10, 15, and 20 cm) above the upper border of the HPZ in the esophagus with 5-mL swallows of water. LSM shortened longitudinally as expected. However, CSM also shortened longitudinally. Surprising, the CSM shortened more than the longitudinal muscle. In addition, LLS of the CSM layers at 5 cm above the HPZ was significantly greater than at 20 cm while shortening of the LSM at 5 versus 20 cm was found to be the same. Thus, in the distal esophagus, the CSM shortened more than the LSM. The explanation for the greater CSM shortening in the distal esophagus is that it was found that the angle of the CSM to the LSM muscle fibers is more oblique in the distal esophagus than the mid or proximal esophagus. This contributes to significantly greater shortening of distal esophagus when compared to the mid and proximal esophagus during peristalsis in which the CSM remains perpendicular to the LSM.
22.3
Gastroesophageal Reflux Disease: Pathophysiologic Mechanisms That Contribute to GERD
Transient lower esophageal sphincter relaxation (TLESR) as a cause of GERD. The GEJ HPZ pressure is known to drop transiently to baseline gastric pressure over extended periods not associated with swallowing, indicating transient loss of sphincteric tone. This phenomenon is referred to as “transient lower esophageal sphincter relaxation (TLESR)” and is known to involve the relaxation of all sphincteric muscle components. TLESR has been the subject of intense research as a potential physiologic explanation for gastroesophageal reflux. By dividing the stomach into different compartments, Franzi and colleagues showed that the cardiac region of the stomach has the lowest threshold for triggering stretch-induced transient relaxation of the sphincter muscles at the GEJ. Stretch of the cardia region is the major trigger for sphincter relaxation, and may be the stimulus for TLESR. Vagal cooling abolishes the triggering of gastric cardia stretch-induced sphincter relaxations, suggesting a vagally mediated reflex. It has been appreciated increasingly that gastric cardia stretch-induced relaxations are integrated motor responses that also involve crural diaphragmatic inhibition.
TLESRs and particularly the receptors involved in the underlying neural pathway have been identified as novel therapeutic drug targets. Animal data indicate that gamma-aminobutyric acid type B (GABA b ) receptors and metabotropic glutamate receptor (mGluR5) are expressed along this pathway, in particular, in the nodose ganglion and nucleus of the tractus solitaries (NTS) in ferret. Clinical studies have clearly demonstrated that GABA b receptor agonists baclofen and lesogaberan and mGluR5 antagonists inhibit TLESRs, thereby reducing the number of reflux episodes and symptoms in healthy patients and GERD patients. However, no suitable pharmacologic agents targeting TLESR have been found that are devoid of significant side effects.
22.3.1
Absence of the Pressure Profile From the Gastric Clasp and Gastric Sling Muscle Fiber Complex and Attenuation of the Pressure Profile From the LECS in GERD
Alterations in the normal anatomy and/or physiology of the antireflux barrier HPZ account for the underlying pathophysiology of GERD. Using simultaneous ultrasound and manometry, with pharmacologic manipulation of the GEJHPZ in GERD patients, it was found that the smooth muscle pressure profiles displayed an absence of the distal pressure peak in both inspiration and expiration, indicating an absence of tone in the gastric sling and gastric clasp muscle complex. The proximal pressure peak, reflecting the physiologic LECS, was present in the same axial location relative to the crural diaphragm as in the normal volunteers but was attenuated in pressure ( Fig. 22.2 ).
22.3.2
Increased Distensibility Within the GEJHPZ in Patients With GERD
Vegesna et al. found an increase in the distensibility of the GEJHPZ in patients with GERD. This increase in distensibility was demonstrated by evaluating yield pressures in GERD patients when compared with normal control subjects. Both the yield pressures and the volume of air in the stomach that are required to cause opening at the GEJ is significantly lower in patients with GERD when compared to normal control subjects. A similar increase in the distensibility of the GEJHPZ was found using FLIP technology by Kwiatek et al. As a group, GERD patients exhibited a two- to threefold increased GEJ distensibility compared to normal controls.
22.3.3
Increased Nicotinic-Mediated Relaxation in Patients With GERD
Pharmacologic studies were performed to further understand the abnormal GEJHPZ in patients with GERD. Muscle strips were evaluated from whole stomachs and esophagi obtained from 16 non-GERD organ donors and 15 organ donors with histologically proven Barretťs esophagus (used as a surrogate marker for chronic GERD). Concentration-response curves with carbachol (a muscarinic and nicotinic agonist) demonstrated a significant decrease in the contractility of both the gastric sling and LECS muscle fibers in the Barretťs donors compared with the non-GERD donors. There was no difference in the contractile response of the gastric clasp muscle fibers. These studies seemed to confirm the prior muscle contraction studies, in which patients with reflux associated, Barretťs esophagus exhibited a reduction in cholinergic muscle contraction while retaining similar features of basal tone and responses to tachykinins. However, the maximal contractile response of the gastric sling and LECS muscle fibers to bethanechol (a pure muscarinic agonist) was actually greater in the Barretťs donors than in non-GERD donors while the gastric clasp muscle showed no difference. To determine if the “decrease in contractility” was due to an exaggerated relaxation response to the nicotinic effects of carbachol, further studies were performed evaluating the relaxation response to nicotine added directly to bethanechol precontracted muscle strips. A significantly greater relaxation response to nicotine as a percent of the maximal contractile response to bethanechol was found in the gastric clasp and gastric sling muscle of Barretťs esophagus as compared with the non-GERD. These enhanced nicotinic receptor mediated relaxations may be involved in the pathophysiology of GERD and may be responsible for the decreased pressure profiles and increased distensibility that were found at the GEJ in patients with GERD. These findings may account for the attenuated pressure profiles that were observed in the in vivo studies in patients with GERD, in that either decreased contractility or increased relaxation of the muscle fibers will have the effect of decreasing the tone of the muscle and the pressure within the GEJHPZ and might subsequently increase the distensibility of the GEJHPZ.
22.3.4
Absence of Mucosal Contraction During Swallowing in Patients With GERD
Vegesna et al. found that the longitudinal contraction of the muscularis mucosa within the distal esophagus and proximal stomach acts as a protective mechanism during swallowing, by forming a mucosal plug or one-way valve, which protects the distal esophageal lumen from gastric reflux when the GEJHPZ relaxes. This mucosal shortening is only seen in normal control subjects and is absent in patients with GERD during swallowing. There are two possible explanations for this. First, due to chronic reflux of gastric contents, there may be an inflammatory reaction within the mucosa/submucosa, which may release substances which secondarily inhibit contraction of the muscularis mucosa or cause direct damage to the muscularis mucosa. However, another possible explanation is that the lack of contraction of the muscularis mucosa may be a primary defective mechanism and the fact that the gastric mucosa/submucosa is not pulled up into the distal esophagus may be one of the pathophysiologic mechanisms leading to GERD.
22.3.5
Treatment of GERD
GERD affects up to 40% of the population. Evidence is mounting that the prevalence is increasing coincident with the increased incidence of obesity. Chronic GERD can result in complications such as esophagitis, esophageal erosions, ulcers, strictures, Barretťs esophagus, adenocarcinoma, laryngitis, chronic bronchitis, chronic cough, asthma, and dental erosions. Lifestyle changes are often very effective to help diminish the symptoms associated with GERD. Current methods for the pharmacological treatment of GERD include antacids, histamine receptor blockers, and proton-pump inhibitors (PPIs). Surgical barrier methods (Nissen fundoplication) are most often performed laparoscopically. Although medical therapy has been shown to be effective, there is inconvenience and cost of long-term drug therapy. In addition, recent epidemiologic evidence suggests that the most effective of these medications, the PPIs, may be associated with numerous adverse side effects ranging from harmful effects on bone, to an alarming increase in the incidence chronic renal failure and inpatient death. None of the medical treatments target the underlying cause of GERD as described in the previous section.
22.3.6
Surgical Therapy for GERD
While surgical therapy targets the defective antireflux barrier and can be very effective, it also has drawbacks, in that many patients may require continued medical therapy after surgery and the fundoplication may eventually breakdown. A meta-analysis of quality-of-life aspects showed a pooled-effect estimate in favor of fundoplication over medical therapy. Heartburn and regurgitation were less frequent after surgical intervention. The surgical patients were significantly more satisfied with their symptom control and showed higher satisfaction with the treatment received. However, problems with both the current medical and surgical therapy have led to the consideration of alternative methods of treatment which will be discussed below.
22.3.7
Stretta Therapy
Strettais an FDA approved endoscopically guided, minimally invasive, outpatient procedure that delivers radiofrequency energy to the lower esophagus and gastric cardia to treat gastroesophageal reflux. In a meta-analysis of 18 studies by Perry et al., Stretta was found to reduce esophageal acid exposure and improve GERD symptoms. This treatment improved heartburn scores ( P = 0.001), and produced improvements in quality of life as measured by GERD-HRQL scale ( P = 0.001) and QOLRAD ( P = 0.001). Esophageal acid exposure decreased from a pre-procedure Johnson-DeMeester score of 44.4–28.5 ( P = 0.007). Some of the long-term uncontrolled trials have demonstrated improvement in symptoms, PPI use, and pH parameters; however, pH values remained in an abnormal range, with few patients normalizing pH scores.
22.3.8
Trans Oral Incisionless Fundoplication
Trans oral incisionless fundoplication (TIF) creates an endoscopic fundoplication. Huang et al. performed a meta-analysis of TIF. A total of 18 studies (963 patients) published between 2007 and 2015 were identified, including five RCTs and 13 prospective observational studies. The pooled relative risk of response rate to TIF versus PPIs/sham was 2.44 (95% CI 1.25–4.79, P = 0.0009) in RCTs in the intention-to-treat analysis. The total number of refluxes was reduced after TIF compared with the PPIs/sham group. The esophageal acid exposure time and acid reflux episodes after TIF were not significantly improved. PPIs usage increased with time and most of the patients resumed PPI treatment at reduced dosage during the long-term follow-up. The total satisfaction rate after TIF was about 69.15% in 6 months and the incidence of severe adverse events 2.4%.
22.3.9
Magnetic Sphincter Augmentation
The Linx device consists of a series of magnetic rings linked to each other. The device is placed surgically on an outpatient basis, around the esophagus/proximal stomach. No randomized controlled trials have been conducted regarding magnetic sphincter augmentation using the LINX device, but there have been prospective, multicenter, long-term (2–5 years) uncontrolled trials with rigorous patient follow-up. These studies demonstrated excellent pH control with more than 50% of patients normalizing pH scores at 1 year and significant improvements in symptom scores and PPI usage, compared to baseline, at the 5-year interval. The clinical data showed significant improvement across all parameters measured, including esophageal acid exposure, heartburn, regurgitation, PPI use, and GERD quality-of-life scores.
22.3.10
Lower Esophageal Sphincter Pacing
Another surgical procedure is pacing of the LES using EndoStim, a surgically implanted pacemaker. Uncontrolled trials, some reported out to 2 years, demonstrate excellent pH control, with pH normalization in more than 50% of patients, and significant improvements in GERD symptoms and PPI use, with 70%–80% of patients reporting complete cessation of PPI use.
22.3.11
Antireflux Mucosectomy
The antireflux mucosectomy (ARMS) procedure is based on the principle that after mucosal resection, the mucosal healing results in scar formation and remodeling of the gastric cardia flap valve. The technique involves resection of gastric (about 2 cm) and esophageal mucosa (about 1 cm) in crescentic fashion, along the lesser curvature. Long-term follow-up is pending.
22.4
Esophageal Motility Disorders
Using the Chicago Classification, based on HRM, motility disorders can be categorized as either, (1) disorders with EGJ outflow obstruction, (2) major disorders of peristalsis, or (3) minor disorders of peristalsis.
22.4.1
High-Resolution Manometry
HRM has become the gold standard for the clinical diagnosis of esophageal motility disorders. The Chicago Classification uses the following measures, during 10 liquid swallows in a supine position, to diagnose esophageal motility disorders: The integrated relaxation pressure (IRP) is used to evaluate EGJ relaxation. IRP is defined as the mean of the 4-s (contiguous or noncontiguous) maximal relaxation in the 10-s deglutitive window, beginning at the upper esophageal sphincter (UES) relaxation. Increased IRP has been shown to be the best metric to identify patients with achalasia. Contractile vigor is assessed using the distal contractile integral (DCI), which is the product of the integral of contractile amplitude > 20 mm/Hg times the duration times the length of the contraction from the transition zone to the proximal margin of the esophagogastric junction (EGJ). Failed peristalsis is defined as a contraction with a DCI < 450 mmHg s cm, weak peristalsis as a contraction with DCI > 100 mmHg s cm, but < 450 mmHg s cm and hypercontractility as a DCI > 8000 mmHg s cm. The contractile deceleration point represents the inflexion point along the 30-mm/Hg isobaric contour of the contraction in the distal esophagus. It demarcates esophageal peristalsis (rapid propagation velocity) from the ampullary emptying (slow velocity). The distal latency (DL) reflects the integrity of inhibitory pathways preceding esophageal contractions. It corresponds to the period that immediately precedes esophageal contraction, and is measured as the interval from UES relaxation to the contractile deceleration point. A premature contraction is defined as a contraction with a DCI > 450 mmHg s cm and a DL < 4.5 s. Only large breaks (> 5 cm) in the 20-mmHg isobaric contour are considered in the Chicago Classification version 3.0. Fragmented contraction is defined as a DCI > 450 mmHg s cm and a defect > 5 cm. The intrabolus pattern is evaluated at 30-mm/Hg isobaric contour (see Fig. 22.3 ).
22.5
Disorders of Esophagogastric Junction Outflow
22.5.1
Achalasia and EGJ Outflow Obstruction
Disorders of EGJ outflow obstruction are characterized by an impaired EGJ relaxation during swallowing. An impaired EGJ relaxation is defined as a median IRP of 10 swallows performed in supine position above the limit of normal. Further disorders of EGJ outflow are divided into achalasia subtypes (I, II, III) and EGJ outflow obstruction. Achalasia is a primary motility disorder of unknown etiology characterized by esophageal aperistalsis and failure of the LES to relax with swallowing. While the pathophysiology is not yet fully understood, achalasia is driven by the loss of neurons in the esophagus, predominantly the neurons facilitating the relaxation of the esophagus. Therefore, the esophagus is unable to truly relax, resulting functional obstruction causes dysphagia, chest pain, regurgitation of esophageal content, and weight loss. All types of achalasia are characterized by an increased IRP with some alteration in peristalsis: Type I achalasia is characterized by 100% of failed contractions and absence of pan-esophageal pressurization, type II by pan-esophageal pressurization for at least 20% of swallows, and type III by at least 20% premature contractions.
22.5.2
Treatment of Achalasia
Treatment is directed at reducing EGJ outflow resistance. This can be accomplished by pharmacologic therapy, forceful dilation, and surgical orendoscopic myotomy.
Pharmacologic therapy uses smooth muscle relaxants such as calcium channel blockers and sublingual nitrates taken immediately before meals to reduce LES pressure. These medications have limited benefit. A double-blind placebo-controlled trial found that sildenafil, significantly reduced HPZ pressure and relaxation pressure in patients with achalasia. Botox injection directly into the sphincter causes sphincter relaxation by inhibiting the release of acetylcholine from neurons at the neuromuscular junction. Divided doses of Botox (80–100 U total) are injected into four quadrants of the sphincter with a sclerotherapy needle. This technique provides a clinical response rate of 90% in 1 month but the effect wears off to 30%–50% at 1 year and to < 5% at 2 years. A number of investigators have found that injecting botulinum toxin type A into the LES of patients with achalasia, not only improved dysphagia and regurgitation but also decreased chest pain significantly. Overall, in these studies, there is a 60%–70% decrease in the severity of chest pain. The benefit of these therapies is limited and is reserved for patients who cannot tolerate more definitive therapies indicated later.
Pneumatic dilation (PD) causes sphincter disruption. Balloon dilators with a diameter of at least 30 mm are used. The most serious complication of PD is esophageal perforation occurring in approximately 2% of patients. Approximately one-third of the patients experience symptom relapse during the following 2 or 3 years. Clinical relapse can be effectively treated by subsequent repeated PD, with good to excellent results in 70%–80% of patients. Achalasia subtypes according to the Chicago classification is a major predictor of treatment outcome. Pan-esophageal pressurization was a significant predictor of a good treatment response, whereas spastic achalasia was predictive of poor treatment response.
Laparoscopic Heller Myotomy (LHM) consists in a myotomy of the muscle fibers of the sphincter (circular layer) without mucosa disruption. Currently, the procedure of choice is performed laparoscopically in association with an antireflux procedure. Adding a fundoplication after a myotomy reduces the frequency of postoperative GERD from approximately 30% to 10% to 15%. Overall, laparoscopic Heller myotomy (LHM) provides adequate symptom relief in 90% of patients with achalasia but, its efficacy decreases to 50%–60% of good/excellent response with longer follow-up periods. Outcome with LHM is influenced by achalasia subtypes. Retrospective studies have reported good results of LHM in 67%–85%, 95%–100%, and 70%–85% of patients with types I, II, and III, respectively. The post hoc analysis of a European RCT reported 81%, 93%, and 86% of response in types I, II, and III, respectively. LHM is the treatment of choice for Type III achalasia.
Peroral Endoscopic Myotomy (POEM) The technique of POEM consists of creating a submucosal tunnel in the esophagus to access the circular muscle fibers. An endoscopic submucosal dissection knife is used for the dissectionand to cut the muscle over a minimum length of 6 cm into the esophagus and 2 cm below the squamocolumnar junction onto the cardia. The reported short-term efficacy of POEM is reliably > 90% among studies, including in a recent European and US multicenter prospective trial. Few severe complications have been reported mainly bleeding, pneumothorax, thoracic effusion, and transmural perforation. However, the prevalence of GERD has been reported to be as high as 30%–50% after POEM as the myotomy is performed without an antireflux procedure. Further studies comparing POEM to LHM or PD are ongoing.
22.5.3
EGJ (Outflow Obstruction)
EGJ outflow obstruction occurs when there is impaired EGJ relaxation in addition to an esophageal body contractility pattern that does not meet the criteria for an achalasia subtype. It may correspond to either early achalasia, infiltrative process of the EGJ, vascular obstruction, or be secondary to hiatal hernia. Opioid medications have been implicated in an increased IRP mimicking EGJ outflow obstruction. While a significant number of patients improve with no intervention, many patients are treated by Botox injections, PD, or LHM In one study the effect of Botox injections into the LES in 36 patients the authors report a success rate (durable response > 6 months) of 58.3%, More recently, Marjoux et al. reported a 60% rate of clinical response at 6 months in six patients with EGJ outflow obstruction.
22.5.4
Major Disorders of Peristalsis: (Absent Contractility, Distal Esophageal Spasm, and Jackhammer Esophagus)
Major disorders of peristalsis may be associated with dysphagia, chest pain, heartburn, and regurgitation. Absent contractility is defined as a normal IRP and 100% failed contractions. Distal esophageal spasm (DES) is defined as normal IRP and at least 20% of premature contractions (DCI > 450 mmHg s cm and DL < 4.5 s). Jackhammer (hypercontractile) esophagus is defined as at least 20% of swallows with a DCI > 8000 mmHg s cm. In some instances, hypercontractility may involve the LES.
Smooth muscle relaxants like calcium channel blockers and nitrates have been proposed for the treatment of DES but have limited efficacy and significant side effects. Small case series suggest that sildenafil may be effective in patients with DES. Pain modulators, especially low-dose antidepressants like trazodone, may be effective in reducing pain occurrence and intensity but do not improve esophageal motility.
Miller et al. used Botox injections to treat symptoms in patients with nonachalasia spastic esophageal motor disorders. Patients with nonachalasia spastic esophageal motility disorders (SEDs) [diffuse esophageal spasm (DES), nonspecific esophageal motility disorders, and LES dysfunction] unresponsive to medical therapy underwent endoscopic injection of botulinum toxin at the level of the gastroesophageal junction. There was significant improvement in chest pain, dysphagia, and regurgitation at 7, 30, 60, and 90 days after treatment. At 1 month after treatment, 11 of 15 (73%) patients had a good or excellent response to treatment. An extension of this study was performed by Miller et al. Symptoms of chest pain, dysphagia, regurgitation, and heartburn were scored before and 1 month after botulinum toxin injection. Seventy-two percent of the patients responded with at least a 50% reduction in chest pain. In these responders, there was a 79% reduction in the mean chest pain score. ( P < 0.0001). The mean duration of the response for chest pain in these patients was 7.3 ± 4.1 months. There was also a significant reduction in the mean regurgitation score, dysphagia score, and total symptom score ( P < 0.0001). Injections within the esophageal body appear to be more adapted to the pathophysiology of this disorder in which no EGJ outflow obstruction is present. Only one cross-over controlled study is currently available. This study compared Botox and saline injections at 2 and 7 cm above EGJ. Among the 22 included patients, 15 had DES and 7 hypertensive peristalsis; only 7 were assessed with HRM. Overall, the response rates were 50% and 10% for Botox and saline, respectively. The response rate was similar in the subgroup of patients with DES, with a sustained response (> 1 year) in 30%. Case reports of successful treatment of DES with POEM have been reported. A recent international multicenter experience using POEM as a treatment modality for patienťs refractory to standard medical management with various SEDs was published. Most patients had moderate-to-severe symptoms, and a majority had chest pain, which is a typical manifestation of these spastic disorders. POEM was carried out in standard fashion, but an extended myotomy was performed. The mean myotomy length was 16 cm, which is double the length that is typically performed during POEM done for achalasia. Chest pain clinically improved in 87% of patients who reported chest pain before POEM. Patients with spastic achalasia (96.3%), DES (100%), and jackhammer esophagus (70%) improved. A clinical response was observed in 93% of patients, and there was a statistically significant decrease in the mean Eckardt score after POEM (6.71 vs. 0.81; P = 0.0001). The majority of patients underwent follow-up HRM, which showed resolution of initial manometric abnormalities. POEM was found to be safe, and no severe adverse events were reported.
Surgical myotomy extended from the LES to the esophageal body has been proposed in patients with severe refractory symptoms, but available data come from small retrospective uncontrolled studies and there are controversies regarding the surgical technique (thoracic or abdominal approach, position and length of the myotomy, need for an antireflux procedure). Nevertheless, provided the extent of the myotomy onto the esophageal body is long enough, good results can be obtained in 80% of patients.
22.5.5
Minor Disorders of Peristalsis: (Ineffective Esophageal Motility and Fragmented Peristalsis)
Ineffective esophageal motility (IEM) is characterized by at least 50% of swallows with a DCI < 450 mmHg s cm in association with a normal IRP. Fragmented peristalsis is characterized by at least 50% of swallows with a defect of > 5 cm and not meeting the criteria for IEM. “Hypertensive peristalsis” (nutcracker esophagus), defined by a mean DCI of > 5000 mmHg s cm, is not considered as abnormal in the last iteration of the Chicago classification. The relevance of this disorder is not widely accepted as it can be observed in asymptomatic subjects. Provocative maneuvers such as multiple rapid swallows (MRSs) or solid swallows could reveal a motor dysfunction missed using the standard 10–5 mL liquid swallow protocol. However, these tests are not yet part of the Chicago Classification algorithm.
The nonachalasia, nongastroesophageal reflux-induced SEDs include DES, nonspecific esophageal motility disorders, type III achalasia and isolated LES dysfunction. These esophageal motility disorders are often associated with chest pain but may also have symptoms of dysphasia and regurgitation. Nonspecific SEDs include high-amplitude esophageal peristaltic contractions (nutcracker esophagus), multipeaked esophageal contractions, prolonged duration esophageal contractions and a positive edrophonium provocation test. Current medical therapy for NCCP due to spastic esophageal disorders includes administration of nitrates, anticholinergic agents, calcium-channel blockers, and psychotropic drugs. In some cases, more invasive treatments aimed at relaxing the distal esophagus and LES, have been utilized; these include large bore esophageal bougienage, and pneumatic dilatation. Unfortunately, none of these therapies is very effective in the majority of patients, and most remain disabled by their symptoms. Thus, there is a need for a safe and effective treatment for patients with NCCP and esophageal motility disorders.
There have been small series of surgical myotomies in patients with SEDs. A long myotomy provided improvement in a series of patients with esophageal spasm, and another series found some improvement. Despite these promising results, the invasive nature of the procedure (often requiring a thoracotomy or at least a thoracoscopy to reach the thoracic esophagus) has limited acceptance of these procedures.
22.6
Treatment of Hypotensive Motility Disorders
Hypotensive motility disorders are absent contractility, IEM, and fragmented peristalsis. The therapeutic options for these disorders are limited and no pharmacological intervention is able to restore smooth muscle contractility and esophageal function. Weijenborg et al. reported the effects of antidepressants in patients with functional esophageal disorders. Antidepressants such as imipramine, amitriptyline, citalopram, and trazodone, may reduce functional chest pain, heartburn, or globus sensation.
22.6.1
Scleroderma Esophagus
GI tract involvement is the third most common clinical manifestation of scleroderma esophagus (SSc) following skin changes and Raynaud’s phenomenon. The esophagus is the most frequent GI tract organ affected in SSc, and esophageal involvement is usually accompanied by significant symptomatology and morbidity. The esophageal manometric pattern is characteristic for SSc and includes reduction in peristaltic amplitude, which eventually can progress to total absence of contraction in the smooth muscle portion of the esophagus. The pathologic changes accompanying SSc esophageal involvement have been studied in autopsy specimens. Initially, there is spotty muscle atrophy and fibrosis. In time, the fibrosis progresses to involve most of the distal esophagus. Miller et al. used high-resolution endoluminal sonography (HRES) to evaluate esophageal structural abnormalities in SSc, to compare these abnormalities with sonographic findings in the normal esophagus, and to correlate the structural abnormalities with functional abnormalities (i.e., manometry and 24-h pH monitoring) in the distal esophagus in patients with SSc. An HRES transducer was used to image the esophagus. Autopsy specimens of normal and SSc esophagi were imaged to define a hyperechoic abnormality in the normally hypoechoic MP. The presence or absence of this hyperechoic abnormality of the esophagus in SSc patients was compared with sonographic findings in normal volunteers. The degree of the hyperechoic abnormality was correlated with the results of functional esophageal studies including esophageal motility, LES pressure, and 24-h pH monitoring in patients with SSc. A hyperechoic abnormality in the normally hypoechoic MP on HRES corresponded with the presence of fibrosis onhistological sections from the distal esophagus in SSc autopsy specimens. There were strong positive correlations between the degree of this hyperechoic abnormality and esophageal manometric abnormalities ( r = 0.89; P < 0.001) and supine ( r = 0.74; P < 0.01) and total ( r = 0.70; P < 0.02) acid reflux on 24-h pH monitoring.
22.6.2
Longitudinal Muscle Contraction as a Cause of Noncardiac Chest Pain
Balaban et al. using simultaneous ultrasound and manometry found a sustained esophageal contraction (SEC) (which represents esophageal shortening) prior to 18 of 24 spontaneous chest pain events. The mean duration of these SECs was 68 s, and these contractions preceded pain by at least 30 s. During these SEC events, there was no increase in intraluminal pressure. Chest pain induced by edrophonium was also associated with a SECs. Pehlivanov et al. conducted a similar study in patients with heartburn and found a close temporal correlation between longitudinal muscle contraction and heartburn symptoms. Longitudinal muscle contraction was found in connection with heartburn associated with acid reflux and heartburn not associated with acid reflux with similar frequency. Acid (0.1N HCl) infusion into the esophagus (Bernstein test) also induced SECs. Subjects responding to acid infusion with heartburn revealed longitudinal muscle contraction prior to the onset of heartburn. The mean duration of longitudinal muscle contraction associated with heartburn was significantly less ( P = 0.02) than that associated with chest pain. The shorter duration of a SEC may induce symptoms of heartburn while the longer duration may induce chest pain.
22.7
Small Intestine and Motility
22.7.1
Normal Motility of the Small Intestine
A normal motility small bowel pattern and preserved migrating motor complex (MMC) is necessary to provide a balanced transit time for food to pass through the small intestine. While the transit time must be long enough to allow for the absorption of nutrients, a prolonged transit time can result in stasis of the food precipitating problems such as small intestinal bacterial overgrowth (SIBO), chronic inflammation, mechanical and visceral pain, and constipation. Generation and regulation of the movements of the small bowel is a complex yet synchronized process involving the central and enteric nervous systems, intestinal muscles, and a myriad of regulatory peptides and hormones.
22.7.2
Impaired Motility of the Small Intestine
Abnormal intestinal motility can manifest as a variety of chronic and nonspecific symptoms that often go unrecognized. Patients oftentimes present with subtle complaints such as abdominal pain, nausea, vomiting, bloating, altered bowel habits, and failure to gain or maintain weight despite adequate nutrition intake. Small bowel dysmotility has been recognized as a contributing factor in the pathogenesis of several GI disorders, including irritable bowel syndrome (IBS). The prevalence and natural history of small bowel motility disorders has not been well established.
22.7.3
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