Esophageal Neuromuscular Function and Motility Disorders


The esophagus is a muscular tube with a sphincter at each end joining the hypopharynx to the stomach with the simple function of transporting food, fluid, and gas between these endpoints. As such, the esophagus encompasses the anatomic and physiologic transition from the striated muscle oropharynx and the smooth muscle gut. Neurologically, the oropharynx is controlled by the cerebral cortex and medulla and capable of precise tactile sensation; the distal esophagus is composed entirely of smooth muscle, controlled by the vagus nerve and enteric nervous system, and comparatively insensitive. Although there is a gradual transition between these endpoints, motor function in the oropharynx and esophageal body are quite distinct. With that in mind, the ensuing discussion includes selected aspects of pharyngeal, gastric, and diaphragmatic function that are inextricably entwined with esophageal function.

Motor and Sensory Function

Oropharynx and Upper Esophageal Sphincter

Within the oral cavity, the lips, teeth, hard palate, soft palate, mandible, floor of the mouth, and tongue serve to form and contain food into a bolus suitable for transfer to the pharynx. The pharynx is divided into 3 segments: nasopharynx, oropharynx, and hypopharynx ( Fig. 44.1 ). The nasopharynx extends from the base of the skull to the distal edge of the soft palate. Muscles in the nasopharynx elevate the soft palate during swallowing, seal the nasopharynx, and prevent nasopharyngeal regurgitation. The oropharynx extends from the soft palate to the base of the tongue. The inferior margin of the oropharynx is demarcated by the valleculae anteriorly and the mobile tip of the epiglottis posteriorly. The hypopharynx extends from the valleculae to the inferior margin of the cricoid cartilage and includes the upper esophageal sphincter (UES).

Fig. 44.1, Anatomy of the pharynx. A, Sagittal view of the pharynx showing the musculoskeletal structures involved in swallowing. Note that the esophagus is collapsed and empty at rest. In the course of a swallow, the laryngeal inlet will be sealed and the mouth of the esophagus will be opened by highly coordinated muscular activity. B, Cutaway view of the musculature of the pharynx. Note that the hyoid bone is positioned as a fulcrum and is instrumental in directing anterior, superior traction forces critical to closing the larynx and opening the esophageal inlet during a swallow. ant., anterior; post., posterior.

Musculature of the soft palate, tongue, and pharynx all participate during swallowing to collapse and shorten the pharyngeal lumen and then expel its contents into the esophagus. Additionally, extrinsic muscles elevate and pull the pharynx forward, thereby sealing the airway and opening the UES. The intrinsic muscles of the pharynx, the superior, middle, and inferior pharyngeal constrictors (see Fig. 44.1 ), overlap and insert into a collagenous sheet, the buccopharyngeal aponeurosis. The inferior constrictor is composed of the thyropharyngeus (superior part) and the cricopharyngeus (inferior part). The thyropharyngeus arises from the thyroid cartilage, passes posteromedially, and inserts in the median raphe. The cricopharyngeus has superior and inferior components, each of which arise bilaterally from the sides of the cricoid lamina; the superior fibers course posteromedially to the median raphe whereas the inferior fibers loop around the esophageal inlet without a median raphe. Killian triangle, a triangular area of thin muscle, is formed posteriorly between these components and is the most common site of origin for pharyngeal pulsion diverticula.

The pharynx also contains 5 single or paired cartilages (see Fig. 44.1 ). The spaces formed between the lateral insertion of the inferior constrictor and the lateral walls of the thyroid cartilage are the pyriform sinuses that end inferiorly at the cricopharyngeus muscle, separating the pharynx from the esophagus. The larynx and trachea are suspended in the neck between the hyoid bone superiorly and the sternum inferiorly. A number of muscles, categorized as the laryngeal strap muscles, contribute to this suspension and, together with the intrinsic elasticity of the trachea, permit the larynx to be raised and lowered. The hyoid bone also serves as the base for the tongue that rests upon it. Laryngeal movement is crucial to the swallow response as the laryngeal inlet is both closed and physically removed from the bolus path in the course of a swallow. Failure to achieve this synchronized laryngeal movement can result in aspiration.

The pharyngeal muscles are densely innervated with motor fibers coming from nuclei of the trigeminal, facial, glossopharyngeal, and hypoglossal nuclei, as well as the nucleus ambiguus of the vagus and spinal segments C1 to C3. All motor neurons within nucleus ambiguus participate in swallowing, with those innervating the striated muscle esophagus situated rostrally and those innervating the pharynx and larynx more caudally. The muscular components of the UES are the cricopharyngeus, adjacent esophagus, and adjacent inferior constrictor with the cricopharyngeus contributing the 1 cm zone of maximal pressure. The closed sphincter has a slit-like configuration, with the cricoid lamina anterior and the cricopharyngeus lateral and posterior. Neural input via vagal trunks originating in the nucleus ambiguus maintains UES pressure and vagal transection abolishes this contractile activity.

Manometric evaluation of UES function is difficult because it is a short, complex anatomic zone that moves briskly during swallowing. Furthermore, UES pressure is heavily influenced by recording methodology, owing both to its marked asymmetry and to its reflexive contraction to pharyngeal and esophageal stimulation. Thus, it is not possible to define a meaningful normal range of UES pressure. UES relaxation during swallowing also poses substantial recording challenges, making for great variability in technique and interpretation. However, HRM using solid-state technology permits accurate tracking of UES relaxation and intrabolus pressure changes during swallowing ( Fig. 44.2 ).

Fig. 44.2, Fluoroscopy combined with high-resolution manometry (HRM). The fluoroscopic images ( top ) are depicted at specific times demarcated on the HRM (color panel by pink arrows) . The time line illustrates the coordination and timing of events within the pharyngeal swallow on fluoroscopy. Each horizontal bar depicts the period during which one of the oropharyngeal valves is in its swallow configuration, as opposed to its configuration during respiration, and is correlated with the images on fluoroscopy: (1) baseline anatomy with bolus in the mouth; (2) glossopalatal opening occurring in synchrony with UES relaxation, which is typically to less than 10 mm Hg; (3) velopharyngeal junction closure, sealing off the nasopharynx to prevent regurgitation (note the elevation depicted by the white arrow ); (4) laryngeal vestibule closure and UES opening occurring as the epiglottis inverts, closing the laryngeal vestibule as the bolus, led by air, is rapidly pushed through the UES; (5) continued bolus transit with the onset of the pharyngeal stripping wave; (6) bolus transfer to the esophagus is completed as the pharyngeal stripping wave traverses the UES while the laryngeal vestibule remains closed; (7) return of the pharynx to a respiratory configuration, with the laryngeal vestibule opened and the epiglottis back in its upright configuration. The black dots on the topography (HRM) plot represent the location of the proximal aspect of the UES at each time point.

The UES maintains closure of the proximal end of the esophagus unless opening is required, necessitated for swallowing or belching. It also constitutes an additional barrier to refluxed material entering the pharynx from the esophagus and prevents air from entering the esophagus by contracting in synchrony with inspiration. Inspiratory augmentation is most evident during periods of low UES pressure and can be exaggerated in individuals experiencing globus sensation. Balloon distension of the esophagus stimulates UES contraction, with the effect being more pronounced with proximal balloon positions. However, when the distension pattern of gas reflux is simulated using a cylindrical bag or rapid air injection into the esophagus, UES relaxation rather than contraction occurs. Belch-induced UES relaxation is also associated with glottic closure. Stress augments UES pressure, whereas anesthesia or sleep virtually eliminates it. Neither experimental acid perfusion of the esophagus nor spontaneous gastroesophageal acid reflux alters continuously recorded UES pressure in either normal volunteers or in individuals with peptic esophagitis.

The Pharyngeal Swallow

Disorders of the oral phase of swallowing occur with many conditions characterized by global neurologic dysfunction, such as traumatic brain injury, brain tumors, or chorea (see Chapter 37 ). Detailed discussion of these conditions can be found in texts on swallow evaluation and therapy. The pharyngeal swallow is the largely subconscious coordinated contraction that transfers oral contents into the esophagus. Afferent sensory fibers capable of triggering the pharyngeal swallow travel centrally via the internal branch of the superior laryngeal nerve (from the larynx) and the glossopharyngeal nerve (from the pharynx). These sensory fibers converge before terminating in the medullary swallow center.

Although understood physiologically as the patterned activation of motor neurons and their corresponding motor units, swallowing is clinically evaluated in mechanical terms and best evaluated by videofluoroscopic or cineradiographic analysis. The pharyngeal swallow rapidly reconfigures pharyngeal structures from a respiratory to an alimentary pathway and then reverses this reconfiguration within 1 second. The pharyngeal swallow response can be dissected into several closely coordinated actions: (1) nasopharyngeal closure by elevation and retraction of the soft palate, (2) UES opening, (3) laryngeal closure, (4) tongue loading (ramping), (5) tongue pulsion, and (6) pharyngeal clearance. Precise coordination of these actions is an obvious imperative, and to some degree the relative timing of these events is affected either by volition or by the volume of the swallowed bolus (see Fig. 44.2 ).

The most fundamental anatomic reconfiguration required to transform the oropharynx from a respiratory to a swallow pathway is to open the inlet to the esophagus and seal the inlet to the larynx. These events occur in close synchrony, facilitated by laryngeal elevation and anterior traction via the hyoid axis. It is critical to recognize the distinction between UES relaxation and UES opening. UES relaxation is due to cessation of excitatory neural input while the larynx is elevating. Once the larynx is elevated, UES opening results from traction on the anterior sphincter wall caused by contraction of the supra- and infrahyoid musculature that also results in a characteristic pattern of hyoid displacement.

Bolus transport out of the oropharynx is facilitated by the tongue and pharyngeal constrictors. Tongue motion adapts to varied swallow conditions and propels most of the bolus into the esophagus prior to the onset of the pharyngeal contraction. On the other hand, the pharyngeal contraction is more stereotyped, functioning to strip the last residue from the pharyngeal walls. UES closure coincides with passage of the pharyngeal contraction. However, the contractile activity of the sphincter has an added dimension as well, exhibiting augmented contractility during laryngeal descent, resulting in a grabbing effect such that the sphincter and laryngeal descent complement each other to clear residue from the hypopharynx. This clearing function probably acts to minimize the risk of postswallow aspiration by preventing residual material from adhering to the laryngeal inlet when respiration resumes.

Esophagus

The esophagus is a 20- to 22-cm tube composed of skeletal and smooth muscle. The proportion of each muscle type is species dependent, but in humans, the proximal 5% is striated, the middle 35% to 40% is mixed with an increasing proportion of smooth muscle distally, and the distal 50% to 60% is entirely smooth muscle. The outer longitudinal muscle arises from the cricoid cartilage with slips from the cricopharyngeus passing dorsolaterally to fuse posteriorly about 3 cm distal to the cricoid cartilage. This results in a posterior triangular area devoid of longitudinal muscle, Laimer triangle. Distal to Laimer triangle, the longitudinal muscles form a continuous sheath of uniform thickness around the esophagus. The adjacent, inner muscle layer is formed of circular or, more precisely, helical muscle also forming a sheath of uniform thickness along the length of the esophagus. There is a decreasing degree of helicity moving distally ranging from 60 degrees in the proximal esophagus to nearly 0 degrees at the lower esophageal sphincter (LES). Unlike the distal GI tract, there is no serosal layer to the esophagus.

The extrinsic innervation of the esophagus is via the vagus nerve with motor neurons in nucleus ambiguus (striated muscle portion) and the dorsal motor nucleus of the vagus (smooth muscle portion). Efferent vagal fibers reach the cervical esophagus by the pharyngoesophageal nerve, and synapse directly on striated muscle neuromuscular junctions. The vagus also provide sensory innervation; in the cervical esophagus, this is via the superior laryngeal nerve with cell bodies in the nodose ganglion, whereas in the remainder of the esophagus, sensory fibers travel via the recurrent laryngeal nerve or, in the most distal esophagus, via the esophageal branches of the vagus. Vagal afferents are strongly stimulated by esophageal distension.

The esophagus also contains an autonomic nerve network, the myenteric plexus, located between the longitudinal and circular muscle layers. Myenteric plexus neurons are sparse in the proximal esophagus, and their function is unclear because the striated muscle is directly controlled by nucleus ambiguus motor neurons. On the other hand, in the smooth muscle esophagus preganglionic neurons in the dorsal motor nucleus of the vagus synapse on relay neurons in the myenteric plexus ganglia. A second nerve network, the submucosal or Meissner plexus, is situated between the muscularis mucosa and the circular muscle layer, but this is sparse in the human esophagus.

Esophageal Peristalsis

The esophagus is normally atonic and its intraluminal pressure closely reflects pleural pressure, becoming negative during inspiration. However, swallowing or focal distention initiates peristalsis. Primary peristalsis is initiated by a swallow and traverses the entire length of the esophagus; secondary peristalsis can be elicited in response to focal esophageal distention with air, fluid, or a balloon, beginning at the locus of distention. The mechanical correlate of peristalsis is of a stripping wave that milks the esophagus clean from its proximal to distal end. The propagation of the stripping wave corresponds closely with that of the manometrically recorded contraction such that the point of luminal closure seen fluoroscopically at each esophageal locus corresponds with the upstroke of the pressure wave on line tracings or the contractile wavefront on esophageal pressure topography (EPT) ( Fig. 44.3 ). The likelihood of achieving complete esophageal emptying from the distal esophagus is inversely related to peristaltic amplitude, such that emptying becomes progressively impaired with peristaltic amplitudes of 30 mm Hg or less. However, emptying is also modified by the pressure gradient across the esophagogastric junction (EGJ), and this interaction can have significant influence on both bolus transit and peristaltic contractility.

Fig. 44.3, Topographic depiction of esophageal peristalsis using HRM showing the segmental architecture of peristalsis and landmarks of contractile propagation. A, The 30-mm Hg isobaric contour plot ( black lines ) demonstrates that progression through the esophagus is not seamless. The proximal striated segment 1 and the distal smooth muscle esophageal contractile segments 2 and 3 are separated by a transition zone (P). The distal esophagus is also divided into 2 distinct contractile segments (2 and 3), separated by a pressure trough (M). The region of the EGJ is also distinguished by a distinct contractile segment that is separated from the adjacent esophagus by another pressure trough (D). B, Same depiction with the topographic landmarks of peristalsis represented. The pink circle located within segment 3 localizes the CDP, the point along the contractile wavefront at which velocity slows, demarcating the transition from peristalsis to sphincter reconstitution. The DL, which is a manifestation of deglutitive inhibition, is measured from UES relaxation to the CDP. Contractile front velocity is measured by taking the best-fit tangent from the CDP to the transition zone, P. Of interest is the concept of concurrent esophageal contraction illustrated by the vertical dashed arrows . The length of the esophagus concurrently contracting, between the onset of the contractile front and the offset of contraction proximally, is, on average, 10 cm and maximizes in close approximation to the CDP. Following the CDP, the length of concurrent contraction lessens as the “rear” catches up with the slowed contraction front.

Another essential feature of peristalsis is deglutitive inhibition. A second swallow initiated while an earlier peristaltic contraction is still progressing in the proximal esophagus completely inhibits the contraction induced by the first swallow. Deglutitive inhibition in the distal esophagus is attributable to hyperpolarization of the circular smooth muscle and is mediated via inhibitory ganglionic neurons in the myenteric plexus. Deglutitive inhibition can be demonstrated experimentally in the esophagus by distending an intraluminal balloon, which stimulates esophageal contraction. Once the high-pressure zone is established, deglutitive inhibition is evident after swallowing while recording intraluminal pressure between the balloon and the esophageal wall.

The physiologic control mechanisms governing the striated and smooth muscle esophagus differ. The striated muscle receives exclusively excitatory vagal innervation, and its peristaltic contraction results from sequential activation of the musculature. These vagal fibers release acetylcholine (ACh) and stimulate nicotinic cholinergic receptors on the striated muscle cells. Striated muscle peristalsis is programmed by the medullary swallowing center in much the same way as is the pharyngeal swallow. The vagus nerves also exhibit control of primary peristalsis in the smooth muscle esophagus, but the mechanism of vagal control is more complex than that of the striated muscle because vagal fibers synapse on myenteric plexus neurons rather than directly on muscle cells. However, the myenteric plexus can also orchestrate peristalsis independently of vagal activation; secondary peristalsis can be elicited anywhere along the smooth muscle esophagus despite extrinsic denervation. In contrast, transection across the striated muscle esophagus does not inhibit peristaltic progression across the transection site or distally.

Regardless of central or ganglionic control, esophageal smooth muscle contraction is ultimately elicited by ganglionic cholinergic neurons. Less clear are the control mechanisms for the direction and velocity of peristalsis. Nerve conduction studies indicate that neural stimuli initiated by swallowing reach the ganglionic neurons along the length of the esophagus essentially simultaneously. However, the latency between the arrival of the vagal stimulus and muscle contraction progressively increases, moving aborally. In humans, the latent period is 2 seconds in the proximal smooth muscle esophagus and 5 to 7 seconds just proximal to the LES. The current hypothesis is that peristaltic direction and velocity result from a neural gradient along the esophagus, wherein excitatory ganglionic neurons dominate proximally and inhibitory ganglionic neurons dominate distally ( Fig. 44.4 ). This organization is consistent with the demonstration of 2 subsegments within the smooth muscle segment with pressure topography plotting, the first of which is strongly reactive to cholinergic drugs. The primary inhibitory neurotransmitter is nitric oxide (NO), produced from l -arginine by the enzyme NO synthase in myenteric neurons. There is also evidence for a role of vasoactive intestinal polypeptide (VIP)-containing neurons mediating inhibition.

Fig. 44.4, Alterations in the balance and gradient of excitatory (cholinergic) and inhibitory (nitrergic) neurons in the distal esophagus as a pathophysiologic mechanism of esophageal motor disorders. The upper panel depicts the ganglionic constituents in the esophagus, and the lower panel illustrates manometric tracings at 3 and 8 cm above the LES. The blue circles represent excitatory neurons, and the red circles represent inhibitory neurons. A, In normal subjects, cholinergic neurons are most dense proximally, becoming increasingly sparse distally. Conversely, inhibitory neurons are more prominent distally and relatively sparse proximally. This inverse neural gradient causes increasing latency of the contraction as it progresses distally. With simultaneous vagal stimulation of ganglia along the length of the esophagus, contraction first occurs proximally and propagates distally only as the effects of increasingly dense inhibition wear off. Thus, pharmacologic manipulation can alter both contractile vigor and timing of propagation. Conceptually, esophageal motor pathophysiology can be explained by alterations in these neural gradients. B, Patients with hypercontractility and normal (or fast) propagation may have a relative increase in excitatory neurons. C, Patients with loss of inhibitory neurons will lose deglutitive inhibition, and contractions will occur simultaneously and prematurely. D, Patients with loss of both excitatory and inhibitory neurons may present with absent or weak peristalsis that does not propagate.

High-resolution EPT allows for the imaging of esophageal contractility as a continuum not only in time, but also along the length of the esophagus. Clouse and colleagues pioneered this technology, noting that peristalsis was not a seamless wave of pressurization, but rather a coordinated sequence of 4 contiguous contractile segments (see Fig. 44.3 ). A transition zone exists between the first and second segments, characterized by the nadir peristaltic amplitude, slightly delayed progression, and occasional failed transmission. The topographic analysis also reveals a segmental characteristic of peristaltic progression within the smooth muscle esophagus, with 2 contractile segments separated by a pressure trough, followed by the LES, which contracts with vigor and persistence quite dissimilar to the adjacent smooth muscle esophagus. More recently, a distinct landmark along the wavefront was recognized localized in the third segment, at which point contractile propagation slows dramatically (see Fig. 44.3 ). This landmark, defined as the contractile deceleration point (CDP), has pathophysiologic significance because it is localized at the proximal aspect of the LES, and it is hypothesized that this represents the locus of termination of peristalsis. Contraction beyond this point is more consistent with reconstitution of the LES that was relaxed, elongated, and effaced during peristalsis to form the phrenic ampulla.

Longitudinal Muscle

The longitudinal muscle of the esophagus also contracts during peristalsis, with the net effect of transiently shortening the structure by 2 to 2.5 cm. Similar to the pattern of circular muscle contraction, longitudinal muscle contraction is propagated distally as an active segment at a rate of 2 to 4 cm/s. Central mechanisms control longitudinal muscle contraction during peristalsis with progressively increasing latency moving distally, similar to that seen with the circular smooth muscle. However, unlike the circular muscle, nerve stimulation studies suggest the longitudinal muscle to be free of inhibitory neural control.

Esophagogastric Junction (EJG)

The anatomy of the EGJ is complex (see also Chapter 43 ). The distal end of the esophagus is anchored to the diaphragm by the phrenoesophageal ligament that inserts circumferentially into the esophageal musculature close to the squamocolumnar junction (SCJ). The esophagus then traverses the diaphragmatic hiatus and joins the stomach almost tangentially. Thus, there are 3 contributors to the EGJ high-pressure zone: the LES, the crural diaphragm, and the musculature of the gastric cardia that constitutes the distal aspect of the EGJ. The LES is a 3- to 4-cm segment of tonically contracted smooth muscle at the distal extreme of the esophagus. Surrounding the LES at the level of the SCJ is the crural diaphragm, most commonly bundles of the right diaphragmatic crus forming a teardrop-shaped canal about 2 cm long on its major axis ( Fig. 44.5 ). The component of the EGJ high-pressure zone distal to the SCJ is largely attributable to the opposing sling and clasp fibers of the middle layer of gastric cardia musculature. In this region, the lateral wall of the esophagus meets the medial aspect of the dome of the stomach at an acute angle, defined as the angle of His. Viewed intraluminally, this region extends within the gastric lumen, appearing as a fold that has been conceptually referred to as a “flap valve” because increased intragastric pressure forces it closed, sealing off the entry to the esophagus.

Fig. 44.5, Anatomy of the diaphragmatic hiatus as viewed from below. The most common anatomy, in which the muscular elements of the crural diaphragm derive from the right diaphragmatic crus, is shown. The right crus arises from the anterior longitudinal ligament overlying the lumbar vertebrae. Once muscular elements emerge from the tendon, 2 flat muscular bands form that cross each other in scissor-like fashion forming the walls of the hiatus and then merging with each other anterior to the esophagus. L1, first lumbar vertebrae.

Physiologically, the EGJ high-pressure zone is attributable to a composite of both the LES and the surrounding crural diaphragm extending 1 to 1.5 cm proximal to the SCJ and about 2 cm distal to it. Resting LES tone ranges from 10 to 30 mm Hg relative to intragastric pressure, with considerable temporal fluctuation. With HRM, this is quantified as the EGJ contractile integral, and the normal value ranges from 28 to 125 mm Hg/cm. The mechanism of LES tonic contraction is likely both myogenic and neurogenic, consistent with the observation that pressure within the sphincter persists after elimination of neural activity with tetrodotoxin. Myogenic LES tone varies directly with membrane potential that leads to an influx of Ca 2+ . Apart from myogenic factors, LES pressure is also modulated by intra-abdominal pressure, gastric distention, peptides, hormones, foods, and many medications. Large increases in LES pressure occur with the migrating motor complex; during phase III of the migrating motor complex, the LES pressure may exceed 80 mm Hg. Lesser fluctuations occur throughout the day, with pressure decreasing in the postprandial state and increasing during sleep.

Superimposed on the myogenic LES contraction, input from vagal, adrenergic, hormonal, and mechanical influences will alter LES pressure. Vagal influence is similar to that of the esophageal body, with vagal stimulation activating both excitatory and inhibitory myenteric neurons. Thus, the LES pressure at any instant reflects the balance between excitatory (cholinergic) and inhibitory (nitrergic) neural input, and altering the pattern of vagal discharge results in LES relaxation. The crural diaphragm is also a major contributor to EGJ pressure. Even after esophagogastrectomy, with consequent removal of the smooth muscle LES, a persistent EGJ pressure of about 6 mm Hg can be demonstrated during expiration. During inspiration, there is substantial augmentation of EGJ pressure attributable to crural diaphragm contraction. Crural diaphragm contraction is also augmented during abdominal compression, straining, or coughing. On the other hand, during esophageal distension, vomiting, and belching, electrical activity in the crural diaphragm is selectively inhibited despite continued respiration, demonstrating a control mechanism independent of the costal diaphragm. This reflex inhibition of crural activity is eliminated with vagotomy.

LES Relaxation

LES relaxation can be triggered by distention from either side of the EGJ or swallowing. Relaxation induced by esophageal distention is an intramural process, unaffected by vagotomy. Relaxation is, however, antagonized by tetrodotoxin, proving that it is mediated by postganglionic nerves. Deglutitive LES relaxation is mediated by the vagus nerve, which synapses with inhibitory neurons in the myenteric plexus. NO, produced by NO synthase from the precursor amino acid l -arginine, is the main neurotransmitter in the postganglionic neurons responsible for LES relaxation. NO is released with neural stimulation in the esophagus, LES, and stomach, and NO synthase inhibitors block neurally mediated LES relaxation. However, NO may not work alone. VIP-containing neurons have been demonstrated in the submucosal plexus and VIP relaxes the LES by direct muscle action. It is thought that VIP acts on NO synthase–containing neural terminals as a prejunctional neurotransmitter, facilitating the release of NO and on gastric muscle cells to stimulate production of NO by the muscle.

Another contributor to intraluminal pressure during bolus transit through the LES is the bolus itself. The LES relaxes during the initial phase of the swallow, but it does not actually open until the bolus enters the sphincter, thereby implicating intrabolus pressure. Hence, EGJ opening is dependent on the balance of forces acting to open it (intrabolus pressure generated by peristalsis) and the forces resisting opening (LES tone and the mechanical properties of the esophageal wall and crural canal). Although each of these factors may dominate in a particular physiologic scenario, it is difficult to tease them apart with conventional manometric recordings. HRM with EPT has improved on this, and the current assessment of EGJ relaxation during swallowing uses an electronic sleeve or “eSleeve” to ascertain the lowest average postdeglutitive pressure for a 4-second time period, skipping inspiratory crural contractions if necessary ( Fig. 44.6 ). This measurement provides an integrated assessment of the pressure dynamics through the EGJ that is sensitive to both pathologic conditions resisting opening, such as impaired LES relaxation with achalasia, and mechanical obstruction at the EGJ related to a structural cause (stricture, tumor, LES hypertrophy).

Fig. 44.6, EGJ relaxation and bolus transit during swallowing. The IRP provides a pressure topography metric of the pressure dynamics across the EGJ during swallowing. The IRP is a complex metric because it involves accurately localizing the margins of the EGJ, demarcating the time window following deglutitive upper sphincter relaxation within which to anticipate EGJ relaxation, and then applying an eSleeve measurement within that 10-sec time box ( delineated by the black brackets ). The eSleeve is referenced to gastric pressure and provides a measure of the greatest pressure across the axial domain of the EGJ at each time point and is plotted as a line tracing. The IRP is the mean value of the 4 sec during which the eSleeve value is the lowest. The time intervals contributing to the IRP are indicated by the white boxes on the plot and by the shaded red area on the red line eSleeve tracing. In this example, the IRP is 1.6 mm Hg, which is normal. The EGJ is closed, and no flow occurs at the beginning of the swallow because the intrabolus pressure is insufficient to overcome EGJ pressure (left fluoroscopic image) . Bolus transit occurs when the intrabolus pressure ahead of the contractile wave front overcomes the resisting forces at the EGJ (right fluoroscopic image) .

Transient LES Relaxations

During rest, the EGJ must prevent gastroesophageal reflux, but also must transiently relax to selectively permit gas venting of the stomach. These functions are accomplished by prolonged LES relaxations that occur without swallowing or peristalsis. These transient LES relaxations (tLESRs) are an important mechanism in GERD pathogenesis and are the most frequent mechanism for reflux during periods of normal LES pressure (see Chapter 46 ). tLESRs are distinguishable from swallow-induced relaxation in several ways: (1) they are prolonged (>10 seconds) and independent of pharyngeal swallowing; (2) they are associated with contraction of the distal esophageal longitudinal muscle, causing esophageal shortening; (3) there is no synchronized esophageal peristalsis; and (4) they are associated with crural diaphragm inhibition, which is not the case with swallow-induced relaxation ( Fig. 44.7 ). tLESRs occur most frequently in the postprandial state during gastric distention. In the setting of the completely relaxed EGJ during tLESRs, even the minimal gastroesophageal pressure gradients observed with gastric distention (3 to 4 mm Hg) are sufficient to facilitate gas venting of the stomach. Thus, tLESRs are the physiologic mechanism of belching.

Fig. 44.7, Esophageal shortening during a tLESR. Fluoroscopic visualization of movement of endoclips (one placed at the SCJ and one 10 cm proximal to the SCJ) during a tLESR is recorded in a high-resolution EPT format. The manometric recording spans the pharynx to the stomach and, in this instance, the tLESR is associated with an abdominal strain and a “microburp” evident by the brief UES relaxation and abrupt depressurization of the esophagus with gas venting. When the clip data are imported into the isobaric contour plot, it is evident that the SCJ clip excursion mirrors movement of the EGJ high-pressure band. Esophageal shortening is most prominent in the distal portion of the 10-cm segment isolated by the endoscopic clips, as seen from the approximately 7-cm movement of the distal SCJ clip concurrent with minimal movement of the proximal clip. Note also the absence of crural diaphragm contractions for the duration of the tLESR .

Proximal gastric distention is the major stimulus for tLESR. Distention stimulates mechanoreceptors (intraganglionic lamellar endings) in the proximal stomach, activating vagal afferent fibers projecting to the nucleus of the solitary tract. The efferent limb of both swallow and nonswallow LES relaxations lies in the preganglionic vagal inhibitory pathway to the LES. Both types of relaxation can be blocked by bilateral cervical vagotomy, cervical vagal cooling, or NO synthase inhibitors. tLESRs triggered by gastric distention likely use NO and CCK as neurotransmitters, evident by increased tLESR frequency after IV CCK infusion and blockade by either NO synthase inhibitors or CCK-A antagonists. Finally, GABA-B agonists, such as baclofen, inhibit tLESRs, acting on both peripheral receptors and receptors located in the dorsal motor nucleus of the vagus.

Esophageal Sensation

The human esophagus can sense mechanical, electrical, chemical, and thermal stimuli, perceived as chest pressure, warmth, or pain, with substantial overlap in perception among stimuli. Esophageal sensation is carried via both the vagal and spinal afferent nerves. The associated vagal neurons are located in the nodose and jugular ganglia, whereas the corresponding spinal neurons are located in thoracic and cervical dorsal root ganglia. Vagal afferents predominantly mediate homeostatic and secretory functions, whereas spinal afferents project centrally in a pattern characterized by overlap among spinal segments and convergence with somatic afferents. Consequently, esophageal pain tends to be poorly localized, accompanied by referred somatic pain and subject to viscerovisceral hyperalgesia. Esophageal sensations are usually perceived substernally; in the instance of pain, radiation to the midline of the back, shoulders, and jaw is very analogous to cardiac pain. These similarities are likely due to convergence of sensory afferent fibers from the heart and esophagus in the same spinal pathways, even to the same dorsal horn neurons in some cases.

Esophageal afferents are predominantly activated by wall stretch, temperature, and acidity. When accompanied by mucosal injury, inflammatory mediators (prostaglandins, bradykinins, etc.) augment the response. The proximal esophagus is more sensitive than the distal esophagus, consistent with the observation that proximal stimuli such as reflux are more likely to be perceived. Excessive proximal sensitivity has been associated with esophageal hypersensitivity and functional heartburn.

With sensory endings concentrated deeply within the muscularis propria beneath a relatively impermeable mucosa, it seems unlikely that intraluminal acid can directly stimulate them. However, these afferents easily respond to mucosally applied bile or capsaicin (a derivative of chili pepper), suggesting that these chemicals induce the release of an endogenous substance that in turn excites the afferents. These responses are thought to be mediated by transient receptor potential vanilloid 1 (TRPV1) receptors and/or acid-sensing ion channels. Consistent with this, current evidence suggests that chronic esophagitis increases mRNA expression of purinergic receptors accompanied by upregulation of TRPV1 and neurotrophic factors mediating sensitization of the inflamed human esophagus.

Owing to its significance in the pathogenesis of GERD, there has been substantial interest in modulating the tLESR reflex (see Chapter 44 ). The current concept is that vagal afferent endings terminating in intraganglionic lamellar endings located in the proximal stomach are primarily responsible for initiating the reflex, which is then mediated through the medulla and back to the esophagus and diaphragm via vagal efferents and the phrenic nerves. Pharmacologic and physiologic studies have demonstrated that the mechanotransduction properties of tension-sensitive vagal afferent fibers can be attenuated by the GABA-B receptor agonist baclofen, thereby reducing the frequency of tLESR. Glutamate receptors are also present in vagal and spinal sensory afferent fibers, and metabotropic glutamate receptor antagonists (especially mGluR5 antagonists) have also been shown to inhibit tLESR.

Recent investigations have also explored functional brain imaging, mainly functional magnetic resonance imaging, as a noninvasive assessment of brain function in visceral sensation and pain. Although the results thus far are quite variable among research groups, the brain regions most consistently activated by esophageal stimuli are the anterior and posterior insula, cingulate cortex, primary sensory cortex, prefrontal cortex, and thalamus. Preliminary studies also suggest differences in functional magnetic resonance imaging activation patterns among subgroups of GERD patients and normal controls.

Esophageal Motility Disorders

A working, albeit restrictive, definition of an esophageal motility disorder is: an esophageal disease attributable to neuromuscular dysfunction that causes symptoms referable to the esophagus, most commonly dysphagia, chest pain, or heartburn. Using this definition, there are only 3 firmly established primary esophageal motility disorders: achalasia, distal esophageal spasm (DES), and GERD. GERD is clearly the most prevalent among the group and, fittingly, it is addressed in detail elsewhere in this text (see Chapter 46 ).

Esophageal motility disorders can also be secondary phenomena, in which case esophageal dysfunction is part of a more global disease, such as in pseudoachalasia, Chagas disease, and PSS (scleroderma). Dysphagia due to pharyngeal or UES dysfunction can also be included in a discussion of esophageal motor disorders, but this is usually as a manifestation of a more global neuromuscular disease process. The major focus of this chapter will be on the primary motility disorders, particularly achalasia. However, mention will be made of the secondary motility disorders and proximal pharyngoesophageal dysfunction when important unique features exist.

Epidemiology

Estimates of the prevalence of dysphagia among individuals older than 50 years range from 16% to 22%, with most of this related to oropharyngeal dysfunction. Most oropharyngeal dysphagia is related to neuromuscular disease; the prevalence of the most common anatomic etiology, Zenker diverticulum, is estimated to range from a meager 0.01% to 0.11% of the population in the USA, with peak incidence in men between the 7th and 9th decades. The consequences of oropharyngeal dysphagia are severe: dehydration, malnutrition, aspiration, choking, pneumonia, and death. Within health care institutions, it is estimated that up to 13% of hospitalized patients and 60% of nursing home residents have feeding problems and, again, most are attributed to oropharyngeal dysfunction as opposed to esophageal dysfunction. Mortality of nursing residents with dysphagia and aspiration can be as high as 45% over 1 year. As the U.S. population continues to age, oropharyngeal dysphagia will become an increasing problem associated with complex medical and ethical issues.

Achalasia is the most easily recognized and best-defined motor disorder of the esophagus. Modern estimates of the incidence of achalasia are about 2.9 per 100,000 population in the USA and 2.6 per 100,000 in south Australia, affecting both genders equally and usually presenting between 25 and 60 years of age. Because achalasia is a chronic condition, its prevalence greatly exceeds its incidence; a recent estimate of achalasia prevalence in Chicago concluded that it may be as high as 76 per 100,000 population, given that the average age of diagnosis was 56 with an expected average survival of 26 years after diagnosis. Reports of familial clustering of achalasia raise the possibility of genetic predisposition. However, arguing against a strong genetic determinant, a survey of 1012 first-degree relatives of 159 achalasics identified no affected relatives. There is a rare genetic achalasia syndrome associated with adrenal insufficiency and alacrima. This syndrome is inherited as an autosomal recessive disease and manifests with the childhood onset of autonomic nervous system dysfunction including achalasia, alacrima, sinoatrial dysfunction, abnormal pupillary responses to light, and delayed gastric emptying. It is caused by mutations in AAAS, which encodes a protein known as ALADIN.

There are no population-based studies on the incidence or prevalence of esophageal motility disorders other than achalasia. Thus, the only way to estimate the incidence or prevalence of spastic disorders is to examine data on populations at risk and reference the observed frequency of spastic disorders to the incidence of achalasia, which, as detailed earlier, is about 2.75 per 100,000 population. Doing so, the prevalence of DES is much lower than that if modern restrictive diagnostic criteria are used. Populations at risk for motility disorders are patients with chest pain and/or dysphagia, so it is among these patients that extensive manometric data have been collected. Manometric abnormalities are prevalent among these groups, but in most cases the manometric findings are of unclear significance.

Pathogenesis

Oropharyngeal Dysphagia

Obstructing lesions of the oral cavity, head, and neck can cause dysphagia. Structural abnormalities may result from trauma, surgery, tumors, caustic injury, congenital anomalies, or acquired deformities. The most common structural abnormalities of the hypopharynx associated with dysphagia are hypopharyngeal diverticula and cricopharyngeal bars.

If the etiology of oropharyngeal dysphagia is not readily apparent after an initial evaluation for anatomic disorders, evidence of functional abnormalities should be sought. Primary neurologic or muscular diseases involving the oropharynx are often associated with dysphagia. Whereas esophageal dysphagia usually results from esophageal diseases, oropharyngeal dysphagia frequently results from neurologic or muscular diseases, with oropharyngeal dysfunction being just one pathologic manifestation. Although the disease specifics vary, the net effect on swallowing can be analyzed according to the mechanical description of the swallow outlined earlier. Table 44.1 summarizes the mechanical elements of the swallow, the manifestation and consequence of dysfunction, and representative pathologic conditions in which they are likely encountered. Neurologic examination may indicate cranial nerve dysfunction, neuromuscular disease, cerebellar dysfunction, or an underlying movement disorder. Functional abnormalities can be due to dysfunction of intrinsic musculature, peripheral nerves, or central nervous system control mechanisms. Of note, contrary to popular belief, the gag reflex is not predictive of pharyngeal swallowing efficiency or aspiration risk. The gag reflex is absent in 20% to 40% of normal adults.

TABLE 44.1
Mechanical Events of the Oropharyngeal Swallow, Evidence of Dysfunction, and Disease Association(s) in Patients with Oropharyngeal Dysphagia
Mechanical Event Evidence of Dysfunction Disease Association(s)
Nasopharyngeal closure Nasopharyngeal regurgitation
Nasal voice
Myasthenia gravis
Laryngeal closure Aspiration during bolus transit Stroke
Traumatic brain injury
UES opening Dysphagia
Postswallow residue/aspiration
Diverticulum formation
Cricopharyngeal bar Parkinson disease
Tongue loading and bolus propulsion Sluggish misdirected bolus Parkinson disease
Surgical defects
Cerebral palsy
Pharyngeal clearance Postswallow residue in hypopharynx/aspiration Polio or post-polio syndrome
Oculopharyngeal dystrophy
Stroke

Evident in Table 44.1 , oropharyngeal dysphagia is frequently the result of neurologic or muscular diseases. Neurologic diseases can damage the neural structures requisite for either the afferent or efferent limbs of the oropharyngeal swallow. Virtually any neuromuscular disease can potentially cause dysphagia (see Chapter 37 ). As there is nothing unique to neurons controlling swallowing, their involvement in disease processes is usually random. Furthermore, in most instances, functions mediated by adjacent neuronal structures are concurrently involved. The following discussion will focus on neuromuscular pathologic processes most commonly encountered.

Stroke

Aspiration pneumonia has been estimated to inflict a 20% death rate in the first year after a stroke, and 10% to 15% each year thereafter. It is usually not the first episode of aspiration pneumonia, but the subsequent recurrences over the years that eventually cause death. The ultimate cause of aspiration pneumonia is dysphagia leading to aspiration that can occur by a number of mechanisms: absence or severe delay in triggering the swallow, reduced lingual control, or weakened laryngo-pharyngeal musculature. Conceptually, these etiologies can involve motor or sensory impairments. Cortical infarcts are less likely to result in severe dysphagia than brainstem strokes. Cortical infarcts are also more likely to demonstrate recovery from dysphagia. Of 86 consecutive patients who sustained an acute cerebral infarct, 37 (43%) experienced dysphagia when evaluated within 4 days of the event. However, 86% of these patients were able to swallow normally 2 weeks later, with recovery resulting from contralateral areas taking over the lost function. Failure to recover was more likely among patients incurring larger infarcts or patients who had prior infarcts.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive neurologic disease characterized by degeneration of motor neurons in the brain, brainstem, and spinal cord. Specific symptoms are dependent upon the locations of affected motor neurons and the relative severity of involvement. When the degenerative process involves the cranial nerve nuclei, swallowing difficulties ensue. Oropharyngeal dysfunction characteristically begins with the tongue and progresses to involve the pharyngeal and laryngeal musculature. Patients experience choking attacks, become volume depleted or malnourished, and incur aspiration pneumonia. The decline in swallowing function is progressive and predictable, invariably leading to gastrostomy feeding. Patients often die as a consequence of their swallowing dysfunction in conjunction with respiratory depression.

Parkinson Disease

Although only 15% to 20% of patients with Parkinson disease complain of swallowing problems, more than 95% have demonstrable defects when studied videofluoroscopically. This disparity suggests that patients compensate in the early stages of the disease and complain of dysphagia only when it becomes severe. Abnormalities include repetitive lingual pumping prior to initiation of a pharyngeal swallow, piecemeal swallowing, and oral residue after the swallow. Patients may also exhibit a delayed swallow response and a weak pharyngeal contraction, resulting in vallecular and pyriform sinus residue. Recent data suggest this to be related to the combination of incomplete UES relaxation and a weakened pharyngeal contraction.

Vagus Nerve Disorders

Unilateral lesions of the vagus can result in hemiparesis of the soft palate and pharyngeal constrictors, as well as of the laryngeal musculature. The recurrent laryngeal nerves can be injured as a result of thyroid surgery, aortic aneurysms, pneumonectomy, primary mediastinal malignancies, or metastatic lesions to the mediastinum. Owing to its more extensive loop in the chest, the left recurrent laryngeal nerve is more vulnerable to involvement by mediastinal malignancy than the right laryngeal nerve. Unilateral recurrent laryngeal nerve injury results in unilateral adductor paralysis of the vocal cord. This defect can result in aspiration during swallowing because of impaired laryngeal closure. It is, however, rare to have any primary pharyngeal dysfunction resultant from recurrent laryngeal nerve injury.

Oculopharyngeal Muscular Dystrophy

Oculopharyngeal muscular dystrophy is a syndrome characterized by ptosis and progressive dysphagia. In the past, afflicted patients reaching age 50 typically died of starvation resulting from pharyngeal paralysis. The disease is now known to be a form of muscular dystrophy and is inherited as an autosomal dominant disorder, with occurrences clustered in families of French-Canadian descent. Genetic studies of an afflicted family indicate linkage to chromosome 14, perhaps involving the region coding for cardiac alpha or beta myosin heavy chains. Oculopharyngeal dystrophy affects the striated pharyngeal muscles and the levator palpebrae. Although other forms of muscular dystrophy occasionally affect the pharyngeal constrictors, this is rarely a dominant manifestation. The first symptom of oculopharyngeal dystrophy is usually ptosis that slowly progresses and eventually dominates the patient’s appearance. Dysphagia may begin after, concomitant with, or even before ptosis. The dominant functional abnormalities are of a weak or absent pharyngeal contraction, reduced cricopharyngeal opening, and hypopharyngeal stasis. Dysphagia is slowly progressive, but may ultimately lead to starvation, aspiration pneumonia, or asphyxia.

Myasthenia Gravis

Myasthenia gravis is a progressive autoimmune disease characterized by high circulating levels of ACh receptor antibody and destruction of ACh receptors at neuromuscular junctions. Musculature controlled by the cranial nerves is almost always involved, particularly the ocular muscles. Dysphagia is prominent in more than a third of patients with myasthenia gravis and, in unusual instances, can be the initial and dominant manifestation of the disease. In mild cases, dysphagia may not be evident until after 15 to 20 minutes of eating. Classically, manometric studies reveal a progressive deterioration in the amplitude of pharyngeal contractions with repeated swallows. Peristaltic amplitude recovers with rest or following the administration of 10 mg edrophonium chloride, an acetylcholinesterase inhibitor. In more advanced cases, the dysphagia can be profound and associated with nasopharyngeal regurgitation and nasality of the voice, even to the extent of being confused with bulbar amyotrophic lateral sclerosis or brainstem stroke.

Hypopharyngeal (Zenker) Diverticula and Cricopharyngeal Bar

Hypopharyngeal diverticula and cricopharyngeal bars are closely related disease entities in that it is a cricopharyngeal bar that can result in diverticulum formation. The most common type, Zenker diverticulum ( Fig. 44.8 ), originates in the midline posteriorly at Killian dehiscence, a point of pharyngeal wall weakness between the oblique fibers of the inferior pharyngeal constrictor and the transverse cricopharyngeus muscle. Other locations of acquired pharyngeal diverticula include: (1) the lateral slit separating the cricopharyngeus muscle from the fibers of the proximal end of the esophagus, through which the recurrent laryngeal nerve and its accompanying vessels run to supply the larynx; (2) at the penetration of the inferior thyroid artery into the hypopharynx; (3) and at the junction of the middle and inferior constrictor muscles. The unifying theme of these locations is that they are sites of potential weakness of the muscular lining of the hypopharynx through which the mucosa herniates, leading to a “false” diverticulum. The best-substantiated explanation for the development of diverticula is that they form as a result of a restrictive myopathy associated with diminished compliance of the cricopharyngeus muscle. Surgical specimens of cricopharyngeus muscle strips from patients with hypopharyngeal diverticula demonstrated structural changes that would decrease UES compliance and opening. The cricopharyngeus samples from these patients had “fibro-adipose tissue replacement and (muscle) fiber degeneration.” Thus, although the muscle relaxes normally during a swallow, it cannot distend normally, resulting in the appearance of a cricopharyngeal indentation, or bar, during a barium swallow ( Fig. 44.9 ). Diminished sphincter compliance necessitates increased hypopharyngeal intrabolus pressure to maintain trans-sphincteric flow through the smaller UES opening. The increased stress on the hypopharynx from the increased intrabolus pressure may ultimately result in diverticulum formation.

Fig. 44.8, Film from a barium swallow study showing a small Zenker diverticulum. Although the point of herniation is midline posterior at Killian dehiscence, the diverticulum migrates laterally in the neck as it enlarges, because there is no potential space between the posterior pharyngeal wall and the vertebral column.

Fig. 44.9, Film from a barium swallow study showing a cricopharyngeal bar in a patient with oropharyngeal dysphagia. The posterior indentation of the barium column is caused by a noncompliant cricopharyngeus muscle.

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