Esophageal Disorders PDF

44 Esophageal Neuromuscular Function and Motility Disorders John E. Pandolfino, Peter J. Kahrilas CHAPTER OUTLINE Additionally, extrinsic muscles elevate...

44 Esophageal Neuromuscular Function and Motility Disorders John E. Pandolfino, Peter J. Kahrilas CHAPTER OUTLINE 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 infe- MOTOR AND SENSORY FUNCTION 638 rior pharyngeal constrictors (see Fig. 44.1), overlap and insert Oropharynx and Upper Esophageal Sphincter  638 into a collagenous sheet, the buccopharyngeal aponeurosis. The The Pharyngeal Swallow 639 inferior constrictor is composed of the thyropharyngeus (supe- Esophagus  640 rior part) and the cricopharyngeus (inferior part). The thyropha- Esophagogastric Junction (EJG) 642 ryngeus arises from the thyroid cartilage, passes posteromedially, Esophageal Sensation 644 and inserts in the median raphe. The cricopharyngeus has supe- ESOPHAGEAL MOTILITY DISORDERS  645 rior and inferior components, each of which arise bilaterally from the sides of the cricoid lamina; the superior fibers course Epidemiology  646 posteromedially to the median raphe whereas the inferior fibers Pathogenesis 646 loop around the esophageal inlet without a median raphe. Killian Clinical Features 650 triangle, a triangular area of thin muscle, is formed posteriorly Differential Diagnosis  651 between these components and is the most common site of origin Diagnostic Methods 652 for pharyngeal pulsion diverticula. Treatment 656 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 cricopharyn- The esophagus is a muscular tube with a sphincter at each end geus muscle, separating the pharynx from the esophagus. The joining the hypopharynx to the stomach with the simple function larynx and trachea are suspended in the neck between the hyoid of transporting food, fluid, and gas between these endpoints. As bone superiorly and the sternum inferiorly. A number of muscles, such, the esophagus encompasses the anatomic and physiologic categorized as the laryngeal strap muscles, contribute to this sus- transition from the striated muscle oropharynx and the smooth pension and, together with the intrinsic elasticity of the trachea, muscle gut. Neurologically, the oropharynx is controlled by the permit the larynx to be raised and lowered. The hyoid bone also cerebral cortex and medulla and capable of precise tactile sensa- serves as the base for the tongue that rests upon it. Laryngeal tion; the distal esophagus is composed entirely of smooth muscle, movement is crucial to the swallow response as the laryngeal inlet controlled by the vagus nerve and enteric nervous system, and is both closed and physically removed from the bolus path in the comparatively insensitive. Although there is a gradual transition course of a swallow. Failure to achieve this synchronized laryn- between these endpoints, motor function in the oropharynx and geal movement can result in aspiration. esophageal body are quite distinct. With that in mind, the ensu- The pharyngeal muscles are densely innervated with motor ing discussion includes selected aspects of pharyngeal, gastric, fibers coming from nuclei of the trigeminal, facial, glossopha- and diaphragmatic function that are inextricably entwined with ryngeal, and hypoglossal nuclei, as well as the nucleus ambiguus esophageal function. 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 MOTOR AND SENSORY FUNCTION those innervating the pharynx and larynx more caudally.1 The muscular components of the UES are the cricopharyngeus, adja- Oropharynx and Upper Esophageal Sphincter cent esophagus, and adjacent inferior constrictor with the crico- Within the oral cavity, the lips, teeth, hard palate, soft palate, pharyngeus contributing the 1 cm zone of maximal pressure.2 mandible, floor of the mouth, and tongue serve to form and con- The closed sphincter has a slit-like configuration, with the cricoid tain food into a bolus suitable for transfer to the pharynx. The lamina anterior and the cricopharyngeus lateral and posterior. pharynx is divided into 3 segments: nasopharynx, oropharynx, Neural input via vagal trunks originating in the nucleus ambiguus and hypopharynx (Fig. 44.1). The nasopharynx extends from the maintains UES pressure and vagal transection abolishes this con- base of the skull to the distal edge of the soft palate. Muscles in tractile activity. the nasopharynx elevate the soft palate during swallowing, seal Manometric evaluation of UES function is difficult because the nasopharynx, and prevent nasopharyngeal regurgitation. The it is a short, complex anatomic zone that moves briskly during oropharynx extends from the soft palate to the base of the tongue. swallowing. Furthermore, UES pressure is heavily influenced by The inferior margin of the oropharynx is demarcated by the val- recording methodology, owing both to its marked asymmetry and leculae anteriorly and the mobile tip of the epiglottis posteriorly. to its reflexive contraction to pharyngeal and esophageal stimula- The hypopharynx extends from the valleculae to the inferior tion. Thus, it is not possible to define a meaningful normal range margin of the cricoid cartilage and includes the upper esophageal of UES pressure.3 UES relaxation during swallowing also poses sphincter (UES). substantial recording challenges, making for great variability in Musculature of the soft palate, tongue, and pharynx all par- technique and interpretation. However, HRM using solid-state ticipate during swallowing to collapse and shorten the pha- technology permits accurate tracking of UES relaxation and ryngeal lumen and then expel its contents into the esophagus. intrabolus pressure changes during swallowing (Fig. 44.2). 638  CHAPTER 44 Esophageal Neuromuscular Function and Motility Disorders 639 44 Digastric (post. belly) Soft palate Superior Hard palate Lateral constrictor Oral cavity pterygoid plate Styloid process Tongue Oral pharynx Buccinator Styloglossus Valleculae Digastric (ant. belly) Stylohyoid ligament Hyoid bone Glossopharyngeus Epiglottis Stylopharyngeus Mylohyoid Laryngeal pharynx Middle constrictor Thyrohyoid membrane (hypopharynx) Mylohyoid Hyoglossus Vocal cord Esophagus Stylohyoid Thyrohyoid membrane Transverse arytenoid Hyoid bone Inferior constrictor Cricothyroid membrane Thyroid cartilage Cricopharyngeus Cricoid cartilage Cricothyroid membrane Esophagus Cricoid cartilage A B 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 ful- crum 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. (Reprinted from Kahrilas PJ, Frost F. Disorders of swallowing and bowel motility. In: Green D, editor. Medical problems of the chronically disabled. Rockville, MD: Aspen Publishers; 1990. p 11-37.) The UES maintains closure of the proximal end of the esoph- Although understood physiologically as the patterned acti- agus unless opening is required, necessitated for swallowing or vation of motor neurons and their corresponding motor units, belching. It also constitutes an additional barrier to refluxed swallowing is clinically evaluated in mechanical terms and best material entering the pharynx from the esophagus and prevents evaluated by videofluoroscopic or cineradiographic analysis. The air from entering the esophagus by contracting in synchrony pharyngeal swallow rapidly reconfigures pharyngeal structures with inspiration. Inspiratory augmentation is most evident dur- from a respiratory to an alimentary pathway and then reverses ing periods of low UES pressure and can be exaggerated in this reconfiguration within 1 second. The pharyngeal swallow individuals experiencing globus sensation.4 Balloon distension response can be dissected into several closely coordinated actions: of the esophagus stimulates UES contraction,5 with the effect (1) nasopharyngeal closure by elevation and retraction of the soft being more pronounced with proximal balloon positions. How- palate, (2) UES opening, (3) laryngeal closure, (4) tongue load- ever, when the distension pattern of gas reflux is simulated using ing (ramping), (5) tongue pulsion, and (6) pharyngeal clearance. a cylindrical bag or rapid air injection into the esophagus, UES Precise coordination of these actions is an obvious imperative, relaxation rather than contraction occurs.2 Belch-induced UES and to some degree the relative timing of these events is affected relaxation is also associated with glottic closure. Stress augments either by volition or by the volume of the swallowed bolus (see UES pressure, whereas anesthesia or sleep6 virtually eliminates it. Fig. 44.2). Neither experimental acid perfusion of the esophagus nor spon- The most fundamental anatomic reconfiguration required to taneous gastroesophageal acid reflux alters continuously recorded transform the oropharynx from a respiratory to a swallow path- UES pressure in either normal volunteers or in individuals with way is to open the inlet to the esophagus and seal the inlet to peptic esophagitis. 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 The Pharyngeal Swallow and UES opening. UES relaxation is due to cessation of excit- Disorders of the oral phase of swallowing occur with many con- atory neural input while the larynx is elevating. Once the larynx ditions characterized by global neurologic dysfunction, such as is elevated, UES opening results from traction on the anterior traumatic brain injury, brain tumors, or chorea (see Chapter 37). sphincter wall caused by contraction of the supra- and infrahyoid Detailed discussion of these conditions can be found in texts on musculature that also results in a characteristic pattern of hyoid swallow evaluation and therapy.7 The pharyngeal swallow is the displacement. largely subconscious coordinated contraction that transfers oral Bolus transport out of the oropharynx is facilitated by the contents into the esophagus. Afferent sensory fibers capable of tongue and pharyngeal constrictors. Tongue motion adapts to triggering the pharyngeal swallow travel centrally via the inter- varied swallow conditions and propels most of the bolus into the nal branch of the superior laryngeal nerve (from the larynx) and esophagus prior to the onset of the pharyngeal contraction. On the glossopharyngeal nerve (from the pharynx). These sensory the other hand, the pharyngeal contraction is more stereotyped, fibers converge before terminating in the medullary swallow functioning to strip the last residue from the pharyngeal walls. center. UES closure coincides with passage of the pharyngeal contraction.  CHAPTER 44 Esophageal Neuromuscular Function and Motility Disorders 639 44 Digastric (post. belly) Soft palate Superior Hard palate Lateral constrictor Oral cavity pterygoid plate Styloid process Tongue Oral pharynx Buccinator Styloglossus Valleculae Digastric (ant. belly) Stylohyoid ligament Hyoid bone Glossopharyngeus Epiglottis Stylopharyngeus Mylohyoid Laryngeal pharynx Middle constrictor Thyrohyoid membrane (hypopharynx) Mylohyoid Hyoglossus Vocal cord Esophagus Stylohyoid Thyrohyoid membrane Transverse arytenoid Hyoid bone Inferior constrictor Cricothyroid membrane Thyroid cartilage Cricopharyngeus Cricoid cartilage Cricothyroid membrane Esophagus Cricoid cartilage A B 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 ful- crum 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. (Reprinted from Kahrilas PJ, Frost F. Disorders of swallowing and bowel motility. In: Green D, editor. Medical problems of the chronically disabled. Rockville, MD: Aspen Publishers; 1990. p 11-37.) The UES maintains closure of the proximal end of the esoph- Although understood physiologically as the patterned acti- agus unless opening is required, necessitated for swallowing or vation of motor neurons and their corresponding motor units, belching. It also constitutes an additional barrier to refluxed swallowing is clinically evaluated in mechanical terms and best material entering the pharynx from the esophagus and prevents evaluated by videofluoroscopic or cineradiographic analysis. The air from entering the esophagus by contracting in synchrony pharyngeal swallow rapidly reconfigures pharyngeal structures with inspiration. Inspiratory augmentation is most evident dur- from a respiratory to an alimentary pathway and then reverses ing periods of low UES pressure and can be exaggerated in this reconfiguration within 1 second. The pharyngeal swallow individuals experiencing globus sensation.4 Balloon distension response can be dissected into several closely coordinated actions: of the esophagus stimulates UES contraction,5 with the effect (1) nasopharyngeal closure by elevation and retraction of the soft being more pronounced with proximal balloon positions. How- palate, (2) UES opening, (3) laryngeal closure, (4) tongue load- ever, when the distension pattern of gas reflux is simulated using ing (ramping), (5) tongue pulsion, and (6) pharyngeal clearance. a cylindrical bag or rapid air injection into the esophagus, UES Precise coordination of these actions is an obvious imperative, relaxation rather than contraction occurs.2 Belch-induced UES and to some degree the relative timing of these events is affected relaxation is also associated with glottic closure. Stress augments either by volition or by the volume of the swallowed bolus (see UES pressure, whereas anesthesia or sleep6 virtually eliminates it. Fig. 44.2). Neither experimental acid perfusion of the esophagus nor spon- The most fundamental anatomic reconfiguration required to taneous gastroesophageal acid reflux alters continuously recorded transform the oropharynx from a respiratory to a swallow path- UES pressure in either normal volunteers or in individuals with way is to open the inlet to the esophagus and seal the inlet to peptic esophagitis. 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 The Pharyngeal Swallow and UES opening. UES relaxation is due to cessation of excit- Disorders of the oral phase of swallowing occur with many con- atory neural input while the larynx is elevating. Once the larynx ditions characterized by global neurologic dysfunction, such as is elevated, UES opening results from traction on the anterior traumatic brain injury, brain tumors, or chorea (see Chapter 37). sphincter wall caused by contraction of the supra- and infrahyoid Detailed discussion of these conditions can be found in texts on musculature that also results in a characteristic pattern of hyoid swallow evaluation and therapy.7 The pharyngeal swallow is the displacement. largely subconscious coordinated contraction that transfers oral Bolus transport out of the oropharynx is facilitated by the contents into the esophagus. Afferent sensory fibers capable of tongue and pharyngeal constrictors. Tongue motion adapts to triggering the pharyngeal swallow travel centrally via the inter- varied swallow conditions and propels most of the bolus into the nal branch of the superior laryngeal nerve (from the larynx) and esophagus prior to the onset of the pharyngeal contraction. On the glossopharyngeal nerve (from the pharynx). These sensory the other hand, the pharyngeal contraction is more stereotyped, fibers converge before terminating in the medullary swallow functioning to strip the last residue from the pharyngeal walls. center. UES closure coincides with passage of the pharyngeal contraction. 640 PART V Esophagus 1 2 3 4 5 6 7 mm Hg 150 100 50 30 0 Glossopalatal junction opening 0.1 Velopharyngeal junction closure sec Laryngeal vestibule closure UES opening 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 con- figuration 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. (With permission from the Esophageal Center at Northwestern.) However, the contractile activity of the sphincter has an added cricoid cartilage with slips from the cricopharyngeus passing dimension as well, exhibiting augmented contractility during dorsolaterally to fuse posteriorly about 3 cm distal to the cricoid laryngeal descent, resulting in a grabbing effect such that the cartilage. This results in a posterior triangular area devoid of lon- sphincter and laryngeal descent complement each other to clear gitudinal muscle, Laimer triangle. Distal to Laimer triangle, the residue from the hypopharynx.8 This clearing function probably longitudinal muscles form a continuous sheath of uniform thick- acts to minimize the risk of postswallow aspiration by prevent- ness around the esophagus. The adjacent, inner muscle layer is ing residual material from adhering to the laryngeal inlet when formed of circular or, more precisely, helical muscle also forming respiration resumes. 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 Esophagus the lower esophageal sphincter (LES).9 Unlike the distal GI tract, The esophagus is a 20- to 22-cm tube composed of skeletal and there is no serosal layer to the esophagus. smooth muscle. The proportion of each muscle type is spe- The extrinsic innervation of the esophagus is via the vagus cies dependent, but in humans, the proximal 5% is striated, the nerve with motor neurons in nucleus ambiguus (striated muscle middle 35% to 40% is mixed with an increasing proportion of portion) and the dorsal motor nucleus of the vagus (smooth mus- smooth muscle distally, and the distal 50% to 60% is entirely cle portion). Efferent vagal fibers reach the cervical esophagus by smooth muscle. The outer longitudinal muscle arises from the the pharyngoesophageal nerve, and synapse directly on striated  CHAPTER 44 Esophageal Neuromuscular Function and Motility Disorders 641 (A) Segmental Architecture (B) Landmarks of Propagation 44 0 UES 5 mm Hg 150 Segment 1 10 P (transition zone) Length along the esophagus (cm) 100 15 Segment 2 M 20 CFV 50 Segment 3 DL 30 25 D CDP 0 EGJ 30 relaxation EGJ 10 s 35 Time (sec) Time (sec) 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 reconsti- tution. 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. (With permission from the Esophageal Center at Northwestern.) muscle neuromuscular junctions. The vagus also provide sensory innervation; in the cervical esophagus, this is via the superior Esophageal Peristalsis laryngeal nerve with cell bodies in the nodose ganglion, whereas The esophagus is normally atonic and its intraluminal pressure in the remainder of the esophagus, sensory fibers travel via the closely reflects pleural pressure, becoming negative during inspi- recurrent laryngeal nerve or, in the most distal esophagus, via ration. However, swallowing or focal distention initiates peristal- the esophageal branches of the vagus. Vagal afferents are strongly sis. Primary peristalsis is initiated by a swallow and traverses the stimulated by esophageal distension. entire length of the esophagus; secondary peristalsis can be elic- The esophagus also contains an autonomic nerve network, the ited in response to focal esophageal distention with air, fluid, or a myenteric plexus, located between the longitudinal and circular balloon, beginning at the locus of distention. The mechanical cor- muscle layers. Myenteric plexus neurons are sparse in the proxi- relate of peristalsis is of a stripping wave that milks the esophagus mal esophagus, and their function is unclear because the striated clean from its proximal to distal end. The propagation of the strip- muscle is directly controlled by nucleus ambiguus motor neurons. ping wave corresponds closely with that of the manometrically On the other hand, in the smooth muscle esophagus pregangli- recorded contraction such that the point of luminal closure seen onic neurons in the dorsal motor nucleus of the vagus synapse on fluoroscopically at each esophageal locus corresponds with the relay neurons in the myenteric plexus ganglia. A second nerve upstroke of the pressure wave on line tracings or the contractile network, the submucosal or Meissner plexus, is situated between wavefront on esophageal pressure topography (EPT) (Fig. 44.3). the muscularis mucosa and the circular muscle layer, but this is The likelihood of achieving complete esophageal emptying from sparse in the human esophagus. the distal esophagus is inversely related to peristaltic amplitude, 642 PART V Esophagus such that emptying becomes progressively impaired with peri- pressure trough, followed by the LES, which contracts with vigor staltic amplitudes of 30 mm Hg or less.10 However, emptying is and persistence quite dissimilar to the adjacent smooth muscle also modified by the pressure gradient across the esophagogastric esophagus.15 More recently, a distinct landmark along the wave- junction (EGJ), and this interaction can have significant influence front was recognized localized in the third segment, at which on both bolus transit and peristaltic contractility. point contractile propagation slows dramatically (see Fig. 44.3).16 Another essential feature of peristalsis is deglutitive inhibition. This landmark, defined as the contractile deceleration point A second swallow initiated while an earlier peristaltic contraction (CDP), has pathophysiologic significance because it is localized is still progressing in the proximal esophagus completely inhibits at the proximal aspect of the LES, and it is hypothesized that this the contraction induced by the first swallow. Deglutitive inhibi- represents the locus of termination of peristalsis.17 Contraction tion in the distal esophagus is attributable to hyperpolarization of beyond this point is more consistent with reconstitution of the the circular smooth muscle and is mediated via inhibitory gangli- LES that was relaxed, elongated, and effaced during peristalsis to onic neurons in the myenteric plexus. Deglutitive inhibition can form the phrenic ampulla. be demonstrated experimentally in the esophagus by distending an intraluminal balloon, which stimulates esophageal contrac- tion.11 Once the high-pressure zone is established, deglutitive Longitudinal Muscle inhibition is evident after swallowing while recording intralumi- The longitudinal muscle of the esophagus also contracts during nal pressure between the balloon and the esophageal wall. peristalsis, with the net effect of transiently shortening the struc- The physiologic control mechanisms governing the stri- ture by 2 to 2.5 cm. Similar to the pattern of circular muscle con- ated and smooth muscle esophagus differ. The striated muscle traction, longitudinal muscle contraction is propagated distally as receives exclusively excitatory vagal innervation, and its peristal- an active segment at a rate of 2 to 4 cm/s.18 Central mechanisms tic contraction results from sequential activation of the muscula- control longitudinal muscle contraction during peristalsis with ture. These vagal fibers release acetylcholine (ACh) and stimulate progressively increasing latency moving distally, similar to that nicotinic cholinergic receptors on the striated muscle cells. Stri- seen with the circular smooth muscle. However, unlike the cir- ated muscle peristalsis is programmed by the medullary swallow- cular muscle, nerve stimulation studies suggest the longitudinal ing center in much the same way as is the pharyngeal swallow. muscle to be free of inhibitory neural control. 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 Esophagogastric Junction (EJG) fibers synapse on myenteric plexus neurons rather than directly The anatomy of the EGJ is complex (see also Chapter 43). The on muscle cells. However, the myenteric plexus can also orches- distal end of the esophagus is anchored to the diaphragm by the trate peristalsis independently of vagal activation; secondary phrenoesophageal ligament that inserts circumferentially into peristalsis can be elicited anywhere along the smooth muscle the esophageal musculature close to the squamocolumnar junc- esophagus despite extrinsic denervation. In contrast, transection tion (SCJ). The esophagus then traverses the diaphragmatic hia- across the striated muscle esophagus does not inhibit peristaltic tus and joins the stomach almost tangentially. Thus, there are 3 progression across the transection site or distally. contributors to the EGJ high-pressure zone: the LES, the crural Regardless of central or ganglionic control, esophageal smooth diaphragm, and the musculature of the gastric cardia that consti- muscle contraction is ultimately elicited by ganglionic choliner- tutes the distal aspect of the EGJ. The LES is a 3- to 4-cm seg- gic neurons. Less clear are the control mechanisms for the direc- ment of tonically contracted smooth muscle at the distal extreme tion and velocity of peristalsis. Nerve conduction studies indicate of the esophagus. Surrounding the LES at the level of the SCJ that neural stimuli initiated by swallowing reach the ganglionic is the crural diaphragm, most commonly bundles of the right neurons along the length of the esophagus essentially simulta- diaphragmatic crus forming a teardrop-shaped canal about 2 cm neously. However, the latency between the arrival of the vagal long on its major axis (Fig. 44.5).19 The component of the EGJ stimulus and muscle contraction progressively increases, moving high-pressure zone distal to the SCJ is largely attributable to the aborally. In humans, the latent period is 2 seconds in the proxi- opposing sling and clasp fibers of the middle layer of gastric car- mal smooth muscle esophagus and 5 to 7 seconds just proximal dia musculature.20 In this region, the lateral wall of the esopha- to the LES. The current hypothesis is that peristaltic direction gus meets the medial aspect of the dome of the stomach at an and velocity result from a neural gradient along the esophagus, acute angle, defined as the angle of His. Viewed intraluminally, wherein excitatory ganglionic neurons dominate proximally and this region extends within the gastric lumen, appearing as a fold inhibitory ganglionic neurons dominate distally (Fig. 44.4). This that has been conceptually referred to as a “flap valve” because organization is consistent with the demonstration of 2 subseg- increased intragastric pressure forces it closed, sealing off the ments within the smooth muscle segment with pressure topogra- entry to the esophagus. phy plotting, the first of which is strongly reactive to cholinergic Physiologically, the EGJ high-pressure zone is attributable drugs.12 The primary inhibitory neurotransmitter is nitric oxide to a composite of both the LES and the surrounding crural dia- (NO), produced from l-arginine by the enzyme NO synthase in phragm extending 1 to 1.5 cm proximal to the SCJ and about 2 myenteric neurons.13 There is also evidence for a role of vasoac- cm distal to it.21 Resting LES tone ranges from 10 to 30 mm Hg tive intestinal polypeptide (VIP)-containing neurons mediating relative to intragastric pressure, with considerable temporal fluc- inhibition.14 tuation. With HRM, this is quantified as the EGJ contractile inte- High-resolution EPT allows for the imaging of esophageal gral, and the normal value ranges from 28 to 125 mm Hg/cm.22 contractility as a continuum not only in time, but also along the The mechanism of LES tonic contraction is likely both myogenic length of the esophagus. Clouse and colleagues pioneered this and neurogenic, consistent with the observation that pressure technology, noting that peristalsis was not a seamless wave of within the sphincter persists after elimination of neural activity pressurization, but rather a coordinated sequence of 4 contigu- with tetrodotoxin. Myogenic LES tone varies directly with mem- ous contractile segments (see Fig. 44.3). A transition zone exists brane potential that leads to an influx of Ca2+. Apart from myo- between the first and second segments, characterized by the nadir genic factors, LES pressure is also modulated by intra-abdominal peristaltic amplitude, slightly delayed progression, and occasional pressure, gastric distention, peptides, hormones, foods, and failed transmission. The topographic analysis also reveals a seg- many medications. Large increases in LES pressure occur with mental characteristic of peristaltic progression within the smooth the migrating motor complex; during phase III of the migrat- muscle esophagus, with 2 contractile segments separated by a ing motor complex, the LES pressure may exceed 80 mm Hg.  CHAPTER 44 Esophageal Neuromuscular Function and Motility Disorders 643 A B C D 44 UES Striated muscle Smooth 8 cm muscle 3 cm LES 200 mm Hg 8 cm 0 mm Hg 200 mm Hg 3 cm 0 mm Hg 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. (Modified from Goyal R, Shaker R, GI Motility Online.) Lesser fluctuations occur throughout the day, with pressure decreasing in the postprandial state and increasing during sleep.23 LES Relaxation Superimposed on the myogenic LES contraction, input from LES relaxation can be triggered by distention from either side vagal, adrenergic, hormonal, and mechanical influences will alter of the EGJ or swallowing. Relaxation induced by esophageal LES pressure. Vagal influence is similar to that of the esophageal distention is an intramural process, unaffected by vagotomy. body, with vagal stimulation activating both excitatory and inhib- Relaxation is, however, antagonized by tetrodotoxin, proving itory myenteric neurons. Thus, the LES pressure at any instant that it is mediated by postganglionic nerves. Deglutitive LES reflects the balance between excitatory (cholinergic) and inhibi- relaxation is mediated by the vagus nerve, which synapses with tory (nitrergic) neural input, and altering the pattern of vagal dis- inhibitory neurons in the myenteric plexus. NO, produced by charge results in LES relaxation. The crural diaphragm is also NO synthase from the precursor amino acid l-arginine, is the a major contributor to EGJ pressure. Even after esophagogas- main neurotransmitter in the postganglionic neurons responsible trectomy, with consequent removal of the smooth muscle LES, a for LES relaxation. NO is released with neural stimulation in the persistent EGJ pressure of about 6 mm Hg can be demonstrated esophagus, LES, and stomach, and NO synthase inhibitors block during expiration. During inspiration, there is substantial aug- neurally mediated LES relaxation.13,25 However, NO may not mentation of EGJ pressure attributable to crural diaphragm con- work alone. VIP-containing neurons have been demonstrated in traction. Crural diaphragm contraction is also augmented during the submucosal plexus and VIP relaxes the LES by direct muscle abdominal compression, straining, or coughing.24 On the other action. It is thought that VIP acts on NO synthase–containing hand, during esophageal distension, vomiting, and belching, neural terminals as a prejunctional neurotransmitter, facilitating electrical activity in the crural diaphragm is selectively inhibited the release of NO and on gastric muscle cells to stimulate produc- despite continued respiration, demonstrating a control mecha- tion of NO by the muscle.26 nism independent of the costal diaphragm. This reflex inhibition Another contributor to intraluminal pressure during bolus of crural activity is eliminated with vagotomy. transit through the LES is the bolus itself. The LES relaxes 644 PART V Esophagus esophageal shortening; (3) there is no synchronized esophageal Esophagus peristalsis; and (4) they are associated with crural diaphragm Aorta inhibition, which is not the case with swallow-induced relaxation (Fig. 44.7).27,28 tLESRs occur most frequently in the postprandial state during gastric distention. In the setting of the completely L1 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. Proximal gastric distention is the major stimulus for tLESR. Distention stimulates mechanoreceptors (intraganglionic lamel- lar 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, cervi- cal vagal cooling, or NO synthase inhibitors. tLESRs triggered Right crus Left crus by gastric distention likely use NO and CCK as neurotransmit- of diaphragm of diaphragm ters, evident by increased tLESR frequency after IV CCK infu- sion 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.29,30 Fig. 44.5 Anatomy of the diaphragmatic hiatus as viewed from below. The most common anatomy, in which the muscular elements of the Esophageal Sensation crural diaphragm derive from the right diaphragmatic crus, is shown. The human esophagus can sense mechanical, electrical, chemical, The right crus arises from the anterior longitudinal ligament overly- and thermal stimuli, perceived as chest pressure, warmth, or pain, ing the lumbar vertebrae. Once muscular elements emerge from the with substantial overlap in perception among stimuli.31 Esophageal tendon, 2 flat muscular bands form that cross each other in scissor-like sensation is carried via both the vagal and spinal afferent nerves. fashion forming the walls of the hiatus and then merging with each The associated vagal neurons are located in the nodose and jugular other anterior to the esophagus. L1, first lumbar vertebrae. (Modified ganglia, whereas the corresponding spinal neurons are located in from Jaffee BM. Surgery of the esophagus. In: Orlando RC, editor. Atlas thoracic and cervical dorsal root ganglia. Vagal afferents predomi- of esophageal diseases. 2nd ed. Philadelphia: Current Medicine, Inc.; nantly mediate homeostatic and secretory functions, whereas spi- 2002. p 221-42.) nal afferents project centrally in a pattern characterized by overlap among spinal segments and convergence with somatic afferents. during the initial phase of the swallow, but it does not actually Consequently, esophageal pain tends to be poorly localized, open until the bolus enters the sphincter, thereby implicating accompanied by referred somatic pain and subject to viscerovis- intrabolus pressure. Hence, EGJ opening is dependent on the ceral hyperalgesia.32 Esophageal sensations are usually perceived balance of forces acting to open it (intrabolus pressure gener- substernally; in the instance of pain, radiation to the midline of the ated by peristalsis) and the forces resisting opening (LES tone back, shoulders, and jaw is very analogous to cardiac pain. These and the mechanical properties of the esophageal wall and crural similarities are likely due to convergence of sensory afferent fibers canal). Although each of these factors may dominate in a par- from the heart and esophagus in the same spinal pathways, even to ticular physiologic scenario, it is difficult to tease them apart the same dorsal horn neurons in some cases. with conventional manometric recordings. HRM with EPT has Esophageal afferents are predominantly activated by wall improved on this, and the current assessment of EGJ relaxation stretch, temperature, and acidity. When accompanied by muco- during swallowing uses an electronic sleeve or “eSleeve” to ascer- sal injury, inflammatory mediators (prostaglandins, bradykinins, tain the lowest average postdeglutitive pressure for a 4-second etc.) augment the response. The proximal esophagus is more sen- time period, skipping inspiratory crural contractions if necessary sitive than the distal esophagus, consistent with the observation (Fig. 44.6). This measurement provides an integrated assessment that proximal stimuli such as reflux are more likely to be per- of the pressure dynamics through the EGJ that is sensitive to both ceived.33 Excessive proximal sensitivity has been associated with pathologic conditions resisting opening, such as impaired LES esophageal hypersensitivity and functional heartburn.34 relaxation with achalasia, and mechanical obstruction at the EGJ With sensory endings concentrated deeply within the muscu- related to a structural cause (stricture, tumor, LES hypertrophy). laris propria beneath a relatively impermeable mucosa, it seems unlikely that intraluminal acid can directly stimulate them. How- ever, these afferents easily respond to mucosally applied bile Transient LES Relaxations or capsaicin (a derivative of chili pepper), suggesting that these During rest, the EGJ must prevent gastroesophageal reflux, but chemicals induce the release of an endogenous substance that also must transiently relax to selectively permit gas venting of the in turn excites the afferents. These responses are thought to be stomach. These functions are accomplished by prolonged LES mediated by transient receptor potential vanilloid 1 (TRPV1) relaxations that occur without swallowing or peristalsis. These receptors and/or acid-sensing ion channels.35,36 Consistent with transient LES relaxations (tLESRs) are an important mechanism this, current evidence suggests that chronic esophagitis increases in GERD pathogenesis and are the most frequent mechanism mRNA expression of purinergic receptors accompanied by for reflux during periods of normal LES pressure (see Chapter upregulation of TRPV1 and neurotrophic factors mediating sen- 46). tLESRs are distinguishable from swallow-induced relaxation sitization of the inflamed human esophagus.37 in several ways: (1) they are prolonged (>10 seconds) and inde- Owing to its significance in the pathogenesis of GERD, there pendent of pharyngeal swallowing; (2) they are associated with has been substantial interest in modulating the tLESR reflex (see contraction of the distal esophageal longitudinal muscle, causing Chapter 44). The current concept is that vagal afferent endings  CHAPTER 44 Esophageal Neuromuscular Function and Motility Disorders 645 0 44 5 mm Hg 100 10 80 Length along the esophagus (cm) 15 60 20 2 sec 40 20 25 0 30 1.6 mm Hg 35 30 eSleeve mm Hg 1.6 mm Hg 0 Gastric 15 mm Hg 2 sec 0 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 sphinc- ter 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). terminating in intraganglionic lamellar endings located in the differences in functional magnetic resonance imaging activa- proximal stomach are primarily responsible for initiating the tion patterns among subgroups of GERD patients and normal reflex, which is then mediated through the medulla and back to controls.40 the esophagus and diaphragm via vagal efferents and the phrenic nerves. Pharmacologic and physiologic studies have demonstrated that the mechanotransduction properties of tension-sensitive ESOPHAGEAL MOTILITY DISORDERS vagal afferent fibers can be attenuated by the GABA-B recep- A working, albeit restrictive, definition of an esophageal motility tor agonist baclofen, thereby reducing the frequency of tLESR. disorder is: an esophageal disease attributable to neuromuscular Glutamate receptors are also present in vagal and spinal sensory dysfunction that causes symptoms referable to the esophagus, afferent fibers, and metabotropic glutamate receptor antagonists most commonly dysphagia, chest pain, or heartburn. Using this (especially mGluR5 antagonists) have also been shown to inhibit definition, there are only 3 firmly established primary esophageal tLESR.38 motility disorders: achalasia, distal esophageal spasm (DES), and Recent investigations have also explored functional brain GERD. GERD is clearly the most prevalent among the group imaging, mainly functional magnetic resonance imaging, as and, fittingly, it is addressed in detail elsewhere in this text (see a noninvasive assessment of brain function in visceral sensa- Chapter 46). tion and pain.39 Although the results thus far are quite variable Esophageal motility disorders can also be secondary phe- among research groups, the brain regions most consistently nomena, in which case esophageal dysfunction is part of a more activated by esophageal stimuli are the anterior and poste- global disease, such as in pseudoachalasia, Chagas disease, and rior insula, cingulate cortex, primary sensory cortex, pre- PSS (scleroderma). Dysphagia due to pharyngeal or UES dys- frontal cortex, and thalamus. Preliminary studies also suggest function can also be included in a discussion of esophageal motor 646 PART V Esophagus Pressure (mm Hg) UES relaxation 30 5 Length along the esophagus 10 Gastroesophageal 20 common cavity 15 Proximal 10 20 esophageal clip 5.0 25 7.0 cm 0 cm SCJ 30 9.5 clip cm Abdominal Onset of –10 35 strain tLESR 4490 4495 4500 4505 4510 4515 Time (sec) 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 as- sociated with an abdominal strain and a “microburp” evident by the brief UES relaxation and abrupt depressur- ization 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. disorders, but this is usually as a manifestation of a more global average survival of 26 years after diagnosis.42 Reports of familial neuromuscular disease process. The major focus of this chapter clustering of achalasia raise the possibility of genetic predisposi- will be on the primary motility disorders, particularly achalasia. tion. However, arguing against a strong genetic determinant, a However, mention will be made of the secondary motility disor- survey of 1012 first-degree relatives of 159 achalasics identified no ders and proximal pharyngoesophageal dysfunction when impor- affected relatives. There is a rare genetic achalasia syndrome asso- tant unique features exist. ciated 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 includ- Epidemiology ing achalasia, alacrima, sinoatrial dysfunction, abnormal pupillary Estimates of the prevalence of dysphagia among individuals older responses to light, and delayed gastric emptying.45 It is caused by than 50 years range from 16% to 22%, with most of this related mutations in AAAS, which encodes a protein known as ALADIN. to oropharyngeal dysfunction. Most oropharyngeal dysphagia There are no population-based studies on the incidence or is related to neuromuscular disease; the prevalence of the most prevalence of esophageal motility disorders other than achalasia. common anatomic etiology, Zenker diverticulum, is estimated Thus, the only way to estimate the incidence or prevalence of to range from a meager 0.01% to 0.11% of the population in spastic disorders is to examine data on populations at risk and the USA, with peak incidence in men between the 7th and 9th reference the observed frequency of spastic disorders to the inci- decades.41 The consequences of oropharyngeal dysphagia are dence of achalasia, which, as detailed earlier, is about 2.75 per severe: dehydration, malnutrition, aspiration, choking, pneumo- 100,000 population. Doing so, the prevalence of DES is much nia, and death. Within health care institutions, it is estimated that lower than that if modern restrictive diagnostic criteria are used. up to 13% of hospitalized patients and 60% of nursing home resi- Populations at risk for motility disorders are patients with chest dents have feeding problems and, again, most are attributed to pain and/or dysphagia, so it is among these patients that extensive oropharyngeal dysfunction as opposed to esophageal dysfunction. manometric data have been collected. Manometric abnormalities Mortality of nursing residents with dysphagia and aspiration can are prevalent among these groups, but in most cases the mano- be as high as 45% over 1 year. As the U.S. population continues metric findings are of unclear significance.46 to age, oropharyngeal dysphagia will become an increasing prob- lem associated with complex medical and ethical issues. Achalasia is the most easily recognized and best-defined motor Pathogenesis disorder of the esophagus. Modern estimates of the incidence of achalasia are about 2.9 per 100,000 population in the USA42 and Oropharyngeal Dysphagia 2.6 per 100,000 in south Australia,43 affecting both genders equally Obstructing lesions of the oral cavity, head, and neck can cause and usually presenting between 25 and 60 years of age.44 Because dysphagia. Structural abnormalities may result from trauma, sur- achalasia is a chronic condition, its prevalence greatly exceeds its gery, tumors, caustic injury, congenital anomalies, or acquired incidence; a recent estimate of achalasia prevalence in Chicago deformities. The most common structural abnormalities of the concluded that it may be as high as 76 per 100,000 population, hypopharynx associated with dysphagia are hypopharyngeal given that the average age of diagnosis was 56 with an expected diverticula and cricopharyngeal bars.  CHAPTER 44 Esophageal Neuromuscular Function and Motility Disorders 647 TABLE 44.1 Mechanical Events of the Oropharyngeal Swallow, or sensory impairments. Cortical infarcts are less likely to result Evidence of Dysfunction, and Disease Association(s) in Patients with in severe dysphagia than brainstem strokes. Cortical infarcts are 44 Oropharyngeal Dysphagia also more likely to demonstrate recovery from dysphagia. Of 86 Evidence of consecutive patients who sustained an acute cerebral infarct, 37 Mechanical Event Dysfunction Disease Association(s) (43%) experienced dysphagia when evaluated within 4 days of the event. However, 86% of these patients were able to swallow nor- Nasopharyngeal Nasopharyngeal Myasthenia gravis mally 2 weeks later, with recovery resulting from contralateral closure regurgitation areas taking over the lost function.48 Failure to recover was more Nasal voice likely among patients incurring larger infarcts or patients who Laryngeal closure Aspiration during bolus Stroke had prior infarcts. transit Traumatic brain injury UES opening Dysphagia Cricopharyngeal bar Postswallow residue/ Parkinson disease Amyotrophic Lateral Sclerosis aspiration Amyotrophic lateral sclerosis is a progressive neurologic disease Diverticulum formation characterized by degeneration of motor neurons in the brain, Tongue loading and Sluggish misdirected Parkinson disease brainstem, and spinal cord. Specific symptoms are dependent bolus propulsion bolus Surgical defects upon the locations of affected motor neurons and the rela- Cerebral palsy tive severity of involvement. When the degenerative process Pharyngeal clearance Postswallow residue Polio or post-polio involves the cranial nerve nuclei, swallowing difficulties ensue. in hypopharynx/ syndrome Oropharyngeal dysfunction characteristically begins with the aspiration Oculopharyngeal tongue and progresses to involve the pharyngeal and laryngeal dystrophy musculature. Patients experience choking attacks, become vol- Stroke ume depleted or malnourished, and incur aspiration pneumonia. The decline in swallowing function is progressive and predict- able, invariably leading to gastrostomy feeding. Patients often die If the etiology of oropharyngeal dysphagia is not readily appar- as a consequence of their swallowing dysfunction in conjunction ent after an initial evaluation for anatomic disorders, evidence of with respiratory depression.49 functional abnormalities should be sought. Primary neurologic or muscular diseases involving the oropharynx are often associated with dysphagia. Whereas esophageal dysphagia usually results Parkinson Disease from esophageal diseases, oropharyngeal dysphagia frequently Although only 15% to 20% of patients with Parkinson disease results from neurologic or muscular diseases, with oropharyngeal complain of swallowing problems, more than 95% have demon- dysfunction being just one pathologic manifestation. Although strable defects when studied videofluoroscopically.50 This dispar- the disease specifics vary, the net effect on swallowing can be ana- ity suggests that patients compensate in the early stages of the lyzed according to the mechanical description of the swallow out- disease and complain of dysphagia only when it becomes severe. lined earlier. Table 44.1 summarizes the mechanical elements of Abnormalities include repetitive lingual pumping prior to ini- the swallow, the manifestation and consequence of dysfunction, tiation of a pharyngeal swallow, piecemeal swallowing, and oral and representative pathologic conditions in which they are likely residue after the swallow. Patients may also exhibit a delayed encountered. Neurologic examination may indicate cranial nerve swallow response and a weak pharyngeal contraction, resulting in dysfunction, neuromuscular disease, cerebellar dysfunction, or an vallecular and pyriform sinus residue. Recent data suggest this to underlying movement disorder. Functional abnormalities can be be related to the combination of incomplete UES relaxation and due to dysfunction of intrinsic musculature, peripheral nerves, or a weakened pharyngeal contraction.50 central nervous system control mechanisms. Of note, contrary to popular belief, the gag reflex is not predictive of pharyngeal swal- lowing efficiency or aspiration risk. The gag reflex is absent in Vagus Nerve Disorders 20% to 40% of normal adults.47 Unilateral lesions of the vagus can result in hemiparesis of the Evident in Table 44.1, oropharyngeal dysphagia is frequently soft palate and pharyngeal constrictors, as well as of the laryngeal the result of neurologic or muscular diseases. Neurologic dis- musculature. The recurrent laryngeal nerves can be injured as a eases can damage the neural structures requisite for either the result of thyroid surgery, aortic aneurysms, pneumonectomy, pri- afferent or efferent limbs of the oropharyngeal swallow. Virtu- mary mediastinal malignancies, or metastatic lesions to the medi- ally any neuromuscular disease can potentially cause dysphagia astinum. Owing to its more extensive loop in the chest, the left (see Chapter 37). As there is nothing unique to neurons control- recurrent laryngeal nerve is more vulnerable to involvement by ling swallowing, their involvement in disease processes is usually mediastinal malignancy than the right laryngeal nerve. Unilateral random. Furthermore, in most instances, functions mediated by recurrent laryngeal nerve injury results in unilateral adductor adjacent neuronal structures are concurrently involved. The fol- paralysis of the vocal cord. This defect can result in aspiration lowing discussion will focus on neuromuscular pathologic pro- during swallowing because of impaired laryngeal closure. It is, cesses most commonly encountered. however, rare to have any primary pharyngeal dysfunction resul- tant from recurrent laryngeal nerve injury. Stroke Aspiration pneumonia has been estimated to inflict a 20% death Oculopharyngeal Muscular Dystrophy rate in the first year after a stroke, and 10% to 15% each year Oculopharyngeal muscular dystrophy is a syndrome character- thereafter. It is usually not the first episode of aspiration pneu- ized by ptosis and progressive dysphagia. In the past, afflicted monia, but the subsequent recurrences over the years that even- patients reaching age 50 typically died of starvation resulting tually cause death. The ultimate cause of aspiration pneumonia from pharyngeal paralysis. The disease is now known to be a form is dysphagia leading to aspiration that can occur by a number of muscular dystrophy and is inherited as an autosomal domi- of mechanisms: absence or severe delay in triggering the swal- nant disorder, with occurrences clustered in families of French- low, reduced lingual control, or weakened laryngo-pharyngeal Canadian descent. Genetic studies of an afflicted family indicate musculature.7 Conceptually, these etiologies can involve motor linkage to chromosome 14, perhaps involving the region coding 648 PART V Esophagus for cardiac alpha or beta myosin heavy chains. Oculopharyngeal dystrophy affects the striated pharyngeal muscles and the leva- tor 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 eventu- ally 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 con- traction, reduced cricopharyngeal opening, and hypopharyngeal stasis.51 Dysphagia is slowly progressive, but may ultimately lead Zenker to starvation, aspiration pneumonia, or asphyxia. diverticulum Myasthenia Gravis Cricopharyngeus Myasthenia gravis is a progressive autoimmune disease char- acterized 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 promi- nent in more than a third of patients with myasthenia gravis and, in unusual instances, can be the initial and dominant manifesta- tion 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 pha- ryngeal contractions with repeated swallows. Peristaltic ampli- tude recovers with rest or following the administration of 10 mg Fig. 44.8 Film from a barium swallow study showing a small Zenker edrophonium chloride, an acetylcholinesterase inhibitor. In more diverticulum. Although the point of herniation is midline posterior at advanced cases, the dysphagia can be profound and associated Killian dehiscence, the diverticulum migrates laterally in the neck as it with nasopharyngeal regurgitation and nasality of the voice, even enlarges, because there is no potential space between the posterior to the extent of being confused with bulbar amyotrophic lateral pharyngeal wall and the vertebral column. sclerosis or brainstem stroke.52 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 poste- riorly at Killian dehiscence, a point of pharyngeal wall weakness between the oblique fibers of the inferior pharyngeal constric- tor 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 Cricopharyngeus larynx; (2) at the penetration of the inferior thyroid artery into the hypopharynx; (3) and at the junction of the middle and infe- rior constrictor muscles. The unifying theme of these locations Esophagus is that they are sites of potential weakness of the muscular lining of the hypopharynx through which the mucosa herniates, lead- ing to a “false” diverticulum. The best-substantiated explanation Trachea for the development of diverticula is that they form as a result of a restrictive myopathy associated with diminished compli- ance of the cricopharyngeus muscle. Surgical specimens of cri- copharyngeus muscle strips from patients with hypopharyngeal diverticula demonstrated structural changes that would decrease UES compliance and opening.53 The cricopharyngeus samples Fig. 44.9 Film from a barium swallow study showing a cricopharyngeal from these patients had “fibro-adipose tissue replacement and bar in a patient with oropharyngeal dysphagia. The posterior indenta- (muscle) fiber degeneration.” Thus, although the muscle relaxes tion of the barium column is caused by a noncompliant cricopharyn- normally during a swallow, it cannot distend normally, resulting geus muscle. (Courtesy Dr. Richard Gore, Evanston, IL.) 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 Achalasia maintain trans-sphincteric flow through the smaller UES open- Achalasia is characterized by impaired LES relaxation with ing. The increased stress on the hypopharynx from the increased swallowing and aperistalsis in the smooth muscle esophagus. intrabolus pressure may ultimately result in diverticulum forma- If there are premature, spastic contractions in the esophageal tion. body, the disease is referred to as spastic (type III) achalasia.54  CHAPTER 44 Esophageal Neuromuscular Function and Motility Disorders 649 These physiologic alterations result from damage to the inner- most cases of esophageal chest pain attributable to reflux disease vation of the smooth muscle segment of the esophagus (includ- or achalasia. Historically, the manometric criteria for diagnos- 44 ing the LES) with loss of ganglion cells within the myenteric ing DES have been nonspecific, leading to over-diagnosis of (Auerbach) plexus. Several observers report fewer ganglion cells the entity. This has been clarified somewhat with the Chicago and ganglion cells surrounded by mononuclear inflammatory Classification of high-resolution manometry and the adoption of cells in the smooth muscle esophagus of achalasics.55 The degree reduced distal latency (DL) of peristalsis as the cardinal abnor- of ganglion cell loss parallels the duration of disease, likely pro- mality in DES.60 gressing from EGJ outflow obstruction to type II achalasia, to Although DES is clearly a disorder of peristalsis, the majority type I achalasia, to end-stage achalasia.55,56 Type III achalasia of afflicted patients exhibit normal peristaltic contractions most seems to have a unique pathogenesis, characterized by myenteric of the time. The neuromuscular pathology responsible for DES is plexus inflammation and altered function, but not destruction.55 unknown and there are no known risk factors. The most striking Physiologic studies in achalasics suggest dysfunction consis- reported pathologic change is of diffuse muscular hypertrophy tent with postganglionic denervation of esophageal smooth mus- or hyperplasia in the distal esophagus with thickening of up to 2 cle potentially affect excitatory ganglion neurons (cholinergic), cm. However, there are other well-documented cases in which inhibitory ganglion neurons (NO ± VIP), or both (see Fig. 44.4). esophageal muscular thickening was not found at thoracotomy, Muscle strips from the circular layer of the esophageal body of and still other instances of patients with muscular thickening not achalasics contract when directly stimulated by ACh but fail to associated with DES symptoms. respond to ganglionic stimulation by nicotine, indicating a post- Despite the absence of defined histopathology, physiologic ganglionic excitatory defect. However, partial preservation of the evidence implicates myenteric plexus neuronal dysfunction in postganglionic cholinergic pathway is suggested by the observa- spasm because the latency of contraction along the smooth muscle tions that in some cases, an achalasic’s LES pressure increases esophagus is a function of postganglionic myenteric plexus neu- after administration of the AChE inhibitor edrophonium and rons. Swallow-induced vagal impulses reach the entire smooth decreases after administration of the muscarinic antagonist atro- muscle segment of the esophagus simultaneously, and it is the pine, crucial observations for understanding why botulinum toxin balance of excitatory and inhibitory ganglionic neurons within may have some therapeutic benefit (see section on treatment). the myenteric plexus that determine the timing of contraction at Regardless of excitatory ganglion neuron impairment, it is clear each esophageal locus. Furthermore, experimental evidence sug- that inhibitory ganglion neuron dysfunction is as an early mani- gests heterogeneity among spasm patients, such that some pri- festation of achalasia. These neurons mediate deglutitive inhibi- marily exhibit reduced inhibitory interneuron function, whereas tion (including LES relaxation) and the sequenced propagation in others the defect is of excess excitation. of esophageal peristalsis; their absence offers a unifying hypoth- Defining DES based on the latency of the postdeglutitive con- esis for the key physiologic abnormalities of achalasia: impaired traction puts it in a pathophysiologic continuum with achalasia, LES relaxation and aperistalsis. Achalasics have been shown to consistent with documented case reports of patients undergo- lack NO synthase and have a marked reduction of VIP-staining ing this evolution.61 Furthermore, there are marked similarities neurons in the gastroesophageal junction. between spastic achalasia and DES because both are character- There is substantial evidence of impaired esophageal post- ized by rapidly propagated contractions in the distal esophagus. ganglionic inhibitory innervation in achalasics. Muscle strips The differentiating features of vigorous achalasia are involvement from the LES do not relax in response to ganglionic stimulation of the LES and the absence of any normal peristalsis. by nicotine as they do in normal controls. Furthermore, CCK, which normally stimulates the inhibitory ganglion neurons and thus reduces LES pressure, paradoxically increases LES pressure Hypercontractile (Jackhammer) Esophagus in achalasics.57 Impaired inhibitory innervation of the smooth Vigorous esophageal contractions with normal DL, defined as muscle esophagus above the LES has been more difficult to dem- esophageal hypercontractility or jackhammer esophagus in the onstrate because of the absence of resting tone in this region. Chicago Classification, can be associated with both dysphagia and