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Disorders of Esophageal Function
the first modern textbooks of the specialty.1–4 The nature of the functional disturbances involved in their pathogenesis and their sometimes elusive symptoms have been understood only recently, when the necessary miniaturized diagnostic tools were developed. Since these conditions were investigated, new clinical situations in which dysmotility plays a role were identified and examined.
Embryology ------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 72
Disorders of Esophageal Function Juan A. Tovar
The esophagus acts as a conduit interposed between the pharynx and the stomach and has no significant secretory or absorptive functions. Its main function is propulsive, and its disorders induce several pathologic conditions that mirror their adult counterparts, although with specific pediatric features. Some of these disorders are related to malformations and manifest themselves during infancy and childhood. Most are incompletely understood due to our limited knowledge of the mechanisms of regulation of gastrointestinal motility and also because of the insufficiencies of the diagnostic tools that are difficult to apply in children due to size and collaboration problems. In the present chapter these motor disorders are addressed.
History ------------------------------------------------------------------------------------------------------------------------------------------------
In contrast with gastroesophageal reflux, the existence of disorders of esophageal function in children has been acknowledged only recently. With the exception of achalasia1,2 and “esophageal diverticulum” likely corresponding to cricopharyngeal achalasia,2 they were not even mentioned in
The esophagus derives from the foregut or cranial part of the endodermal tube that runs longitudinally along the embryonal body. Cranially it starts at the lower end of the pharynx and caudally it is in continuity with the stomach, which is an expansion of the foregut.5 The endodermal lining of this foregut is surrounded by muscle fibers that originate from the mesoderm and arrange themselves in two layers: the external, in which they are disposed longitudinally, and the internal, in which they adopt a circular pattern. On the fourth week of gestation the respiratory anlage appears on the ventral side of the foregut and progressively undergoes branching until configurating the definitive tracheobronchial tree.5 Endodermal-mesenchymal interactions and the influence of various genes, transcription factors, and growth factors contribute to shaping the lung and its multiple types of cells.6,7 The endodermal lining undergoes changes leading to differentiation into either esophageal or tracheobronchial epithelia.8 Tracheo-esophageal separation is crucial for normal organogenesis, and several malformations or dysfunctions of the esophagus have their origin at this point. On completion of these phases, the esophagus acquires its final configuration with two muscular layers, a submucosa and a polystratified, nonkeratinized mucosa. The reason why the muscle of the upper third of the organ is striated while that of the distal two thirds is smooth is unclear,9 as is the mechanism by which this mucosa, which was originally endodermal, acquires its final ectodermal pattern. Esophageal glands derived from the endoderm form in the submucosal layer and secrete alkaline fluid that contributes to buffering acid.10 From weeks 4 to 11, neuroblasts issued from the cranial neural crest colonize the foregut in a cranio-caudal direction11 and settle in the intermuscular and submucosal layers establishing fibrillar connections that will account for neural control of esophageal function by the parasympathetic and sympathetic systems.12 Nonadrenergic noncholinergic (NANC) or nitrergic innervation is present in the myenteric plexus on week 12 and in the submucosal plexus on week 14. It is fully developed by week 2213 or 23.14 Both the vagus nerves and the sympathetic paravertebral chains are of neural crest origin, and their development parallels that of the intramural innervation. The diaphragm is functionally related to the distal esophagus: The stomach and a part of the esophagus are located below the diaphragm, whereas most of the organ remains intrathoracic. Parts of the muscle fibers of the diaphragm have truncal mesodermal origin, and some are originally cervical.15,16 The central tendon and other connective structures derive from the posthepatic mesenchymal plate that contributes to the closure of the pleuroperitoneal canals.17 939
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Anatomy ------------------------------------------------------------------------------------------------------------------------------------------------
The upper end of the esophagus is in continuity with the pharynx. Its muscle fibers fuse with those of the cricopharyngeal muscle, the lower portion of the inferior pharyngeal constrictor that acts as an upper esophageal sphincter (UES). The esophageal body is located into the posterior mediastinum in close contact with the spine posteriorly, with the trachea and heart anteriorly, and with both pleural spaces on the sides. The vagal trunks run and branch on the surface of the esophagus. Esophageal length ranges from 10 cm in the newborn to 35 to 40 cm in adults. The lower end of the esophagus traverses the hiatus to become intra-abdominal before joining the stomach. On this end there is no distinct sphincter, but the circular fibers adopt at the gastroesophageal junction a horizontal U shape on the right side (clasp fibers), whereas on the left side they arrange themselves in another U-shaped structure that overrides the gastric incisura extending downward on the anterior and posterior faces of the stomach (sling fibers).18 The diaphragmatic sling that forms the hiatus departing from the right crus overlaps the distal esophagus and the sphincter. Its striated fibers are closely attached to the esophagus separating the thoracic space lined by pleura from the abdominal one lined by peritoneum. These structures constitute altogether a zone of high pressure in which the lower esophageal sphincter (LES) and the crural sling are the main functional structures. In contrast with other segments of the gastrointestinal tract, the esophagus is devoid of serosal layer, although it is in part in close contact laterally with the right and left mediastinal pleurae in the thorax and anteriorly with the peritoneum in its short intra-abdominal portion. The muscle layers are quite similar to those of the intestine except for the nature of the muscle fibers, which are striated in the upper third and smooth for the remaining extent of the organ. The intermuscular and submucosal plexuses contain ganglion cells connected among themselves and with the parasympathetic vagi and recurrent nerves, thoracic sympathetic trunks, and celiac plexus by a dense fibrillar network. The respective cholinergic and adrenergic mediators exert respectively positive and negative motor influences on the organ. Relaxation is mediated by nitrergic nerve endings that have their neurons in the intramural plexuses.19 The c kit-positive interstitial cells of Cajal are distributed among the muscle fibers, where they may play a pacemaker role.20–23 The extent to which these cells are related to neural control is not fully clear yet.24
Physiology ------------------------------------------------------------------------------------------------------------------------------------------------
The function of the esophagus is the transport of the alimentary bolus from the pharynx to the stomach. Secondarily, this organ takes in charge the clearance of the fluid that eventually refluxes from the stomach. As a mechanism to avoid the invasion of the larynx by digestive juices and the insufflation of the esophagus by air during inspiration, the UES keeps a permanent tone that only relaxes during deglutition, when the glottis is closed and respiration ceases.25 On the other hand, the unfavorable pressure conditions imposed on the esophagus by its intrathoracic location require permanent closure of the distal end to prevent
reflux. This function is ensured by the LES, which also maintains its permanent tone except during deglutition.26 The balance between the cholinergic and the nitrergic mediators regulates the permanent closure of the sphincter and its relaxations.27 The intrathoracic location of most of the esophagus and the intra-abdominal location of the stomach maintain an abdomino-thoracic pressure gradient. The intermittent negative inspiratory thoracic pressures coupled with the permanently positive abdominal pressures thus tend to push the gastric contents back into the esophagus.28 The resting tone of the LES opposes this gradient assisted by the rhythmic contractions of the diaphragmatic crural sling, which further close the lumen during inspiration. At this moment the unfavorable gradient is more powerful and the sling displaces the cardia downward, accentuating the angle of His and lengthening the intra-abdominal segment of the esophagus.29 The synergic play of these smooth and striated muscular structures has been extensively studied in animals30–32 and bears some resemblance with the mechanism of anorectal continence in which the permanent resting tone is provided by the internal sphincter, and the intermittently required additional closure is achieved by voluntary contraction of the striated muscle complex and the external sphincter. Deglutition is only possible if the upper and lower esophageal sphincters relax. This happens whenever the pharyngeal muscles mount a propulsive wave, and relaxation lasts until the peristalsis of the esophageal body triggered by pharyngeal contractions reaches the lower end of the organ. In order to effect these propulsive waves, the muscles of the esophagus contract in a coordinated craniocaudal manner progressing along the entire length of the organ to push the esophageal contents into the stomach. These are “primary” waves. Normal muscle layers and neural control are necessary for achieving this complex function, and motor disorders of the esophagus are likely the result of their anomalies. Reflux is the retrograde passage of gastric contents into the esophagus and it is to a certain extent normal because the permanent tone of the LES fails several times every day, particularly during meals, allowing the permanent gastroesophageal pressure gradient to push gastric juice backwards. This sphincter may be permanently insufficient in some patients, particularly in neurologically impaired ones,33 but it is presently acknowledged that most episodes of reflux in adults and children are due to nondeglutitory extemporaneous relaxations of the sphincter.26,34,35 During these relaxations, the esophageal lumen is invaded by acid gastric juice. The mucosa is not prepared for this insult, and it has to clear this fluid promptly in order to avoid permanent damage. For this purpose the esophagus mounts peristaltic contractions that may be independent of deglutition, that arise at different levels of the organ and that are progressive and therefore able to force the refluxed material back into the stomach. These are “secondary” waves36 aimed at clearing the esophagus of the bulk of the refluxed fluid. Complete clearance is only achieved after several swallows of alkaline saliva with some help from the alkaline secretion of esophageal glands.37,38 The normal esophagus may also produce a limited number of simultaneous nonpropulsive motor waves that close the lumen along its entire length. These are known as “tertiary” waves, and when they are too frequent they contribute to some of the motor disturbances of the esophagus.39–43
CHAPTER 72
Methods Used for Evaluating Esophageal Function
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pharynx
------------------------------------------------------------------------------------------------------------------------------------------------
For many years the barium swallow has been the main tool for investigating the esophagus. It shows not only anatomic anomalies of the organ but also abnormal contractility and relaxation of the upper or lower esophageal sphincters. However, irradiation is unavoidable if prolonged assessment is required and this has progressively limited its use. This method remains necessary for some of the conditions alluded to in this chapter, as we show later. Scintigraphy with liquid or solid radionuclide-tagged meals has helped to clarify the normal mechanisms of esophageal clearance and is useful for assessing esophageal transit and esophageal and gastric emptying. However, it is of relatively limited use in children.44–47 Endoscopy with suitable fiberscopes allows direct inspection of the esophageal lumen and mucosa. Some contractility disorders may be detected by this procedure, but its main usefulness resides in the information obtained by inspection and biopsy of the mucosa. Some of the functional disorders are related to esophagitis and this can be adequately detected by endoscopy and biopsy. Extended pH-metry is primarily intended to quantitate the extent of acid exposure of the esophagus. Because there is a clear correlation between the motor function and the clearance capacity of the organ, the information gained by pH probes may be crucial for understanding some of the motor disturbances.34,44,48–50 Manometry is the main tool for examining the motor function of the esophagus. This procedure is based on the principle of Pascal that states that the pressures exerted on any point of a liquid are transmitted in all directions with similar strength. Using tip-occluded probes with lateral holes perfused at constant rates, the pressure at any point of the esophageal lumen can be recorded through pressure transducers connected in a “T” to the perfusion system. Assemblies of several probes with spaced holes can explore the progression of pressure waves along the organ (Fig. 72-1).34,35,40,50–60 Solid-state sensors can replace the perfused probes, but their fragility and high cost limit their use. Manometry is also helpful for assessing the sphincteric function. Using one single perfused probe or assemblies of several of them with radially arranged orifices and withdrawing the recording orifices at a constant speed through the gastroesophageal junction allows recording of the pressure profile of both the UES and LES.35,40,52,61,62 For the LES the profile shows the gastric pressure followed by a “plateau” corresponding to the overlapping LES pressure and the crural sling contractions.63 Furthermore, it allows detection of the point at which the esophagus becomes intrathoracic because there is an “inversion point” at which the positive pressure inspiratory deflections become negative (Fig. 72-2). Stationary sphincter manometry with one of the orifices at the sphincteric level allows detection and assessment of the extent of relaxation. However, because it was understood that reflux is possible with normal sphincteric pressures, more attention was paid to relaxations; therefore continuous sphincteric recording probes with constantly perfused sleeves located at the appropriate level were developed.26,34,35,64,65 This, coupled with
UES
UES
upper esophagus
middle esophagus
lower esophagus LES
LES
FIGURE 72-1 Schematic drawing of the pressures recorded manometrically within the lumen of the esophagus during deglutition. Contraction of the pharyngeal constrictors is accompanied by relaxation of the cricopharyngeal muscle or upper esophageal sphincter (UES). Progressive peristaltic waves are generated in the body of the esophagus. The lower esophageal sphincter (LES) remains relaxed during the entire process and closes subsequently with a postrelaxation peak.
the availability of fine extruded Silastic probes, has permitted the study of gastroesophageal physiology in small and premature babies during relatively long periods of time.66,67 Manometry requires bulky, expensive, and delicate equipment and some collaboration on the side of the patient that may be difficult to obtain in children in whom sedation might change the registered pressures.68,69 High-resolution manometry could provide more detailed data on esophageal motor function in children.70 The recently introduced 24-hour ambulatory manometry coupled with pH-metry generated important information on several esophageal disorders in adults and also in children.71–80 However, the size of the solid-state sensor probes and the bulk of the equipment have limited these tests to older children for the moment.43,50,59,81 These techniques benefit from the development of extended recording of pressures or pH, reduced to electrical signals that can be analyzed and measured with the assistance of purposefully designed software. It is likely that these diagnostic tools will be further miniaturized and adapted to children in the near future, thus enlarging the scope of manometric studies. The more recent tool available for the assessment of esophageal function is multichannel intraluminal impedance (MII) coupled with manometry and/or pH-metry.82,83 Changes in esophageal width cause proportional changes in luminal impedance and, with the assistance of several electrodes and adequate storing systems, a long-duration recording is possible. MII allows sequential analysis of the impedance variations caused by the passage of gas or liquid in either
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mm Hg
2s
50 25 0
rip
FIGURE 72-2 Pull-through manometric recording of the lower esophageal sphincter (LES) in a normal child (upper tracing) with simultaneous recording of the abdominal pressures (lower tracing). Intragastric pressures are first recorded with positive inspiratory deflections. A “plateau” corresponds to the high pressure zone of the LES. When the probe enters the thoracic esophagus, intraluminal inspiratory deflections become negative (respiratory inversion point, rip). From then on the pressure baseline is lower and the inspirations are recorded by negative waves. Withdrawal speed is 1 mm/sec, and time between vertical marks is 2 seconds.
be observed in children with Chiari syndrome,93,94 22q11.2 deletion,95 or after diazepam medication.96 Absence of relaxation (cricopharyngeal achalasia) occurs rarely as a primary phenomenon or secondary to neuromuscular disorders.92,97 In all these conditions the leading symptoms are choking during feeding and respiratory distress during early infancy, which may prompt urgent diagnostic workup. Barium meal or cineradiography depicts simultaneous opacification of the respiratory and digestive tracts in cases of permanent relaxation and dilated pharynx with permanent upper esophageal closure and occasional passage of contrast into the trachea in cases of delayed or absent relaxation.97,98 Manometry is useful for the diagnosis of cricopharyngeal disorders because it shows the incompleteness or absence of relaxation of the muscle during deglutition.92,93,99,100 However, it is particularly difficult to perform in infants because the use of perfused catheters in the upper esophagus is unpleasant for the baby who chokes, coughs, and does not collaborate. Recordings with sphincteric sleeves depict better the lack of relaxation with less risk of fluid aspiration.101 Gastrostomy may be necessary for feeding babies with permanent cricopharyngeal relaxation and also in those with UES achalasia.94,102 Achalasia of the muscle can be treated by balloon dilatation,103–105 but extramucosal myotomy is more effective.99,106 If reflux is present, a concurrent fundoplication should be considered because insufficiency of both the upper and lower esophageal closure mechanisms may be devastating.107 Some nonspecific histologic changes of the muscle obtained during myotomy have been reported in cricopharyngeal achalasia.108
Disorders of Esophageal Body ------------------------------------------------------------------------------------------------------------------------------------------------
direction. Reflux detection is possible and, when the measurements are coupled with pH recordings, its acid or nonacid nature can be ascertained. Furthermore, MII allows assessment of deglutition and esophageal motor activity (Fig. 72-3). However, there are several limitations for the use of MII: Although this procedure sheds light on the little known field of nonacid or alkaline reflux, analysis of 24-hour tracings requires ample expertise and specialist time that considerably limit its use. Computer-assisted analysis has been used for reflux studies, but little has been done in terms of esophageal function investigation.84–91 Furthermore, these limitations are even greater in children because of size, the need for patient cooperation, and the ethical restraints for establishing baseline control values, which also apply to other invasive functional tests in children.
Disorders of the Upper Esophagus ------------------------------------------------------------------------------------------------------------------------------------------------
The cricopharyngeus occasionally fails to maintain its permanent tonus or to relax during deglutition. This leads to difficult swallowing and consequent choking that may threaten life during early infancy. Permanent cricopharyngeal relaxation is sometimes seen in neurologically impaired patients who undergo repeated episodes of aspiration.92 Delayed or incomplete relaxation may
PRIMARY MOTOR DISORDERS Abnormal motility of the body of the esophagus is a frequent cause of symptoms in adults in whom diffuse esophageal spasm,72,109–112 nutcracker esophagus,113,114 or other abnormal motor patterns impairing the propulsion of the bolus are occasionally diagnosed after investigation for dysphagia, noncardiac chest pain, or suspected reflux. Simultaneous, nonpropulsive contractions or an excessive proportion of long-duration waves alternating with normal ones are found in the first of these conditions, whereas extremely powerful, high-amplitude waves that can be peristaltic or retrograde are demonstrated in the second one.72,76,115 Nutcracker esophagus has been seen to evolve into achalasia.116 Manometry is the main diagnostic tool, and its accuracy has improved considerably since 24-hour ambulatory recordings became available because the disturbances may not be permanent and appear only occasionally at some point of the circadian cycle. Because of the difficulties of performing this procedure in children, primary motor disorders of the esophageal body were practically unheard of in them until recently, although apnea, bradycardia,117 and bizarre posturing118 had been considered as expressions of motor disturbances. However, introduction of better manometric techniques produced growing evidence of their existence at this age. Food impaction in the absence of stenosis has been found in association with manometric patterns similar to those of adult nutcracker esophagus (Fig. 72-4), but this
CHAPTER 72
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FIGURE 72-3 Multichannel intraluminal impedance (MII) tracing in a 6-year-old child with gastroesophageal reflux. The lower pH tracing reveals a pH fall that unchains a retrograde fall of impedance revealing increased esophageal lumen width (reflux episode). Shortly after, the baseline width is nearly recovered in an antegrade sequence revealing swallowing. However, this event does not clear completely the refluxed acid because the pH tracing does not come back to normal. Using a pH of 4 as a threshold for defining reflux, this episode would have been disregarded. With this technique, it is considered as a weakly acidic reflux episode.
disorder might not be primary because most patients have either reflux58,59,119,120 or eosinophilic esophagitis.121,122 Pharmacologic treatment of primary motor disorders with prokinetics or calcium channel blockers123,124 is rarely indicated in children with these conditions.125 Sildenafil, a drug that helps to induce NO-related relaxation of the esophageal body and LES, has been introduced for the treatment of motor disorders in adults,126–128 but it has not been used in children until now. Balloon dilatation or extended myotomy, procedures occasionally used in adults, have not been used in children.
SECONDARY MOTOR DISORDERS Abnormal esophageal motility has been demonstrated in several syndromes and chromosomal disorders: Damaged peristalsis sometimes associated with reflux was found in children with both Down syndrome129–131 and Cornelia de Lange syndrome.132–136 Scleroderma,137–139 polymyositisdermatomyositis,140 and lupus,141 which are well-known causes of esophageal dysmotility in adults, may rarely start during childhood. Babies breast-fed by mothers with silicone implants142 may also undergo esophageal motor disturbances similar to those of scleroderma.
FIGURE 72-4 Nocturnal ambulatory manometric recording of intraluminal lower esophageal pH (1) and upper (4), middle (5), and lower (6) esophageal pressures in a 10-year-old boy with recurrent episodes of nonobstructive food impaction. The tracing demonstrates a pattern of nutcracker esophagus with long-duration, apparently peristaltic waves that are extremely powerful, particularly at the lower end of esophageal body (>200 mm Hg or 3 to 4 times above normal). This happens during sleep and without reflux, as seen in the pH tracing.
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More relevant for pediatric surgeons are the motor disturbances of the esophagus suffered by survivors of neonatal operations for esophageal atresia with or without tracheoesophageal fistula.47,143–147 In this malformation the structure of the muscle layers148 and the abnormal extrinsic149,150 and intrinsic151,152 innervations impair the peristaltic pump for life. This is particularly harmful in this condition in which the function of the LES is also abnormal because both failures make gastroesophageal reflux (GER) a nearly constant part of the disease independently of the type of repair.61,153 In addition, esophageal shortening due to the neonatal anastomosis,154 abnormal hiatus,155 and perhaps operative denervation may influence dysmotility. Many studies demonstrated that the LES function is abnormal in survivors of neonatal operations for esophageal atresia,61,146 and some others showed that peristalsis is permanently damaged even many years after the anastomosis.60,89,144,147,156,157 The clinical relevance of these disorders is probably greater than it was previously thought. Patients operated on for esophageal atresia have swallowing problems that are perceived by them as minor but that are almost constant when specifically searched for.144,158 Their esophagus cannot fight reflux and, because of the structural basis of these dysfunctions, not much benefit can be expected from prokinetic medication. Furthermore, the spontaneous improvement of reflux with age that is part of the natural history of the disease in children cannot be expected in patients operated on for esophageal atresia, whether by thoracotomy or through a minimally invasive approach.159 GER should be treated in patients with esophageal atresia when it is symptomatic and/or when it causes esophagitis. Dysmotility, a constant problem with this malformation, does not preclude a complete fundoplication, which should be loose. Gravity is probably the main esophageal emptying force before or after the plication and there should be no problem if the wrap is loose enough. However, the proportion of longterm failures of the plication is high in this group of patients because all the causes of GER and dysmotility remain active in spite of the new valve.160,161 Other conditions relevant to pediatric surgeons involve esophageal motor disorders: chronic intestinal pseudoobstruction, a heterogeneous group of gastrointestinal dysfunctions with myogenic or neural basis, is characterized by distal esophageal dysmotility with simultaneous, short-lasting, low-amplitude waves162–164 that may help in the diagnosis. However, dysmotility is widespread and the esophageal part is not the most significant.165 Patients with Hirschsprung disease have simultaneous and double-peaked esophageal waves,166 and children with congenital central hypoventilation syndrome167 or Goldenhar syndrome168 also have dysmotility. Survivors of neonatal operations for congenital diaphragmatic hernia have radiologic and clinical evidence of abnormal esophageal motor function157,169–172 that might be related to innervation anomalies.173 Esophageal dysfunction involving lowered sphincteric pressures or abnormal distal esophageal contractility has been described in children with chronic renal failure,174 Noonan syndrome,175 and Pierre-Robin sequence.176 The same anomalies were found in adults with celiac disease.177 A number of children with this disease also have eosinophilic esophagitis, and this could explain the esophageal disturbances.178 Children with corrosive injuries of the esophagus have impaired peristaltic activity both in the acute postinjury
FIGURE 72-5 Typical “multiple-ring” pattern of the esophagus on fiberoptic endoscopy in an 11-year-old girl with dysphagia due to eosinophilic esophagitis. On biopsy the mucosa was heavily infiltrated with eosinophils. pH-metry was normal, and the patient did well after a course of treatment with steroids.
period179 and when scars are established.180 These manometric findings were confirmed by radionuclide181 and combined studies.182 The contribution of dysmotility to the clinical course and prognosis in this condition is still unclear, although it is believed that secondary esophagitis aggravates them. In the past few years we have treated a growing number of patients with eosinophilic esophagitis, a condition of probably allergic origin in which there are symptoms of reflux or food impaction.121,183–186 Reflux and stenosis are usually ruled out, and a typical aspect of Schatzki ring187 or multiple rings188 is seen on endoscopy (Fig. 72-5); heavy infiltration of the mucosa by eosinophils is found on biopsy, particularly with the Luna eosinophil granule stain.189 Strictures are rarely observed in eosinophilic esophagitis, and they respond to treatment.190,191 Dilatations may be indicated even in cases of severe dysphagia without stenosis.192 Eosinophilic esophagitis has been seen in patients previously operated on for esophageal atresia in whom reflux is common.193 Oral corticosteroids,183 fluticasone,194,195 and eosinophil stabilizers like montelukast196,197 are usually helpful in the management of this condition.190 However, there seems to be a dissociation between the symptoms and the histologic findings during treatment.198
Disorders of the Distal Esophagus ------------------------------------------------------------------------------------------------------------------------------------------------
Primary gastroesophageal reflux involves both the failure of the gastroesophageal barrier and abnormal esophageal motility. The causes for the sphincteric failure are not completely understood, but there is increasing evidence of prolonged nondeglutitory relaxations as the main mechanism.26,34,35 They permit the creation of a “common cavity” phenomenon
CHAPTER 72
that allows the full action of the untoward gastroesophageal pressure gradients between the stomach and the esophagus. The gastric fluid refluxed into the esophagus must be pushed back to the stomach by peristalsis, but this second defensive mechanism is also damaged with the consequent risk of esophagitis. The proportion of peristaltic contractions after deglutition or reflux and the amplitude of the waves are decreased, particularly at the lower end of the organ.40,43,57 Whether dysmotility in gastroesophageal reflux disease is a primary phenomenon or secondary to esophageal inflammation is unclear. There are solid clinical and experimental arguments to maintain that chronic esophagitis damages previously healthy peristalsis,199,200 but at least in some cases motor function remains abnormal even after medical or surgical cure of reflux and esophagitis.40,51,199,201,202 The success of prokinetic treatment used extensively in the past decades illustrates the relevance of the dysmotility in GER disease. These drugs act by reinforcing the failing sphincter, hastening gastric emptying, and improving peristalsis. The more characteristic motor disorder of the lower end of the esophagus is achalasia in which the LES is hypertonic and does not relax during deglutition. In addition, in part by dilatation of the esophagus and also because of primary hypoperistalsis, its propulsive function is totally ineffective. This condition is rare in young children and, although some cases have early onset, most are diagnosed in late childhood or early adolescence. Only a few pediatric studies include more than a limited number of cases,81,203–210 and the largest multicenter series involves only 175 cases.211 The cause of achalasia is unknown, but there is increasing evidence of a progressive disturbance of the intrinsic innervation with reduced or absent nitric oxide synthase (NOS) activity.19,23 This enzyme is in charge of synthesizing NO, the nonadrenergic-noncholinergic neurotransmitter of smooth muscle relaxation.19 nNOS( / ) mice with nitric oxide synthase disruption have hypertensive, nonrelaxing LESs.212 Recent evidence indicates a correlation between paucity of c-kit positive interstitial cells of Cajal and depletion of neuronal nitric oxide synthase (N-NOS) immunoreactivity in the esophagus of patients with achalasia showing that these cells are in some way related to relaxation.213 The progressive degeneration of the intrinsic innervation has some bearing with that seen in Chagas’ disease, a South American parasitic condition caused by Trypanosoma cruzi that causes degeneration of the neural structures leading to megaesophagus214,215 and abnormal esophageal function. However, in Chagas’ disease the pressures in the LES are not increased but rather reduced.216 Achalasia may be associated with Allgrove syndrome, an autosomal recessive familial condition217 caused by a mutation of the AAAS gene on chromosome 12q13218–223 in which, in addition to the esophageal motor dysfunction, there are adrenocortical insufficiency and alacrima. This association is also addressed as ALADIN syndrome (alacrima, achalasia, adrenal insufficiency, and neurologic disorder).224 Achalasia is more frequent in boys and is occasionally associated with Down syndrome.130,131,225 Achalasia patients complain of progressive dysphagia and regurgitation of food retained in the esophagus that should not be confounded with vomiting. Some have retrosternal pain that may become distressing. They lose weight and often have foul breath and respiratory symptoms like nocturnal cough or repeated pneumonia due to frequent
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microaspiration.208,226,227 In cases of Allgrove syndrome there are also symptoms of adrenocortical insufficiency such as progressive pigmentation and asthenia and eventually absence of tears (alacrima), but these symptoms and other manifestations of neurologic disease224 may appear later after the full clinical picture of achalasia has developed. Barium meal is often diagnostic: The esophagus is large (megaesophagus) and contains stagnant fluid above the barium column. There is a marked aperistalsis and the esophagogastric junction is filiform, adopting a classical “bird’s beak” shape.208 The contrast progresses into the stomach after a long time, and most of it is retained in the esophagus for hours (Fig. 72-6). Radionuclide scintigraphy may depict the lack of progression of the esophageal content and allows more prolonged observation with less irradiation, but it is less informative of the shape of the distal esophagus.130,228 Fiberoptic endoscopy rules out the presence of stricture, and the instrument can be advanced in the stomach with relative ease. After suctioning of the retained fluid, a picture of esophagitis may be seen but it is secondary to fermentation of the stagnant fluid. pH-metry is not useful at this stage and can be misleading because this fluid is often acid and the probe reading may suggest GER, which is in fact impossible. Manometry is the best diagnostic tool for achalasia: The sphincter is hypertonic and does not relax or does it incompletely during deglutition. The esophageal peristalsis is absent and the scarce contractions present, particularly during meals, are recorded simultaneously at all points of the lumen, which is in fact a common chamber (Fig. 72-7).70,203,207 Twentyfour-hour ambulatory recordings performed with probes equipped with multiple solid-state sensors show that the aperistalsis is constant along the entire circadian cycle
FIGURE 72-6 Barium meal in a 9-year-old patient with achalasia. The esophagus is enlarged and contained stagnant fluid before the contrast was given. Emptying is slow and the cardia has a typical pattern of “carrot” or “bird’s beak” (left). Some feeble esophageal contractions are seen (right), but peristalsis is impossible because the esophageal walls remain widely separated.
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FIGURE 72-8 Ambulatory esophageal manometry during meal in a 24-year-old woman 12 years after Heller myotomy for achalasia. She was asymptomatic, but esophageal motility remained poor. The motor waves at the upper (4), middle (5), and lower (6) levels of the esophagus showed peristaltic organization, but they were weak (<25 mm Hg, roughly half the normal). Time between vertical marks is 5 seconds.
FIGURE 72-7 Ambulatory esophageal manometry in an 8-year-old boy with achalasia. In the upper picture, the pressures at the upper (4), middle (5), and lower (6) levels of the esophagus are identical and no waves are seen. In the lower picture, corresponding to a meal, some waves are generated but they are simultaneous and nonpropulsive (time between vertical marks, 5 seconds).
including meals, when motor waves are normally more active.81 Impedance studies confirmed and reinforced these data.83 The differential diagnosis includes extrinsic and intrinsic causes; in the latter group, acquired strictures and congenital stenosis from tracheobronchial remnants are usually easily eliminated by endoscopy. Leiomyomas and leiomyomatosis, either isolated or as part of Alport syndrome (hereditary X-linked nephropathy and deafness), may be suspected on endoscopy but require cross-sectional imaging with computed tomography or magnetic resonance imaging for confirmation.228a Medication, particularly calcium channel blockers such as nifedipine, may alleviate the spasm in some cases,229 but they cannot be relied on as a long-term treatment in children with achalasia.124 Forceful balloon dilatation of the distal esophagus is often successful in adults, but this modality of treatment has not brought permanent relief in children,203,204,230 although some favorable results were reported,209,231 particularly older than the age of 6.232 The local injection of
botulinum toxin has been also tried in children, but its success has been limited as well.226,233–236 Like in adults,237 extramucosal Heller myotomy remains the best treatment at this age and it can be performed through either the thorax or the abdomen.81,203,204,207,208,211,238 Perioperative lower esophageal manometry239 or endoscopy240 may ensure the completeness of the myotomy. An abdominal approach probably allows for a more complete myotomy on the gastric side and facilitates fundoplication. In fact, if sought after, reflux is rather constant after Heller myotomy and some form of fundoplication is probably indicated in children, whose long life expectancy after the operation supports the use of this procedure to prevent complications of GER.81,204,206,207,226,241,242 A Nissen procedure may be inadequate due to the often large diameter of the thickened esophagus; the posterior Toupet or anterior Thal-Dor hemifundoplications are preferred.81,207,242 Some authors prefer to omit antireflux procedures in these patients.209,243 All these procedures can be performed laparoscopically, and this approach has become the gold standard.209,238,242,244–247 Postoperatively patients are relieved of their symptoms at once and they can feed properly and regain weight. However, the esophagus remains dilated for months or even years and its function only rarely returns to normal. Most patients maintain scarce and ineffective peristalsis in spite of the decrease in sphincteric pressure provided by myotomy (Fig. 72-8).81,204,241,248,249 Some patients continue to have minor symptoms such as dysphagia and often require a few swallows of water during meals, but surgery brings back a good quality of life. Esophageal replacement has been reported in some rare cases of achalasia in which all other treatments failed.250,251 The complete reference list is available online at www. expertconsult.com.
Embryology ------------------------------------------------------------------------------------------------------------------------------------------------
CHAPTER 72
Disorders of Esophageal Function Juan A. Tovar
The esophagus acts as a conduit interposed between the pharynx and the stomach and has no significant secretory or absorptive functions. Its main function is propulsive, and its disorders induce several pathologic conditions that mirror their adult counterparts, although with specific pediatric features. Some of these disorders are related to malformations and manifest themselves during infancy and childhood. Most are incompletely understood due to our limited knowledge of the mechanisms of regulation of gastrointestinal motility and also because of the insufficiencies of the diagnostic tools that are difficult to apply in children due to size and collaboration problems. In the present chapter these motor disorders are addressed.
History ------------------------------------------------------------------------------------------------------------------------------------------------
In contrast with gastroesophageal reflux, the existence of disorders of esophageal function in children has been acknowledged only recently. With the exception of achalasia1,2 and “esophageal diverticulum” likely corresponding to cricopharyngeal achalasia,2 they were not even mentioned in
The esophagus derives from the foregut or cranial part of the endodermal tube that runs longitudinally along the embryonal body. Cranially it starts at the lower end of the pharynx and caudally it is in continuity with the stomach, which is an expansion of the foregut.5 The endodermal lining of this foregut is surrounded by muscle fibers that originate from the mesoderm and arrange themselves in two layers: the external, in which they are disposed longitudinally, and the internal, in which they adopt a circular pattern. On the fourth week of gestation the respiratory anlage appears on the ventral side of the foregut and progressively undergoes branching until configurating the definitive tracheobronchial tree.5 Endodermal-mesenchymal interactions and the influence of various genes, transcription factors, and growth factors contribute to shaping the lung and its multiple types of cells.6,7 The endodermal lining undergoes changes leading to differentiation into either esophageal or tracheobronchial epithelia.8 Tracheo-esophageal separation is crucial for normal organogenesis, and several malformations or dysfunctions of the esophagus have their origin at this point. On completion of these phases, the esophagus acquires its final configuration with two muscular layers, a submucosa and a polystratified, nonkeratinized mucosa. The reason why the muscle of the upper third of the organ is striated while that of the distal two thirds is smooth is unclear,9 as is the mechanism by which this mucosa, which was originally endodermal, acquires its final ectodermal pattern. Esophageal glands derived from the endoderm form in the submucosal layer and secrete alkaline fluid that contributes to buffering acid.10 From weeks 4 to 11, neuroblasts issued from the cranial neural crest colonize the foregut in a cranio-caudal direction11 and settle in the intermuscular and submucosal layers establishing fibrillar connections that will account for neural control of esophageal function by the parasympathetic and sympathetic systems.12 Nonadrenergic noncholinergic (NANC) or nitrergic innervation is present in the myenteric plexus on week 12 and in the submucosal plexus on week 14. It is fully developed by week 2213 or 23.14 Both the vagus nerves and the sympathetic paravertebral chains are of neural crest origin, and their development parallels that of the intramural innervation. The diaphragm is functionally related to the distal esophagus: The stomach and a part of the esophagus are located below the diaphragm, whereas most of the organ remains intrathoracic. Parts of the muscle fibers of the diaphragm have truncal mesodermal origin, and some are originally cervical.15,16 The central tendon and other connective structures derive from the posthepatic mesenchymal plate that contributes to the closure of the pleuroperitoneal canals.17 939
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Anatomy ------------------------------------------------------------------------------------------------------------------------------------------------
The upper end of the esophagus is in continuity with the pharynx. Its muscle fibers fuse with those of the cricopharyngeal muscle, the lower portion of the inferior pharyngeal constrictor that acts as an upper esophageal sphincter (UES). The esophageal body is located into the posterior mediastinum in close contact with the spine posteriorly, with the trachea and heart anteriorly, and with both pleural spaces on the sides. The vagal trunks run and branch on the surface of the esophagus. Esophageal length ranges from 10 cm in the newborn to 35 to 40 cm in adults. The lower end of the esophagus traverses the hiatus to become intra-abdominal before joining the stomach. On this end there is no distinct sphincter, but the circular fibers adopt at the gastroesophageal junction a horizontal U shape on the right side (clasp fibers), whereas on the left side they arrange themselves in another U-shaped structure that overrides the gastric incisura extending downward on the anterior and posterior faces of the stomach (sling fibers).18 The diaphragmatic sling that forms the hiatus departing from the right crus overlaps the distal esophagus and the sphincter. Its striated fibers are closely attached to the esophagus separating the thoracic space lined by pleura from the abdominal one lined by peritoneum. These structures constitute altogether a zone of high pressure in which the lower esophageal sphincter (LES) and the crural sling are the main functional structures. In contrast with other segments of the gastrointestinal tract, the esophagus is devoid of serosal layer, although it is in part in close contact laterally with the right and left mediastinal pleurae in the thorax and anteriorly with the peritoneum in its short intra-abdominal portion. The muscle layers are quite similar to those of the intestine except for the nature of the muscle fibers, which are striated in the upper third and smooth for the remaining extent of the organ. The intermuscular and submucosal plexuses contain ganglion cells connected among themselves and with the parasympathetic vagi and recurrent nerves, thoracic sympathetic trunks, and celiac plexus by a dense fibrillar network. The respective cholinergic and adrenergic mediators exert respectively positive and negative motor influences on the organ. Relaxation is mediated by nitrergic nerve endings that have their neurons in the intramural plexuses.19 The c kit-positive interstitial cells of Cajal are distributed among the muscle fibers, where they may play a pacemaker role.20–23 The extent to which these cells are related to neural control is not fully clear yet.24
Physiology ------------------------------------------------------------------------------------------------------------------------------------------------
The function of the esophagus is the transport of the alimentary bolus from the pharynx to the stomach. Secondarily, this organ takes in charge the clearance of the fluid that eventually refluxes from the stomach. As a mechanism to avoid the invasion of the larynx by digestive juices and the insufflation of the esophagus by air during inspiration, the UES keeps a permanent tone that only relaxes during deglutition, when the glottis is closed and respiration ceases.25 On the other hand, the unfavorable pressure conditions imposed on the esophagus by its intrathoracic location require permanent closure of the distal end to prevent
reflux. This function is ensured by the LES, which also maintains its permanent tone except during deglutition.26 The balance between the cholinergic and the nitrergic mediators regulates the permanent closure of the sphincter and its relaxations.27 The intrathoracic location of most of the esophagus and the intra-abdominal location of the stomach maintain an abdomino-thoracic pressure gradient. The intermittent negative inspiratory thoracic pressures coupled with the permanently positive abdominal pressures thus tend to push the gastric contents back into the esophagus.28 The resting tone of the LES opposes this gradient assisted by the rhythmic contractions of the diaphragmatic crural sling, which further close the lumen during inspiration. At this moment the unfavorable gradient is more powerful and the sling displaces the cardia downward, accentuating the angle of His and lengthening the intra-abdominal segment of the esophagus.29 The synergic play of these smooth and striated muscular structures has been extensively studied in animals30–32 and bears some resemblance with the mechanism of anorectal continence in which the permanent resting tone is provided by the internal sphincter, and the intermittently required additional closure is achieved by voluntary contraction of the striated muscle complex and the external sphincter. Deglutition is only possible if the upper and lower esophageal sphincters relax. This happens whenever the pharyngeal muscles mount a propulsive wave, and relaxation lasts until the peristalsis of the esophageal body triggered by pharyngeal contractions reaches the lower end of the organ. In order to effect these propulsive waves, the muscles of the esophagus contract in a coordinated craniocaudal manner progressing along the entire length of the organ to push the esophageal contents into the stomach. These are “primary” waves. Normal muscle layers and neural control are necessary for achieving this complex function, and motor disorders of the esophagus are likely the result of their anomalies. Reflux is the retrograde passage of gastric contents into the esophagus and it is to a certain extent normal because the permanent tone of the LES fails several times every day, particularly during meals, allowing the permanent gastroesophageal pressure gradient to push gastric juice backwards. This sphincter may be permanently insufficient in some patients, particularly in neurologically impaired ones,33 but it is presently acknowledged that most episodes of reflux in adults and children are due to nondeglutitory extemporaneous relaxations of the sphincter.26,34,35 During these relaxations, the esophageal lumen is invaded by acid gastric juice. The mucosa is not prepared for this insult, and it has to clear this fluid promptly in order to avoid permanent damage. For this purpose the esophagus mounts peristaltic contractions that may be independent of deglutition, that arise at different levels of the organ and that are progressive and therefore able to force the refluxed material back into the stomach. These are “secondary” waves36 aimed at clearing the esophagus of the bulk of the refluxed fluid. Complete clearance is only achieved after several swallows of alkaline saliva with some help from the alkaline secretion of esophageal glands.37,38 The normal esophagus may also produce a limited number of simultaneous nonpropulsive motor waves that close the lumen along its entire length. These are known as “tertiary” waves, and when they are too frequent they contribute to some of the motor disturbances of the esophagus.39–43
CHAPTER 72
Methods Used for Evaluating Esophageal Function
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pharynx
------------------------------------------------------------------------------------------------------------------------------------------------
For many years the barium swallow has been the main tool for investigating the esophagus. It shows not only anatomic anomalies of the organ but also abnormal contractility and relaxation of the upper or lower esophageal sphincters. However, irradiation is unavoidable if prolonged assessment is required and this has progressively limited its use. This method remains necessary for some of the conditions alluded to in this chapter, as we show later. Scintigraphy with liquid or solid radionuclide-tagged meals has helped to clarify the normal mechanisms of esophageal clearance and is useful for assessing esophageal transit and esophageal and gastric emptying. However, it is of relatively limited use in children.44–47 Endoscopy with suitable fiberscopes allows direct inspection of the esophageal lumen and mucosa. Some contractility disorders may be detected by this procedure, but its main usefulness resides in the information obtained by inspection and biopsy of the mucosa. Some of the functional disorders are related to esophagitis and this can be adequately detected by endoscopy and biopsy. Extended pH-metry is primarily intended to quantitate the extent of acid exposure of the esophagus. Because there is a clear correlation between the motor function and the clearance capacity of the organ, the information gained by pH probes may be crucial for understanding some of the motor disturbances.34,44,48–50 Manometry is the main tool for examining the motor function of the esophagus. This procedure is based on the principle of Pascal that states that the pressures exerted on any point of a liquid are transmitted in all directions with similar strength. Using tip-occluded probes with lateral holes perfused at constant rates, the pressure at any point of the esophageal lumen can be recorded through pressure transducers connected in a “T” to the perfusion system. Assemblies of several probes with spaced holes can explore the progression of pressure waves along the organ (Fig. 72-1).34,35,40,50–60 Solid-state sensors can replace the perfused probes, but their fragility and high cost limit their use. Manometry is also helpful for assessing the sphincteric function. Using one single perfused probe or assemblies of several of them with radially arranged orifices and withdrawing the recording orifices at a constant speed through the gastroesophageal junction allows recording of the pressure profile of both the UES and LES.35,40,52,61,62 For the LES the profile shows the gastric pressure followed by a “plateau” corresponding to the overlapping LES pressure and the crural sling contractions.63 Furthermore, it allows detection of the point at which the esophagus becomes intrathoracic because there is an “inversion point” at which the positive pressure inspiratory deflections become negative (Fig. 72-2). Stationary sphincter manometry with one of the orifices at the sphincteric level allows detection and assessment of the extent of relaxation. However, because it was understood that reflux is possible with normal sphincteric pressures, more attention was paid to relaxations; therefore continuous sphincteric recording probes with constantly perfused sleeves located at the appropriate level were developed.26,34,35,64,65 This, coupled with
UES
UES
upper esophagus
middle esophagus
lower esophagus LES
LES
FIGURE 72-1 Schematic drawing of the pressures recorded manometrically within the lumen of the esophagus during deglutition. Contraction of the pharyngeal constrictors is accompanied by relaxation of the cricopharyngeal muscle or upper esophageal sphincter (UES). Progressive peristaltic waves are generated in the body of the esophagus. The lower esophageal sphincter (LES) remains relaxed during the entire process and closes subsequently with a postrelaxation peak.
the availability of fine extruded Silastic probes, has permitted the study of gastroesophageal physiology in small and premature babies during relatively long periods of time.66,67 Manometry requires bulky, expensive, and delicate equipment and some collaboration on the side of the patient that may be difficult to obtain in children in whom sedation might change the registered pressures.68,69 High-resolution manometry could provide more detailed data on esophageal motor function in children.70 The recently introduced 24-hour ambulatory manometry coupled with pH-metry generated important information on several esophageal disorders in adults and also in children.71–80 However, the size of the solid-state sensor probes and the bulk of the equipment have limited these tests to older children for the moment.43,50,59,81 These techniques benefit from the development of extended recording of pressures or pH, reduced to electrical signals that can be analyzed and measured with the assistance of purposefully designed software. It is likely that these diagnostic tools will be further miniaturized and adapted to children in the near future, thus enlarging the scope of manometric studies. The more recent tool available for the assessment of esophageal function is multichannel intraluminal impedance (MII) coupled with manometry and/or pH-metry.82,83 Changes in esophageal width cause proportional changes in luminal impedance and, with the assistance of several electrodes and adequate storing systems, a long-duration recording is possible. MII allows sequential analysis of the impedance variations caused by the passage of gas or liquid in either
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mm Hg
2s
50 25 0
rip
FIGURE 72-2 Pull-through manometric recording of the lower esophageal sphincter (LES) in a normal child (upper tracing) with simultaneous recording of the abdominal pressures (lower tracing). Intragastric pressures are first recorded with positive inspiratory deflections. A “plateau” corresponds to the high pressure zone of the LES. When the probe enters the thoracic esophagus, intraluminal inspiratory deflections become negative (respiratory inversion point, rip). From then on the pressure baseline is lower and the inspirations are recorded by negative waves. Withdrawal speed is 1 mm/sec, and time between vertical marks is 2 seconds.
be observed in children with Chiari syndrome,93,94 22q11.2 deletion,95 or after diazepam medication.96 Absence of relaxation (cricopharyngeal achalasia) occurs rarely as a primary phenomenon or secondary to neuromuscular disorders.92,97 In all these conditions the leading symptoms are choking during feeding and respiratory distress during early infancy, which may prompt urgent diagnostic workup. Barium meal or cineradiography depicts simultaneous opacification of the respiratory and digestive tracts in cases of permanent relaxation and dilated pharynx with permanent upper esophageal closure and occasional passage of contrast into the trachea in cases of delayed or absent relaxation.97,98 Manometry is useful for the diagnosis of cricopharyngeal disorders because it shows the incompleteness or absence of relaxation of the muscle during deglutition.92,93,99,100 However, it is particularly difficult to perform in infants because the use of perfused catheters in the upper esophagus is unpleasant for the baby who chokes, coughs, and does not collaborate. Recordings with sphincteric sleeves depict better the lack of relaxation with less risk of fluid aspiration.101 Gastrostomy may be necessary for feeding babies with permanent cricopharyngeal relaxation and also in those with UES achalasia.94,102 Achalasia of the muscle can be treated by balloon dilatation,103–105 but extramucosal myotomy is more effective.99,106 If reflux is present, a concurrent fundoplication should be considered because insufficiency of both the upper and lower esophageal closure mechanisms may be devastating.107 Some nonspecific histologic changes of the muscle obtained during myotomy have been reported in cricopharyngeal achalasia.108
Disorders of Esophageal Body ------------------------------------------------------------------------------------------------------------------------------------------------
direction. Reflux detection is possible and, when the measurements are coupled with pH recordings, its acid or nonacid nature can be ascertained. Furthermore, MII allows assessment of deglutition and esophageal motor activity (Fig. 72-3). However, there are several limitations for the use of MII: Although this procedure sheds light on the little known field of nonacid or alkaline reflux, analysis of 24-hour tracings requires ample expertise and specialist time that considerably limit its use. Computer-assisted analysis has been used for reflux studies, but little has been done in terms of esophageal function investigation.84–91 Furthermore, these limitations are even greater in children because of size, the need for patient cooperation, and the ethical restraints for establishing baseline control values, which also apply to other invasive functional tests in children.
Disorders of the Upper Esophagus ------------------------------------------------------------------------------------------------------------------------------------------------
The cricopharyngeus occasionally fails to maintain its permanent tonus or to relax during deglutition. This leads to difficult swallowing and consequent choking that may threaten life during early infancy. Permanent cricopharyngeal relaxation is sometimes seen in neurologically impaired patients who undergo repeated episodes of aspiration.92 Delayed or incomplete relaxation may
PRIMARY MOTOR DISORDERS Abnormal motility of the body of the esophagus is a frequent cause of symptoms in adults in whom diffuse esophageal spasm,72,109–112 nutcracker esophagus,113,114 or other abnormal motor patterns impairing the propulsion of the bolus are occasionally diagnosed after investigation for dysphagia, noncardiac chest pain, or suspected reflux. Simultaneous, nonpropulsive contractions or an excessive proportion of long-duration waves alternating with normal ones are found in the first of these conditions, whereas extremely powerful, high-amplitude waves that can be peristaltic or retrograde are demonstrated in the second one.72,76,115 Nutcracker esophagus has been seen to evolve into achalasia.116 Manometry is the main diagnostic tool, and its accuracy has improved considerably since 24-hour ambulatory recordings became available because the disturbances may not be permanent and appear only occasionally at some point of the circadian cycle. Because of the difficulties of performing this procedure in children, primary motor disorders of the esophageal body were practically unheard of in them until recently, although apnea, bradycardia,117 and bizarre posturing118 had been considered as expressions of motor disturbances. However, introduction of better manometric techniques produced growing evidence of their existence at this age. Food impaction in the absence of stenosis has been found in association with manometric patterns similar to those of adult nutcracker esophagus (Fig. 72-4), but this
CHAPTER 72
DISORDERS OF ESOPHAGEAL FUNCTION
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FIGURE 72-3 Multichannel intraluminal impedance (MII) tracing in a 6-year-old child with gastroesophageal reflux. The lower pH tracing reveals a pH fall that unchains a retrograde fall of impedance revealing increased esophageal lumen width (reflux episode). Shortly after, the baseline width is nearly recovered in an antegrade sequence revealing swallowing. However, this event does not clear completely the refluxed acid because the pH tracing does not come back to normal. Using a pH of 4 as a threshold for defining reflux, this episode would have been disregarded. With this technique, it is considered as a weakly acidic reflux episode.
disorder might not be primary because most patients have either reflux58,59,119,120 or eosinophilic esophagitis.121,122 Pharmacologic treatment of primary motor disorders with prokinetics or calcium channel blockers123,124 is rarely indicated in children with these conditions.125 Sildenafil, a drug that helps to induce NO-related relaxation of the esophageal body and LES, has been introduced for the treatment of motor disorders in adults,126–128 but it has not been used in children until now. Balloon dilatation or extended myotomy, procedures occasionally used in adults, have not been used in children.
SECONDARY MOTOR DISORDERS Abnormal esophageal motility has been demonstrated in several syndromes and chromosomal disorders: Damaged peristalsis sometimes associated with reflux was found in children with both Down syndrome129–131 and Cornelia de Lange syndrome.132–136 Scleroderma,137–139 polymyositisdermatomyositis,140 and lupus,141 which are well-known causes of esophageal dysmotility in adults, may rarely start during childhood. Babies breast-fed by mothers with silicone implants142 may also undergo esophageal motor disturbances similar to those of scleroderma.
FIGURE 72-4 Nocturnal ambulatory manometric recording of intraluminal lower esophageal pH (1) and upper (4), middle (5), and lower (6) esophageal pressures in a 10-year-old boy with recurrent episodes of nonobstructive food impaction. The tracing demonstrates a pattern of nutcracker esophagus with long-duration, apparently peristaltic waves that are extremely powerful, particularly at the lower end of esophageal body (>200 mm Hg or 3 to 4 times above normal). This happens during sleep and without reflux, as seen in the pH tracing.
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More relevant for pediatric surgeons are the motor disturbances of the esophagus suffered by survivors of neonatal operations for esophageal atresia with or without tracheoesophageal fistula.47,143–147 In this malformation the structure of the muscle layers148 and the abnormal extrinsic149,150 and intrinsic151,152 innervations impair the peristaltic pump for life. This is particularly harmful in this condition in which the function of the LES is also abnormal because both failures make gastroesophageal reflux (GER) a nearly constant part of the disease independently of the type of repair.61,153 In addition, esophageal shortening due to the neonatal anastomosis,154 abnormal hiatus,155 and perhaps operative denervation may influence dysmotility. Many studies demonstrated that the LES function is abnormal in survivors of neonatal operations for esophageal atresia,61,146 and some others showed that peristalsis is permanently damaged even many years after the anastomosis.60,89,144,147,156,157 The clinical relevance of these disorders is probably greater than it was previously thought. Patients operated on for esophageal atresia have swallowing problems that are perceived by them as minor but that are almost constant when specifically searched for.144,158 Their esophagus cannot fight reflux and, because of the structural basis of these dysfunctions, not much benefit can be expected from prokinetic medication. Furthermore, the spontaneous improvement of reflux with age that is part of the natural history of the disease in children cannot be expected in patients operated on for esophageal atresia, whether by thoracotomy or through a minimally invasive approach.159 GER should be treated in patients with esophageal atresia when it is symptomatic and/or when it causes esophagitis. Dysmotility, a constant problem with this malformation, does not preclude a complete fundoplication, which should be loose. Gravity is probably the main esophageal emptying force before or after the plication and there should be no problem if the wrap is loose enough. However, the proportion of longterm failures of the plication is high in this group of patients because all the causes of GER and dysmotility remain active in spite of the new valve.160,161 Other conditions relevant to pediatric surgeons involve esophageal motor disorders: chronic intestinal pseudoobstruction, a heterogeneous group of gastrointestinal dysfunctions with myogenic or neural basis, is characterized by distal esophageal dysmotility with simultaneous, short-lasting, low-amplitude waves162–164 that may help in the diagnosis. However, dysmotility is widespread and the esophageal part is not the most significant.165 Patients with Hirschsprung disease have simultaneous and double-peaked esophageal waves,166 and children with congenital central hypoventilation syndrome167 or Goldenhar syndrome168 also have dysmotility. Survivors of neonatal operations for congenital diaphragmatic hernia have radiologic and clinical evidence of abnormal esophageal motor function157,169–172 that might be related to innervation anomalies.173 Esophageal dysfunction involving lowered sphincteric pressures or abnormal distal esophageal contractility has been described in children with chronic renal failure,174 Noonan syndrome,175 and Pierre-Robin sequence.176 The same anomalies were found in adults with celiac disease.177 A number of children with this disease also have eosinophilic esophagitis, and this could explain the esophageal disturbances.178 Children with corrosive injuries of the esophagus have impaired peristaltic activity both in the acute postinjury
FIGURE 72-5 Typical “multiple-ring” pattern of the esophagus on fiberoptic endoscopy in an 11-year-old girl with dysphagia due to eosinophilic esophagitis. On biopsy the mucosa was heavily infiltrated with eosinophils. pH-metry was normal, and the patient did well after a course of treatment with steroids.
period179 and when scars are established.180 These manometric findings were confirmed by radionuclide181 and combined studies.182 The contribution of dysmotility to the clinical course and prognosis in this condition is still unclear, although it is believed that secondary esophagitis aggravates them. In the past few years we have treated a growing number of patients with eosinophilic esophagitis, a condition of probably allergic origin in which there are symptoms of reflux or food impaction.121,183–186 Reflux and stenosis are usually ruled out, and a typical aspect of Schatzki ring187 or multiple rings188 is seen on endoscopy (Fig. 72-5); heavy infiltration of the mucosa by eosinophils is found on biopsy, particularly with the Luna eosinophil granule stain.189 Strictures are rarely observed in eosinophilic esophagitis, and they respond to treatment.190,191 Dilatations may be indicated even in cases of severe dysphagia without stenosis.192 Eosinophilic esophagitis has been seen in patients previously operated on for esophageal atresia in whom reflux is common.193 Oral corticosteroids,183 fluticasone,194,195 and eosinophil stabilizers like montelukast196,197 are usually helpful in the management of this condition.190 However, there seems to be a dissociation between the symptoms and the histologic findings during treatment.198
Disorders of the Distal Esophagus ------------------------------------------------------------------------------------------------------------------------------------------------
Primary gastroesophageal reflux involves both the failure of the gastroesophageal barrier and abnormal esophageal motility. The causes for the sphincteric failure are not completely understood, but there is increasing evidence of prolonged nondeglutitory relaxations as the main mechanism.26,34,35 They permit the creation of a “common cavity” phenomenon
CHAPTER 72
that allows the full action of the untoward gastroesophageal pressure gradients between the stomach and the esophagus. The gastric fluid refluxed into the esophagus must be pushed back to the stomach by peristalsis, but this second defensive mechanism is also damaged with the consequent risk of esophagitis. The proportion of peristaltic contractions after deglutition or reflux and the amplitude of the waves are decreased, particularly at the lower end of the organ.40,43,57 Whether dysmotility in gastroesophageal reflux disease is a primary phenomenon or secondary to esophageal inflammation is unclear. There are solid clinical and experimental arguments to maintain that chronic esophagitis damages previously healthy peristalsis,199,200 but at least in some cases motor function remains abnormal even after medical or surgical cure of reflux and esophagitis.40,51,199,201,202 The success of prokinetic treatment used extensively in the past decades illustrates the relevance of the dysmotility in GER disease. These drugs act by reinforcing the failing sphincter, hastening gastric emptying, and improving peristalsis. The more characteristic motor disorder of the lower end of the esophagus is achalasia in which the LES is hypertonic and does not relax during deglutition. In addition, in part by dilatation of the esophagus and also because of primary hypoperistalsis, its propulsive function is totally ineffective. This condition is rare in young children and, although some cases have early onset, most are diagnosed in late childhood or early adolescence. Only a few pediatric studies include more than a limited number of cases,81,203–210 and the largest multicenter series involves only 175 cases.211 The cause of achalasia is unknown, but there is increasing evidence of a progressive disturbance of the intrinsic innervation with reduced or absent nitric oxide synthase (NOS) activity.19,23 This enzyme is in charge of synthesizing NO, the nonadrenergic-noncholinergic neurotransmitter of smooth muscle relaxation.19 nNOS( / ) mice with nitric oxide synthase disruption have hypertensive, nonrelaxing LESs.212 Recent evidence indicates a correlation between paucity of c-kit positive interstitial cells of Cajal and depletion of neuronal nitric oxide synthase (N-NOS) immunoreactivity in the esophagus of patients with achalasia showing that these cells are in some way related to relaxation.213 The progressive degeneration of the intrinsic innervation has some bearing with that seen in Chagas’ disease, a South American parasitic condition caused by Trypanosoma cruzi that causes degeneration of the neural structures leading to megaesophagus214,215 and abnormal esophageal function. However, in Chagas’ disease the pressures in the LES are not increased but rather reduced.216 Achalasia may be associated with Allgrove syndrome, an autosomal recessive familial condition217 caused by a mutation of the AAAS gene on chromosome 12q13218–223 in which, in addition to the esophageal motor dysfunction, there are adrenocortical insufficiency and alacrima. This association is also addressed as ALADIN syndrome (alacrima, achalasia, adrenal insufficiency, and neurologic disorder).224 Achalasia is more frequent in boys and is occasionally associated with Down syndrome.130,131,225 Achalasia patients complain of progressive dysphagia and regurgitation of food retained in the esophagus that should not be confounded with vomiting. Some have retrosternal pain that may become distressing. They lose weight and often have foul breath and respiratory symptoms like nocturnal cough or repeated pneumonia due to frequent
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microaspiration.208,226,227 In cases of Allgrove syndrome there are also symptoms of adrenocortical insufficiency such as progressive pigmentation and asthenia and eventually absence of tears (alacrima), but these symptoms and other manifestations of neurologic disease224 may appear later after the full clinical picture of achalasia has developed. Barium meal is often diagnostic: The esophagus is large (megaesophagus) and contains stagnant fluid above the barium column. There is a marked aperistalsis and the esophagogastric junction is filiform, adopting a classical “bird’s beak” shape.208 The contrast progresses into the stomach after a long time, and most of it is retained in the esophagus for hours (Fig. 72-6). Radionuclide scintigraphy may depict the lack of progression of the esophageal content and allows more prolonged observation with less irradiation, but it is less informative of the shape of the distal esophagus.130,228 Fiberoptic endoscopy rules out the presence of stricture, and the instrument can be advanced in the stomach with relative ease. After suctioning of the retained fluid, a picture of esophagitis may be seen but it is secondary to fermentation of the stagnant fluid. pH-metry is not useful at this stage and can be misleading because this fluid is often acid and the probe reading may suggest GER, which is in fact impossible. Manometry is the best diagnostic tool for achalasia: The sphincter is hypertonic and does not relax or does it incompletely during deglutition. The esophageal peristalsis is absent and the scarce contractions present, particularly during meals, are recorded simultaneously at all points of the lumen, which is in fact a common chamber (Fig. 72-7).70,203,207 Twentyfour-hour ambulatory recordings performed with probes equipped with multiple solid-state sensors show that the aperistalsis is constant along the entire circadian cycle
FIGURE 72-6 Barium meal in a 9-year-old patient with achalasia. The esophagus is enlarged and contained stagnant fluid before the contrast was given. Emptying is slow and the cardia has a typical pattern of “carrot” or “bird’s beak” (left). Some feeble esophageal contractions are seen (right), but peristalsis is impossible because the esophageal walls remain widely separated.
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PART VI
THORAX
FIGURE 72-8 Ambulatory esophageal manometry during meal in a 24-year-old woman 12 years after Heller myotomy for achalasia. She was asymptomatic, but esophageal motility remained poor. The motor waves at the upper (4), middle (5), and lower (6) levels of the esophagus showed peristaltic organization, but they were weak (<25 mm Hg, roughly half the normal). Time between vertical marks is 5 seconds.
FIGURE 72-7 Ambulatory esophageal manometry in an 8-year-old boy with achalasia. In the upper picture, the pressures at the upper (4), middle (5), and lower (6) levels of the esophagus are identical and no waves are seen. In the lower picture, corresponding to a meal, some waves are generated but they are simultaneous and nonpropulsive (time between vertical marks, 5 seconds).
including meals, when motor waves are normally more active.81 Impedance studies confirmed and reinforced these data.83 The differential diagnosis includes extrinsic and intrinsic causes; in the latter group, acquired strictures and congenital stenosis from tracheobronchial remnants are usually easily eliminated by endoscopy. Leiomyomas and leiomyomatosis, either isolated or as part of Alport syndrome (hereditary X-linked nephropathy and deafness), may be suspected on endoscopy but require cross-sectional imaging with computed tomography or magnetic resonance imaging for confirmation.228a Medication, particularly calcium channel blockers such as nifedipine, may alleviate the spasm in some cases,229 but they cannot be relied on as a long-term treatment in children with achalasia.124 Forceful balloon dilatation of the distal esophagus is often successful in adults, but this modality of treatment has not brought permanent relief in children,203,204,230 although some favorable results were reported,209,231 particularly older than the age of 6.232 The local injection of
botulinum toxin has been also tried in children, but its success has been limited as well.226,233–236 Like in adults,237 extramucosal Heller myotomy remains the best treatment at this age and it can be performed through either the thorax or the abdomen.81,203,204,207,208,211,238 Perioperative lower esophageal manometry239 or endoscopy240 may ensure the completeness of the myotomy. An abdominal approach probably allows for a more complete myotomy on the gastric side and facilitates fundoplication. In fact, if sought after, reflux is rather constant after Heller myotomy and some form of fundoplication is probably indicated in children, whose long life expectancy after the operation supports the use of this procedure to prevent complications of GER.81,204,206,207,226,241,242 A Nissen procedure may be inadequate due to the often large diameter of the thickened esophagus; the posterior Toupet or anterior Thal-Dor hemifundoplications are preferred.81,207,242 Some authors prefer to omit antireflux procedures in these patients.209,243 All these procedures can be performed laparoscopically, and this approach has become the gold standard.209,238,242,244–247 Postoperatively patients are relieved of their symptoms at once and they can feed properly and regain weight. However, the esophagus remains dilated for months or even years and its function only rarely returns to normal. Most patients maintain scarce and ineffective peristalsis in spite of the decrease in sphincteric pressure provided by myotomy (Fig. 72-8).81,204,241,248,249 Some patients continue to have minor symptoms such as dysphagia and often require a few swallows of water during meals, but surgery brings back a good quality of life. Esophageal replacement has been reported in some rare cases of achalasia in which all other treatments failed.250,251 The complete reference list is available online at www. expertconsult.com.