A working, albeit restrictive, definition of an esophageal motility disorder is an esophageal disease attributable to neuromuscular dysfunction that causes symptoms referable to the esophagus, most commonly dysphagia, chest pain, or heartburn. Employing this definition, there are relatively few firmly established primary esophageal motility disorders: achalasia, distal esophageal spasm (DES), and gastroesophageal reflux disease (GERD). GERD is clearly the most prevalent among the group and, fittingly, it is addressed in detail elsewhere in this text (see Chapter 43). Esophageal motility disorders also can be secondary phenomena in which case esophageal dysfunction is part of a more global disease: pseudoachalasia, Chagas disease, and scleroderma. Dysphagia attributable to pharyngeal or UES dysfunction can be included in a discussion of esophageal motor disorders, but this is usually as a manifestation of a more global neuromuscular disease process. The major focus of this chapter is on the primary esophageal motility disorders, particularly achalasia. However, mention is made of the secondary motility disorders and proximal pharyngoesophageal dysfunction when important unique features exist. EPIDEMIOLOGY Estimates of the prevalence of dysphagia among individuals older than 50 years of age range from 16% to 22%[181,182] with most of this related to oropharyngeal dysfunction. Within health care institutions, it is estimated that up to 13% of hospitalized patients and 60% of nursing home residents[183] have feeding problems, most of which are attributed to oropharyngeal dysfunction as opposed to esophageal dysfunction. Most oropharyngeal dysphagia is related to impaired neuromuscular function; the prevalence of the most common anatomic etiology, Zenker's diverticulum (discussed in Chapter 23), is estimated to range from a meager 0.01% to 0.11% of the U.S. population, with a peak incidence in men between the seventh and ninth decades.[184] The consequences of oropharyngeal dysphagia are severe: volume depletion, malnutrition, aspiration, choking, pneumonia, and death. In fact, mortality of nursing residents with dysphagia and aspiration can be as high as 45% over one year.[185] As the U.S. population continues to age, oropharyngeal dysphagia will become an increasing problem associated with complex medical and ethical issues. Achalasia is the most easily recognized and best-defined motor disorder of the esophagus. The annual incidence of achalasia is about 1/100,000 population in the United States and Europe,[186,187] affecting both genders equally and usually presenting between ages 25 and 60.[188] Because achalasia is a chronic condition, its prevalence greatly exceeds its incidence, with prevalence estimates in Europe ranging from 7.1/100,000 in Wales to 13.4/100,000 in Ireland.[189] Reports of familial clustering of achalasia raise the possibility of genetic predisposition. Achalasia has been reported in one pair of monozygotic twins,[190] in siblings,[191] and in children of affected parents.[192] However, a genetic determinant for achalasia is not strong.[193] Emphasizing this point, a survey of 1012 first-degree relatives of 159 achalasic patients identified no affected relatives.[194] Familial adrenal insufficiency with alacrima is a rare genetic achalasia syndrome. This condition is inherited as an autosomal recessive disease that manifests itself with the childhood onset of autonomic nervous system dysfunction including achalasia, alacrima, sinoatrial dysfunction, abnormal pupillary responses to light, and delayed gastric emptying.[195] It is caused by mutations in AAAS, a gene which encodes a protein known as ALADIN. No population-based studies exist on the incidence or prevalence of esophageal motility disorders other than achalasia. Thus, the only way to estimate the incidence or prevalence of spastic disorders is to examine data on populations at risk and reference the observed frequency of spastic disorders to the incidence of achalasia which, as detailed earlier, is about 1 per 100,000 population. Doing so, the prevalence of DES is similar to that of achalasia (or much lower if more restrictive diagnostic criteria are used). Populations at risk for motility disorders are patients with chest pain or dysphagia, so it is among these patients that extensive manometric data have been collected. Manometric abnormalities are prevalent among these groups,[196-205] but in most cases the manometric findings are of unclear significance.[197]PATHOGENESIS Oropharyngeal Dysphagia Obstructing lesions of the oral cavity, head, and neck can cause dysphagia, and must be excluded before diagnosing a neuromuscular disorder. Structural abnormalities may result from trauma, surgery, tumors, caustic injury, congenital anomalies, or acquired deformities. The most common structural abnormalities of the hypopharynx associated with dysphagia are hypopharyngeal (Zenker's) diverticula and cricopharyngeal bars. If the etiology of oropharyngeal dysphagia is not readily apparent after initial evaluation for anatomic disorders, evidence of functional abnormalities should be sought. Primary neurologic or muscular diseases involving the oropharynx are often associated with dysphagia. Thus, whereas esophageal dysphagia usually results from esophageal diseases, oropharyngeal dysphagia frequently results from neurologic or muscular diseases, with oropharyngeal dysfunction being just one pathologic manifestation. Although the specifics vary from disease to disease, the net effect on swallowing can be analyzed according to the mechanical description of the swallow outlined earlier. Table 42-1 summarizes the mechanical elements of the swallow along with the manifestation and consequence of dysfunction and provides representative pathologic conditions in which they are likely encountered. Neurologic examination may indicate cranial nerve dysfunction, neuromuscular disease, cerebellar dysfunction, or an underlying movement disorder. Functional abnormalities can be attributable to dysfunction of intrinsic musculature, peripheral nerves, or central nervous system control mechanisms. Of note, contrary to popular belief, the gag reflex is not predictive of pharyngeal swallowing efficiency or aspiration risk. The gag reflex is absent in 20% to 40% of normal adults.[206]
Table 42-1 -- Affected Phases, Manifestations, and Typical Disease Conditions Causing Oropharyngeal Dysphagia
Evident in Table 42-1, oropharyngeal dysphagia is frequently the result of neurologic or muscular diseases. Neurologic diseases can damage the neural structures requisite for either the afferent or efferent limbs of the oropharyngeal swallow. Virtually any neuromuscular disease can cause dysphagia. Because there is nothing unique to neurons controlling swallowing, their involvement in disease processes is usually random. Furthermore, in most instances, functions mediated by adjacent neuronal structures are concurrently involved. The following discussion focuses on neuromuscular pathologic processes most commonly encountered. These entities are also discussed in Chapter 35. Stroke Aspiration pneumonia has been estimated to inflict a 20% death rate in the first year after a stroke, and 10% to 15% each year thereafter.[207] It is usually not the first episode of aspiration pneumonia, but the subsequent recurrences over the years that eventually causes death.[208] The ultimate cause of aspiration pneumonia is dysphagia leading to aspiration that can occur by at least three mechanisms: absence or severe delay in triggering the swallow, reduced lingual control, or weakened laryngopharyngeal musculature.[17] Conceptually, these mechanisms can involve motor or sensory impairments. Cortical strokes are less likely to result in severe dysphagia than brainstem strokes.[209] Cortical strokes are also more likely to demonstrate neurologic recovery. Of 86 consecutive patients who sustained an acute cerebral infarct, 37 (43%) experienced dysphagia when evaluated within four days of the event. However, 86% of these patients were able to swallow normally two weeks later,[209] with recovery resulting from contralateral areas taking over the lost function.[210] Failure to recover swallowing function was more likely among patients incurring larger strokes or patients who have had prior infarcts. Poliomyelitis Most cases of poliomyelitis involve only the spinal cord. However, the fatality rate from bulbar polio far exceeds that of spinal disease, primarily a consequence of respiratory depression. Bulbar poliomyelitis is also associated with dysphagia. In one analysis of the persistent sequelae of bulbar poliomyelitis, 28 of 47 patients (60%) had recurrent or continued involvement of the pharynx 17 or more months after their acute illness.[211] Speech and swallowing dysfunction result from weakness of the pharyngeal musculature.[212] Neurologists have also observed an increasing number of patients with new paretic symptoms traceable to their remote polio infection 30 to 40 years earlier. The new, slowly progressive post-polio muscular atrophy may occur in muscles that were clinically unaffected by the acute illness.[211] One investigation studied 13 patients with post-polio dysphagia and demonstrated palatal, pharyngeal, and laryngeal weakness.[213] More than half of the patients evaluated demonstrated silent aspiration. Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is a progressive neurologic disease characterized by degeneration of motor neurons in the brain, brainstem, and spinal cord. Specific symptoms are dependent on the locations of affected motor neurons and the relative severity of involvement. When the degenerative process involves the cranial nerve nuclei, swallowing difficulties ensue. Oropharyngeal dysfunction characteristically begins with the tongue and progresses to involve the pharyngeal and laryngeal musculature. Patients experience choking attacks, become volume depleted and/or malnourished, and incur aspiration pneumonia. The decline in swallowing function is progressive and predictable, invariably leading to gastrostomy feeding. Patients often die as a consequence of their swallowing dysfunction in conjunction with respiratory depression.[214]Parkinson's Disease Although only 15% to 20% of patients with Parkinson's disease complain of swallowing problems, more than 95% have demonstrable defects when studied videofluoroscopically.[215] This disparity suggests that patients compensate in the early stages of the disease and complain of dysphagia only when it becomes severe. Abnormalities include repetitive lingual pumping prior to initiation of a pharyngeal swallow, piecemeal swallowing, and oral residue after the swallow. Patients may also exhibit a delayed swallow response and a weak pharyngeal contraction, resulting in vallecular and pyriform sinus residue. Recent data suggest this to be related to the combination of incomplete UES relaxation and a weakened pharyngeal contraction.[215]Tumors Medullary or vagal tumors are potentially debilitating with respect to swallowing. Astrocytomas are the most common tumor subtype affecting adults whereas medulloblastomas are the most common type encountered in children.[216] The morbidity of these tumors is often substantially increased as a result of the relative inaccessibility of the medulla to surgery. Unilateral lesions of the vagus can result in hemiparesis of the soft palate and pharyngeal constrictors, as well as of the laryngeal musculature. Surgical manipulation of this region can even result in complete loss of the pharyngeal swallow response.[217] The recurrent laryngeal nerves can be injured as a result of thyroid surgery, aortic aneurysms, pneumonectomy, primary mediastinal malignancies, or metastatic lesions to the mediastinum. Owing to its more extensive loop in the chest, the left recurrent laryngeal nerve is more vulnerable than the right to involvement with mediastinal node malignancy. Unilateral recurrent laryngeal nerve injury results in unilateral adductor paralysis of the vocal cords. This defect can result in aspiration during swallowing because of impaired laryngeal closure. It is rare, however, to have any primary pharyngeal dysfunction resultant from recurrent laryngeal nerve injury.[218]Oculopharyngeal Dystrophy Oculopharyngeal muscular dystrophy is a syndrome characterized by progressive dysphagia and ptosis. Historically, afflicted patients reaching age 50 typically died of starvation resulting from pharyngeal paralysis.[219] The disease is now known to be a form of muscular dystrophy and is inherited as an autosomal dominant disorder with occurrences clustered in families of French-Canadian descent. Genetic studies of an afflicted family indicate linkage to chromosome 14, perhaps involving the region coding for cardiac alpha or beta myosin heavy chains.[220] Oculopharyngeal dystrophy affects the striated pharyngeal muscles and the levator palpebrae. Although other forms of muscular dystrophy occasionally affect the pharyngeal constrictors, this is rarely a dominant manifestation. The first symptom of oculopharyngeal dystrophy is usually ptosis that slowly progresses and eventually dominates the patient's appearance. Dysphagia may begin before, be concomitant with, or occur after ptosis. The dominant functional abnormalities are of a weak or absent pharyngeal contraction with hypopharyngeal stasis.[219] Dysphagia is slowly progressive, but may ultimately lead to starvation, aspiration pneumonia, or asphyxia. Myotonic Dystrophy Myotonic dystrophy is a rare disorder characterized by prolonged contraction and difficulty in relaxation of affected skeletal musculature. Recent investigations suggest that even though only half of the patients complain of dysphagia, pharyngeal and esophageal motor abnormalities can be universally demonstrated. The pattern of abnormality is of a weakened pharyngeal contraction, absent peristalsis in the striated muscle esophagus, and diminished or absent peristalsis in the smooth muscle segment of the esophagus. Myotonia has not been demonstrated in any part of the esophagus.[29] Thus, the risk of aspiration in this disease is similar to other forms of muscular dystrophy. Aspiration can occur during the swallow due to poor pharyngeal clearance combined with concurrent weakness of the laryngeal elevators or after the swallow when the substantial pharyngeal residue might fall into the reopened airway. Myasthenia Gravis Myasthenia gravis is a progressive autoimmune disease characterized by high circulating levels of acetylcholine receptor antibody and destruction of acetylcholine receptors at neuromuscular junctions. Musculature controlled by the cranial nerves is almost always involved, particularly the ocular muscles. Dysphagia is prominent in more than a third of cases and, in unusual instances, can be the initial and dominant manifestation of the disease.[17] In mild cases, dysphagia may not be evident until after 15 to 20 minutes of eating. Classically, manometric studies reveal a progressive deterioration in the amplitude of pharyngeal contractions with repeated swallows. Peristaltic amplitude recovers with rest or following the administration of 10 mg edrophonium chloride, an acetylcholinesterase inhibitor. In more advanced cases, the dysphagia can be profound and associated with nasopharyngeal regurgitation and nasality of the voice, even to the extent of being confused with bulbar ALS or a brainstem stroke.[221]Hypopharyngeal (Zenker's) Diverticulum and Cricopharyngeal Bar Hypopharyngeal diverticulum and cricopharyngeal bars are closely related disease entities in that it is a cricopharyngeal bar that can result in diverticulum formation. Zenker's diverticulum (Fig. 42-7), is discussed in Chapter 23. Zenker's diverticulum originates in the midline posteriorly at Killian's dehiscence, a point of pharyngeal wall weakness between the oblique fibers of the inferior pharyngeal constrictor and the transverse cricopharyngeus muscle (see Fig. 42-6).[222] Other locations of acquired pharyngeal diverticula include (1) the lateral slit separating the cricopharyngeus muscle from the fibers of the proximal end of the esophagus through which the recurrent laryngeal nerve and its accompanying vessels run to supply the larynx; (2) at the penetration of the inferior thyroid artery into the hypopharynx; and (3) at the junction of the middle and inferior constrictor muscles. The unifying theme of these locations is that they are sites of potential weakness of the muscular lining of the hypopharynx through which the mucosa herniates, leading to a “false” diverticulum. The best-substantiated explanation for the development of diverticula is that they form as a result of a restrictive myopathy associated with diminished compliance of the cricopharyngeus muscle. Surgical specimens of cricopharyngeus muscle strips from 14 patients with hypopharyngeal (Zenker's) diverticula demonstrated structural changes that would decrease UES compliance and opening.[223] The cricopharyngeus samples from these patients had “fibro-adipose tissue replacement and (muscle) fiber degeneration.” Thus, although the muscle relaxes normally during a swallow, it cannot distend normally, resulting in the appearance of a cricopharyngeal indentation, or bar, during a barium swallow (Fig. 42-8). Diminished sphincter compliance necessitates increased hypopharyngeal intrabolus pressure to maintain trans-sphincteric flow through the smaller UES opening. The increased stress on the hypopharynx from the increased intrabolus pressure may ultimately result in diverticulum formation.
Achalasia Achalasia is characterized by impaired LES relaxation with swallowing, and aperistalsis in the smooth muscle esophagus. The resting LES pressure is elevated in about 60% of cases. If there are nonperistaltic, spastic contractions in the esophageal body, the disease is referred to as vigorous achalasia or, more recently, spastic achalasia.[224] These physiologic alterations result from damage to the innervation of the smooth muscle segment of the esophagus (including the LES). Proposed neuroanatomic changes responsible for achalasia include loss of ganglion cells within the myenteric (Auerbach's) plexus, degeneration of the vagus nerve, and degeneration of the dorsal motor nucleus of the vagus. Of these three possibilities, only the loss of ganglion cells is well substantiated. Several observers report fewer ganglion cells and ganglion cells surrounded by mononuclear inflammatory cells in the smooth muscle esophagus of achalasics.[225] One report additionally noted ganglion cell degeneration extending into the proximal stomach in half of 34 specimens analyzed.[226] The degree of ganglion cell loss parallels the duration of disease such that ganglion cells are almost absent in patients afflicted for 10 or more years.[227] A morphologic study of 42 esophagi resected from patients with advanced achalasia reported reduced numbers of ganglion cells and inflammation within the myenteric plexus in all cases.[228] The ultimate cause of ganglion cell degeneration in achalasia is gradually being unraveled, with increasing evidence pointing toward an autoimmune process attributable to a latent infection with human herpes simplex virus 1 (HSV-1) in genetically susceptible individuals.[229,230] Immunohistochemical analysis of the myenteric plexus infiltrate in achalasia patients revealed that the majority of inflammatory cells are either resting or activated cytotoxic T cells.[231] In addition, immunoglobulin M (IgM) antibodies and evidence of complement activation have been demonstrated within myenteric ganglia.[232] Antibodies against myenteric neurons have been repeatedly shown in serum of achalasia patients,[233,234] especially in patients with HLA DQA1* 0103 and DQB1* 0603 alleles.[235] The trigger for initiating the autoimmune response leading to the development of achalasia is suspected to be a viral infection, but studies implicating varicella zoster or measles virus have been contradictory.[232,236,237] However, an elegant recent study provided strong evidence implicating HSV-1 as the culprit.[230] T cells of achalasia patients exhibited clonal expansion within the myenteric plexus of the LES, and were activated by HSV-1 antigens, but not by cytomegaloviral, adenoviral, or enteroviral antigens. Furthermore, HSV-1 antibodies and HSV-1 deoxyribonucleic acid (DNA) were isolated in 84% and 63% of achalasic patients, respectively, potentially implicating HSV-1 in the majority of achalasia cases. Interestingly, HSV-1 was also detected in LES tissue from non-achalasic organ donors, suggesting that the development of achalasia is dependent on both the virus and a genetic predisposition as indicated by the specific HLA associations. Achalasia may also be associated with degenerative neurologic disorders such as Parkinson's disease. Patients with both achalasia and Parkinson's disease were noted to have Lewy bodies (intracytoplasmic hyaline or spherical eosinophilic inclusions) in the degenerating ganglion cells of the myenteric plexus.[238] Physiologic studies in individuals with achalasia also suggest dysfunction consistent with postganglionic denervation of esophageal smooth muscle. Such damage can affect excitatory ganglion neurons (cholinergic), inhibitory ganglion neurons (NO ? VIP), or both. Consider first the excitatory ganglion neurons. Muscle strips from the circular layer of the esophageal body of achalasic patients contract when directly stimulated by acetylcholine but fail to respond to ganglionic stimulation by nicotine, indicating a postganglionic excitatory defect. However, it is likely that loss of excitatory innervation is variable among achalasic patients. Partial preservation of the postganglionic cholinergic pathway is suggested by the observations that an achalasic patient's LES pressure increases after administration of the acetycholinesterase inhibitor, edrophonium, and decreases after administration of the muscarinic antagonist, atropine.[239] These observations are crucial to understanding why botulinum toxin may have therapeutic benefit in achalasia (see section on treatment). Regardless of excitatory ganglion neuron impairment, it is clear that inhibitory ganglion neuron dysfunction is an early manifestation of achalasia. These neurons mediate deglutitive inhibition (including LES relaxation) and the sequenced propagation of esophageal peristalsis; their absence offers a unifying hypothesis for the key physiologic abnormalities of achalasia, namely, impaired LES relaxation and aperistalsis. Inhibitory ganglion neurons use NO as a neurotransmitter, and patients with achalasia have been shown to lack NO synthase in the gastroesophageal junction.[240] VIP may be a co-transmitter in these neurons and immunohistochemical studies have demonstrated a marked reduction of VIP-staining neurons in achalasic individuals.[112] A multitude of evidence supports impaired physiologic function of post-ganglionic inhibitory innervation in the smooth muscle esophagus of achalasic patients. Muscle strips from their LES do not relax in response to ganglionic stimulation as they do in normal controls[241] and CCK, which normally stimulates the inhibitory ganglion neurons, thereby reducing LES pressure, paradoxically increases the LES pressure in achalasics.[242] Impaired inhibitory innervation of the smooth muscle esophagus above the LES is more difficult to demonstrate because of the absence of resting tone in this region. However, in a clever experiment, Sifrim and colleagues used an intraesophageal balloon to create a high-pressure zone in the tubular esophagus that then relaxed with the onset of deglutitive inhibition. This deglutitive relaxation in the esophageal body was absent in early, nondilated cases of achalasia.[243]Distal Esophageal Spasm The term “diffuse esophageal spasm” and our present concept of this entity dates to Fleshler's 1967 description of a “clinical syndrome characterized by symptoms of substernal distress or dysphagia or both, the roentgenographic appearance of localized, nonprogressive waves (tertiary contractions), and an increased incidence of nonperistaltic contractions recorded by intraluminal manometry.”[244] Because only the smooth muscle esophagus is affected, the entity was subsequently more precisely labeled “distal esophageal spasm.”[245,246] Clearly, distal esophageal spasm is a disorder of peristalsis. However, in most afflicted patients, the esophagus retains the ability to propagate normal peristaltic contractions the majority of the time suggesting that the neuromuscular pathology is more subtle than with achalasia. Partly because of this fact, the criteria for diagnosing DES remain variable and confusing.[245] The neuromuscular pathology responsible for DES is unknown and there are no known risk factors or other conditions associated with DES. Furthermore, because neither the esophageal muscularis propria or myenteric plexus is readily accessible for biopsy and patients with spastic disorders of the esophagus rarely undergo esophageal surgery, only a paucity of pathologic material has been available for analysis. The most striking reported pathologic change is diffuse muscular hypertrophy or hyperplasia in the distal two thirds of the esophagus. Muscular thickening of up to 2 cm has been reported in patients with clinical and manometric evidence of DES.[247] However, there are other well-documented cases of spasm in which esophageal muscular thickening was not found at thoracotomy[248] and still other instances of patients with muscular thickening not associated with DES symptoms.[249] Similarly, little evidence of neuropathology has been reported; diffuse fragmentation of vagal filaments, increased endoneural collagen, and mitochondrial fragmentation have been described, but the significance of these findings is unclear.[250] Despite the absence of defined histopathology, physiologic evidence implicates myenteric plexus neuronal dysfunction in spastic disorders of the esophagus. During peristalsis, vagal impulses reach the entire smooth muscle segment of the esophagus simultaneously and activate myenteric plexus neurons between the longitudinal and circular muscle layers.[51] Ganglionic neurons then intervene between the efferent vagal fibers and the smooth muscle, belonging to either an inhibitory population that hyperpolarizes the muscle cell membrane and inhibits contraction or to an excitatory population that depolarizes the membrane, thereby prompting contraction. Thus, the instantaneous activity of the musculature at each esophageal locus is determined by the balance between these controlling influences from the myenteric plexus. Experimental evidence suggests heterogeneity among patients with spastic disorders, such that some primarily exhibit a defect of inhibitory interneuron function, whereas in others the defect is of excess excitation. Two in vivo experiments implicate a defect of myenteric plexus inhibitory interneuron function in the genesis of simultaneous contractions in the distal esophagus. In one, the propagation of a swallow-induced contraction was timed in normal subjects and in a group of patients with a simultaneous contraction in the distal esophagus.[251] Within the proximal esophagus the two groups exhibited similar contraction propagation, consistent with this timing being the result of the sequenced activation of motor units by vagal efferent nerves programmed within the medullary swallow center. However, once entering the smooth muscle segment, the patients' contractions diverged from those of the normal subjects, resulting in a simultaneous contraction in the distal esophagus. The distal esophageal contractions were otherwise normal, but the progressive delay of initiation of the contraction at more distal loci, a function attributable to increasing dominance of inhibitory interneurons in the distal esophagus, was absent. Furthermore, if these patients swallowed twice within a five-second interval, there was no deglutitive inhibition of the first peristaltic contraction within the smooth muscle esophagus, as is observed in normal subjects. A second experiment demonstrating impaired deglutitive inhibition in DES comes from work using an artificial high-pressure zone within the distal esophagus. Patients with motor disorders characterized by rapidly propagating or simultaneous contractions exhibited only partial relaxation of the artificial high-pressure zone, proportional to the impairment of propagation velocity.[243] Taken together these findings strongly suggest that one potential neuropathologic process in DES is a selective, intermittent dysfunction of myenteric plexus inhibitory interneurons. A second group of patients in the analysis of Behar and Biancani had normal propagation latency but exhibited frequent spontaneous distal esophageal contractions. These patients had significantly longer and higher-amplitude contractions at each locus within the distal esophagus.[251] Patients with peristaltic disorders characterized by excess excitation demonstrate heightened sensitivity to stimulation with cholinergic agents,[112,252] the cholinesterase inhibitor edrophonium,[253] pentagastrin,[254] and ergonovine.[255] An electromyographic correlate of this excitability is found from bipolar ring electrode recordings from the distal esophagus.[256] Whereas normal individuals uniformly exhibited spiking activity prior to each esophageal contraction, DES patients exhibited spike-independent spontaneous esophageal contractions. The preceding discussion suggests that the physiologic abnormalities of patients with spastic disorders are heterogeneous, but all are characterized by an imbalance between the excitatory and inhibitory influences on the esophageal smooth muscle. The suggestion of an impairment of the pathway of deglutitive inhibition is particularly interesting in that it places DES in a pathophysiologic continuum with achalasia, consistent with documented case reports of patients undergoing this evolution.[257] Furthermore, there are marked similarities between spastic achalasia and DES, both characterized by rapidly propagated contractions in the distal esophagus, with the only differences being involvement of the LES and constancy of the disorder in vigorous achalasia. Similar to achalasia, the simultaneous contractions typifying DES impair bolus transit through the esophagus, potentially explaining the associated dysphagia.[258]CLINICAL FEATURES Dysphagia is a fundamental symptom of esophageal motility disorders. Esophageal, as opposed to oropharyngeal, dysphagia is suggested by the absence of associated aspiration, cough, nasopharyngeal regurgitation, dry mouth, drooling, pharyngeal residue following swallow, or co-occurring neuromuscular dysfunction (e.g., weakness, paresthesia, slurred speech). The associated conditions of heartburn, esophagopharyngeal regurgitation, chest pain, odynophagia, or intermittent esophageal obstruction suggest esophageal dysphagia. However, an important limitation of the patient history with esophageal dysphagia is that a patient's identification of the location of obstruction is of limited accuracy. Specifically, a distal esophageal obstruction caused by an esophageal ring or achalasia often is perceived as cervical dysphagia, such that patients correctly localize distal dysfunction only 60% of the time.[259] Because of this subjective difficulty in distinguishing proximal from distal lesions within the esophagus, an evaluation for cervical dysphagia should encompass the entire length of the esophagus. Another important consideration in patient management is that esophageal motility disorders are much less common than mechanical or inflammatory etiologies of dysphagia, such as tumors, strictures, rings, and peptic, pill-induced, or infectious esophagitis. Historical points suggestive of a motor disorder are difficulty with solids and liquids as opposed to only solids, which is more suggestive of mechanical obstruction. However, the functional consequences of mechanical or inflammatory disorders can exactly mimic those of primary motility disorders. Thus, as with the evaluation of oropharyngeal dysphagia, an esophageal motility disorder should be considered as an etiology for dysphagia only after exclusion of other more common diagnoses by endoscopic, histologic, or radiographic examination. Achalasia Clinical manifestations of achalasia may include dysphagia, regurgitation, chest pain, hiccups, halitosis, weight loss, aspiration pneumonia, and heartburn. All patients have solid food dysphagia; the majority of patients also have variable degrees of liquid dysphagia. The onset of dysphagia is usually gradual, with the duration of symptoms averaging two years at presentation.[188] The severity of dysphagia fluctuates, but eventually plateaus. With long-standing disease there is progressive esophageal dilatation, and regurgitation becomes frequent when large amounts of food and fluid are retained in the dilated esophagus. The regurgitant is often recognized as food that has been eaten hours, or even days, previously. It tends to be nonbilious, non-acid, and mixed with copious amounts of saliva. Patients often fail to recognize the slimy mucoid regurgitant as saliva, being unfamiliar with its normal consistency. Chest pain is a frequent complaint early in the course of achalasia, occurring in approximately two thirds of patients.[260] Its etiology is unknown, but is speculated to be related to the occurrence of esophageal spasm (more recently, spasm of longitudinal muscle) or to the process of esophageal dilatation associated with disease progression. Treatment of achalasia (discussed later) is less effective in relieving chest pain than it is in relieving dysphagia or regurgitation. However, unlike dysphagia or regurgitation, chest pain may spontaneously improve or disappear over time.[260] An estimated 10% of people with achalasia have bronchopulmonary complications as a result of regurgitation and aspiration; in some instances, it is these complications rather than dysphagia that prompts them to seek medical care.[261] Another interesting, but fortunately rare, symptom of achalasia is airway compromise and stridor as a result of the dilated esophagus compressing the membranous trachea in the neck.[262] This is hypothesized to result from dysfunction of the belch reflex.[263] It is paradoxical that many achalasic patients complain of heartburn, even after the onset of dysphagia.[264] Although gastroesophageal reflux may be a common sequela of the treatments for achalasia, it seems physiologically inconsistent to simultaneously have dysphagia from impaired LES relaxation and reflux from excessive LES relaxation. In support of this skepticism, ambulatory 24-hour esophageal pH studies of achalasic patients have only shown periods of esophageal acidification caused by the bacterial fermentation of retained food in the esophagus rather than discrete gastroesophageal reflux events.[265] Furthermore, prolonged LES recordings have shown nearly a complete absence of transient LES relaxations in achalasics.[266] However, there are occasional exceptions to this, evident from a well-documented case of an achalasic patient with intact transient LES relaxation despite the absence of deglutitive LES relaxation.[267] The cause of the heartburn often reported by patients with achalasia is unknown. Distal Esophageal Spasm The major symptoms of DES are dysphagia and chest pain. Weight loss is rare. Dysphagia is usually intermittent and sometimes related to swallowing specific substances such as red wine or liquids at extreme hot or cold temperature. In some instances, patients experience episodes of esophageal obstruction while eating that persists until relieved by emesis. Esophageal chest pain is very similar in character to angina and is often described as crushing or squeezing in character, radiating to the neck, jaw, arms, or midline of the back. Pain episodes may last from minutes to hours, but continued swallowing is not always impaired. The mechanism producing esophageal pain is poorly understood. Recent data suggest that it may be related to sustained contraction of esophageal longitudinal muscle.[268] Chest pain is also prevalent in patients subsequently found to have manometric abnormalities that are insufficient to establish a diagnosis of achalasia or DES. Among such individuals, there is a high prevalence of reflux and of psychiatric diagnoses, particularly anxiety and depression.[197] Evidence also suggests a lower visceral pain threshold in this group, and symptoms of irritable bowel syndrome (Chapter 118) may be seen in more than 50% of these patients.[269]DIFFERENTIAL DIAGNOSIS The history is crucial in the evaluation of dysphagia. Major objectives of the history are to differentiate oropharyngeal dysphagia from esophageal dysphagia, xerostomia (hyposalivation), or globus sensation. All are frequently confused with each other. Globus sensation, in particular, is frequently confused with dysphagia. Unlike dysphagia, which occurs only during swallowing, globus sensation is prominent between swallows. Patients relate the nearly constant sensation of having a lump in their throat or feeling a foreign object caught in their throat. In some instances globus is associated with reflux symptoms and in others with substantial anxiety. It is the linkage with anxiety that led to the older nomenclature, “globus hystericus.” Unfortunately, studies have failed to define an objective anatomic or physiologic cause for globus and we are left with the crucial data being in the history; globus sensation persists regardless of the act of swallowing. Achalasia The differential diagnosis of achalasia includes other esophageal motility disorders, with functional attributes overlapping those of achalasia and diseases of distinct pathophysiology that duplicate the functional consequences of achalasia. With respect to other motility disorders, there are many similarities between DES and achalasia, especially the subtype of spastic achalasia. In fact, the only distinction between these entities is the demonstration of incomplete LES relaxation in vigorous achalasia. Thus, some have speculated that DES and vigorous (spastic) achalasia may represent early disease and subsequently evolve into full-fledged achalasia.[257] Testing this hypothesis, a report on a prospective cohort of patients diagnosed with esophageal spasm between 1992 and 2003 revealed that achalasia was subsequently diagnosed in only one.[270] Given that rarity and the possibility of the case initially being misdiagnosed, it seems reasonable to conclude that at most only a small minority of DES cases are part of the continuum with achalasia. With respect to other diseases that duplicate the functional consequences of idiopathic achalasia, the main considerations are Chagas disease, pseudoachalasia associated with malignancy or infiltrative diseases, or various surgical procedures, as discussed following. Chagas Disease Esophageal involvement in Chagas disease (see Chapter 109), which is endemic in areas of central Brazil, Venezuela, and northern Argentina, can be indistinguishable from idiopathic achalasia. An estimated 20 million South Americans are infected. Due to immigration, about 500,000 people in the United States are believed infected. Chagas disease is spread by the bite of reduvid (kissing) bug that transmits the parasitic protozoan, Trypanosoma cruzi. An acute septicemic phase of the illness follows that varies in severity from going unnoticed to being fatal.[271] The chronic phase of the disease develops up to 20 years after infection and results from destruction of autonomic ganglion cells throughout the body, including the heart, gut, urinary tract, and respiratory tract. Chronic cardiomyopathy with conduction system disturbances and arrhythmias is the most common cause of death. Within the digestive tract, the organs most commonly affected are the esophagus, duodenum, and colon. The severity of esophageal dysfunction is directly proportional to the degree of intramural ganglion cell loss. Abnormal peristalsis is first detectable after 50% of ganglion cells are destroyed, whereas esophageal dilatation occurs only after 90% are destroyed. Paralleling this, the initial dysfunction is confined to the esophageal body, with LES dysfunction occurring late in the course of the disease.[271] The most obvious clinical distinction between idiopathic achalasia and esophageal involvement in Chagas disease is evidence of additional organ involvement (megaureter, cardiomyopathy, megaduodenum, megacolon, megarectum) in Chagas disease. With respect to esophageal pathology, the two are otherwise indistinguishable. The diagnosis of Chagas disease is made in the acute phase by visualizing the parasite in a blood smear. In the chronic phase, the diagnosis is confirmed by serologic tests using complement fixation or polymerase chain reaction. The treatment of the achalasia syndrome in Chagas disease is similar to that for idiopathic achalasia (discussed later). Treatment of the infection itself is of limited efficacy in the acute phase and of no proven efficacy with chronic disease. Pseudoachalasia Neither the radiographic nor the manometric features of achalasia are specific for idiopathic achalasia or achalasia associated with Chagas disease. Tumor-related pseudoachalasia accounts for up to 5% of cases with manometrically defined achalasia. Pseudoachalasia is more likely in older age groups (sixth decade and beyond), in patients with recent onset of symptoms (within the past year), and in those with early weight loss in excess of 7 kg.[188] However, even though these criteria make pseudoachalasia more likely, they still have a poor predictive value.[272] Tumor infiltration (especially carcinoma in the gastric fundus) can completely mimic the functional impairment seen with idiopathic achalasia.[273] It is because of this potential pitfall that a thorough anatomic examination including endoscopy should be done as part of the diagnostic evaluation of every new case of achalasia. A clue to the presence of pseudoachalasia on endoscopic examination is of more than the slightest resistance of passage of the endoscope across the gastroesophageal junction. In idiopathic achalasia, the endoscope should pop through with only gentle pressure required. If suspicion of pseudoachalasia is high, endoscopic biopsy, computerized tomography, magnetic resonance imaging, or endoscopic ultrasound should be considered for further evaluation, depending on the individual circumstances. Adenocarcinoma of the gastroesophageal junction accounts for more than one half of pseudoachalasia cases, with myriad other tumors and miscellaneous conditions accounting for the remainder. Within the spectrum of malignancies, pancreatic, hepatoma, lung (small cell or non–small cell), esophageal squamous cell, prostate, and lymphoma cases have been reported.[188] These tumors produce an achalasia syndrome by infiltrating the wall of the esophagus at the gastroesophageal junction, causing a malignant obstruction at the LES with proximal esophageal dilatation.[273] Similarly, pseudoachalasia has also been reported to result from esophageal infiltration by amyloid,[274] eosinophilic gastroenteritis,[275] and sarcoidosis.[276] Although often speculated in the literature, it is less certain, and certainly much less common, that an achalasic syndrome occurs as a paraneoplastic syndrome without direct tumor stenosis of the gastroesophageal junction.[188]Postsurgical Dysphagia is common following fundoplication in the early postoperative period and patients are often advised to consume soft diets for the first two to four weeks. Dysphagia that persists beyond two to four weeks should be evaluated with an upper endoscopy or barium esophagogram to assess the integrity of the wrap and evaluate for possible paraesophageal hernia. Subjects without an overt mechanical disruption should be evaluated with manometry to assess peristaltic function, LES pressure, and LES relaxation to determine whether the wrap is too tight or an underlying motility disorder, such as achalasia, exists. Diagnosing achalasia in the context of fundoplication can be difficult, because aperistalsis and impaired LES relaxation can be seen in both entities. In order to distinguish mechanical obstruction due to an obstructive fundoplication (or crural repair) from achalasia, one can administer amyl nitrite during manometry and observe the effect on the EGJ high-pressure zone. The mechanical effect of a fundoplication is less affected by the smooth-muscle relaxing effects of the amyl nitrite than the hypertensive sphincter of a person with achalasia.[277] Bariatric surgery, especially laparoscopic adjustable gastric banding, can be complicated by development of a pseudoachalasia syndrome. A recent report examined 121 patients a year after this procedure and found that 14% of them had esophageal dilatation in excess of 3.5 cm. Affected patients developed an achalasia-type syndrome with dysphagia and vomiting.[278] This form of pseudoachalasia is usually, but not always, reversible with removal of the gastric band.[279]Distal Esophageal Spasm The pain associated with DES can closely mimic that of angina pectoris. Given the potentially fatal consequences of the latter, this must always be considered carefully in the differential diagnosis. Features suggesting an esophageal, as opposed to a cardiac, etiology of chest pain include (1) prolonged, nonexertional pain; (2) pain that interrupts sleep; (3) meal-related pain; (4) relief with antacids; and (5) additional accompanying esophageal symptoms such as heartburn, dysphagia, or regurgitation. However, even these characteristics occasionally exhibit overlap with cardiac pain. Furthermore, even within the spectrum of esophageal diseases, neither chest pain nor dysphagia is specific for DES because both symptoms are also characteristic of common esophageal disorders including peptic or infectious esophagitis. Hence, only after these more common diagnostic possibilities have been excluded by appropriate radiographic evaluation, endoscopic evaluation, and in some instances, a therapeutic trial of antisecretory medications, should DES be considered as the etiology of the still unexplained symptoms. DIAGNOSTIC METHODS Endoscopy Upper endoscopy should be the first test for evaluating new onset dysphagia because it combines the ability to detect most structural causes of dysphagia with the ability to obtain biopsies. The increasing recognition of eosinophilic esophagitis (Chapter 27) as a confounding clinical entity has increased the potential value of biopsies when performing upper endoscopy in the evaluation of dysphagia.[280] The endoscopist should have a very low threshold for obtaining multiple (preferably five) esophageal mucosal biopsy specimens to evaluate for eosinophilic esophagitis even with a normal appearing esophageal mucosa.[281] Additionally, should a stricture or mucosal ring be detected, dilation can be accomplished in the same session. However, even though upper endoscopy is an excellent tool for evaluating dysphagia, it has substantial limitations in assessing extraluminal structures and abnormal esophageal motility. It also has the potential to miss subtle obstructing lesions, such as webs and rings. Contrast Imaging Contrast studies of the oropharynx and esophagus are useful in assessing dysphagia after endoscopy if the latter was inconclusive or instead of it, if endoscopy is not readily available. Videofluoroscopy is particularly useful for a functional evaluation of the oropharyngeal phase of swallowing following an examination for anatomic explanations. Frequently referred to as a modified barium swallow, Logemann has described a protocol composed of a series of swallow tasks.[17] Images are obtained in a lateral projection, framed to include the oropharynx, palate, proximal esophagus, and proximal airway. These images are then evaluated with respect to four major categories of oropharyngeal dysfunction: (1) inability or excessive delay in initiation of pharyngeal swallowing; (2) aspiration; (3) nasopharyngeal regurgitation; and (4) residue of the ingestate within the pharyngeal cavity after swallowing. Furthermore, the procedure allows for evaluation of the efficacy of various compensatory dietary modifications, postures, and swallowing maneuvers in compensating for observed swallowing dysfunction. A barium esophagogram can also provide useful information regarding UES function, peristalsis, and bolus clearance through the EGJ. With advanced cases of achalasia (Fig. 42-9) the findings are somewhat obvious and it is only necessary clinically to differentiate between primary and secondary etiologies. However, with good technique, normal peristalsis can also be verified with 91% to 95% specificity.[282,283] Peristalsis is best evaluated in the prone position so that clearance does not occur by gravity. In the prone position, the primary peristaltic wave manifests as an inverted “V” (∧), the peak of which represents the tail of the bolus. Luminal closure at the tail of the bolus corresponds closely to the leading edge, or upstroke, of the peristaltic wavefront as recorded manometrically (Fig. 42-10). Peristaltic abnormalities are inferred by retrograde escape of the bolus through the peristaltic wavefront resulting in incomplete esophageal emptying. Normally the EGJ will become widely patent when the bolus reaches this area and impaired relaxation can be inferred when either a smooth tapering is noted at the EGJ or bolus transit across the EGJ is impeded. Alternatively, fluoroscopy will occasionally demonstrate spastic contractions, evident by a corkscrew appearance (Fig. 42-11).
Esophageal Manometry (High-Resolution Esophageal Pressure Topography) Esophageal manometry is a test in which intraluminal pressure sensors, either water perfused or solid state, are positioned within the esophagus to quantify the contractile characteristics of the esophagus and segregate it into functional regions. The concept of high-resolution esophageal manometry is to use a sufficient number of pressure sensors within the esophagus such that intraluminal pressure can be monitored as a continuum along the length of the esophagus, much as time is viewed as a continuum in line tracings of conventional manometry such as those in Figure 42-10. When high-resolution manometry is coupled with sophisticated algorithms to display the manometric data as pressure topography plots, esophageal contractility is visualized with isobaric conditions among sensors indicated by isocoloric regions on the pressure topography plots. Figure 42-12 depicts a normal swallow in a high-resolution esophageal pressure topography plot encompassing both sphincters (UES and LES) and the intervening esophagus. The relative timing of sphincter relaxation and segmental contraction as well as the position of the transition zone are all readily demonstrated.
The manometric evaluation of deglutitive EGJ relaxation is probably the most important measurement made during clinical esophageal manometry. Incomplete EGJ relaxation is an essential feature in the diagnosis of achalasia and achalasia is not only the best-defined esophageal motor disorder, but also the one with the most specific treatments. Despite this cardinal significance, there was no convention for defining incomplete deglutitive EGJ relaxation with conventional manometry. Furthermore, numerous potential confounding factors exist including crural diaphragm contraction during relaxation, deglutitive esophageal shortening, hiatal hernia, sphincter radial asymmetry, and movement of the recording sensor relative to the EGJ.[8] With high-resolution esophageal pressure topography, this situation is greatly improved. A study comparing criteria for detecting impaired deglutitive EGJ relaxation within the deglutitive relaxation window (see Fig. 42-12) in a large group of patients and control subjects concluded that the optimal measure for quantifying deglutitive relaxation was the integrated relaxation pressure (IRP), with normal being defined as 15 mm Hg or less.[284] Conceptually, the IRP is the average EGJ pressure for the four seconds of greatest relaxation within the relaxation window. This single measure of deglutitive EGJ relaxation exhibited 98% sensitivity and 96% specificity for distinguishing well-defined achalasia patients from control subjects and patients with other diagnoses.[284] Apart from improving the sensitivity of manometry in the detection of achalasia, high-resolution esophageal pressure topography has also defined a clinically relevant subclassification of achalasia.[224] A diagnosis of achalasia requires both aperistalsis and impaired deglutitive EGJ relaxation. In its most obvious form this occurs in the setting of esophageal dilatation with negligible pressurization within the esophagus (Fig. 42-13A). However, despite there being no peristalsis, there can still be substantial pressurization within the esophagus. In fact, a very common pattern encountered is achalasia with esophageal compression and panesophageal pressurization (see Fig. 42-13B). The other, less common pattern is of spastic achalasia in which there is a spastic contraction within the distal esophageal segment (see Fig. 42-13C and D). In a series of 99 consecutive patients with newly diagnosed achalasia, 21 had the classical pattern in Figure 42-13A, 49 had the panesophageal pressurization pattern of Figure 42-13B, and 29 had the spastic achalasia pattern of Figure 42-13C.[224] Logistic regression analysis found panesophageal pressurization (see Fig. 42-13B) to be a predictor of response to treatment, whereas spastic achalasia (see Fig. 42-13C) and pretreatment esophageal dilatation were predictive of a poorer response to treatment.
Following the analysis of the EGJ, a swallow is further categorized by the characteristics of the distal esophageal contraction. This analysis is largely facilitated by the generation of a pressure topography plot highlighting the 30 mm Hg isobaric contour. Under circumstances of normal deglutitive EGJ relaxation, the 30 mm Hg pressure threshold reliably delineates the wavefront of the peristaltic contraction.[285] Contractile front velocity (CFV) is calculated from the 30 mm Hg isobaric contour plots by calculating the slope of the line connecting the 30 mm Hg isobaric contour at the proximal margin of the first subsegment and the distal margin of the second subsegment (see Fig. 42-12). A CFV of more than 8 cm/second is indicative of a spastic contraction.[285,286] Although the CFV is easily definable in the circumstance of normal EGJ relaxation, it is more complex when EGJ relaxation is impaired (Fig. 42-14). With impaired EGJ relaxation, there is compartmentalized pressurization between the contractile front of the distal esophageal contraction and the EGJ with a high intrabolus pressure residing between the two. In such instances, the slope of the 30 mm Hg isobaric contour is no longer indicative of the CFV but now indicates increased intrabolus pressure as a result of functional obstruction at the EGJ. In such circumstances, the algorithm for computing CFV defaults to computing the slope of an isobaric contour line of magnitude greater than the EGJ relaxation pressure (e.g., 50 mm Hg in a given patient) so as to consistently represent the timing of luminal closure (see Fig. 42-14).
Apart from a rapid CFV, other common abnormalities of the distal esophageal contraction are weak or absent peristalsis. In such instances, the 30 mm Hg isobaric contour is either discontinuous or absent, reflective of either focal or diffuse hypotensive contraction within the distal segment. Each swallow is thus characterized as normal (intact 30 mm Hg isobaric contour and a CFV < 8 cm/second), hypotensive (3 cm or greater defect in the 30 mm Hg isobaric contour), or absent (complete failure of contraction with no pressure domain > 30 mm Hg). Weak or absent peristalsis is a risk factor for impaired bolus clearance, but, whether impaired bolus clearance occurs depends on the balance between the severity of weakness and the magnitude of outflow resistance at the EGJ.[287] Once swallows are characterized by the integrity of deglutitive EGJ relaxation and normality of the CFV, the distal esophageal contraction is further analyzed for the vigor of contraction using a newly developed measure for high-resolution esophageal pressure topography, the distal contractile integral (DCI). The DCI integrates the length, vigor, and persistence of the two subsegments of the distal esophageal segment contraction, expressed as mm Hg?s?cm. A DCI value greater than 5000 mm Hg?s?cm is considered elevated.[288] Adopting the nomenclature “nutcracker esophagus” from conventional manometry, this is the high-resolution manometry criterion defining hypertensive peristalsis and was seen in 9% of a 400-patient series.[285] However, there was substantial heterogeneity as to the locus of the hypertensive contraction within this group, potentially involving either or both of the subsegments within the distal esophageal contraction. Similarly, the LES can exhibit a hypertensive postdeglutitive contraction, defined as exceeding 180 mm Hg. Furthermore, one particularly interesting subgroup, defined by having a higher threshold DCI (>8000 mm Hg?s?cm), exhibited repetitive high-amplitude contractions and was clinically distinguishable by the uniform association with dysphagia or chest pain. Similar to DES, this “spastic nutcracker” pattern is very rare, found in only 12 (3%) of this 400-patient series (Fig. 42-15).
Following analysis of individual swallows by the criteria outlined, the component results are synthesized into a global manometric diagnosis by the criteria detailed in Table 42-2. Patients with normal EGJ relaxation, normal CFV, and a DCI less than 5000 mm Hg?s?cm are normal. The abnormalities encountered are described in specific functional terms with the intent that these then be interpreted within the clinical context of the patient. The classification detailed in Table 42-2 represents an incremental update on the Chicago classification,[289] the task of a newly convened international working group focused on the standardization of the performance and interpretation of high-resolution esophageal pressure topography studies.
Intraluminal Impedance Measurement Intraluminal impedance monitoring was described more than a decade ago as a method to assess intraluminal bolus transit without using fluoroscopy. The technique uses an intraluminal catheter with multiple, closely spaced pairs of metal rings (see Fig. 42-10). An alternating current is applied across each pair of adjacent rings and the resultant current flow between the rings is dependent on the impedance of the tissue and luminal content between the rings. Impedance decreases when the electrodes are bridged by liquid and increases when they are surrounded by air thereby providing data on the direction, content, and completeness of bolus transit. Validation data suggest that liquid bolus entry at the level of an electrode pair is indicated by a 50% drop in impedance and return of the impedance tracing to 50% of baseline correlates with the passage of the tail of the bolus on fluoroscopy, also indicated by the contractile upstroke noted on manometry (see Fig. 42-10). Validation studies of intraluminal impedance measurement against videofluoroscopy have shown excellent concordance in ascertaining bolus transit, reporting agreement in 97% (83/86) of swallows analyzed.[290] Intraluminal impedance measurement has also recently been combined with manometry to assess the efficacy of esophageal emptying as a function of distal peristaltic amplitude. In a receiver operating characteristic (ROC) analysis of a large number of swallows, a 30 mm Hg cutoff had 85% sensitivity and 66% specificity for identifying incomplete bolus transit.[291] With diminishing peristaltic amplitudes, the sensitivity progressively decreased and the specificity progressively increased. This study illustrates the complementary nature of manometry and impedance testing in assessing esophageal function and may develop into a valuable clinical tool for the assessment of dysphagia. Sensory Testing Esophageal sensory nerves play a key role in determining symptoms of esophageal neuromuscular diseases because the esophagus is sensitive to a variety of stimuli including mechanical (elicited by luminal distention or high-amplitude contractions), chemical (acid or other constituents of reflux), and temperature.[292] Typically the visceral input is not perceived consciously. However, some patients may experience symptoms attributed to hyperalgesia (exaggerated pain perception) or allodynia (perception of pain to a stimulus that is usually not painful).[155,293] Esophageal symptoms may be described as burning, pressing, pricking, or heat sensations. Nevertheless, these symptoms are not specific to a given stimulus, and substantial overlap in perception among stimuli is common. Although the precise mechanism by which an esophageal stimulus causes pain or the perception of dysphagia is unclear, methodologies devised to evoke or stimulate pain by simulating physiologic events are available to assess the possible relationship between ongoing symptoms and suspected causes. These tests typically use forms of distention studies (balloon, barostat, impedance planimetry, or volume challenges) or direct mucosal stimulation (chemical, electrical, or thermal). Balloon distention studies have shown that esophageal distention can provoke chest pain and that patients with esophageal chest pain tend to have lower threshold volumes for both first perception and first pain perception compared with controls.[294,295] Combining impedance planimetry with balloon distention allowed other investigators to correlate biomechanical properties of the esophagus with the generation of chest pain.[296,297] Results of those studies suggested that the tension-strain curve in chest pain patients was shifted to the left when compared with controls, a finding consistent with reduced compliance of the esophageal wall.[269] The standard test of chemosensitivity is the Bernstein test wherein 0.1 normal hydrochloric acid is perfused in the esophagus to reproduce chest pain or heartburn. Typically, acid infusion is alternated with saline perfusion in a blinded fashion to increase the objectivity of the test, but no standardized protocol exists. Beyond the standard Bernstein perfusion test to assess esophageal sensitivity to acid, newer probes have been devised to test esophageal responsiveness to thermal challenges and transmucosal electrical nerve stimulation. However, although these tools have unquestionably been useful in improving our understanding of the interaction between peripheral receptors and central pain perception, their clinical utility remains limited owing to the lack of protocol standardization and the somewhat cumbersome nature of the studies. Currently, use of these devices is limited to subspecialty centers and further refinement will be required before mainstream clinical use can be advocated. TREATMENT Oropharyngeal Dysphagia Management of oropharyngeal dysphagia is focused on four specific issues: (1) identification of an underlying systemic disease, (2) characterization of a disorder amenable to surgery or dilation, (3) identification of specific patterns of dysphagia amenable to swallowing therapy, and (4) assessment of aspiration risk. Identifying Underlying Disease A potential outcome of the evaluation is the identification of an underlying neuromuscular, neoplastic, or metabolic disorder that dictates specific management. For example, dysphagia can be the presenting symptom in patients with myopathy, myasthenia, thyrotoxicosis, motor neuron disease, or Parkinson's disease. In each instance, managing the underlying disease requires a specific treatment. Whether or not treatment of the underlying disorder improves swallowing function depends on the natural history of the specific disease and whether effective treatment exists. Disorders Amenable to Surgery The most common surgical treatment for oropharyngeal dysphagia is cricopharyngeal myotomy but the efficacy of myotomy in neurogenic or myogenic dysphagia is variable. Most series evaluating the efficacy of myotomy in these circumstances are uncontrolled and lack validated or even specific outcome measures. Thus, although an overall favorable response rate in excess of 60% is reported in this literature, there are no validated criteria for patient selection. Theoretically, the functional limitation faced by patients with neurogenic or myogenic dysphagia is of weak pharyngeal propulsion and the potential benefit of myotomy in that circumstance is less obvious than in the case of obstruction at the level of the cricopharyngeus.[298]Patterns of Oropharyngeal Dysphagia Amenable to Swallow Therapy Identifying potential treatments for oropharyngeal dysphagia begins with definition of the aberrant physiology as categorized in Table 42-1. This is best accomplished with a videofluoroscopic swallowing study that first characterizes a patient's swallow dysfunction and then proceeds to test the effectiveness of selected compensatory or therapeutic treatment strategies. Compensatory treatments include postural changes, modifying food delivery or consistency, or the use of prosthetics. For instance, head turning can eliminate aspiration or pharyngeal residue by favoring the more functional side in patients with hemiparesis.[17] Similarly, diet modifications can reduce the “difficulty” of the swallow. Therapeutic strategies are designed to alter the physiology of the swallow, usually by improving the range of motion of oral or pharyngeal structures using voluntary control of oropharyngeal movement during a swallow. Depending on the severity of the impairment, level of motivation, and global neurologic integrity, defective elements of the swallow can be selectively rehabilitated. For a detailed description of the techniques and limitations of swallow therapy, the reader is referred to treatises on the topic.[17,299]Evaluating Aspiration Risk Oropharyngeal dysphagia is responsible for an estimated 40,000 deaths a year due to aspiration pneumonia.[300] Videoflouroscopy is considered the most sensitive test for detecting aspiration, reportedly detecting instances not evident by bedside evaluation in 42% to 60% of patients. However, despite the logical association between deglutitive aspiration and the subsequent development of pneumonia, this sequence is not inevitable. In fact, available data suggest that radiographic aspiration has a positive predictive value of only 19% to 68% and a negative predictive value of 55% to 97% for pneumonia.[300] Nonetheless, the balance of evidence suggests that detection of aspiration is a predictor of pneumonia risk, and that its detection dictates that compensatory swallowing strategies, non-oral feeding or corrective surgery be instituted. Whether non-oral feeding eliminates the risk of aspiration is controversial. In one study of 22 patients with radiographic aspiration, pneumonia and death were more frequent among patients who received feeding tubes.[185] This suggests that aspiration of oral secretions may be the essential element in pneumonia risk and has led some to consider procedures such as tracheostomy to protect the airway. Hypopharyngeal (Zenker's) Diverticulum and Cricopharyngeal Bar The treatment of hypopharyngeal diverticulum is cricopharyngeal myotomy with or without a diverticulectomy (see Chapter 23). Cricopharyngeal myotomy reduces both the resting sphincter tone and resistance to flow across the UES. A study found that the compliance of the sphincter following diverticulectomy with myotomy was restored to normal following surgery, as indicated by normal hypopharyngeal intrabolus pressure during swallowing.[301] Good or excellent results are reported in 80% to 100% of Zenker's patients treated by transcervical myotomy combined with diverticulectomy or diverticulopexy.[299] There are instances in which a limited procedure would be adequate, but a definitive approach to the problem of pulsion diverticula should generally involve myotomy and diverticulectomy. Diverticulectomy alone risks recurrence because the underlying stenosis at the level of the cricopharyngeus is not remedied. Similarly, myotomy alone may not solve the problem of food accumulation within the diverticulum, with attendant regurgitation and aspiration. Small diverticula may, however, disappear spontaneously following myotomy. A more recent trend is to treat Zenker's diverticula via either rigid or flexible endoscopy. With both techniques, the principle is to divide the septum between the lumen of the diverticulum and the lumen of the esophagus. The division allows food and liquid to flow out of the diverticulum distal to the cricopharyngeus (which was within the septum) rather than to accumulate within the diverticulum. In the case of rigid endoscopy the procedure is performed under general anesthesia with a stapling device. In the case of flexible endoscopy the procedure is performed under light sedation with a needle knife, argon plasma coagulation, or hot biopsy forceps. Controlled trials have not been done comparing the two procedures, but a recent summary of 376 reported cases treated with flexible endoscopic methods found treatment to result in clinical resolution in 43% to 100% of cases among series.[184] Whether a cricopharyngeal bar in the absence of a diverticulum requires treatment is less clear. Certainly, if dysphagia is present and combined fluoroscopic/manometric analysis demonstrates reduced sphincter opening in conjunction with elevated upstream intrabolus pressure, there is good rationale for treatment. One recent uncontrolled series suggests that in this scenario dilation with a large-caliber bougie may be efficacious in relieving dysphagia and this approach is certainly a reasonable treatment option prior to myotomy.[302]Achalasia Because the underlying neuropathology of achalasia cannot be corrected, treatment is directed at compensating for the poor esophageal emptying and preventing complications. In practical terms this amounts to reducing LES pressure so that gravity promotes esophageal emptying. Peristalsis is not restored with therapy. LES pressure can be reduced by pharmacologic therapy, forceful dilation, or surgical myotomy. Pharmacologic treatments, on the whole, are not very effective, making them more appropriate as temporizing maneuvers than definitive therapies. The definitive treatments of achalasia are disruption of the LES either surgically (Heller myotomy) or with a pneumatic dilator. Which of these is the optimal approach remains an issue of debate given the paucity of randomized controlled trials with accepted criteria for assessing efficacy. A further limitation of the previous studies is failing to stratify patients by disease severity or, as more recently defined, by disease subtype.[224] High-resolution esophageal pressure topography allows the subtyping of achalasia into three distinct patterns: I, classic achalasia; II, achalasia with compression; and III, spastic achalasia (see Fig. 42-13). From a conceptual vantage point types I and II represent a continuum, with type II representing early disease before the progression of esophageal dilatation characteristic of type I. Type III, on the other hand, is a subtype characterized by spasm of the distal esophagus. The significance of these disease subtypes is in how differently they responded to therapy, be it botulinum toxin injection, pneumatic dilation, or Heller myotomy. In a series of 99 new cases of achalasia, the overall treatment response was 56% with type I, 96% with type II, and only 29% with type III. The literature pertinent to achalasia treatment is mainly composed of numerous uncontrolled case series using a variety of qualitative endpoints as indications of efficacy. As noted, there is also minimal standardization as to the criteria for defining achalasia, the disease severity included in one series versus another, or the technical details of how pneumatic dilation or Heller myotomy are performed. Furthermore, some series were collected prospectively, some retrospectively, and some a combination. Given all of these limitations, there is little merit to embarking on a detailed comparison of outcomes between techniques. The existing treatment data are summarized next. Pharmacologic Therapy Smooth muscle relaxants such as nitrates or calcium channel blockers, administered sublingually immediately prior to eating can relieve dysphagia in achalasia by reducing the LES pressure. Amyl nitrite,[303] sublingual nitroglycerin, theophylline, and β2-adrenergic agonists[304] have also been tried. The largest reported experience has been with isosorbide dinitrate (Isordil) and nifedipine.[305] Isosorbide dinitrate, 5 to 10 mg sublingually before meals, reduces LES pressure by 66% for about 90 minutes, with the degree of dysphagia relief paralleling the magnitude of the LES response over the 19-month trial.[306] Side effects, particularly headache, are common. Placebo-controlled trials have not been reported. Calcium channel blockers (diltiazem, nifedipine, verapamil) reduce LES pressure by 30% to 40% for more than an hour.[306,307] The largest clinical experience in achalasia has been with nifedipine (Procardia). Nifedipine, 10 mg sublingually (capsules are crushed in the mouth) administered before meals (30 to 40 mg per day) was studied in 29 patients with early achalasia (prior to esophageal dilatation) in a placebo-controlled trial. Nifedipine was significantly better that placebo (which had no benefit), with good results in 70% of achalasic patients followed for 6 to 18 months.[305] However, subsequent placebo-controlled crossover trials have found only minimal benefit with nifedipine.[308] Side effects of nifedipine include flushing, dizziness, headache, peripheral edema, and orthostasis. Sildenafil (Viagra) is another smooth muscle relaxant that can decrease LES pressure in patients with achalasia by blocking phosphodiesterase type 5, the enzyme that destroys cyclic guanosine monophosphate induced by NO. A double-blind placebo controlled trial found that 50 mg of sildenafil significantly reduced LES pressure and relaxation pressure when compared with placebo.[309] The effect peaked at 15 to 20 minutes after administration and persisted for less than one hour. Although conceptually appealing, the practicality of using sildenafil clinically is limited by its cost that is rarely, if ever, covered by health care insurance. Botulinum Toxin Injection The initial landmark study of botulinum toxin in achalasia reported that intrasphincteric injection of 80 units of botulinum toxin decreased LES pressure by 33% and improved dysphagia in 66% of patients for a six-month period.[310] Botulinum toxin irreversibly inhibits the release of acetylcholine from presynaptic cholinergic terminals, effectively eliminating the neurogenic component of LES pressure. However, because this inhibitory effect is eventually reversed by the growth of new axons, botulinum toxin is not a long-lasting therapy. The technique involves injecting divided doses of botulinum toxin into four quadrants of the LES with a sclerotherapy catheter. Side effects are rare, but include chest discomfort for several days and rash. Although many patients initially experience a good response, there is minimal continued efficacy at one year.[311-313] Repeat injection can be effective for a reasonable subset of patients, but the injection leads to a local inflammatory reaction and fibrosis, ultimately limiting this strategy. Doses greater than 100 units do not have increased efficacy.[314] Studies comparing botulinum toxin injection to pneumatic dilation suggest that the expense of repeated injection outweighs the potential economic benefits of added safety, unless the patient's life expectancy is minimal.[315] Thus, this option is mainly reserved for older adults or frail individuals who are poor risks for definitive treatments. Pneumatic Dilation Therapeutic dilation for achalasia requires distention of the LES to a diameter of at least 3 cm to produce a lasting reduction of LES pressure, presumably by partially disrupting the circular muscle of the sphincter. Dilation with an endoscope, standard bougies (up to 60 French), or with through-the-scope balloon dilators (up to 2 cm) provides very temporary benefit at best. Only dilators specifically designed to treat achalasia achieve adequate diameter for lasting effectiveness. The basic element of an achalasia dilator is a long, noncompliant, cylindrical balloon that can be positioned across the LES fluoroscopically (Rigiflex dilator) or endoscopically (Witzel dilator) and then inflated to a characteristic diameter in a controlled fashion using a handheld manometer. There is general agreement that pneumatic dilation can be done on an outpatient basis with the patient under conscious sedation. The technique of pneumatic dilation is variable among practitioners in terms of patient preparation, parameters of balloon inflation, and postdilation monitoring. In patients with substantial esophageal retention, it is useful to impose a liquid diet for one or more days prior to the procedure. Reported balloon inflation periods range from several seconds to five minutes.[316] Although there is minimal methodologic consistency among authors, a cautious approach of beginning with a small-diameter dilator (3 cm) and progressing to larger diameters (3.5 and 4 cm) only when the smaller dilator proved ineffective is fairly universal. As for inflation pressures, these are of minimal relevance with modern noncompliant balloon dilators because they do not distend beyond their specified diameter regardless of inflation pressure. Hence, it is simply necessary to observe under fluoroscopy that the balloon is properly positioned to capture the LES, observed as the “waist” of the hourglass-shaped balloon silhouette and that the waist fully effaces as the inflation proceeds. As for technical details of the procedure other than balloon diameter, there is minimal evidence that they influence outcome. The major complication of pneumatic dilation is esophageal perforation (see Chapter 40); mortality is fortunately rare.[317] The reported incidence of esophageal perforation consequent from pneumatic dilation ranges between 1% and 5%[261,316] with a global average of 3%. Because most perforations are readily evident or at least suspected within an hour of the procedure, patients should be observed closely for signs of an esophageal leak for at least two hours after pneumatic dilation. Alternatively, some practitioners routinely obtain a fluoroscopic examination of the esophagus following pneumatic dilation to ensure that perforation has not occurred. Usually, water-soluble contrast is given first, followed by barium. If a perforation appears small and contained or intramural, conservative management in the hospital consisting of close observation while maintaining the patient on nothing per mouth status and administering intravenous antibiotics is appropriate.[261] If a perforation is substantial, or if worsening pain and fever occur during observation of what was thought to be a small perforation, surgical repair should be pursued expediently. Patients with a perforation from pneumatic dilation that is recognized and promptly treated surgically (within six to eight hours) have outcomes comparable with those of patients undergoing elective Heller myotomy.[318] The best predictor of efficacy following a pneumatic dilation is the postdilation LES pressure; neither sphincter relaxation nor peristaltic function is significantly changed. A postdilation LES pressure less than 10 mm Hg is associated with prolonged remission, whereas a postdilation LES pressure greater than 20 mm Hg predicts that little benefit will occur from the procedure.[319] In instances of an unsatisfactory result, it is reasonable to perform a subsequent dilation within a matter of weeks using an incrementally larger dilator. If the benefit of dilation persisted for a year or more, it is neither unusual nor dangerous to repeat pneumatic dilation as necessary. The clinical efficacy of dilation has been reported to range from 32% to 98%.[311] Patients having a poor initial result or rapid recurrence of symptoms have diminished likelihood of responding to additional dilations.[311] Subsequent response to surgical myotomy is not influenced by the history of previous dilations.[261]Heller Myotomy Current surgical procedures for treating achalasia are variations on the esophagomyotomy described by Heller in 1913 consisting of an anterior and posterior myotomy performed through either a laparotomy or a thoracotomy.[311] Subsequently, this was modified to an anterior myotomy via thoracotomy. The appeal of myotomy is that it offers a more predictable method of reducing LES pressure than does pneumatic dilation.[320] Although clearly efficacious, open Heller myotomy is associated with considerable morbidity related to thoracotomy, which led most patients to pursue pneumatic dilation as the initial intervention. However, adoption of the laparoscopic approach for achalasia surgery has led many practitioners to reconsider this. Published series of the efficacy of Heller myotomy in treating achalasia report good to excellent results in 62% to 100% of patients, with persistent dysphagia troubling less than 10% of patients.[311] Recent studies suggest that a laparoscopic approach is associated with similar efficacy, reduced morbidity, and shorter hospital stay when compared with myotomy via thoracotomy, laparotomy, or thoracoscopy.[311,321-325] The overall mortality from Heller myotomy is less than 2%. Historically, postmyotomy reflux in achalasic patients could be particularly severe, making this a hotly disputed detail of the surgical technique.[326] However, with the broad use of proton pump inhibitors, reflux is usually easily controlled, making these complications very unlikely. Thus, laparoscopic Heller myotomy combined with a partial fundoplication (Toupet or Dor) has become the preferred surgical procedure for achalasia. An unsatisfactory result following Heller myotomy can result from incomplete myotomy, scarring of the myotomy, functional esophageal obstruction from the antireflux component of the operation, paraesophageal hernia, or severe esophageal dilatation. Heller Myotomy versus Medical Treatment Although pharmacologic therapy is simple and safe, it is increasingly clear that this should be reserved for use as a temporizing measure while more definitive therapy is being considered. Thus, practically speaking, the therapeutic choice is between pneumatic dilation and laparoscopic Heller myotomy as the primary therapy for achalasia. However, there are as yet no prospective controlled trials comparing these treatments. One controlled trial compares pneumatic dilation to myotomy via thoracotomy. That study reported 95% symptom resolution with myotomy and 51% symptom resolution in the dilation group, but the study was criticized for the methodology of pneumatic dilation used.[327] Most case series report symptom resolution in approximately 70% of patients with pneumatic dilation, substantially higher than the 51% reported in the controlled trial, but still substantially lower than that reported in uncontrolled series of laparoscopic Heller myotomy (85% to 91%). Furthermore, although laparoscopic Heller myotomy is invasive, its morbidity and mortality are low. On the other hand, pneumatic dilation has a reported perforation rate that averages 3%, an incidence that probably exceeds that sustained by clinicians with substantial experience. Even though these patients do well if the perforation is recognized and addressed promptly, they may require a thoracotomy. Thus, it appears that cogent arguments can be made for each of these therapies and likely one should assess the local skills available, as well a patient preference, in selecting the most appropriate initial therapy. Treatment Failures Persistent dysphagia after treatment suggests treatment failure and should be evaluated with some combination of endoscopy, esophageal manometry, and fluoroscopic imaging. Endoscopy may detect esophagitis, stricture, paraesophageal hernia, or anatomic deformity. Manometry may be useful to quantify residual LES pressure, with values exceeding 10 mm Hg arguing for further therapy targeting the LES. Fluoroscopy is useful to identify anatomic problems as well as to evaluate esophageal emptying by using a timed barium swallow, a standardized method of measuring the height of the esophageal barium column one and five minutes after ingestion.[328] In some instances these evaluations will lead to further intervention. In the case of a patient not previously operated on this could potentially be either repeat dilation or Heller myotomy. In patients who have already undergone myotomy, detection of an excessively short myotomy or functional esophageal obstruction from the antireflux component of the surgery usually requires reoperation, but pneumatic dilation can be pursued as an alternative. Reoperation, in general, is less effective than an initial operation for any indication in achalasia.[329] Occasionally patients fail to respond to optimally performed dilation or myotomy and require alternative approaches. In extremely advanced or refractory cases of achalasia, esophageal resection with gastric pull-up or interposition of a segment of transverse colon or small bowel may be the only surgical option.[330] Indications for this intervention include unresolvable obstructive symptoms, starvation, chronic aspiration, cancer, and perforation during dilation. Although excellent long-term functional results can be achieved, the reported mortality rate of this surgery is about 4%, consistent with the mortality rate of esophagectomy done for other indications. Risk of Squamous Cell Cancer Numerous series report cases of squamous cell carcinoma developing in the achalasic esophagus (see Chapter 46).[331] The relative risk of developing squamous cell cancer has been estimated to be 33-fold relative to the non-achalasic population.[332] The pathogenesis of the carcinoma is obscure, but stasis esophagitis is the likely precipitating factor. The tumors develop many years after the diagnosis of achalasia and usually arise in a greatly dilated esophagus, often in the middle third of the esophagus. Symptoms attributable to the cancer can be delayed, and the neoplasms are often large and advanced at the time of detection. These considerations raise the issue of surveillance endoscopy in achalasic individuals to detect early squamous cell cancer. However, an elegant analysis of a database encompassing the entire Swedish population of 1062 achalasic patients suggests that after discounting incident carcinomas, the overall odds ratio of squamous cell cancer for these people compared with age-matched controls was 17, corresponding to a 0.15% incidence of squamous cell cancer among the achalasic subjects.[333] The authors calculated that if surveillance endoscopy was done annually, 406 examinations would need to be done in men and 2220 in women before one potentially treatable tumor was found. However, even that calculation is optimistic given that detection of a small cancer in a massively dilated esophagus with retained food and stasis esophagitis is far from ensured. Given these considerations, a surveillance program is currently not the standard of practice. Distal Esophageal Spasm Despite the dogma of treatment with smooth muscle relaxants, minimal controlled data exist regarding pharmacologic therapy of DES. Long-term studies are not available, and the entire basis for this therapy is anecdotal. Furthermore, most instances of esophageal chest pain are attributable to reflux rather than DES, and reflux symptoms will likely be made worse by treating with smooth muscle relaxants. Uncontrolled trials of small numbers of DES patients report clinical response to nitrates,[334] calcium channel blockers,[335] hydralazine,[336] botulinum toxin,[337] and anxiolytics. The only controlled trial showing efficacy was with the anxiolytic trazodone, suggesting that reassurance and control of anxiety are important therapeutic goals.[338] Also consistent with that conclusion, success has been reported using behavioral modification and biofeedback.[339] Although the rationale for dilation is unclear, use of bougie dilators has been suggested as a therapy for dysphagia or chest pain in patients with spastic disorders. However, in the only controlled trial of this therapy, dilation with an 8-mm “placebo” dilator was as effective as an 18-mm “therapeutic” dilator in producing transient symptom relief.[340] Alternatively, pneumatic dilation has been used in DES patients with severe dysphagia. In one practitioner's experience, 45% of DES patients noted relief from pneumatic dilation, compared with 80% of achalasic patients.[261] In another series of nine patients with DES and LES dysfunction treated with pneumatic dilation, dysphagia but not chest pain was improved during 37 months of observation.[341] However, it is not clear that the patients who benefited by pneumatic dilation in these series would not be more properly categorized as spastic achalasia, emphasizing the need for accurate manometric classification.[224] If dysphagia becomes so severe in DES that weight loss is observed or if pain becomes unbearable, surgical therapy consisting of a Heller myotomy across the LES with proximal extension of the incision up the distal esophagus to include the involved area of spasm or even esophagectomy should be considered.[186,342] However, there are no controlled studies of these procedures in well-defined DES patients and the indication is, fortunately, extremely rare. Esophageal Hypersensitivity Therapies for esophageal motor disorders have traditionally centered on improving esophageal contractility and emptying. However, the efficacy of these therapies is very limited except in the instance of achalasia. More recently, there has been a paradigm shift with the realization that minor manometric findings formerly interpreted as indicative of symptomatic hypercontractile conditions were often an epiphenomenon indicative of hypersensitivity syndromes. Hence, there is substantial interest in developing treatments directed at reducing esophageal hypersensitivity, and a number of pharmacologic and behavioral therapies have been identified with the potential to modulate pain perception and improve esophageal symptoms associated with swallowing. Pharmacologic Treatments Numerous neuropeptides and pharmacologic agents can reduce chemical and mechanical visceral sensitivity suggesting a possible role in the treatment of esophageal pain syndromes. Although data on these agents specific to esophageal motor disorders are sparse, there is substantial literature focused on the treatment of noncardiac chest pain with or without motor abnormalities, and it is reasonable to generalize these findings to the treatment of esophageal hypersensitivity (see Chapter 12). Antidepressants are the most common medications prescribed for visceral pain modulation or chest pain of esophageal origin. Among antidepressants, the tricyclic antidepressants (TCAs) are the best studied. The mechanism of action for this therapeutic benefit is unknown because these agents act centrally as well as peripherally and have multiple receptor targets (acetylcholine, histamine, α-adrenergic). In a randomized placebo-controlled study, imipramine at a dose of 50 mg nightly was shown to be effective in reducing chest pain in patients with normal coronary angiograms.[343] Similar results have been reported with other TCAs, and treatment with these agents at doses lower than those used for mood altering effects is common. Typical starting doses for TCAs (amitriptyline, nortriptyline) are 10 to 25 mg at bedtime with escalation of 10- to 25-mg increments to a target of 50 to 75 mg.[344] Low-dose trazodone also has been used to treat noncardiac chest pain associated with esophageal dysmotility.[338] In a double-blind placebo-controlled study in patients with noncardiac chest pain, the group taking 100 to 150 mg of trazodone had significant symptomatic improvement and less residual distress related to their esophageal symptoms. Esophageal motor function was not altered. Recent data also support the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in the treatment of esophageal hypersensitivity. Intravenous citalopram at a dose of 20 mg was studied in a randomized, double-blinded, crossover study and found to significantly reduce both chemical (acid perfusion) and mechanical (balloon distention) esophageal sensitivity.[345] Although clinical trials are not yet available, mechanistic studies assessing other SSRIs have also yielded encouraging results. Along similar lines, there has been a substantial interest in developing serotonin (5-HT) medications.[293,346] 5-HT3 antagonists and 5-HT4 agonists have been the most extensively studied given their effects on gut motility and as treatments for nausea. Unfortunately, several of these medications have proven to have unacceptable risks related to cardiac dysrhythmias or gut ischemia that led to their withdrawal. Theophylline has shown promising effects in the treatment of noncardiac chest pain, presumably by adenosine receptor blockade. In a recent placebo-controlled double-blind study, sensory and biomechanical properties of the esophagus were assessed using impedance planimetry in 16 patients with esophageal hypersensitivity.[347] Chest pain thresholds increased after intravenous theophylline and the esophageal wall was shown to relax and become more distensible. In a parallel study using oral theophylline and placebo in 24 chest pain patients there was a significant reduction in chest pain episodes, chest pain duration, and chest pain severity in the theophylline group.[347] Although limited, these are very promising results for patients with symptoms thought to be attributable to mechanical hypersensitivity. Nonpharmacologic Treatments Although the link between esophageal hypersensitivity, psychological factors, and psychiatric abnormalities is unclear, therapy focused on reassurance, behavioral modification, and relaxation techniques may be helpful. These therapies will most likely benefit patients with comorbidities such as panic disorder, generalized anxiety, and depression. However, it is also possible that therapies using controlled breathing, relaxation techniques, or hypnotherapy may benefit patients with hypersensitivity by diverting mental attention and reducing hypervigilance for visceral stimuli. Well-performed prospective trials are necessary to define the clinical role of these therapies.
Table 42-1 -- Affected Phases, Manifestations, and Typical Disease Conditions Causing Oropharyngeal Dysphagia
Evident in Table 42-1, oropharyngeal dysphagia is frequently the result of neurologic or muscular diseases. Neurologic diseases can damage the neural structures requisite for either the afferent or efferent limbs of the oropharyngeal swallow. Virtually any neuromuscular disease can cause dysphagia. Because there is nothing unique to neurons controlling swallowing, their involvement in disease processes is usually random. Furthermore, in most instances, functions mediated by adjacent neuronal structures are concurrently involved. The following discussion focuses on neuromuscular pathologic processes most commonly encountered. These entities are also discussed in Chapter 35. Stroke Aspiration pneumonia has been estimated to inflict a 20% death rate in the first year after a stroke, and 10% to 15% each year thereafter.[207] It is usually not the first episode of aspiration pneumonia, but the subsequent recurrences over the years that eventually causes death.[208] The ultimate cause of aspiration pneumonia is dysphagia leading to aspiration that can occur by at least three mechanisms: absence or severe delay in triggering the swallow, reduced lingual control, or weakened laryngopharyngeal musculature.[17] Conceptually, these mechanisms can involve motor or sensory impairments. Cortical strokes are less likely to result in severe dysphagia than brainstem strokes.[209] Cortical strokes are also more likely to demonstrate neurologic recovery. Of 86 consecutive patients who sustained an acute cerebral infarct, 37 (43%) experienced dysphagia when evaluated within four days of the event. However, 86% of these patients were able to swallow normally two weeks later,[209] with recovery resulting from contralateral areas taking over the lost function.[210] Failure to recover swallowing function was more likely among patients incurring larger strokes or patients who have had prior infarcts. Poliomyelitis Most cases of poliomyelitis involve only the spinal cord. However, the fatality rate from bulbar polio far exceeds that of spinal disease, primarily a consequence of respiratory depression. Bulbar poliomyelitis is also associated with dysphagia. In one analysis of the persistent sequelae of bulbar poliomyelitis, 28 of 47 patients (60%) had recurrent or continued involvement of the pharynx 17 or more months after their acute illness.[211] Speech and swallowing dysfunction result from weakness of the pharyngeal musculature.[212] Neurologists have also observed an increasing number of patients with new paretic symptoms traceable to their remote polio infection 30 to 40 years earlier. The new, slowly progressive post-polio muscular atrophy may occur in muscles that were clinically unaffected by the acute illness.[211] One investigation studied 13 patients with post-polio dysphagia and demonstrated palatal, pharyngeal, and laryngeal weakness.[213] More than half of the patients evaluated demonstrated silent aspiration. Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is a progressive neurologic disease characterized by degeneration of motor neurons in the brain, brainstem, and spinal cord. Specific symptoms are dependent on the locations of affected motor neurons and the relative severity of involvement. When the degenerative process involves the cranial nerve nuclei, swallowing difficulties ensue. Oropharyngeal dysfunction characteristically begins with the tongue and progresses to involve the pharyngeal and laryngeal musculature. Patients experience choking attacks, become volume depleted and/or malnourished, and incur aspiration pneumonia. The decline in swallowing function is progressive and predictable, invariably leading to gastrostomy feeding. Patients often die as a consequence of their swallowing dysfunction in conjunction with respiratory depression.[214]Parkinson's Disease Although only 15% to 20% of patients with Parkinson's disease complain of swallowing problems, more than 95% have demonstrable defects when studied videofluoroscopically.[215] This disparity suggests that patients compensate in the early stages of the disease and complain of dysphagia only when it becomes severe. Abnormalities include repetitive lingual pumping prior to initiation of a pharyngeal swallow, piecemeal swallowing, and oral residue after the swallow. Patients may also exhibit a delayed swallow response and a weak pharyngeal contraction, resulting in vallecular and pyriform sinus residue. Recent data suggest this to be related to the combination of incomplete UES relaxation and a weakened pharyngeal contraction.[215]Tumors Medullary or vagal tumors are potentially debilitating with respect to swallowing. Astrocytomas are the most common tumor subtype affecting adults whereas medulloblastomas are the most common type encountered in children.[216] The morbidity of these tumors is often substantially increased as a result of the relative inaccessibility of the medulla to surgery. Unilateral lesions of the vagus can result in hemiparesis of the soft palate and pharyngeal constrictors, as well as of the laryngeal musculature. Surgical manipulation of this region can even result in complete loss of the pharyngeal swallow response.[217] The recurrent laryngeal nerves can be injured as a result of thyroid surgery, aortic aneurysms, pneumonectomy, primary mediastinal malignancies, or metastatic lesions to the mediastinum. Owing to its more extensive loop in the chest, the left recurrent laryngeal nerve is more vulnerable than the right to involvement with mediastinal node malignancy. Unilateral recurrent laryngeal nerve injury results in unilateral adductor paralysis of the vocal cords. This defect can result in aspiration during swallowing because of impaired laryngeal closure. It is rare, however, to have any primary pharyngeal dysfunction resultant from recurrent laryngeal nerve injury.[218]Oculopharyngeal Dystrophy Oculopharyngeal muscular dystrophy is a syndrome characterized by progressive dysphagia and ptosis. Historically, afflicted patients reaching age 50 typically died of starvation resulting from pharyngeal paralysis.[219] The disease is now known to be a form of muscular dystrophy and is inherited as an autosomal dominant disorder with occurrences clustered in families of French-Canadian descent. Genetic studies of an afflicted family indicate linkage to chromosome 14, perhaps involving the region coding for cardiac alpha or beta myosin heavy chains.[220] Oculopharyngeal dystrophy affects the striated pharyngeal muscles and the levator palpebrae. Although other forms of muscular dystrophy occasionally affect the pharyngeal constrictors, this is rarely a dominant manifestation. The first symptom of oculopharyngeal dystrophy is usually ptosis that slowly progresses and eventually dominates the patient's appearance. Dysphagia may begin before, be concomitant with, or occur after ptosis. The dominant functional abnormalities are of a weak or absent pharyngeal contraction with hypopharyngeal stasis.[219] Dysphagia is slowly progressive, but may ultimately lead to starvation, aspiration pneumonia, or asphyxia. Myotonic Dystrophy Myotonic dystrophy is a rare disorder characterized by prolonged contraction and difficulty in relaxation of affected skeletal musculature. Recent investigations suggest that even though only half of the patients complain of dysphagia, pharyngeal and esophageal motor abnormalities can be universally demonstrated. The pattern of abnormality is of a weakened pharyngeal contraction, absent peristalsis in the striated muscle esophagus, and diminished or absent peristalsis in the smooth muscle segment of the esophagus. Myotonia has not been demonstrated in any part of the esophagus.[29] Thus, the risk of aspiration in this disease is similar to other forms of muscular dystrophy. Aspiration can occur during the swallow due to poor pharyngeal clearance combined with concurrent weakness of the laryngeal elevators or after the swallow when the substantial pharyngeal residue might fall into the reopened airway. Myasthenia Gravis Myasthenia gravis is a progressive autoimmune disease characterized by high circulating levels of acetylcholine receptor antibody and destruction of acetylcholine receptors at neuromuscular junctions. Musculature controlled by the cranial nerves is almost always involved, particularly the ocular muscles. Dysphagia is prominent in more than a third of cases and, in unusual instances, can be the initial and dominant manifestation of the disease.[17] In mild cases, dysphagia may not be evident until after 15 to 20 minutes of eating. Classically, manometric studies reveal a progressive deterioration in the amplitude of pharyngeal contractions with repeated swallows. Peristaltic amplitude recovers with rest or following the administration of 10 mg edrophonium chloride, an acetylcholinesterase inhibitor. In more advanced cases, the dysphagia can be profound and associated with nasopharyngeal regurgitation and nasality of the voice, even to the extent of being confused with bulbar ALS or a brainstem stroke.[221]Hypopharyngeal (Zenker's) Diverticulum and Cricopharyngeal Bar Hypopharyngeal diverticulum and cricopharyngeal bars are closely related disease entities in that it is a cricopharyngeal bar that can result in diverticulum formation. Zenker's diverticulum (Fig. 42-7), is discussed in Chapter 23. Zenker's diverticulum originates in the midline posteriorly at Killian's dehiscence, a point of pharyngeal wall weakness between the oblique fibers of the inferior pharyngeal constrictor and the transverse cricopharyngeus muscle (see Fig. 42-6).[222] Other locations of acquired pharyngeal diverticula include (1) the lateral slit separating the cricopharyngeus muscle from the fibers of the proximal end of the esophagus through which the recurrent laryngeal nerve and its accompanying vessels run to supply the larynx; (2) at the penetration of the inferior thyroid artery into the hypopharynx; and (3) at the junction of the middle and inferior constrictor muscles. The unifying theme of these locations is that they are sites of potential weakness of the muscular lining of the hypopharynx through which the mucosa herniates, leading to a “false” diverticulum. The best-substantiated explanation for the development of diverticula is that they form as a result of a restrictive myopathy associated with diminished compliance of the cricopharyngeus muscle. Surgical specimens of cricopharyngeus muscle strips from 14 patients with hypopharyngeal (Zenker's) diverticula demonstrated structural changes that would decrease UES compliance and opening.[223] The cricopharyngeus samples from these patients had “fibro-adipose tissue replacement and (muscle) fiber degeneration.” Thus, although the muscle relaxes normally during a swallow, it cannot distend normally, resulting in the appearance of a cricopharyngeal indentation, or bar, during a barium swallow (Fig. 42-8). Diminished sphincter compliance necessitates increased hypopharyngeal intrabolus pressure to maintain trans-sphincteric flow through the smaller UES opening. The increased stress on the hypopharynx from the increased intrabolus pressure may ultimately result in diverticulum formation.
 | |
| Figure 42-7. Radiograph of a small Zenker's diverticulum filled with barium. Although the point of herniation is midline and posterior at Killian's dehiscence, the diverticulum migrates laterally in the neck as it enlarges because there is no potential space between the posterior pharyngeal wall and the vertebral column. Other sites of herniation can occur (see text). |  |
 | |
| Figure 42-8. Cricopharyngeal bar in a patient with oropharyngeal dysphagia. The posterior indentation of the barium column is caused by a noncompliant cricopharyngeus muscle. (Courtesy of Dr. Richard Gore, Evanston, Illinois.) | |
Achalasia Achalasia is characterized by impaired LES relaxation with swallowing, and aperistalsis in the smooth muscle esophagus. The resting LES pressure is elevated in about 60% of cases. If there are nonperistaltic, spastic contractions in the esophageal body, the disease is referred to as vigorous achalasia or, more recently, spastic achalasia.[224] These physiologic alterations result from damage to the innervation of the smooth muscle segment of the esophagus (including the LES). Proposed neuroanatomic changes responsible for achalasia include loss of ganglion cells within the myenteric (Auerbach's) plexus, degeneration of the vagus nerve, and degeneration of the dorsal motor nucleus of the vagus. Of these three possibilities, only the loss of ganglion cells is well substantiated. Several observers report fewer ganglion cells and ganglion cells surrounded by mononuclear inflammatory cells in the smooth muscle esophagus of achalasics.[225] One report additionally noted ganglion cell degeneration extending into the proximal stomach in half of 34 specimens analyzed.[226] The degree of ganglion cell loss parallels the duration of disease such that ganglion cells are almost absent in patients afflicted for 10 or more years.[227] A morphologic study of 42 esophagi resected from patients with advanced achalasia reported reduced numbers of ganglion cells and inflammation within the myenteric plexus in all cases.[228] The ultimate cause of ganglion cell degeneration in achalasia is gradually being unraveled, with increasing evidence pointing toward an autoimmune process attributable to a latent infection with human herpes simplex virus 1 (HSV-1) in genetically susceptible individuals.[229,230] Immunohistochemical analysis of the myenteric plexus infiltrate in achalasia patients revealed that the majority of inflammatory cells are either resting or activated cytotoxic T cells.[231] In addition, immunoglobulin M (IgM) antibodies and evidence of complement activation have been demonstrated within myenteric ganglia.[232] Antibodies against myenteric neurons have been repeatedly shown in serum of achalasia patients,[233,234] especially in patients with HLA DQA1* 0103 and DQB1* 0603 alleles.[235] The trigger for initiating the autoimmune response leading to the development of achalasia is suspected to be a viral infection, but studies implicating varicella zoster or measles virus have been contradictory.[232,236,237] However, an elegant recent study provided strong evidence implicating HSV-1 as the culprit.[230] T cells of achalasia patients exhibited clonal expansion within the myenteric plexus of the LES, and were activated by HSV-1 antigens, but not by cytomegaloviral, adenoviral, or enteroviral antigens. Furthermore, HSV-1 antibodies and HSV-1 deoxyribonucleic acid (DNA) were isolated in 84% and 63% of achalasic patients, respectively, potentially implicating HSV-1 in the majority of achalasia cases. Interestingly, HSV-1 was also detected in LES tissue from non-achalasic organ donors, suggesting that the development of achalasia is dependent on both the virus and a genetic predisposition as indicated by the specific HLA associations. Achalasia may also be associated with degenerative neurologic disorders such as Parkinson's disease. Patients with both achalasia and Parkinson's disease were noted to have Lewy bodies (intracytoplasmic hyaline or spherical eosinophilic inclusions) in the degenerating ganglion cells of the myenteric plexus.[238] Physiologic studies in individuals with achalasia also suggest dysfunction consistent with postganglionic denervation of esophageal smooth muscle. Such damage can affect excitatory ganglion neurons (cholinergic), inhibitory ganglion neurons (NO ? VIP), or both. Consider first the excitatory ganglion neurons. Muscle strips from the circular layer of the esophageal body of achalasic patients contract when directly stimulated by acetylcholine but fail to respond to ganglionic stimulation by nicotine, indicating a postganglionic excitatory defect. However, it is likely that loss of excitatory innervation is variable among achalasic patients. Partial preservation of the postganglionic cholinergic pathway is suggested by the observations that an achalasic patient's LES pressure increases after administration of the acetycholinesterase inhibitor, edrophonium, and decreases after administration of the muscarinic antagonist, atropine.[239] These observations are crucial to understanding why botulinum toxin may have therapeutic benefit in achalasia (see section on treatment). Regardless of excitatory ganglion neuron impairment, it is clear that inhibitory ganglion neuron dysfunction is an early manifestation of achalasia. These neurons mediate deglutitive inhibition (including LES relaxation) and the sequenced propagation of esophageal peristalsis; their absence offers a unifying hypothesis for the key physiologic abnormalities of achalasia, namely, impaired LES relaxation and aperistalsis. Inhibitory ganglion neurons use NO as a neurotransmitter, and patients with achalasia have been shown to lack NO synthase in the gastroesophageal junction.[240] VIP may be a co-transmitter in these neurons and immunohistochemical studies have demonstrated a marked reduction of VIP-staining neurons in achalasic individuals.[112] A multitude of evidence supports impaired physiologic function of post-ganglionic inhibitory innervation in the smooth muscle esophagus of achalasic patients. Muscle strips from their LES do not relax in response to ganglionic stimulation as they do in normal controls[241] and CCK, which normally stimulates the inhibitory ganglion neurons, thereby reducing LES pressure, paradoxically increases the LES pressure in achalasics.[242] Impaired inhibitory innervation of the smooth muscle esophagus above the LES is more difficult to demonstrate because of the absence of resting tone in this region. However, in a clever experiment, Sifrim and colleagues used an intraesophageal balloon to create a high-pressure zone in the tubular esophagus that then relaxed with the onset of deglutitive inhibition. This deglutitive relaxation in the esophageal body was absent in early, nondilated cases of achalasia.[243]Distal Esophageal Spasm The term “diffuse esophageal spasm” and our present concept of this entity dates to Fleshler's 1967 description of a “clinical syndrome characterized by symptoms of substernal distress or dysphagia or both, the roentgenographic appearance of localized, nonprogressive waves (tertiary contractions), and an increased incidence of nonperistaltic contractions recorded by intraluminal manometry.”[244] Because only the smooth muscle esophagus is affected, the entity was subsequently more precisely labeled “distal esophageal spasm.”[245,246] Clearly, distal esophageal spasm is a disorder of peristalsis. However, in most afflicted patients, the esophagus retains the ability to propagate normal peristaltic contractions the majority of the time suggesting that the neuromuscular pathology is more subtle than with achalasia. Partly because of this fact, the criteria for diagnosing DES remain variable and confusing.[245] The neuromuscular pathology responsible for DES is unknown and there are no known risk factors or other conditions associated with DES. Furthermore, because neither the esophageal muscularis propria or myenteric plexus is readily accessible for biopsy and patients with spastic disorders of the esophagus rarely undergo esophageal surgery, only a paucity of pathologic material has been available for analysis. The most striking reported pathologic change is diffuse muscular hypertrophy or hyperplasia in the distal two thirds of the esophagus. Muscular thickening of up to 2 cm has been reported in patients with clinical and manometric evidence of DES.[247] However, there are other well-documented cases of spasm in which esophageal muscular thickening was not found at thoracotomy[248] and still other instances of patients with muscular thickening not associated with DES symptoms.[249] Similarly, little evidence of neuropathology has been reported; diffuse fragmentation of vagal filaments, increased endoneural collagen, and mitochondrial fragmentation have been described, but the significance of these findings is unclear.[250] Despite the absence of defined histopathology, physiologic evidence implicates myenteric plexus neuronal dysfunction in spastic disorders of the esophagus. During peristalsis, vagal impulses reach the entire smooth muscle segment of the esophagus simultaneously and activate myenteric plexus neurons between the longitudinal and circular muscle layers.[51] Ganglionic neurons then intervene between the efferent vagal fibers and the smooth muscle, belonging to either an inhibitory population that hyperpolarizes the muscle cell membrane and inhibits contraction or to an excitatory population that depolarizes the membrane, thereby prompting contraction. Thus, the instantaneous activity of the musculature at each esophageal locus is determined by the balance between these controlling influences from the myenteric plexus. Experimental evidence suggests heterogeneity among patients with spastic disorders, such that some primarily exhibit a defect of inhibitory interneuron function, whereas in others the defect is of excess excitation. Two in vivo experiments implicate a defect of myenteric plexus inhibitory interneuron function in the genesis of simultaneous contractions in the distal esophagus. In one, the propagation of a swallow-induced contraction was timed in normal subjects and in a group of patients with a simultaneous contraction in the distal esophagus.[251] Within the proximal esophagus the two groups exhibited similar contraction propagation, consistent with this timing being the result of the sequenced activation of motor units by vagal efferent nerves programmed within the medullary swallow center. However, once entering the smooth muscle segment, the patients' contractions diverged from those of the normal subjects, resulting in a simultaneous contraction in the distal esophagus. The distal esophageal contractions were otherwise normal, but the progressive delay of initiation of the contraction at more distal loci, a function attributable to increasing dominance of inhibitory interneurons in the distal esophagus, was absent. Furthermore, if these patients swallowed twice within a five-second interval, there was no deglutitive inhibition of the first peristaltic contraction within the smooth muscle esophagus, as is observed in normal subjects. A second experiment demonstrating impaired deglutitive inhibition in DES comes from work using an artificial high-pressure zone within the distal esophagus. Patients with motor disorders characterized by rapidly propagating or simultaneous contractions exhibited only partial relaxation of the artificial high-pressure zone, proportional to the impairment of propagation velocity.[243] Taken together these findings strongly suggest that one potential neuropathologic process in DES is a selective, intermittent dysfunction of myenteric plexus inhibitory interneurons. A second group of patients in the analysis of Behar and Biancani had normal propagation latency but exhibited frequent spontaneous distal esophageal contractions. These patients had significantly longer and higher-amplitude contractions at each locus within the distal esophagus.[251] Patients with peristaltic disorders characterized by excess excitation demonstrate heightened sensitivity to stimulation with cholinergic agents,[112,252] the cholinesterase inhibitor edrophonium,[253] pentagastrin,[254] and ergonovine.[255] An electromyographic correlate of this excitability is found from bipolar ring electrode recordings from the distal esophagus.[256] Whereas normal individuals uniformly exhibited spiking activity prior to each esophageal contraction, DES patients exhibited spike-independent spontaneous esophageal contractions. The preceding discussion suggests that the physiologic abnormalities of patients with spastic disorders are heterogeneous, but all are characterized by an imbalance between the excitatory and inhibitory influences on the esophageal smooth muscle. The suggestion of an impairment of the pathway of deglutitive inhibition is particularly interesting in that it places DES in a pathophysiologic continuum with achalasia, consistent with documented case reports of patients undergoing this evolution.[257] Furthermore, there are marked similarities between spastic achalasia and DES, both characterized by rapidly propagated contractions in the distal esophagus, with the only differences being involvement of the LES and constancy of the disorder in vigorous achalasia. Similar to achalasia, the simultaneous contractions typifying DES impair bolus transit through the esophagus, potentially explaining the associated dysphagia.[258]CLINICAL FEATURES Dysphagia is a fundamental symptom of esophageal motility disorders. Esophageal, as opposed to oropharyngeal, dysphagia is suggested by the absence of associated aspiration, cough, nasopharyngeal regurgitation, dry mouth, drooling, pharyngeal residue following swallow, or co-occurring neuromuscular dysfunction (e.g., weakness, paresthesia, slurred speech). The associated conditions of heartburn, esophagopharyngeal regurgitation, chest pain, odynophagia, or intermittent esophageal obstruction suggest esophageal dysphagia. However, an important limitation of the patient history with esophageal dysphagia is that a patient's identification of the location of obstruction is of limited accuracy. Specifically, a distal esophageal obstruction caused by an esophageal ring or achalasia often is perceived as cervical dysphagia, such that patients correctly localize distal dysfunction only 60% of the time.[259] Because of this subjective difficulty in distinguishing proximal from distal lesions within the esophagus, an evaluation for cervical dysphagia should encompass the entire length of the esophagus. Another important consideration in patient management is that esophageal motility disorders are much less common than mechanical or inflammatory etiologies of dysphagia, such as tumors, strictures, rings, and peptic, pill-induced, or infectious esophagitis. Historical points suggestive of a motor disorder are difficulty with solids and liquids as opposed to only solids, which is more suggestive of mechanical obstruction. However, the functional consequences of mechanical or inflammatory disorders can exactly mimic those of primary motility disorders. Thus, as with the evaluation of oropharyngeal dysphagia, an esophageal motility disorder should be considered as an etiology for dysphagia only after exclusion of other more common diagnoses by endoscopic, histologic, or radiographic examination. Achalasia Clinical manifestations of achalasia may include dysphagia, regurgitation, chest pain, hiccups, halitosis, weight loss, aspiration pneumonia, and heartburn. All patients have solid food dysphagia; the majority of patients also have variable degrees of liquid dysphagia. The onset of dysphagia is usually gradual, with the duration of symptoms averaging two years at presentation.[188] The severity of dysphagia fluctuates, but eventually plateaus. With long-standing disease there is progressive esophageal dilatation, and regurgitation becomes frequent when large amounts of food and fluid are retained in the dilated esophagus. The regurgitant is often recognized as food that has been eaten hours, or even days, previously. It tends to be nonbilious, non-acid, and mixed with copious amounts of saliva. Patients often fail to recognize the slimy mucoid regurgitant as saliva, being unfamiliar with its normal consistency. Chest pain is a frequent complaint early in the course of achalasia, occurring in approximately two thirds of patients.[260] Its etiology is unknown, but is speculated to be related to the occurrence of esophageal spasm (more recently, spasm of longitudinal muscle) or to the process of esophageal dilatation associated with disease progression. Treatment of achalasia (discussed later) is less effective in relieving chest pain than it is in relieving dysphagia or regurgitation. However, unlike dysphagia or regurgitation, chest pain may spontaneously improve or disappear over time.[260] An estimated 10% of people with achalasia have bronchopulmonary complications as a result of regurgitation and aspiration; in some instances, it is these complications rather than dysphagia that prompts them to seek medical care.[261] Another interesting, but fortunately rare, symptom of achalasia is airway compromise and stridor as a result of the dilated esophagus compressing the membranous trachea in the neck.[262] This is hypothesized to result from dysfunction of the belch reflex.[263] It is paradoxical that many achalasic patients complain of heartburn, even after the onset of dysphagia.[264] Although gastroesophageal reflux may be a common sequela of the treatments for achalasia, it seems physiologically inconsistent to simultaneously have dysphagia from impaired LES relaxation and reflux from excessive LES relaxation. In support of this skepticism, ambulatory 24-hour esophageal pH studies of achalasic patients have only shown periods of esophageal acidification caused by the bacterial fermentation of retained food in the esophagus rather than discrete gastroesophageal reflux events.[265] Furthermore, prolonged LES recordings have shown nearly a complete absence of transient LES relaxations in achalasics.[266] However, there are occasional exceptions to this, evident from a well-documented case of an achalasic patient with intact transient LES relaxation despite the absence of deglutitive LES relaxation.[267] The cause of the heartburn often reported by patients with achalasia is unknown. Distal Esophageal Spasm The major symptoms of DES are dysphagia and chest pain. Weight loss is rare. Dysphagia is usually intermittent and sometimes related to swallowing specific substances such as red wine or liquids at extreme hot or cold temperature. In some instances, patients experience episodes of esophageal obstruction while eating that persists until relieved by emesis. Esophageal chest pain is very similar in character to angina and is often described as crushing or squeezing in character, radiating to the neck, jaw, arms, or midline of the back. Pain episodes may last from minutes to hours, but continued swallowing is not always impaired. The mechanism producing esophageal pain is poorly understood. Recent data suggest that it may be related to sustained contraction of esophageal longitudinal muscle.[268] Chest pain is also prevalent in patients subsequently found to have manometric abnormalities that are insufficient to establish a diagnosis of achalasia or DES. Among such individuals, there is a high prevalence of reflux and of psychiatric diagnoses, particularly anxiety and depression.[197] Evidence also suggests a lower visceral pain threshold in this group, and symptoms of irritable bowel syndrome (Chapter 118) may be seen in more than 50% of these patients.[269]DIFFERENTIAL DIAGNOSIS The history is crucial in the evaluation of dysphagia. Major objectives of the history are to differentiate oropharyngeal dysphagia from esophageal dysphagia, xerostomia (hyposalivation), or globus sensation. All are frequently confused with each other. Globus sensation, in particular, is frequently confused with dysphagia. Unlike dysphagia, which occurs only during swallowing, globus sensation is prominent between swallows. Patients relate the nearly constant sensation of having a lump in their throat or feeling a foreign object caught in their throat. In some instances globus is associated with reflux symptoms and in others with substantial anxiety. It is the linkage with anxiety that led to the older nomenclature, “globus hystericus.” Unfortunately, studies have failed to define an objective anatomic or physiologic cause for globus and we are left with the crucial data being in the history; globus sensation persists regardless of the act of swallowing. Achalasia The differential diagnosis of achalasia includes other esophageal motility disorders, with functional attributes overlapping those of achalasia and diseases of distinct pathophysiology that duplicate the functional consequences of achalasia. With respect to other motility disorders, there are many similarities between DES and achalasia, especially the subtype of spastic achalasia. In fact, the only distinction between these entities is the demonstration of incomplete LES relaxation in vigorous achalasia. Thus, some have speculated that DES and vigorous (spastic) achalasia may represent early disease and subsequently evolve into full-fledged achalasia.[257] Testing this hypothesis, a report on a prospective cohort of patients diagnosed with esophageal spasm between 1992 and 2003 revealed that achalasia was subsequently diagnosed in only one.[270] Given that rarity and the possibility of the case initially being misdiagnosed, it seems reasonable to conclude that at most only a small minority of DES cases are part of the continuum with achalasia. With respect to other diseases that duplicate the functional consequences of idiopathic achalasia, the main considerations are Chagas disease, pseudoachalasia associated with malignancy or infiltrative diseases, or various surgical procedures, as discussed following. Chagas Disease Esophageal involvement in Chagas disease (see Chapter 109), which is endemic in areas of central Brazil, Venezuela, and northern Argentina, can be indistinguishable from idiopathic achalasia. An estimated 20 million South Americans are infected. Due to immigration, about 500,000 people in the United States are believed infected. Chagas disease is spread by the bite of reduvid (kissing) bug that transmits the parasitic protozoan, Trypanosoma cruzi. An acute septicemic phase of the illness follows that varies in severity from going unnoticed to being fatal.[271] The chronic phase of the disease develops up to 20 years after infection and results from destruction of autonomic ganglion cells throughout the body, including the heart, gut, urinary tract, and respiratory tract. Chronic cardiomyopathy with conduction system disturbances and arrhythmias is the most common cause of death. Within the digestive tract, the organs most commonly affected are the esophagus, duodenum, and colon. The severity of esophageal dysfunction is directly proportional to the degree of intramural ganglion cell loss. Abnormal peristalsis is first detectable after 50% of ganglion cells are destroyed, whereas esophageal dilatation occurs only after 90% are destroyed. Paralleling this, the initial dysfunction is confined to the esophageal body, with LES dysfunction occurring late in the course of the disease.[271] The most obvious clinical distinction between idiopathic achalasia and esophageal involvement in Chagas disease is evidence of additional organ involvement (megaureter, cardiomyopathy, megaduodenum, megacolon, megarectum) in Chagas disease. With respect to esophageal pathology, the two are otherwise indistinguishable. The diagnosis of Chagas disease is made in the acute phase by visualizing the parasite in a blood smear. In the chronic phase, the diagnosis is confirmed by serologic tests using complement fixation or polymerase chain reaction. The treatment of the achalasia syndrome in Chagas disease is similar to that for idiopathic achalasia (discussed later). Treatment of the infection itself is of limited efficacy in the acute phase and of no proven efficacy with chronic disease. Pseudoachalasia Neither the radiographic nor the manometric features of achalasia are specific for idiopathic achalasia or achalasia associated with Chagas disease. Tumor-related pseudoachalasia accounts for up to 5% of cases with manometrically defined achalasia. Pseudoachalasia is more likely in older age groups (sixth decade and beyond), in patients with recent onset of symptoms (within the past year), and in those with early weight loss in excess of 7 kg.[188] However, even though these criteria make pseudoachalasia more likely, they still have a poor predictive value.[272] Tumor infiltration (especially carcinoma in the gastric fundus) can completely mimic the functional impairment seen with idiopathic achalasia.[273] It is because of this potential pitfall that a thorough anatomic examination including endoscopy should be done as part of the diagnostic evaluation of every new case of achalasia. A clue to the presence of pseudoachalasia on endoscopic examination is of more than the slightest resistance of passage of the endoscope across the gastroesophageal junction. In idiopathic achalasia, the endoscope should pop through with only gentle pressure required. If suspicion of pseudoachalasia is high, endoscopic biopsy, computerized tomography, magnetic resonance imaging, or endoscopic ultrasound should be considered for further evaluation, depending on the individual circumstances. Adenocarcinoma of the gastroesophageal junction accounts for more than one half of pseudoachalasia cases, with myriad other tumors and miscellaneous conditions accounting for the remainder. Within the spectrum of malignancies, pancreatic, hepatoma, lung (small cell or non–small cell), esophageal squamous cell, prostate, and lymphoma cases have been reported.[188] These tumors produce an achalasia syndrome by infiltrating the wall of the esophagus at the gastroesophageal junction, causing a malignant obstruction at the LES with proximal esophageal dilatation.[273] Similarly, pseudoachalasia has also been reported to result from esophageal infiltration by amyloid,[274] eosinophilic gastroenteritis,[275] and sarcoidosis.[276] Although often speculated in the literature, it is less certain, and certainly much less common, that an achalasic syndrome occurs as a paraneoplastic syndrome without direct tumor stenosis of the gastroesophageal junction.[188]Postsurgical Dysphagia is common following fundoplication in the early postoperative period and patients are often advised to consume soft diets for the first two to four weeks. Dysphagia that persists beyond two to four weeks should be evaluated with an upper endoscopy or barium esophagogram to assess the integrity of the wrap and evaluate for possible paraesophageal hernia. Subjects without an overt mechanical disruption should be evaluated with manometry to assess peristaltic function, LES pressure, and LES relaxation to determine whether the wrap is too tight or an underlying motility disorder, such as achalasia, exists. Diagnosing achalasia in the context of fundoplication can be difficult, because aperistalsis and impaired LES relaxation can be seen in both entities. In order to distinguish mechanical obstruction due to an obstructive fundoplication (or crural repair) from achalasia, one can administer amyl nitrite during manometry and observe the effect on the EGJ high-pressure zone. The mechanical effect of a fundoplication is less affected by the smooth-muscle relaxing effects of the amyl nitrite than the hypertensive sphincter of a person with achalasia.[277] Bariatric surgery, especially laparoscopic adjustable gastric banding, can be complicated by development of a pseudoachalasia syndrome. A recent report examined 121 patients a year after this procedure and found that 14% of them had esophageal dilatation in excess of 3.5 cm. Affected patients developed an achalasia-type syndrome with dysphagia and vomiting.[278] This form of pseudoachalasia is usually, but not always, reversible with removal of the gastric band.[279]Distal Esophageal Spasm The pain associated with DES can closely mimic that of angina pectoris. Given the potentially fatal consequences of the latter, this must always be considered carefully in the differential diagnosis. Features suggesting an esophageal, as opposed to a cardiac, etiology of chest pain include (1) prolonged, nonexertional pain; (2) pain that interrupts sleep; (3) meal-related pain; (4) relief with antacids; and (5) additional accompanying esophageal symptoms such as heartburn, dysphagia, or regurgitation. However, even these characteristics occasionally exhibit overlap with cardiac pain. Furthermore, even within the spectrum of esophageal diseases, neither chest pain nor dysphagia is specific for DES because both symptoms are also characteristic of common esophageal disorders including peptic or infectious esophagitis. Hence, only after these more common diagnostic possibilities have been excluded by appropriate radiographic evaluation, endoscopic evaluation, and in some instances, a therapeutic trial of antisecretory medications, should DES be considered as the etiology of the still unexplained symptoms. DIAGNOSTIC METHODS Endoscopy Upper endoscopy should be the first test for evaluating new onset dysphagia because it combines the ability to detect most structural causes of dysphagia with the ability to obtain biopsies. The increasing recognition of eosinophilic esophagitis (Chapter 27) as a confounding clinical entity has increased the potential value of biopsies when performing upper endoscopy in the evaluation of dysphagia.[280] The endoscopist should have a very low threshold for obtaining multiple (preferably five) esophageal mucosal biopsy specimens to evaluate for eosinophilic esophagitis even with a normal appearing esophageal mucosa.[281] Additionally, should a stricture or mucosal ring be detected, dilation can be accomplished in the same session. However, even though upper endoscopy is an excellent tool for evaluating dysphagia, it has substantial limitations in assessing extraluminal structures and abnormal esophageal motility. It also has the potential to miss subtle obstructing lesions, such as webs and rings. Contrast Imaging Contrast studies of the oropharynx and esophagus are useful in assessing dysphagia after endoscopy if the latter was inconclusive or instead of it, if endoscopy is not readily available. Videofluoroscopy is particularly useful for a functional evaluation of the oropharyngeal phase of swallowing following an examination for anatomic explanations. Frequently referred to as a modified barium swallow, Logemann has described a protocol composed of a series of swallow tasks.[17] Images are obtained in a lateral projection, framed to include the oropharynx, palate, proximal esophagus, and proximal airway. These images are then evaluated with respect to four major categories of oropharyngeal dysfunction: (1) inability or excessive delay in initiation of pharyngeal swallowing; (2) aspiration; (3) nasopharyngeal regurgitation; and (4) residue of the ingestate within the pharyngeal cavity after swallowing. Furthermore, the procedure allows for evaluation of the efficacy of various compensatory dietary modifications, postures, and swallowing maneuvers in compensating for observed swallowing dysfunction. A barium esophagogram can also provide useful information regarding UES function, peristalsis, and bolus clearance through the EGJ. With advanced cases of achalasia (Fig. 42-9) the findings are somewhat obvious and it is only necessary clinically to differentiate between primary and secondary etiologies. However, with good technique, normal peristalsis can also be verified with 91% to 95% specificity.[282,283] Peristalsis is best evaluated in the prone position so that clearance does not occur by gravity. In the prone position, the primary peristaltic wave manifests as an inverted “V” (∧), the peak of which represents the tail of the bolus. Luminal closure at the tail of the bolus corresponds closely to the leading edge, or upstroke, of the peristaltic wavefront as recorded manometrically (Fig. 42-10). Peristaltic abnormalities are inferred by retrograde escape of the bolus through the peristaltic wavefront resulting in incomplete esophageal emptying. Normally the EGJ will become widely patent when the bolus reaches this area and impaired relaxation can be inferred when either a smooth tapering is noted at the EGJ or bolus transit across the EGJ is impeded. Alternatively, fluoroscopy will occasionally demonstrate spastic contractions, evident by a corkscrew appearance (Fig. 42-11).
 | |
| Figure 42-9. Characteristic barium swallow findings in three cases of advanced idiopathic achalasia. Note esophageal dilatation with an air-fluid level (left radiograph) and the tapering at the gastroesophageal junction. Radiographic findings can be subtle in the early phases of the disease. The example on the right was taken from a timed barium swallow examination indicating that barium was retained within the dilated esophagus for five minutes. | |
 | |
| Figure 42-10. Representative physiologic data, modified to illustrate the relationship among videofluoroscopic, manometric, and impedance representations of esophageal peristalsis. Schematic drawing of placement of a combined manometry/intraluminal impedance monitoring system with five manometric side holes spaced 4 cm apart and a 6-cm sleeve sensor placed just distal to the last manometric port. The impedance rings (Ω) are also spaced 4 cm apart with the rings straddling the manometric ports. The arrows to the right panel point to the corresponding data tracings obtained from each combined manometry/impedance or sleeve recording site. The right panel illustrates the concurrent videofluoroscopic, manometric, and multichannel intraluminal impedance recordings of a 5-mL diatrizoate (Renografin) swallow that was completely cleared by one peristaltic sequence. Representative tracings from the videofluoroscopic sequence overlaid on the combined manometric/impedance tracing show the distribution of the bolus at the times indicated by the vertical arrows. At each recording site, the black line intersecting the pressure scale (mm Hg) on the left represents the manometric tracing and the blue line intersecting the impedance scale in ohms (Ω) on the right represents the impedance recording tracing. Bolus entry at each combined manometry/impedance recording site is signaled by a subtle increase in pressure (intrabolus pressure) and a sharp decrease in impedance. In this example, the bolus propagates past Ω#4 rapidly, as indicated by an abrupt reduction in impedance in Ω#2, Ω#3, and Ω#4 at time 1.5 seconds. Luminal closure and hence the tail of the barium bolus (inverted “V”) is evident at each recording site by the upstroke of the peristaltic contraction and an increase in recorded impedance. Hence, at 5 seconds, the peristaltic contraction was beginning at side-hole sensor #3, corresponding to an increase in impedance and the tail of the barium bolus at the same esophageal locus. Finally, after completion of the peristaltic contraction (time 12 seconds), all diatrizoate was in the stomach. | |
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| Figure 42-11. Corkscrew esophagus on barium esophagogram in a patient with symptomatic distal esophageal spasm. | |
Esophageal Manometry (High-Resolution Esophageal Pressure Topography) Esophageal manometry is a test in which intraluminal pressure sensors, either water perfused or solid state, are positioned within the esophagus to quantify the contractile characteristics of the esophagus and segregate it into functional regions. The concept of high-resolution esophageal manometry is to use a sufficient number of pressure sensors within the esophagus such that intraluminal pressure can be monitored as a continuum along the length of the esophagus, much as time is viewed as a continuum in line tracings of conventional manometry such as those in Figure 42-10. When high-resolution manometry is coupled with sophisticated algorithms to display the manometric data as pressure topography plots, esophageal contractility is visualized with isobaric conditions among sensors indicated by isocoloric regions on the pressure topography plots. Figure 42-12 depicts a normal swallow in a high-resolution esophageal pressure topography plot encompassing both sphincters (UES and LES) and the intervening esophagus. The relative timing of sphincter relaxation and segmental contraction as well as the position of the transition zone are all readily demonstrated.
 | |
| Figure 42-12. High-resolution esophageal pressure topography spanning from the pharynx (locations 0 to 2 cm) to the stomach (locations 29 to 35 cm) of a normal subject with normal peristalsis and normal esophagogastric junction (EGJ) relaxation. The transition zone, demarcating the end of the proximal esophageal segment S1 (striated muscle) and the beginning of the distal esophageal segment S2 (smooth muscle), is readily identified as a pressure minimum. Note that the distal esophageal segment, in fact, has three subsegments (S2, S3, S4) within it, each with an identifiable pressure peak. S4, the lower esophageal sphincter (LES), contracts at the termination of peristalsis and then descends back to the level of the crural diaphragm as the period of swallow-related esophageal shortening ends. The onset of the deglutitive relaxation window is at the onset of upper esophageal sphincter (UES) relaxation, whereas the offset is 10 seconds later. The spatial domain within which EGJ relaxation is assessed (the eSleeve range) is user defined, spanning at least 6 cm (in this example, labeled 0 and 6 cm), depending on the extent of esophageal shortening after the swallow. The contractile front velocity (CFV) is the slope of the line connecting points on the 30 mm Hg isobaric contour at the proximal margin of S2 and the distal margin of S3. | |
The manometric evaluation of deglutitive EGJ relaxation is probably the most important measurement made during clinical esophageal manometry. Incomplete EGJ relaxation is an essential feature in the diagnosis of achalasia and achalasia is not only the best-defined esophageal motor disorder, but also the one with the most specific treatments. Despite this cardinal significance, there was no convention for defining incomplete deglutitive EGJ relaxation with conventional manometry. Furthermore, numerous potential confounding factors exist including crural diaphragm contraction during relaxation, deglutitive esophageal shortening, hiatal hernia, sphincter radial asymmetry, and movement of the recording sensor relative to the EGJ.[8] With high-resolution esophageal pressure topography, this situation is greatly improved. A study comparing criteria for detecting impaired deglutitive EGJ relaxation within the deglutitive relaxation window (see Fig. 42-12) in a large group of patients and control subjects concluded that the optimal measure for quantifying deglutitive relaxation was the integrated relaxation pressure (IRP), with normal being defined as 15 mm Hg or less.[284] Conceptually, the IRP is the average EGJ pressure for the four seconds of greatest relaxation within the relaxation window. This single measure of deglutitive EGJ relaxation exhibited 98% sensitivity and 96% specificity for distinguishing well-defined achalasia patients from control subjects and patients with other diagnoses.[284] Apart from improving the sensitivity of manometry in the detection of achalasia, high-resolution esophageal pressure topography has also defined a clinically relevant subclassification of achalasia.[224] A diagnosis of achalasia requires both aperistalsis and impaired deglutitive EGJ relaxation. In its most obvious form this occurs in the setting of esophageal dilatation with negligible pressurization within the esophagus (Fig. 42-13A). However, despite there being no peristalsis, there can still be substantial pressurization within the esophagus. In fact, a very common pattern encountered is achalasia with esophageal compression and panesophageal pressurization (see Fig. 42-13B). The other, less common pattern is of spastic achalasia in which there is a spastic contraction within the distal esophageal segment (see Fig. 42-13C and D). In a series of 99 consecutive patients with newly diagnosed achalasia, 21 had the classical pattern in Figure 42-13A, 49 had the panesophageal pressurization pattern of Figure 42-13B, and 29 had the spastic achalasia pattern of Figure 42-13C.[224] Logistic regression analysis found panesophageal pressurization (see Fig. 42-13B) to be a predictor of response to treatment, whereas spastic achalasia (see Fig. 42-13C) and pretreatment esophageal dilatation were predictive of a poorer response to treatment.
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| Figure 42-13. Achalasia subtypes are distinguished by three distinct manometric patterns of esophageal body contractility (panels A-C). In classic achalasia (panel A), there is no significant pressurization within the body of the esophagus and impaired esophagogastric junction (EGJ) relaxation. The integrated relaxation pressure (IRP) was 42 mm Hg in this example. Panel B represents a swallow from a patient with the “achalasia with compression” subtype exhibiting rapid panesophageal pressurization of the fluid column trapped between the sphincters as the esophagus shortens at seven to eight seconds. Panel C illustrates a pressure topography plot typical of spastic achalasia. Although this swallow is also associated with rapidly propagated pressurization, the pressurization is attributable to an abnormal lumen-obliterating contraction. A three-dimensional rendering of these same pressure data (panel D) illustrates the peaks and valleys of that spastic contraction (brown vs. red); this swallow would likely appear as a rosary-bead or corkscrew pattern on fluoroscopy. (Modified from Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: A new clinically relevant classification by high resolution manometry. Gastroenterology 2008; 135:1526-33.) | |
Following the analysis of the EGJ, a swallow is further categorized by the characteristics of the distal esophageal contraction. This analysis is largely facilitated by the generation of a pressure topography plot highlighting the 30 mm Hg isobaric contour. Under circumstances of normal deglutitive EGJ relaxation, the 30 mm Hg pressure threshold reliably delineates the wavefront of the peristaltic contraction.[285] Contractile front velocity (CFV) is calculated from the 30 mm Hg isobaric contour plots by calculating the slope of the line connecting the 30 mm Hg isobaric contour at the proximal margin of the first subsegment and the distal margin of the second subsegment (see Fig. 42-12). A CFV of more than 8 cm/second is indicative of a spastic contraction.[285,286] Although the CFV is easily definable in the circumstance of normal EGJ relaxation, it is more complex when EGJ relaxation is impaired (Fig. 42-14). With impaired EGJ relaxation, there is compartmentalized pressurization between the contractile front of the distal esophageal contraction and the EGJ with a high intrabolus pressure residing between the two. In such instances, the slope of the 30 mm Hg isobaric contour is no longer indicative of the CFV but now indicates increased intrabolus pressure as a result of functional obstruction at the EGJ. In such circumstances, the algorithm for computing CFV defaults to computing the slope of an isobaric contour line of magnitude greater than the EGJ relaxation pressure (e.g., 50 mm Hg in a given patient) so as to consistently represent the timing of luminal closure (see Fig. 42-14).
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| Figure 42-14. Differentiating increased intrabolus pressure (IBP) from a rapidly propagated spastic contraction (bottom). A, Swallow with functional obstruction at the esophagogastric junction (EGJ). Note that the 30 mm Hg isobaric contour (IBC) line deviates quickly from the 50 mm Hg isobaric contour line (arrows). In this case the contraction front velocity (CFV) was normal, reflecting the propagation velocity of the 50 mm Hg isobaric contour rather than the 30 mm Hg isobaric contour. B, Swallow with rapid CFV attributable to spasm. EGJ relaxation is normal and the 30 and 50 mm Hg isobaric contours parallel each other, indicating that no compartmentalized esophageal pressurization has occurred. The entire distal esophagus is contracting simultaneously. (Modified from Pandolfino JE, Ghosh SK, Rice J, et al. Classifying esophageal motility by pressure topography characteristics: A study of 400 patients and 75 controls. Am J Gastroenterol 2008; 103:27-37.) | |
Apart from a rapid CFV, other common abnormalities of the distal esophageal contraction are weak or absent peristalsis. In such instances, the 30 mm Hg isobaric contour is either discontinuous or absent, reflective of either focal or diffuse hypotensive contraction within the distal segment. Each swallow is thus characterized as normal (intact 30 mm Hg isobaric contour and a CFV < 8 cm/second), hypotensive (3 cm or greater defect in the 30 mm Hg isobaric contour), or absent (complete failure of contraction with no pressure domain > 30 mm Hg). Weak or absent peristalsis is a risk factor for impaired bolus clearance, but, whether impaired bolus clearance occurs depends on the balance between the severity of weakness and the magnitude of outflow resistance at the EGJ.[287] Once swallows are characterized by the integrity of deglutitive EGJ relaxation and normality of the CFV, the distal esophageal contraction is further analyzed for the vigor of contraction using a newly developed measure for high-resolution esophageal pressure topography, the distal contractile integral (DCI). The DCI integrates the length, vigor, and persistence of the two subsegments of the distal esophageal segment contraction, expressed as mm Hg?s?cm. A DCI value greater than 5000 mm Hg?s?cm is considered elevated.[288] Adopting the nomenclature “nutcracker esophagus” from conventional manometry, this is the high-resolution manometry criterion defining hypertensive peristalsis and was seen in 9% of a 400-patient series.[285] However, there was substantial heterogeneity as to the locus of the hypertensive contraction within this group, potentially involving either or both of the subsegments within the distal esophageal contraction. Similarly, the LES can exhibit a hypertensive postdeglutitive contraction, defined as exceeding 180 mm Hg. Furthermore, one particularly interesting subgroup, defined by having a higher threshold DCI (>8000 mm Hg?s?cm), exhibited repetitive high-amplitude contractions and was clinically distinguishable by the uniform association with dysphagia or chest pain. Similar to DES, this “spastic nutcracker” pattern is very rare, found in only 12 (3%) of this 400-patient series (Fig. 42-15).
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| Figure 42-15. An uncommon spastic variant of hypertensive peristalsis (spastic nutcracker) identifiable by a distal contractile integral value greater than 8000 mm Hg?s?cm. In this example, the contraction did not meet contractile front velocity criteria for spasm (8 cm/s). The contraction has a spastic component that occurs after the wavefront propagates to the esophagogastric junction. Clinically these patients uniformly experience chest pain and dysphagia. | |
Following analysis of individual swallows by the criteria outlined, the component results are synthesized into a global manometric diagnosis by the criteria detailed in Table 42-2. Patients with normal EGJ relaxation, normal CFV, and a DCI less than 5000 mm Hg?s?cm are normal. The abnormalities encountered are described in specific functional terms with the intent that these then be interpreted within the clinical context of the patient. The classification detailed in Table 42-2 represents an incremental update on the Chicago classification,[289] the task of a newly convened international working group focused on the standardization of the performance and interpretation of high-resolution esophageal pressure topography studies.
| With Normal EGJ Relaxation (Mean Integrated Relaxation Pressure <15 mm Hg) | |
|---|---|
| DISORDER | CRITERIA |
| Aperistalsis | 100% of swallows with absent peristalsis |
| Hypotensive peristalsis | |
| Intermittent | More than 30% of swallows with peristaltic defects ≥3 cm in 30 mm Hg pressure isocontour |
| Frequent | 70% or more of swallows with peristaltic defects ≥3 cm in 30 mm Hg pressure isocontour |
| Hypertensive peristalsis | Normal CFV, mean DCI >5000 and <8000 mm Hg?s?cm or LES after-contraction >180 mm Hg |
| Spastic nutcracker | Normal CFV, mean DCI >8000 mm Hg?s?cm (Fig. 42-15) |
| Distal esophageal spasm (DES) | Normal EGJ relaxation and spasm (CFV >8 cm/s) with ≥20% of swallows (see Fig. 42-14B) |
| With Impaired EGJ Relaxation (Mean Integrated Relaxation Pressure ≥15 mm Hg) | |
|---|---|
| DISORDER | CRITERIA |
| Achalasia | |
| Classic achalasia | Impaired EGJ relaxation and aperistalsis (see Fig 42-13A) |
| Achalasia with esophageal compression | Impaired EGJ relaxation, aperistalsis, and panesophageal pressurization with ≥20% of swallows (see Fig. 42-13B) |
| Spastic achalasia | Impaired EGJ relaxation, aperistalsis, and spasm (CFV >8 cm/s) with ≥20% of swallows (see Fig. 42-13C and D) |
| Functional EGJ obstruction* | IBP >30 mm Hg compartmentalized between the peristaltic wavefront (normal or nutcracker) and EGJ (see Fig. 42-14A) |
| CFV, contractile front velocity; DCI, distal contractile integral; EGJ, esophagogastric junction; IBP, intrabolus pressure; LES, lower esophageal sphincter. |
Intraluminal Impedance Measurement Intraluminal impedance monitoring was described more than a decade ago as a method to assess intraluminal bolus transit without using fluoroscopy. The technique uses an intraluminal catheter with multiple, closely spaced pairs of metal rings (see Fig. 42-10). An alternating current is applied across each pair of adjacent rings and the resultant current flow between the rings is dependent on the impedance of the tissue and luminal content between the rings. Impedance decreases when the electrodes are bridged by liquid and increases when they are surrounded by air thereby providing data on the direction, content, and completeness of bolus transit. Validation data suggest that liquid bolus entry at the level of an electrode pair is indicated by a 50% drop in impedance and return of the impedance tracing to 50% of baseline correlates with the passage of the tail of the bolus on fluoroscopy, also indicated by the contractile upstroke noted on manometry (see Fig. 42-10). Validation studies of intraluminal impedance measurement against videofluoroscopy have shown excellent concordance in ascertaining bolus transit, reporting agreement in 97% (83/86) of swallows analyzed.[290] Intraluminal impedance measurement has also recently been combined with manometry to assess the efficacy of esophageal emptying as a function of distal peristaltic amplitude. In a receiver operating characteristic (ROC) analysis of a large number of swallows, a 30 mm Hg cutoff had 85% sensitivity and 66% specificity for identifying incomplete bolus transit.[291] With diminishing peristaltic amplitudes, the sensitivity progressively decreased and the specificity progressively increased. This study illustrates the complementary nature of manometry and impedance testing in assessing esophageal function and may develop into a valuable clinical tool for the assessment of dysphagia. Sensory Testing Esophageal sensory nerves play a key role in determining symptoms of esophageal neuromuscular diseases because the esophagus is sensitive to a variety of stimuli including mechanical (elicited by luminal distention or high-amplitude contractions), chemical (acid or other constituents of reflux), and temperature.[292] Typically the visceral input is not perceived consciously. However, some patients may experience symptoms attributed to hyperalgesia (exaggerated pain perception) or allodynia (perception of pain to a stimulus that is usually not painful).[155,293] Esophageal symptoms may be described as burning, pressing, pricking, or heat sensations. Nevertheless, these symptoms are not specific to a given stimulus, and substantial overlap in perception among stimuli is common. Although the precise mechanism by which an esophageal stimulus causes pain or the perception of dysphagia is unclear, methodologies devised to evoke or stimulate pain by simulating physiologic events are available to assess the possible relationship between ongoing symptoms and suspected causes. These tests typically use forms of distention studies (balloon, barostat, impedance planimetry, or volume challenges) or direct mucosal stimulation (chemical, electrical, or thermal). Balloon distention studies have shown that esophageal distention can provoke chest pain and that patients with esophageal chest pain tend to have lower threshold volumes for both first perception and first pain perception compared with controls.[294,295] Combining impedance planimetry with balloon distention allowed other investigators to correlate biomechanical properties of the esophagus with the generation of chest pain.[296,297] Results of those studies suggested that the tension-strain curve in chest pain patients was shifted to the left when compared with controls, a finding consistent with reduced compliance of the esophageal wall.[269] The standard test of chemosensitivity is the Bernstein test wherein 0.1 normal hydrochloric acid is perfused in the esophagus to reproduce chest pain or heartburn. Typically, acid infusion is alternated with saline perfusion in a blinded fashion to increase the objectivity of the test, but no standardized protocol exists. Beyond the standard Bernstein perfusion test to assess esophageal sensitivity to acid, newer probes have been devised to test esophageal responsiveness to thermal challenges and transmucosal electrical nerve stimulation. However, although these tools have unquestionably been useful in improving our understanding of the interaction between peripheral receptors and central pain perception, their clinical utility remains limited owing to the lack of protocol standardization and the somewhat cumbersome nature of the studies. Currently, use of these devices is limited to subspecialty centers and further refinement will be required before mainstream clinical use can be advocated. TREATMENT Oropharyngeal Dysphagia Management of oropharyngeal dysphagia is focused on four specific issues: (1) identification of an underlying systemic disease, (2) characterization of a disorder amenable to surgery or dilation, (3) identification of specific patterns of dysphagia amenable to swallowing therapy, and (4) assessment of aspiration risk. Identifying Underlying Disease A potential outcome of the evaluation is the identification of an underlying neuromuscular, neoplastic, or metabolic disorder that dictates specific management. For example, dysphagia can be the presenting symptom in patients with myopathy, myasthenia, thyrotoxicosis, motor neuron disease, or Parkinson's disease. In each instance, managing the underlying disease requires a specific treatment. Whether or not treatment of the underlying disorder improves swallowing function depends on the natural history of the specific disease and whether effective treatment exists. Disorders Amenable to Surgery The most common surgical treatment for oropharyngeal dysphagia is cricopharyngeal myotomy but the efficacy of myotomy in neurogenic or myogenic dysphagia is variable. Most series evaluating the efficacy of myotomy in these circumstances are uncontrolled and lack validated or even specific outcome measures. Thus, although an overall favorable response rate in excess of 60% is reported in this literature, there are no validated criteria for patient selection. Theoretically, the functional limitation faced by patients with neurogenic or myogenic dysphagia is of weak pharyngeal propulsion and the potential benefit of myotomy in that circumstance is less obvious than in the case of obstruction at the level of the cricopharyngeus.[298]Patterns of Oropharyngeal Dysphagia Amenable to Swallow Therapy Identifying potential treatments for oropharyngeal dysphagia begins with definition of the aberrant physiology as categorized in Table 42-1. This is best accomplished with a videofluoroscopic swallowing study that first characterizes a patient's swallow dysfunction and then proceeds to test the effectiveness of selected compensatory or therapeutic treatment strategies. Compensatory treatments include postural changes, modifying food delivery or consistency, or the use of prosthetics. For instance, head turning can eliminate aspiration or pharyngeal residue by favoring the more functional side in patients with hemiparesis.[17] Similarly, diet modifications can reduce the “difficulty” of the swallow. Therapeutic strategies are designed to alter the physiology of the swallow, usually by improving the range of motion of oral or pharyngeal structures using voluntary control of oropharyngeal movement during a swallow. Depending on the severity of the impairment, level of motivation, and global neurologic integrity, defective elements of the swallow can be selectively rehabilitated. For a detailed description of the techniques and limitations of swallow therapy, the reader is referred to treatises on the topic.[17,299]Evaluating Aspiration Risk Oropharyngeal dysphagia is responsible for an estimated 40,000 deaths a year due to aspiration pneumonia.[300] Videoflouroscopy is considered the most sensitive test for detecting aspiration, reportedly detecting instances not evident by bedside evaluation in 42% to 60% of patients. However, despite the logical association between deglutitive aspiration and the subsequent development of pneumonia, this sequence is not inevitable. In fact, available data suggest that radiographic aspiration has a positive predictive value of only 19% to 68% and a negative predictive value of 55% to 97% for pneumonia.[300] Nonetheless, the balance of evidence suggests that detection of aspiration is a predictor of pneumonia risk, and that its detection dictates that compensatory swallowing strategies, non-oral feeding or corrective surgery be instituted. Whether non-oral feeding eliminates the risk of aspiration is controversial. In one study of 22 patients with radiographic aspiration, pneumonia and death were more frequent among patients who received feeding tubes.[185] This suggests that aspiration of oral secretions may be the essential element in pneumonia risk and has led some to consider procedures such as tracheostomy to protect the airway. Hypopharyngeal (Zenker's) Diverticulum and Cricopharyngeal Bar The treatment of hypopharyngeal diverticulum is cricopharyngeal myotomy with or without a diverticulectomy (see Chapter 23). Cricopharyngeal myotomy reduces both the resting sphincter tone and resistance to flow across the UES. A study found that the compliance of the sphincter following diverticulectomy with myotomy was restored to normal following surgery, as indicated by normal hypopharyngeal intrabolus pressure during swallowing.[301] Good or excellent results are reported in 80% to 100% of Zenker's patients treated by transcervical myotomy combined with diverticulectomy or diverticulopexy.[299] There are instances in which a limited procedure would be adequate, but a definitive approach to the problem of pulsion diverticula should generally involve myotomy and diverticulectomy. Diverticulectomy alone risks recurrence because the underlying stenosis at the level of the cricopharyngeus is not remedied. Similarly, myotomy alone may not solve the problem of food accumulation within the diverticulum, with attendant regurgitation and aspiration. Small diverticula may, however, disappear spontaneously following myotomy. A more recent trend is to treat Zenker's diverticula via either rigid or flexible endoscopy. With both techniques, the principle is to divide the septum between the lumen of the diverticulum and the lumen of the esophagus. The division allows food and liquid to flow out of the diverticulum distal to the cricopharyngeus (which was within the septum) rather than to accumulate within the diverticulum. In the case of rigid endoscopy the procedure is performed under general anesthesia with a stapling device. In the case of flexible endoscopy the procedure is performed under light sedation with a needle knife, argon plasma coagulation, or hot biopsy forceps. Controlled trials have not been done comparing the two procedures, but a recent summary of 376 reported cases treated with flexible endoscopic methods found treatment to result in clinical resolution in 43% to 100% of cases among series.[184] Whether a cricopharyngeal bar in the absence of a diverticulum requires treatment is less clear. Certainly, if dysphagia is present and combined fluoroscopic/manometric analysis demonstrates reduced sphincter opening in conjunction with elevated upstream intrabolus pressure, there is good rationale for treatment. One recent uncontrolled series suggests that in this scenario dilation with a large-caliber bougie may be efficacious in relieving dysphagia and this approach is certainly a reasonable treatment option prior to myotomy.[302]Achalasia Because the underlying neuropathology of achalasia cannot be corrected, treatment is directed at compensating for the poor esophageal emptying and preventing complications. In practical terms this amounts to reducing LES pressure so that gravity promotes esophageal emptying. Peristalsis is not restored with therapy. LES pressure can be reduced by pharmacologic therapy, forceful dilation, or surgical myotomy. Pharmacologic treatments, on the whole, are not very effective, making them more appropriate as temporizing maneuvers than definitive therapies. The definitive treatments of achalasia are disruption of the LES either surgically (Heller myotomy) or with a pneumatic dilator. Which of these is the optimal approach remains an issue of debate given the paucity of randomized controlled trials with accepted criteria for assessing efficacy. A further limitation of the previous studies is failing to stratify patients by disease severity or, as more recently defined, by disease subtype.[224] High-resolution esophageal pressure topography allows the subtyping of achalasia into three distinct patterns: I, classic achalasia; II, achalasia with compression; and III, spastic achalasia (see Fig. 42-13). From a conceptual vantage point types I and II represent a continuum, with type II representing early disease before the progression of esophageal dilatation characteristic of type I. Type III, on the other hand, is a subtype characterized by spasm of the distal esophagus. The significance of these disease subtypes is in how differently they responded to therapy, be it botulinum toxin injection, pneumatic dilation, or Heller myotomy. In a series of 99 new cases of achalasia, the overall treatment response was 56% with type I, 96% with type II, and only 29% with type III. The literature pertinent to achalasia treatment is mainly composed of numerous uncontrolled case series using a variety of qualitative endpoints as indications of efficacy. As noted, there is also minimal standardization as to the criteria for defining achalasia, the disease severity included in one series versus another, or the technical details of how pneumatic dilation or Heller myotomy are performed. Furthermore, some series were collected prospectively, some retrospectively, and some a combination. Given all of these limitations, there is little merit to embarking on a detailed comparison of outcomes between techniques. The existing treatment data are summarized next. Pharmacologic Therapy Smooth muscle relaxants such as nitrates or calcium channel blockers, administered sublingually immediately prior to eating can relieve dysphagia in achalasia by reducing the LES pressure. Amyl nitrite,[303] sublingual nitroglycerin, theophylline, and β2-adrenergic agonists[304] have also been tried. The largest reported experience has been with isosorbide dinitrate (Isordil) and nifedipine.[305] Isosorbide dinitrate, 5 to 10 mg sublingually before meals, reduces LES pressure by 66% for about 90 minutes, with the degree of dysphagia relief paralleling the magnitude of the LES response over the 19-month trial.[306] Side effects, particularly headache, are common. Placebo-controlled trials have not been reported. Calcium channel blockers (diltiazem, nifedipine, verapamil) reduce LES pressure by 30% to 40% for more than an hour.[306,307] The largest clinical experience in achalasia has been with nifedipine (Procardia). Nifedipine, 10 mg sublingually (capsules are crushed in the mouth) administered before meals (30 to 40 mg per day) was studied in 29 patients with early achalasia (prior to esophageal dilatation) in a placebo-controlled trial. Nifedipine was significantly better that placebo (which had no benefit), with good results in 70% of achalasic patients followed for 6 to 18 months.[305] However, subsequent placebo-controlled crossover trials have found only minimal benefit with nifedipine.[308] Side effects of nifedipine include flushing, dizziness, headache, peripheral edema, and orthostasis. Sildenafil (Viagra) is another smooth muscle relaxant that can decrease LES pressure in patients with achalasia by blocking phosphodiesterase type 5, the enzyme that destroys cyclic guanosine monophosphate induced by NO. A double-blind placebo controlled trial found that 50 mg of sildenafil significantly reduced LES pressure and relaxation pressure when compared with placebo.[309] The effect peaked at 15 to 20 minutes after administration and persisted for less than one hour. Although conceptually appealing, the practicality of using sildenafil clinically is limited by its cost that is rarely, if ever, covered by health care insurance. Botulinum Toxin Injection The initial landmark study of botulinum toxin in achalasia reported that intrasphincteric injection of 80 units of botulinum toxin decreased LES pressure by 33% and improved dysphagia in 66% of patients for a six-month period.[310] Botulinum toxin irreversibly inhibits the release of acetylcholine from presynaptic cholinergic terminals, effectively eliminating the neurogenic component of LES pressure. However, because this inhibitory effect is eventually reversed by the growth of new axons, botulinum toxin is not a long-lasting therapy. The technique involves injecting divided doses of botulinum toxin into four quadrants of the LES with a sclerotherapy catheter. Side effects are rare, but include chest discomfort for several days and rash. Although many patients initially experience a good response, there is minimal continued efficacy at one year.[311-313] Repeat injection can be effective for a reasonable subset of patients, but the injection leads to a local inflammatory reaction and fibrosis, ultimately limiting this strategy. Doses greater than 100 units do not have increased efficacy.[314] Studies comparing botulinum toxin injection to pneumatic dilation suggest that the expense of repeated injection outweighs the potential economic benefits of added safety, unless the patient's life expectancy is minimal.[315] Thus, this option is mainly reserved for older adults or frail individuals who are poor risks for definitive treatments. Pneumatic Dilation Therapeutic dilation for achalasia requires distention of the LES to a diameter of at least 3 cm to produce a lasting reduction of LES pressure, presumably by partially disrupting the circular muscle of the sphincter. Dilation with an endoscope, standard bougies (up to 60 French), or with through-the-scope balloon dilators (up to 2 cm) provides very temporary benefit at best. Only dilators specifically designed to treat achalasia achieve adequate diameter for lasting effectiveness. The basic element of an achalasia dilator is a long, noncompliant, cylindrical balloon that can be positioned across the LES fluoroscopically (Rigiflex dilator) or endoscopically (Witzel dilator) and then inflated to a characteristic diameter in a controlled fashion using a handheld manometer. There is general agreement that pneumatic dilation can be done on an outpatient basis with the patient under conscious sedation. The technique of pneumatic dilation is variable among practitioners in terms of patient preparation, parameters of balloon inflation, and postdilation monitoring. In patients with substantial esophageal retention, it is useful to impose a liquid diet for one or more days prior to the procedure. Reported balloon inflation periods range from several seconds to five minutes.[316] Although there is minimal methodologic consistency among authors, a cautious approach of beginning with a small-diameter dilator (3 cm) and progressing to larger diameters (3.5 and 4 cm) only when the smaller dilator proved ineffective is fairly universal. As for inflation pressures, these are of minimal relevance with modern noncompliant balloon dilators because they do not distend beyond their specified diameter regardless of inflation pressure. Hence, it is simply necessary to observe under fluoroscopy that the balloon is properly positioned to capture the LES, observed as the “waist” of the hourglass-shaped balloon silhouette and that the waist fully effaces as the inflation proceeds. As for technical details of the procedure other than balloon diameter, there is minimal evidence that they influence outcome. The major complication of pneumatic dilation is esophageal perforation (see Chapter 40); mortality is fortunately rare.[317] The reported incidence of esophageal perforation consequent from pneumatic dilation ranges between 1% and 5%[261,316] with a global average of 3%. Because most perforations are readily evident or at least suspected within an hour of the procedure, patients should be observed closely for signs of an esophageal leak for at least two hours after pneumatic dilation. Alternatively, some practitioners routinely obtain a fluoroscopic examination of the esophagus following pneumatic dilation to ensure that perforation has not occurred. Usually, water-soluble contrast is given first, followed by barium. If a perforation appears small and contained or intramural, conservative management in the hospital consisting of close observation while maintaining the patient on nothing per mouth status and administering intravenous antibiotics is appropriate.[261] If a perforation is substantial, or if worsening pain and fever occur during observation of what was thought to be a small perforation, surgical repair should be pursued expediently. Patients with a perforation from pneumatic dilation that is recognized and promptly treated surgically (within six to eight hours) have outcomes comparable with those of patients undergoing elective Heller myotomy.[318] The best predictor of efficacy following a pneumatic dilation is the postdilation LES pressure; neither sphincter relaxation nor peristaltic function is significantly changed. A postdilation LES pressure less than 10 mm Hg is associated with prolonged remission, whereas a postdilation LES pressure greater than 20 mm Hg predicts that little benefit will occur from the procedure.[319] In instances of an unsatisfactory result, it is reasonable to perform a subsequent dilation within a matter of weeks using an incrementally larger dilator. If the benefit of dilation persisted for a year or more, it is neither unusual nor dangerous to repeat pneumatic dilation as necessary. The clinical efficacy of dilation has been reported to range from 32% to 98%.[311] Patients having a poor initial result or rapid recurrence of symptoms have diminished likelihood of responding to additional dilations.[311] Subsequent response to surgical myotomy is not influenced by the history of previous dilations.[261]Heller Myotomy Current surgical procedures for treating achalasia are variations on the esophagomyotomy described by Heller in 1913 consisting of an anterior and posterior myotomy performed through either a laparotomy or a thoracotomy.[311] Subsequently, this was modified to an anterior myotomy via thoracotomy. The appeal of myotomy is that it offers a more predictable method of reducing LES pressure than does pneumatic dilation.[320] Although clearly efficacious, open Heller myotomy is associated with considerable morbidity related to thoracotomy, which led most patients to pursue pneumatic dilation as the initial intervention. However, adoption of the laparoscopic approach for achalasia surgery has led many practitioners to reconsider this. Published series of the efficacy of Heller myotomy in treating achalasia report good to excellent results in 62% to 100% of patients, with persistent dysphagia troubling less than 10% of patients.[311] Recent studies suggest that a laparoscopic approach is associated with similar efficacy, reduced morbidity, and shorter hospital stay when compared with myotomy via thoracotomy, laparotomy, or thoracoscopy.[311,321-325] The overall mortality from Heller myotomy is less than 2%. Historically, postmyotomy reflux in achalasic patients could be particularly severe, making this a hotly disputed detail of the surgical technique.[326] However, with the broad use of proton pump inhibitors, reflux is usually easily controlled, making these complications very unlikely. Thus, laparoscopic Heller myotomy combined with a partial fundoplication (Toupet or Dor) has become the preferred surgical procedure for achalasia. An unsatisfactory result following Heller myotomy can result from incomplete myotomy, scarring of the myotomy, functional esophageal obstruction from the antireflux component of the operation, paraesophageal hernia, or severe esophageal dilatation. Heller Myotomy versus Medical Treatment Although pharmacologic therapy is simple and safe, it is increasingly clear that this should be reserved for use as a temporizing measure while more definitive therapy is being considered. Thus, practically speaking, the therapeutic choice is between pneumatic dilation and laparoscopic Heller myotomy as the primary therapy for achalasia. However, there are as yet no prospective controlled trials comparing these treatments. One controlled trial compares pneumatic dilation to myotomy via thoracotomy. That study reported 95% symptom resolution with myotomy and 51% symptom resolution in the dilation group, but the study was criticized for the methodology of pneumatic dilation used.[327] Most case series report symptom resolution in approximately 70% of patients with pneumatic dilation, substantially higher than the 51% reported in the controlled trial, but still substantially lower than that reported in uncontrolled series of laparoscopic Heller myotomy (85% to 91%). Furthermore, although laparoscopic Heller myotomy is invasive, its morbidity and mortality are low. On the other hand, pneumatic dilation has a reported perforation rate that averages 3%, an incidence that probably exceeds that sustained by clinicians with substantial experience. Even though these patients do well if the perforation is recognized and addressed promptly, they may require a thoracotomy. Thus, it appears that cogent arguments can be made for each of these therapies and likely one should assess the local skills available, as well a patient preference, in selecting the most appropriate initial therapy. Treatment Failures Persistent dysphagia after treatment suggests treatment failure and should be evaluated with some combination of endoscopy, esophageal manometry, and fluoroscopic imaging. Endoscopy may detect esophagitis, stricture, paraesophageal hernia, or anatomic deformity. Manometry may be useful to quantify residual LES pressure, with values exceeding 10 mm Hg arguing for further therapy targeting the LES. Fluoroscopy is useful to identify anatomic problems as well as to evaluate esophageal emptying by using a timed barium swallow, a standardized method of measuring the height of the esophageal barium column one and five minutes after ingestion.[328] In some instances these evaluations will lead to further intervention. In the case of a patient not previously operated on this could potentially be either repeat dilation or Heller myotomy. In patients who have already undergone myotomy, detection of an excessively short myotomy or functional esophageal obstruction from the antireflux component of the surgery usually requires reoperation, but pneumatic dilation can be pursued as an alternative. Reoperation, in general, is less effective than an initial operation for any indication in achalasia.[329] Occasionally patients fail to respond to optimally performed dilation or myotomy and require alternative approaches. In extremely advanced or refractory cases of achalasia, esophageal resection with gastric pull-up or interposition of a segment of transverse colon or small bowel may be the only surgical option.[330] Indications for this intervention include unresolvable obstructive symptoms, starvation, chronic aspiration, cancer, and perforation during dilation. Although excellent long-term functional results can be achieved, the reported mortality rate of this surgery is about 4%, consistent with the mortality rate of esophagectomy done for other indications. Risk of Squamous Cell Cancer Numerous series report cases of squamous cell carcinoma developing in the achalasic esophagus (see Chapter 46).[331] The relative risk of developing squamous cell cancer has been estimated to be 33-fold relative to the non-achalasic population.[332] The pathogenesis of the carcinoma is obscure, but stasis esophagitis is the likely precipitating factor. The tumors develop many years after the diagnosis of achalasia and usually arise in a greatly dilated esophagus, often in the middle third of the esophagus. Symptoms attributable to the cancer can be delayed, and the neoplasms are often large and advanced at the time of detection. These considerations raise the issue of surveillance endoscopy in achalasic individuals to detect early squamous cell cancer. However, an elegant analysis of a database encompassing the entire Swedish population of 1062 achalasic patients suggests that after discounting incident carcinomas, the overall odds ratio of squamous cell cancer for these people compared with age-matched controls was 17, corresponding to a 0.15% incidence of squamous cell cancer among the achalasic subjects.[333] The authors calculated that if surveillance endoscopy was done annually, 406 examinations would need to be done in men and 2220 in women before one potentially treatable tumor was found. However, even that calculation is optimistic given that detection of a small cancer in a massively dilated esophagus with retained food and stasis esophagitis is far from ensured. Given these considerations, a surveillance program is currently not the standard of practice. Distal Esophageal Spasm Despite the dogma of treatment with smooth muscle relaxants, minimal controlled data exist regarding pharmacologic therapy of DES. Long-term studies are not available, and the entire basis for this therapy is anecdotal. Furthermore, most instances of esophageal chest pain are attributable to reflux rather than DES, and reflux symptoms will likely be made worse by treating with smooth muscle relaxants. Uncontrolled trials of small numbers of DES patients report clinical response to nitrates,[334] calcium channel blockers,[335] hydralazine,[336] botulinum toxin,[337] and anxiolytics. The only controlled trial showing efficacy was with the anxiolytic trazodone, suggesting that reassurance and control of anxiety are important therapeutic goals.[338] Also consistent with that conclusion, success has been reported using behavioral modification and biofeedback.[339] Although the rationale for dilation is unclear, use of bougie dilators has been suggested as a therapy for dysphagia or chest pain in patients with spastic disorders. However, in the only controlled trial of this therapy, dilation with an 8-mm “placebo” dilator was as effective as an 18-mm “therapeutic” dilator in producing transient symptom relief.[340] Alternatively, pneumatic dilation has been used in DES patients with severe dysphagia. In one practitioner's experience, 45% of DES patients noted relief from pneumatic dilation, compared with 80% of achalasic patients.[261] In another series of nine patients with DES and LES dysfunction treated with pneumatic dilation, dysphagia but not chest pain was improved during 37 months of observation.[341] However, it is not clear that the patients who benefited by pneumatic dilation in these series would not be more properly categorized as spastic achalasia, emphasizing the need for accurate manometric classification.[224] If dysphagia becomes so severe in DES that weight loss is observed or if pain becomes unbearable, surgical therapy consisting of a Heller myotomy across the LES with proximal extension of the incision up the distal esophagus to include the involved area of spasm or even esophagectomy should be considered.[186,342] However, there are no controlled studies of these procedures in well-defined DES patients and the indication is, fortunately, extremely rare. Esophageal Hypersensitivity Therapies for esophageal motor disorders have traditionally centered on improving esophageal contractility and emptying. However, the efficacy of these therapies is very limited except in the instance of achalasia. More recently, there has been a paradigm shift with the realization that minor manometric findings formerly interpreted as indicative of symptomatic hypercontractile conditions were often an epiphenomenon indicative of hypersensitivity syndromes. Hence, there is substantial interest in developing treatments directed at reducing esophageal hypersensitivity, and a number of pharmacologic and behavioral therapies have been identified with the potential to modulate pain perception and improve esophageal symptoms associated with swallowing. Pharmacologic Treatments Numerous neuropeptides and pharmacologic agents can reduce chemical and mechanical visceral sensitivity suggesting a possible role in the treatment of esophageal pain syndromes. Although data on these agents specific to esophageal motor disorders are sparse, there is substantial literature focused on the treatment of noncardiac chest pain with or without motor abnormalities, and it is reasonable to generalize these findings to the treatment of esophageal hypersensitivity (see Chapter 12). Antidepressants are the most common medications prescribed for visceral pain modulation or chest pain of esophageal origin. Among antidepressants, the tricyclic antidepressants (TCAs) are the best studied. The mechanism of action for this therapeutic benefit is unknown because these agents act centrally as well as peripherally and have multiple receptor targets (acetylcholine, histamine, α-adrenergic). In a randomized placebo-controlled study, imipramine at a dose of 50 mg nightly was shown to be effective in reducing chest pain in patients with normal coronary angiograms.[343] Similar results have been reported with other TCAs, and treatment with these agents at doses lower than those used for mood altering effects is common. Typical starting doses for TCAs (amitriptyline, nortriptyline) are 10 to 25 mg at bedtime with escalation of 10- to 25-mg increments to a target of 50 to 75 mg.[344] Low-dose trazodone also has been used to treat noncardiac chest pain associated with esophageal dysmotility.[338] In a double-blind placebo-controlled study in patients with noncardiac chest pain, the group taking 100 to 150 mg of trazodone had significant symptomatic improvement and less residual distress related to their esophageal symptoms. Esophageal motor function was not altered. Recent data also support the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in the treatment of esophageal hypersensitivity. Intravenous citalopram at a dose of 20 mg was studied in a randomized, double-blinded, crossover study and found to significantly reduce both chemical (acid perfusion) and mechanical (balloon distention) esophageal sensitivity.[345] Although clinical trials are not yet available, mechanistic studies assessing other SSRIs have also yielded encouraging results. Along similar lines, there has been a substantial interest in developing serotonin (5-HT) medications.[293,346] 5-HT3 antagonists and 5-HT4 agonists have been the most extensively studied given their effects on gut motility and as treatments for nausea. Unfortunately, several of these medications have proven to have unacceptable risks related to cardiac dysrhythmias or gut ischemia that led to their withdrawal. Theophylline has shown promising effects in the treatment of noncardiac chest pain, presumably by adenosine receptor blockade. In a recent placebo-controlled double-blind study, sensory and biomechanical properties of the esophagus were assessed using impedance planimetry in 16 patients with esophageal hypersensitivity.[347] Chest pain thresholds increased after intravenous theophylline and the esophageal wall was shown to relax and become more distensible. In a parallel study using oral theophylline and placebo in 24 chest pain patients there was a significant reduction in chest pain episodes, chest pain duration, and chest pain severity in the theophylline group.[347] Although limited, these are very promising results for patients with symptoms thought to be attributable to mechanical hypersensitivity. Nonpharmacologic Treatments Although the link between esophageal hypersensitivity, psychological factors, and psychiatric abnormalities is unclear, therapy focused on reassurance, behavioral modification, and relaxation techniques may be helpful. These therapies will most likely benefit patients with comorbidities such as panic disorder, generalized anxiety, and depression. However, it is also possible that therapies using controlled breathing, relaxation techniques, or hypnotherapy may benefit patients with hypersensitivity by diverting mental attention and reducing hypervigilance for visceral stimuli. Well-performed prospective trials are necessary to define the clinical role of these therapies.
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