Unexplained Chest Pain
0025-7125/91 $0.00
+
.20
Esophageal Motility Disorders and Chest Pain Serge Langevin, MD, * and Donald O. Castell, MDt
Recurrent noncardiac chest pain is a common clinical condition that is often quite frustrating to the clinician. Identifying the etiology of the chest pain represents one of the most challenging tasks in current clinical practice. 14. 20. 21. ,56, 73, 7,0, k2 Patients with angiographically normal or nearnormal coronary arteries have a low risk of cardiac death and a low risk of nonfatal myocardial infarction. 96 Despite the reasonable exclusion of coronary artery disease, these patients continue to have chest pain that compromises their lifestyle and repeatedly visit their physician's office or the emergency room. 64 ,67 Approximately 50% of them remain strongly convinced that they still have heart disease, and the reassurance that the heart is normal is often not enough. During the last decade, we have observed a growing awareness of the potential for certain esophageal abnormalities as etiologic factors in patients with episodes of recurrent substernal chest pain. Motility abnormalities have long been recognized as a possible esophageal cause of chest pain. However, there is considerable controversy regarding the prevalence of esophageal motility abnormalities in these patients. Diffuse esophageal spasm was initially considered as the common prototype of these painful esophageal events. Recent advances in methodology and standardization of stationary manometry, and a more widespread use of this tool, have revealed that the most commonly observed esophageal motility findings exhibit less dramatic contraction abnormalities than those usually described in classic diffuse esophageal spasm. Consequently, many new types of manometry abnormalities have been characterized, although their exact role and relevance remain controversial. The advent of prolonged ambulatory monitoring of intraesophageal pressure has provided additional information in this area and promises to resolve some of these complex questions. Clinically, the chest pain of esophageal origin often mimics classical *Assistant Professor of Medicine, Division of Gastroenterology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada tProfessor of Medicine, and Chief, Division of Gastroenterology and Hepatology, Jefferson Medical College, Philadelphia, Pennsylvania
Medical Clinics of North America-Vo!' 75, No. 5, September 1991
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CASTELL
angina pectoris. Unfortunately, there is no pattern of chest pain that is pathognomonic of esophageal motility disorders. The chest discomfort tends to be central and substernal in location, occasionally with neck radiation. It may also radiate into the back, and even into the left arm. The intensity is quite variable, from a dull ache to severe pain. Usually the discomfort occurs spontaneously and is rarely precipitated by swallowing. The relief of pain with nitrate preparations may also contribute to the confusion with angina. The pain event that lasts many minutes to hours or leaves a residual dull discomfort should suggest an esophageal cause. A pain episode unrelated to exertion and associated with dysphagia may also support an esophagealorigin. However, history alone cannot distinguish an esophageal disorder from a cardiac cause. 4, 29, 62
CONVENTIONAL MANOMETRY AND PROVOCATIVE TESTS Baseline Manometry The baseline manometric study may be useful in implicating the esophagus as the probable cause of symptoms. However, patients rarely have their symptoms at the time of stationary manometry. Therefore, abnormalities of motility during routine manometry only provide suggestive evidence of etiology in the absence of typical chest pain. It is important to remember that this test assesses patients under standardized conditions when they are relatively free of exogenous influences. Different types of motility abnormalities have been described in patients with noncardiac chest pain, and their manometric criteria are summarized in Table 1.40, 62, 75,82 Although achalasia and diffuse esophageal spasm are commonly recognized as producing chest pain, the specific mechanisms by which this occurs are unclear. These aspects of the other entities (nutcracker esophagus, nonspecific esophageal disorder, and hypertensive lower esophageal sphincter) are more controversial. Using a more standardized and liberal definition, diffuse esophageal spasm is now recognized as a relatively uncommon finding during manometric testing for possible esophageal chest pain. 32. 76 Achalasia is the best understood and the best characterized of the primary motility disorders. These patients usually present with an insidious and progressive dysphagia for both liquids and solids. Nevertheless, some patients with early achalasia may have angina-like pain, usually associated with frequent, simultaneous, and repetitive contractions (vigorous achalasia).69 By reviewing the records of 910 patients referred to the esophageal function laboratory for evaluation of noncardiac chest pain, Katz et al50 found that only 28% of the patients had abnormal motility during the baseline esophageal manometry. This report describes the retrospective evaluation of the largest group of patients with non cardiac chest pain studied to date. They confirmed that diffuse spasm and achalasia were infrequent, present in only 10% and 2%, respectively, of the patients with abnormal motility (Fig. 1). The nutcracker esophagus was the most common motility abnormality (48%), and nonspecific motility disorders were the
1047
ESOPHAGEAL MOTILITY DISORDERS AND CHEST PAIN
Table 1. Manometric Criteria for Primary Esophageal Motility Disorders MOTILITY DIAGNOSIS
Achalasia
ASSOCIATED FINDI]I;GS
REQUIRED CRITERIA
Aperistalsis of esophageal body
Diffuse esophageal spasm Simultaneous contractions (occurring> 10% of wet swallows) Intermittent normal peristalsis
Nutcracker esophagus Hypertensive LES
Nonspecific motility disorder
Incomplete LES relaxation Elevated LES pressure (>45 mmHg) Elevated intraesophageal pressure Repetitive contractions (2:3 peaks) Prolonged duration of contractions (>6 sec) Spontaneous contractions High amplitude contractions (>180 mm Hg) Incomplete LES relaxation Elevated LES pressure Increased duration (>6 sec)
Normal peristaltic contractions with increased distal amplitude (>180 mm Hg) Elevated LES pressure (>45 mm Hg) Poor relaxation (residual pressure: 5--10 mm Hg) Normal peristalsis Any combination of the following criteria: Increased nontransmitted contractions (> 20%) Prolonged duration contractions (>6 sec) . Triple peak contractions Decreased amplitude of esophageal peristalsis «30 mm Hg) Spontaneous contractions
second largest group (36%). This high prevalence of high-amplitude peristaltic contractions has also been reported in other smaller studies. H , 15,28, 43, 66, 90 Despite its common occurrence, this type of dysmotility is also the most controversial. 30,31,92 It is far from clear that these abnormal contractions produce an aberrant physiologic state causing chest pain. As noted previously, one problem related to the observation that these patients are usually pain-free when this motility pattern is observed. In addition, this type of dysmotility itself does not usually lead to major disruption in esophageal function, as demonstrated by lack of impairment in esophageal transit assessed by barium or scintigraphic studies. 72 CHEST PAIN (255/910 Patients)
Figure 1. Comparison of types of esophageal motility disorders found during manometric testing in 910 patients with chest pain (255 positive = 28%) and in 251 patients with dysphagia (132 positive = 53%). NE MD = nonspecific esophageal motility disorder; i LES = ·hypertensive lower esophageal sphincter; DES = diffuse esophageal spasm.
DYSPHAGIA (132/251 Patients)
El Nutcracker 0 tLES 1Nl NEMO ~ DES Cl Achalasia
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There is, however, some evidence that the finding of high-amplitude peristalsis may be a marker for other dysmotility occurring during episodes of pain. This evidence comes from three sources. One scintigraphic study has shown that a majority (94%) of these patients will have at least intermittent abnormal esophageal transport of liquids. 12 Isolated reports have documented transition of the nutcracker esophagus to either diffuse spasm 61 or achalasia. 6 Finally, a recent study using prolonged ambulatory intraesophageal pressure recording has shown that a majority of these patients will have an overall motility score similar to that found in patients showing diffuse spasm on stationary manometry. 87 Most therapeutic trials with the calcium antagonist nifedipine have revealed that this medication did not alter the frequency or magnitude of chest pain compared to placebo despite a reduction in the amplitude of peristaltic contractions. 2.77 However, a recent double-blind, crossover study with diltiazem in patients with the nutcracker esophagus did reveal significant improvement in both chest pain and peristaltic contractions compared to placebo. 23 Although the presence of nutcracker esophagus is not an accurate predictor of chest pain elicited by pharmacologic provocative tests, it was significantly better than other manometric abnormalities, including diffuse spasm. 50 These findings underscore the problems present in clarifying the relationship of chest pain and high-amplitude esophageal peristaltic waves. The picture is further complicated by increasing evidence that patients with chest pain and abnormal stationary motility have a high prevalence of psychiatric disorders. With a structured psychiatric interview, psychiatric diagnoses were made in 84% of patients with distal esophageal motility disorders compared with only 31% of those with normal manometric readings. Somatization, anxiety, and depression disorders were the most common psychiatric diagnoses. 25 Unpredictable loud noise and a difficult cognitive task have been shown to produce significant increases in mean distal esophageal contraction amplitude in both healthy subjects and patients with chest pain. 5 . 86 Patients with nutcracker esophagus demonstrated a more significant increase in contraction amplitude than did control subjects. 5 In addition, patients with esophageal contraction abnormalities complain of more gastrointestinal symptoms and are more often diagnosed as having the irritable bowel syndrome. 24 Patients with chest pain syndrome and nutcracker esophagus may have a score on the Millon Behavioral Health Inventory similar to that of patients with irritable bowel syndrome characterized by high levels of anxiety regarding bodily dysfunction, hypochondriacal concerns, and exacerbation of gastrointestinal symptoms under emotional stress. 80 Patients with irritable bowel syndrome have also been shown to present a greater increase in esophageal contraction amplitude than controls during different stresses. 7 From the preceding information, it should be evident that the exact significance of high-amplitude peristalSis and its role in chest pain remains elusive. The nutcracker esophagus may appear merely as a manometric marker of a clinical pain syndrome or other stressful events rather than being directly responsible for chest pain. 5 The use of prolonged ambulatory pressure monitoring should allow a better understanding of this unresolved issue.
ESOPIIACEAL MOTILITY DISORDERS AND CHEST PAIN
1049
The presence of excessively high resting lower esophageal sphincter pressure characterizes the hypertensive lower esophageal sphincter (LES). This condition also has a controversial clinical and pathophysiologic significance. In the study of Friedin et al,39 all of the patients suffered from ~hest pain and 9 of 16 from dysphagia. Their LES residual pressures during swallow-induced relaxation (9.2 ± 5.0 mm Hg) were significantly greater than those observed in normal controls (1.8 ± 2.2 mm Hg). Fifty-six percent also had the manometric parameters of nutcracker esophagus. In a few patients, the liquid barium studies revealed some delay in the bolus transit. Most patients achieved a good to fair symptomatic response in their chest pain from pharmacologic treatment with nifedipine. 33 Waterman et al 94 also reported similar clinical and manometric data in 15 patients with hypertensive LES. The nonspecific esophageal motility disorders (NEMD) represent abnormal patterns of esophageal contraction that are not readily categorized according to the definitions of the other primary motility disorders. A broad spectrum of abnormalities has been described, and their true clinical significance remains to be elucidated. This "catch-all" category represents the second most common group observed with routine manometry in patients with noncardiac chest pain. Provocative Tests (Pharmacologic) In most patients, the chest pain episodes are sporadic and rarely present at the time of diagnostic studies. Various provocative agents have been proposed to improve the sensitivity of the investigation in an approach similar to the "stress test" used by the cardiologists. These provocative agents have been suggested as pharmacologic provokers of esophageal abnormality and chest pain in patients with normal baseline manometry. These various agents include edrophonium, bethanechol, pentagastrin, and ergonovine. None of them is the ideal esophageal provocative test, and they have a relatively low diagnostic yield. The assessment of the esophageal provocative tests has been also greatly hampered by the lack of a gold standard for diagnosing esophageal chest pain. Edrophonium (80 mg/kg intravenously) has been shown to be the most reliable and the safest agent for routine use in the clinical esophageal laboratory. 55•.57, 58, 79 The reported positive response rate varies from 18% to 55% and is highly specific, because normal subjects rarely experience chest pain. No serious side effects have been reported, nor do any patients need atropine to reverse any untoward effects. Edrophonium was shown to have no effect on coronary vessel diameter. 79 A prospective evaluation with different provocative agents showed that edrophonium offered the greatest yield. 13 However, a positive test does not necessarily support a motility disorder as the cause of chest pain. A positive result appears to indicate an esophageal origin for the pain but does not identify the specific pathophysiologic cause of this pain. Using logistic regression analysis, Hewson et al44 found that acid-induced pain events during ambulatory monitoring were significantly associated with a positive edrophonium response, but for spontaneous motility-induced chest pain events, no such relationship could be demonstrated. Other studies have
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CASTELL
also confirmed this frequent association between a positive edrophonium test and acid-induced chest pain by 24-hour studies. 2.5. 93 Bethanechol has been reported to reproduce chest pain with an exceptionally high positive response rate. N ostrant et al observed that bethanechol (50 mg/kg subcutaneously) replicated chest pain in 46% of patients after a single injection, and that this increased to 77% after a second injection, 15 minutes later. 6:3 At these higher serial doses, bethanechol may provoke quite intense chest pain and be associated with frequent side effects. This high positive rate suggests that this test could produce sufficient stress to evoke a nonspecific pain response. Deschner et aP4 subsequently reported no significant contribution above that obtained with edrophonium, with a high dose (80 mg/kg subcutaneously) of bethanechol. Pentagastrin is also a poor provocative test, replicating chest pain in less than 10% of patients. 13 The intravenous ergonovine test produces increased esophageal contractions and reproduces chest pain in 22% to 60% of patients with noncardiac chest pain syndrome. 1.36. 53.58 However, it may provoke coronary artery spasm and may cause chest pain in up to 20% of healthy volunteers. It is associated with a high incidence of side effects, particularly cardiac arrhythmias. Other Provocative Tests Howard et al 47 reported a study of 30 patients with chest pain or dysphagia who were asked to swallow bread while standard manometry was performed as a provocative test. No patient experienced symptoms while swallowing water, but one developed symptomatic esophageal spasm while eating; eight other patients had recurrence of their chest pain and dysphagia associated with transient aperistalsis with bread swallowing. In contrast, YlellowS
0025-7125/91 $0.00
+
.20
Esophageal Motility Disorders and Chest Pain Serge Langevin, MD, * and Donald O. Castell, MDt
Recurrent noncardiac chest pain is a common clinical condition that is often quite frustrating to the clinician. Identifying the etiology of the chest pain represents one of the most challenging tasks in current clinical practice. 14. 20. 21. ,56, 73, 7,0, k2 Patients with angiographically normal or nearnormal coronary arteries have a low risk of cardiac death and a low risk of nonfatal myocardial infarction. 96 Despite the reasonable exclusion of coronary artery disease, these patients continue to have chest pain that compromises their lifestyle and repeatedly visit their physician's office or the emergency room. 64 ,67 Approximately 50% of them remain strongly convinced that they still have heart disease, and the reassurance that the heart is normal is often not enough. During the last decade, we have observed a growing awareness of the potential for certain esophageal abnormalities as etiologic factors in patients with episodes of recurrent substernal chest pain. Motility abnormalities have long been recognized as a possible esophageal cause of chest pain. However, there is considerable controversy regarding the prevalence of esophageal motility abnormalities in these patients. Diffuse esophageal spasm was initially considered as the common prototype of these painful esophageal events. Recent advances in methodology and standardization of stationary manometry, and a more widespread use of this tool, have revealed that the most commonly observed esophageal motility findings exhibit less dramatic contraction abnormalities than those usually described in classic diffuse esophageal spasm. Consequently, many new types of manometry abnormalities have been characterized, although their exact role and relevance remain controversial. The advent of prolonged ambulatory monitoring of intraesophageal pressure has provided additional information in this area and promises to resolve some of these complex questions. Clinically, the chest pain of esophageal origin often mimics classical *Assistant Professor of Medicine, Division of Gastroenterology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada tProfessor of Medicine, and Chief, Division of Gastroenterology and Hepatology, Jefferson Medical College, Philadelphia, Pennsylvania
Medical Clinics of North America-Vo!' 75, No. 5, September 1991
1045
1046
SERGE LANGEVIN AND DONALD
O.
CASTELL
angina pectoris. Unfortunately, there is no pattern of chest pain that is pathognomonic of esophageal motility disorders. The chest discomfort tends to be central and substernal in location, occasionally with neck radiation. It may also radiate into the back, and even into the left arm. The intensity is quite variable, from a dull ache to severe pain. Usually the discomfort occurs spontaneously and is rarely precipitated by swallowing. The relief of pain with nitrate preparations may also contribute to the confusion with angina. The pain event that lasts many minutes to hours or leaves a residual dull discomfort should suggest an esophageal cause. A pain episode unrelated to exertion and associated with dysphagia may also support an esophagealorigin. However, history alone cannot distinguish an esophageal disorder from a cardiac cause. 4, 29, 62
CONVENTIONAL MANOMETRY AND PROVOCATIVE TESTS Baseline Manometry The baseline manometric study may be useful in implicating the esophagus as the probable cause of symptoms. However, patients rarely have their symptoms at the time of stationary manometry. Therefore, abnormalities of motility during routine manometry only provide suggestive evidence of etiology in the absence of typical chest pain. It is important to remember that this test assesses patients under standardized conditions when they are relatively free of exogenous influences. Different types of motility abnormalities have been described in patients with noncardiac chest pain, and their manometric criteria are summarized in Table 1.40, 62, 75,82 Although achalasia and diffuse esophageal spasm are commonly recognized as producing chest pain, the specific mechanisms by which this occurs are unclear. These aspects of the other entities (nutcracker esophagus, nonspecific esophageal disorder, and hypertensive lower esophageal sphincter) are more controversial. Using a more standardized and liberal definition, diffuse esophageal spasm is now recognized as a relatively uncommon finding during manometric testing for possible esophageal chest pain. 32. 76 Achalasia is the best understood and the best characterized of the primary motility disorders. These patients usually present with an insidious and progressive dysphagia for both liquids and solids. Nevertheless, some patients with early achalasia may have angina-like pain, usually associated with frequent, simultaneous, and repetitive contractions (vigorous achalasia).69 By reviewing the records of 910 patients referred to the esophageal function laboratory for evaluation of noncardiac chest pain, Katz et al50 found that only 28% of the patients had abnormal motility during the baseline esophageal manometry. This report describes the retrospective evaluation of the largest group of patients with non cardiac chest pain studied to date. They confirmed that diffuse spasm and achalasia were infrequent, present in only 10% and 2%, respectively, of the patients with abnormal motility (Fig. 1). The nutcracker esophagus was the most common motility abnormality (48%), and nonspecific motility disorders were the
1047
ESOPHAGEAL MOTILITY DISORDERS AND CHEST PAIN
Table 1. Manometric Criteria for Primary Esophageal Motility Disorders MOTILITY DIAGNOSIS
Achalasia
ASSOCIATED FINDI]I;GS
REQUIRED CRITERIA
Aperistalsis of esophageal body
Diffuse esophageal spasm Simultaneous contractions (occurring> 10% of wet swallows) Intermittent normal peristalsis
Nutcracker esophagus Hypertensive LES
Nonspecific motility disorder
Incomplete LES relaxation Elevated LES pressure (>45 mmHg) Elevated intraesophageal pressure Repetitive contractions (2:3 peaks) Prolonged duration of contractions (>6 sec) Spontaneous contractions High amplitude contractions (>180 mm Hg) Incomplete LES relaxation Elevated LES pressure Increased duration (>6 sec)
Normal peristaltic contractions with increased distal amplitude (>180 mm Hg) Elevated LES pressure (>45 mm Hg) Poor relaxation (residual pressure: 5--10 mm Hg) Normal peristalsis Any combination of the following criteria: Increased nontransmitted contractions (> 20%) Prolonged duration contractions (>6 sec) . Triple peak contractions Decreased amplitude of esophageal peristalsis «30 mm Hg) Spontaneous contractions
second largest group (36%). This high prevalence of high-amplitude peristaltic contractions has also been reported in other smaller studies. H , 15,28, 43, 66, 90 Despite its common occurrence, this type of dysmotility is also the most controversial. 30,31,92 It is far from clear that these abnormal contractions produce an aberrant physiologic state causing chest pain. As noted previously, one problem related to the observation that these patients are usually pain-free when this motility pattern is observed. In addition, this type of dysmotility itself does not usually lead to major disruption in esophageal function, as demonstrated by lack of impairment in esophageal transit assessed by barium or scintigraphic studies. 72 CHEST PAIN (255/910 Patients)
Figure 1. Comparison of types of esophageal motility disorders found during manometric testing in 910 patients with chest pain (255 positive = 28%) and in 251 patients with dysphagia (132 positive = 53%). NE MD = nonspecific esophageal motility disorder; i LES = ·hypertensive lower esophageal sphincter; DES = diffuse esophageal spasm.
DYSPHAGIA (132/251 Patients)
El Nutcracker 0 tLES 1Nl NEMO ~ DES Cl Achalasia
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SERGE LANGEVIN AND DONALD
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CASTELL
There is, however, some evidence that the finding of high-amplitude peristalsis may be a marker for other dysmotility occurring during episodes of pain. This evidence comes from three sources. One scintigraphic study has shown that a majority (94%) of these patients will have at least intermittent abnormal esophageal transport of liquids. 12 Isolated reports have documented transition of the nutcracker esophagus to either diffuse spasm 61 or achalasia. 6 Finally, a recent study using prolonged ambulatory intraesophageal pressure recording has shown that a majority of these patients will have an overall motility score similar to that found in patients showing diffuse spasm on stationary manometry. 87 Most therapeutic trials with the calcium antagonist nifedipine have revealed that this medication did not alter the frequency or magnitude of chest pain compared to placebo despite a reduction in the amplitude of peristaltic contractions. 2.77 However, a recent double-blind, crossover study with diltiazem in patients with the nutcracker esophagus did reveal significant improvement in both chest pain and peristaltic contractions compared to placebo. 23 Although the presence of nutcracker esophagus is not an accurate predictor of chest pain elicited by pharmacologic provocative tests, it was significantly better than other manometric abnormalities, including diffuse spasm. 50 These findings underscore the problems present in clarifying the relationship of chest pain and high-amplitude esophageal peristaltic waves. The picture is further complicated by increasing evidence that patients with chest pain and abnormal stationary motility have a high prevalence of psychiatric disorders. With a structured psychiatric interview, psychiatric diagnoses were made in 84% of patients with distal esophageal motility disorders compared with only 31% of those with normal manometric readings. Somatization, anxiety, and depression disorders were the most common psychiatric diagnoses. 25 Unpredictable loud noise and a difficult cognitive task have been shown to produce significant increases in mean distal esophageal contraction amplitude in both healthy subjects and patients with chest pain. 5 . 86 Patients with nutcracker esophagus demonstrated a more significant increase in contraction amplitude than did control subjects. 5 In addition, patients with esophageal contraction abnormalities complain of more gastrointestinal symptoms and are more often diagnosed as having the irritable bowel syndrome. 24 Patients with chest pain syndrome and nutcracker esophagus may have a score on the Millon Behavioral Health Inventory similar to that of patients with irritable bowel syndrome characterized by high levels of anxiety regarding bodily dysfunction, hypochondriacal concerns, and exacerbation of gastrointestinal symptoms under emotional stress. 80 Patients with irritable bowel syndrome have also been shown to present a greater increase in esophageal contraction amplitude than controls during different stresses. 7 From the preceding information, it should be evident that the exact significance of high-amplitude peristalSis and its role in chest pain remains elusive. The nutcracker esophagus may appear merely as a manometric marker of a clinical pain syndrome or other stressful events rather than being directly responsible for chest pain. 5 The use of prolonged ambulatory pressure monitoring should allow a better understanding of this unresolved issue.
ESOPIIACEAL MOTILITY DISORDERS AND CHEST PAIN
1049
The presence of excessively high resting lower esophageal sphincter pressure characterizes the hypertensive lower esophageal sphincter (LES). This condition also has a controversial clinical and pathophysiologic significance. In the study of Friedin et al,39 all of the patients suffered from ~hest pain and 9 of 16 from dysphagia. Their LES residual pressures during swallow-induced relaxation (9.2 ± 5.0 mm Hg) were significantly greater than those observed in normal controls (1.8 ± 2.2 mm Hg). Fifty-six percent also had the manometric parameters of nutcracker esophagus. In a few patients, the liquid barium studies revealed some delay in the bolus transit. Most patients achieved a good to fair symptomatic response in their chest pain from pharmacologic treatment with nifedipine. 33 Waterman et al 94 also reported similar clinical and manometric data in 15 patients with hypertensive LES. The nonspecific esophageal motility disorders (NEMD) represent abnormal patterns of esophageal contraction that are not readily categorized according to the definitions of the other primary motility disorders. A broad spectrum of abnormalities has been described, and their true clinical significance remains to be elucidated. This "catch-all" category represents the second most common group observed with routine manometry in patients with noncardiac chest pain. Provocative Tests (Pharmacologic) In most patients, the chest pain episodes are sporadic and rarely present at the time of diagnostic studies. Various provocative agents have been proposed to improve the sensitivity of the investigation in an approach similar to the "stress test" used by the cardiologists. These provocative agents have been suggested as pharmacologic provokers of esophageal abnormality and chest pain in patients with normal baseline manometry. These various agents include edrophonium, bethanechol, pentagastrin, and ergonovine. None of them is the ideal esophageal provocative test, and they have a relatively low diagnostic yield. The assessment of the esophageal provocative tests has been also greatly hampered by the lack of a gold standard for diagnosing esophageal chest pain. Edrophonium (80 mg/kg intravenously) has been shown to be the most reliable and the safest agent for routine use in the clinical esophageal laboratory. 55•.57, 58, 79 The reported positive response rate varies from 18% to 55% and is highly specific, because normal subjects rarely experience chest pain. No serious side effects have been reported, nor do any patients need atropine to reverse any untoward effects. Edrophonium was shown to have no effect on coronary vessel diameter. 79 A prospective evaluation with different provocative agents showed that edrophonium offered the greatest yield. 13 However, a positive test does not necessarily support a motility disorder as the cause of chest pain. A positive result appears to indicate an esophageal origin for the pain but does not identify the specific pathophysiologic cause of this pain. Using logistic regression analysis, Hewson et al44 found that acid-induced pain events during ambulatory monitoring were significantly associated with a positive edrophonium response, but for spontaneous motility-induced chest pain events, no such relationship could be demonstrated. Other studies have
1050
SEI\GE LA:'\IGEVIN AND DONALD
O.
CASTELL
also confirmed this frequent association between a positive edrophonium test and acid-induced chest pain by 24-hour studies. 2.5. 93 Bethanechol has been reported to reproduce chest pain with an exceptionally high positive response rate. N ostrant et al observed that bethanechol (50 mg/kg subcutaneously) replicated chest pain in 46% of patients after a single injection, and that this increased to 77% after a second injection, 15 minutes later. 6:3 At these higher serial doses, bethanechol may provoke quite intense chest pain and be associated with frequent side effects. This high positive rate suggests that this test could produce sufficient stress to evoke a nonspecific pain response. Deschner et aP4 subsequently reported no significant contribution above that obtained with edrophonium, with a high dose (80 mg/kg subcutaneously) of bethanechol. Pentagastrin is also a poor provocative test, replicating chest pain in less than 10% of patients. 13 The intravenous ergonovine test produces increased esophageal contractions and reproduces chest pain in 22% to 60% of patients with noncardiac chest pain syndrome. 1.36. 53.58 However, it may provoke coronary artery spasm and may cause chest pain in up to 20% of healthy volunteers. It is associated with a high incidence of side effects, particularly cardiac arrhythmias. Other Provocative Tests Howard et al 47 reported a study of 30 patients with chest pain or dysphagia who were asked to swallow bread while standard manometry was performed as a provocative test. No patient experienced symptoms while swallowing water, but one developed symptomatic esophageal spasm while eating; eight other patients had recurrence of their chest pain and dysphagia associated with transient aperistalsis with bread swallowing. In contrast, YlellowS
