Gastrointestinal Motility Disorders, An Issue of Gastroenterology Clinics (The Clinics: Internal Medicine)

Gastroenterol Clin N Am 36 (2007) xiii–xiv GASTROENTEROLOGY CLINICS OF NORTH AMERICA Preface Henry P. Parkman, MD Gu...

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Gastroenterol Clin N Am 36 (2007) xiii–xiv

GASTROENTEROLOGY CLINICS OF NORTH AMERICA

Preface

Henry P. Parkman, MD Guest Editor

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his issue of Gastroenterology Clinics of North America focuses on an important area in gastroenterology for both clinicians and researchers: neurogastroenterology and gastrointestinal (GI) motility disorders. GI motility and functional GI disorders are common reasons for patients to see physicians. Knowledge of GI motility disorders, including the evaluation and treatment of these disorders, is important for gastroenterologists, clinicians, and health care providers to appropriately care for these frequently seen patients in clinical practice. Gastrointestinal motility can be defined as motor activity in the digestive tract that mixes ingested food with digestive juices and moves luminal contents of the gastrointestinal tract in an aboral direction from the mouth toward the anus. A better understanding of the pathophysiology of GI motility disorders has revealed a crucial role of the enteric, autonomic, and central nervous system. In fact, the term neurogastroenterology was introduced in the early 1990s to account for the study of these processes. As with any new term, there was resistance to its introduction. The breakthrough came when the editorial board of the Journal of Gastrointestinal Motility changed its name to Neurogastroenterology and Motility in 1994. The European Society changed its name in 1996; recently, the American Society became the American Neurogastroenterology and Motility Society, and the International Group became the International Society of Neurogastroenterology. Neurogastroenterology emphasizes clinical and experimental gastroenterology embracing the concept of brain–gut interactions and refers to motor disorders of the gastrointestinal tract attributable to neural control mechanisms, including the psychophysiology of clinical disorders of visceral perception and motor function. As defined in the free online encyclopedia Wikipedia, ‘‘neurogastroenterology is a research area in the field of 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.011

ª 2007 Elsevier Inc. All rights reserved. gastro.theclinics.com

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PREFACE

gastroenterology which regards interactions of the central nervous system (brain) and the gut—the so-called brain–gut axis. Important research focuses upon upward (sensory) and downward (motor and regulatory) neural connections and upon endocrine influences on gut function and the enteric nervous system in itself. Clinical research deals on many levels involving GI motility disorders and functional bowel disorders.’’ The articles in this issue discuss key aspects of GI motility disorders, focusing on how they relate to practicing gastroenterologists, clinical investigators, and other health care providers. Current knowledge in the area as well as evolving concepts from clinical investigations and translational research from basic sciences is discussed. The rapid explosion of new technology used in the evaluation of patients is also addressed. Most of the articles in this issue were written by members of the American Neurogastroenterology and Motility Society, formerly known as the American Motility Society. The mission of the American Neurogastroenterology and Motility Society (ANMS) is to advance the study of neurogastroenterology, GI motility, and related enteric sciences; to promote the training of basic scientists and clinician investigators; to translate the scientific advances to patient care; and to disseminate the knowledge to patients and caregivers to improve the diagnosis and treatment of patients with GI motility and functional GI disorders. I hope you enjoy this edition of the Gastroenterology Clinics of North America! It was a pleasure putting it together. Henry P. Parkman, MD Gastroenterology Section Department of Medicine Temple University Hospital 3401 North Broad Street Philadelphia, PA 19104, USA E-mail address: [email protected]

Gastroenterol Clin N Am 36 (2007) 485–498


Overview of NeurogastroenterologyGastrointestinal Motility and Functional GI Disorders: Classification, Prevalence, and Epidemiology Ann Ouyang, MDa, G. Richard Locke III, MDb,* a

Division of Gastroenterology and Hepatology, Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA b Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA

‘‘

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he times they are a-changing.’’ This famous title from a Bob Dylan track and album sums up state of the understanding of functional gastrointestinal disorders and motility disorders. Advancing technology, the increased application of pharmacogenomics, and an expansion of an integrative approach to understanding disease pathophysiology has led to significant changes in how clinicians view the conditions that are encompassed by the term ‘‘neurogastroenterology and motility disorders,’’ which is being increasingly applied to these conditions. Classically, these conditions have been described as functional gastrointestinal disorders (FGIDs) if patients complain of symptoms related to the gastrointestinal tract in the absence of anatomic and biochemical abnormalities [1] or motility disorders when a distinct and measurable alteration of motor function occurs (eg, achalasia, scleroderma, gastroparesis). The overlap between these two groups of conditions has caused significant confusion in both nomenclature and in the literature. The rationale and genesis of the Rome classification resulted from a need to change the focus from a group of conditions serving as a catch-all diagnosis after exclusion of organic conditions to ones with a positive diagnosis [1,2] and has been helpful toward achieving this goal. This classification has been a useful tool for clinical studies to decrease the heterogeneity of subjects recruited and to improve general acceptance that these conditions are clustered in a manner that suggests that there is a common pathophysiology that can be determined with time and appropriate study. The last decade has resulted in tremendous advances in understanding the pathophysiology related to these conditions. It is

*Corresponding author. E-mail address: [email protected] (G.R. Locke III). 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.009


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anticipated that the next decade will move these conditions from being symptom based to pathophysiology based. The term ‘‘neurogastroenterology’’ was introduced to include the processing of information between the viscera and the brain [3]. Research in the ensuing decade has shown overlap between conditions affecting the end organ and the brain-gut axis. The term ‘‘neurogastroenterology and motility disorders’’ encompasses the organ systems that contribute to the symptom constellation that are experienced by patients with these disorders: the central nervous system (CNS), contributing to the sensory and motor control of the gastrointestinal tract; and the gastrointestinal functional unit, which includes the enteric nerves and smooth muscle. Most of the motor and sensory function of the gut occurs subconsciously and cerebral cortical activity is a key to the perception of gastrointestinal activity. The patient’s experience of visceral activity is influenced by psychologic context, which can affect both the severity of the sensation and the degree of unpleasantness of the sensations. This issue highlights some of the advances in the understanding of these conditions and how to translate this knowledge into the diagnosis and management of patients. This article focuses on the classification and epidemiology of these conditions. CLASSIFICATION OF NEUROGASTROENTEROLOGY DISORDERS The Rome III classification of FGID is outlined below [4]. In comparison with the Rome II criteria, the current classification has expanded the pediatric categories and provided more restrictive criteria for functional disorders of the gallbladder and sphincter of Oddi. In addition, functional abdominal pain was separated from functional bowel disorders and placed into its own category as recognition that this was primarily related to disorders of CNS functioning, which results in a perceived sensation of pain in the presence of normal visceral signals. These changes in the classification imply an acceptance that the classification will eventually change to one based on pathophysiology rather than symptom complexes. A. Functional esophageal disorders A1. Functional heartburn A2. Functional chest pain of presumed esophageal origin A3. Functional dysphagia A4. Globus B. Functional gastroduodenal disorders B1. Functional dyspepsia B1a. Postprandial distress syndrome B1b. Epigastric pain syndrome B2. Belching disorders B2a. Aerophagia B2b. Unspecified excessive belching B3. Nausea and vomiting syndromes

OVERVIEW OF NEUROGASTROENTEROLOGY

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B3a. Chronic idiopathic nausea B3b. Functional vomiting B3c. Cyclic vomiting syndrome C. Functional bowel disorders C1. Irritable bowel syndrome C2. Functional bloating C3. Functional constipation C4. Functional diarrhea C5. Unspecified functional bowel disorder D. Functional abdominal pain syndrome E. Functional gallbladder and sphincter of Oddi disorders E1. Functional gallbladder dysfunction E2. Functional biliary sphincter of Oddi disorder E3. Functional pancreatic sphincter of Oddi disorder F. Functional anorectal disorders F1. Functional fecal incontinence F2. Functional anorectal pain F2a. Chronic proctalgia F2a1. Levator ani syndrome F2a2. Unspecified functional anorectal pain F3. Functional defecation disorders F3a. Dyssynergic defecation F3b. Inadequate defecatory propulsion G. Functional disorders: neonates and toddlers G1. Infant regurgitation G2. Infant rumination syndrome G3. Cyclic vomiting syndrome G4. Infant colic G5. Functional diarrhea G6. Infant dyschezia G7. Functional constipation H. Functional disorders: children and adolescents H1. Vomiting and aerophagia H1a. Adolescent rumination syndrome H1b. Cyclic vomiting syndrome H1c. Aerophagia H2. Abdominal pain-related functional gastrointestinal disorders H2a. Functional dyspepsia H2b. Irritable bowel syndrome H2c. Abdominal migraine H2d. Childhood functional abdominal pain H2d1. Childhood functional abdominal pain syndrome H3. Constipation and incontinence H3a. Functional constipation H3b. Nonretentive fecal incontinence

Table 1 provides a classification of the conditions that are considered neurogastroenterology and motility disorders based on the current understanding of the neuroanatomic level at which dysfunction can be recognized. This includes

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Table 1 Neurogastroenterology and motility disorders: classification based on brain-gut axis model Location

Evidence for GI dysmotility

Both motor and sensory dysfunction

Primarily sensory

Primarily CNS processing

Esophagus

Achalasia

Diffuse esophageal spasm Nutcracker esophagus Hypertensive LES

Functional heartburn Functional dysphagia

Globus

Scleroderma Hypotensive LES-GERD Stomach

Gastroparesis Tachygastria Scleroderma

Biliary tract

Intestine and colon

Gallbladder dysmotility Sphincter of Oddi dysfunction Chronic idiopathic intestinal pseudoobstruction Colonic inertia Scleroderma

Anorectal

Hirschsprung’s disease Pelvic floor dyssynergia

GERD-normal LES Dumping syndrome Cyclic vomiting syndrome Rumination syndrome Belching disorders

Irritable bowel syndrome

Bacterial overgrowth Functional diarrhea Functional constipation Functional constipation Functional anorectal pain Functional defecation disorders

Functional dyspepsia Functional nausea

Functional bloating

Functional abdominal pain

Functional proctalgia

Abbreviations: CNS, central nervous system; GERD, gastroesophageal reflux disease; GI, gastrointestinal; LES, lower esophageal sphincter.

the end organ (at the gut level, which includes the enteric nerves, interstitial cells of Cajal, and smooth muscle); sensory dysfunction alone (including the afferent pathway from the gut and CNS processing); and disorders in which there is a combined sensory and motor dysfunction. This classification is possible because of the development of technologies to assess these pathways separately. Examples of these technologies include the electrogastrogram, which allows an assessment of motor activity in the stomach; advances in interpretation of videofluoroscopy and measurements of motor activity [5]; the barostat,


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which allows a measurement of the sensory pathway [6] particularly if used in conjunction with pharmacologic blockade of motor activity; and a variety of CNS imaging modalities including positron emission tomography scans and functional MRI [7]. In the future, the next level of classification will be based on the underlying pathophysiology, which might include a combination of factors including prior inflammatory conditions with peripheral sensitization of the visceral pain pathway. Such a classification will necessarily depend on the ability to detect such alterations in the immune and cytokine pathways and assessment of the neurotransmitter function in the brain and gut [8–11]. One Disease or Many Although a classification system based on physiology is the goal for the future, the Rome criteria are the accepted classification scheme of the present for FGID. Still, the question remains as to whether 27 separate adult and 13 separate pediatric disorders exist. Some of these disorders are symptom complexes, whereas others are single symptoms. One might argue whether or not a single symptom should qualify as a unique disorder. The hope was that homogeneity would lead to better studies of pathogenesis and therapy. These disorders occur within the human body, however, and many similarities exist from esophagus to stomach to small and large intestine. Patients often present with multiple symptoms from different regions of the body. Disorders of sensorimotor function might affect multiple sites along the gastrointestinal tract. For example, half of people with irritable bowel syndrome (IBS) also have symptoms of reflux [12]. Symptoms may change over time and a patient may have IBS symptoms one year and then dyspepsia symptoms the next year [13]. One approach is to split these into separate conditions and manage them separately. An alternative, however, is to think of the patient as having one ‘‘pan-gut’’ or systemic disorder and manage the patient accordingly. In the future, much will be learned about the prevalence and epidemiology of these pathophysiologic abnormalities. This will shed light on the appropriate classification scheme. At present clinicians must continue to rely on symptoms to define many of the neurogastroenterology and motility disorders. These symptom-based diagnoses have been used extensively over the past 20 years to understand the epidemiology of these conditions. EPIDEMIOLOGY Neurogastroenterology and motility disorders include the currently accepted FGIDs and other primarily motor disorders, such as achalasia. FGIDs are extremely common conditions [14,15]. Studies have shown that many people with FGIDs do not seek care. The decision to seek care introduces bias in clinic-based research [16]. For this reason, population-based research has been used to evaluate fully the epidemiology and clinical symptoms in individuals with FGIDs. Many gender- and age-related issues arise related to the

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FGIDs. Extensive epidemiologic data exist for IBS, dyspepsia, heartburn, constipation, and fecal incontinence, but less is known about the other neurogastroenterology conditions. For many FGIDs, such as globus, rumination, and sphincter of Oddi dysfunction, the only data on prevalence by age come from a single study [14]. Similarly, other motility disorders, such as achalasia and gastroparesis, which are defined by physiologic or anatomic criteria, do not lend themselves to epidemiologic studies except in small, very well characterized populations [17,18]. To date, the epidemiologic studies have been conducted primarily in western populations; data from other areas of the world are limited but growing [19]. Esophageal Disorders The functional esophageal disorders include globus, rumination syndrome, functional chest pain, functional heartburn, and functional dysphagia. Studies have shown that these functional esophageal disorders are all quite common [14,20]. Globus sensation is reported by 7% to 12.5% of the population [14,20] and is more common in women. Rumination syndrome is reported by 10.9% of the population [14]. No difference in gender has been reported. The prevalence estimates of functional chest pain have varied between 12.5% and 23.1% [14,20,21]. These population-based estimates have relied on the person’s self-report of not having cardiac disease. Still, noncardiac chest pain and functional chest pain of esophageal origin are not synonymous. People with noncardiac chest pain can have many underlying causes [22]. In the community, noncardiac chest pain has an equal gender prevalence [14,20,21], but a higher female-to-male ratio in tertiary care referral centers [23]. The prevalence of most of these disorders decreases with age. Specifically, globus, rumination syndrome, and self-reported functional chest pain are all more common in younger people [14,20,21]. Many of the symptoms of functional esophageal disorders are experienced by people with gastroesophageal reflux disease [20]. Estimating the true prevalence of functional heartburn in the community is quite difficult. In population-based studies, pH monitoring is not a real option because invasive studies greatly reduce response rates [24]. The data are on symptoms rather than a diagnosis. The prevalence of heartburn does not vary by gender and is similar among people ages 25 to 74 [20]. Dysphagia is reported by 7% to 13% of the population [14,20]. Whether dysphagia is associated with gender is not clear. One study found that a difference of 6.3% in men and 8.5% in women was statistically significant [14], whereas in another study, the difference between 12.4% of men and 14.6% of women was not statistically significant [18]. A gender effect may exist but it is small. The prevalence of dysphagia increases with age, most notably in participants in the 65- to 74-year category [18]. The proportion of these people who have functional dysphagia versus another esophageal disorder (eg, esophageal obstruction or a motility disorder) is not known. Many conditions that affect motor function of the oropharynx and esophagus, such as stroke and Parkinson’s disease, are more prevalent in the elderly [25].


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Esophageal motility disorders, which primarily involve the end organ (eg, achalasia), are defined by the abnormal motility pattern of aperistalsis and impaired lower esophageal relaxation. Clearly, a population-based study that involves an invasive diagnostic test is not feasible. Studies of the prevalence of achalasia have often relied on hospital admissions and are retrospective. Studies from Iceland and Great Britain indicate an incidence of about 0.55 cases per 100,000 population per year [17,18]. Gastroduodenal Disorders Dyspepsia is not a condition; it is a symptom complex. Dyspepsia can be defined as persistent or recurrent abdominal pain or abdominal discomfort centered in the upper abdomen [26]. The term ‘‘discomfort’’ includes symptoms of nausea, vomiting, early satiety, postprandial fullness, and upper abdominal bloating. Symptoms are typically associated with eating but not with bowel movements. In early studies, the symptoms of heartburn and acid regurgitation were often included as symptoms of dyspepsia. Yet, if these symptoms are the main symptoms, the patient should be considered to have reflux rather than dyspepsia. Right upper quadrant pain or epigastric pain radiating to the back should not be included in the dyspepsia definition. Functional dyspepsia can then be defined as dyspepsia symptoms of more than 3 months’ duration without an anatomic or biochemical abnormality [26]. Typically, this means negative blood tests and a negative evaluation of the upper gastrointestinal tract with either an endoscopy or barium radiograph. Defining a negative endoscopy, however, can be difficult. Does this include biopsies of the esophagus for esophagitis or biopsies of the stomach for gastritis or Helicobacter pylori? Are erythema, erosions, or histologic inflammation meaningful findings? These are somewhat controversial issues. What about other tests like ultrasounds, CT scans, gastric emptying studies, or ambulatory pH monitoring? Do these have to be done before making a diagnosis of functional dyspepsia? These are issues that still need to be resolved. Many surveys have evaluated how many people experience symptoms of dyspepsia in the community. The rates vary in large part because of the definitions used. The surveys that include the symptom of heartburn in the definition of dyspepsia report a prevalence of 40% [27]. Other surveys exclude subjects with symptoms of heartburn or IBS and report prevalence rates below 5% [14]. Nonetheless, it is reasonable to say that 15% (about one in seven) of the adult population has dyspepsia [28]. Not all these people with dyspepsia have functional dyspepsia. In one study, a random sample of the population with dyspepsia underwent endoscopy [29]. Only 53% had a normal endoscopy. The abnormal findings were esophagitis, peptic ulcer disease, duodenitis, and duodenogastric reflux. Only 66% of the asymptomatic controls in this study, however, had normal endoscopy. Peptic ulcer disease and duodenitis were more common in the dyspepsia cases than the controls, but the other findings, such as gastritis, were seen in similar numbers of cases and asymptomatic controls.

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The prevalence of dyspepsia does not vary by gender [14,30]. Distinct subgroups of dyspepsia have been defined: ulcer-like dyspepsia, dysmotility-like dyspepsia, and unspecified dyspepsia [26]. The prevalence of the ulcer-like and dysmotility-like dyspepsia subgroups also do not vary by gender. Some studies have suggested that the prevalence of dyspepsia decreases with age [31–33]. The distribution of subtypes (ulcer-like and dysmotility-like), however, does not vary by age. The prevalence of aerophagia has been estimated to be 23.4% to 29% [14,34]. Men are slightly more likely to report aerophagia than women. Young people are slightly more likely to report aerophagia than older people. The overall prevalence of functional vomiting is 2.3%, but there is no association with gender. In general, more men than women reported vomiting, but this is not a statistically significant difference [30,31]. Vomiting decreases with age. The prevalence of gastroparesis, as defined by delayed gastric emptying, is unclear. Although delayed gastric emptying has been recognized as a consequence of systemic conditions, such as diabetes mellitus and systemic sclerosis, it is also reported in functional dyspepsia and gastroesophageal reflux [35]. The true prevalence is unknown because, in its strictest sense, the diagnosis depends on a study that, although relatively noninvasive, is not applicable to a large population. The issues related to gastroparesis are discussed elsewhere in this issue. Bowel Disorders Affecting Small Intestine and Colon IBS is the best studied of all the FGIDs and can be defined as a constellation of recurrent or chronic abdominal pain that is associated with defecation and a chronically altered bowel habit [2]. How common is IBS? The answer depends greatly on the definition used. In an early study, a representative random sample of the United States population was asked if they had active symptoms of spastic colon or mucous colitis. The prevalence varied by age and gender but overall was roughly 20 per thousand [36]. This study, however, required that the patient needed to know if they in fact had one of these diagnoses. Because not everyone with IBS goes to the doctor and receives a diagnosis, an alternative strategy to determining prevalence was required. Many population-based surveys have assessed the individual symptoms of IBS. The survey responses are then used to make a diagnosis of IBS. The prevalence rates in these studies have varied between 8 and 22 per hundred [14,15,37–39]. Note the 10-fold difference in prevalence rates between asking about a diagnosis and asking about the symptoms of IBS. Why do the prevalence rates from the IBS-specific symptom surveys vary threefold? Although this may represent true differences in populations, it more likely reflects differences in the IBS definition. Higher prevalence rates are identified using a threshold of two of six Manning criteria [40]. Lower prevalence rates are identified using more specific criteria, whether by increasing the threshold of Manning criteria necessary to make the diagnosis or using the Rome criteria. In a direct comparison, prevalence using standard


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Rome criteria is comparable with using a threshold of three of six Manning criteria [40]. In clinic-based studies, IBS is strongly associated with gender. Of interest, however, the female to male ratio in the community is approximately 2:1. Gender may have a role in the onset of IBS but also has a role in health care seeking behavior [16]. Gender may also play a role in symptom severity. In a study of patients having general examinations in a health maintenance organization, overall 68% of those with IBS symptoms were female. In those with mild symptoms (M ¼M ¼M ¼M >M

# # # ¼ "

F¼M M >F ¼ F

# # # "

F F M >F Discordant studies F >M F >M (at home) M >F (nursing homes) F >M F

# " # Discordant studies # " # ¼

Of note, some of the data in this table are based on single studies or multiple small-scale studies and should be interpreted with caution. Abbreviations: CFAP, chronic functional abdominal pain; FGID, functional gastrointestinal disorder; GI, gastrointestinal; IBS, irritable bowel syndrome.

studies have been conducted in Western populations with IBS, constipation, heartburn, and dyspepsia but not the other FGID. Some FGID increase with age, whereas others decrease. The challenge is that these studies do not include diagnostic tests and they measure symptom reporting rather than being true estimates of the prevalence of the FGIDs. Exclusions are often done based on self-report but this is not entirely accurate. Any shift in classification to a pathophysiologic basis requires different approaches to determine the prevalence. Most of the studies have been of middle-aged populations. More recently studies have been more focused on patients at the two extremes of age, children and the elderly. The presence of FGIDs in children is well recognized [62]. Only recently, however, have studies begun to examine the relationship between gastrointestinal symptoms in children and adults. The exact age of onset of FGIDs remains to be determined. The classification of FGID and motility disorders is in a state of transition. Over time, the emphasis will likely shift from symptoms to pathophysiology. Nonetheless, the epidemiology of these conditions is based on symptom surveys. This article reviewed the epidemiology of these common disorders from the esophagus to the anorectum.

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[47] Sandler RS, Stewart WF, Liberman JN, et al. Abdominal pain, bloating, and diarrhea in the United States: prevalence and impact. Dig Dis Sci 2000;45:1166–71. [48] Talley NJ. Diagnosing an irritable bowel: does sex matter? Gastroenterology 1991;100: 834–7. [49] Everhart JE, Go VL, Johannes RS, et al. A longitudinal survey of self-reported bowel habits in the United States. Dig Dis Sci 1989;34:1153–62. [50] Stewart WF, Liberman JN, Sandler RS, et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol 1999;94:3530–40. [51] Pare P, Ferrazzi S, Thompson WG, et al. An epidemiological survey of constipation in Canada: definitions, rates, demographics, and predictors of health care seeking. Am J Gastroenterol 2001;96:3130–7. [52] Chen GD, Hu SW, Chen YC, et al. Prevalence and correlations of anal incontinence and constipation in Taiwanese women. Neurourol Urodyn 2003;22:664–9. [53] Wong ML, Wee S, Pin CH, et al. Sociodemographic and lifestyle factors associated with constipation in an elderly Asian community. Am J Gastroenterol 1999;94:1283–91. [54] Wei X, Chen M, Wang J. [The epidemiology of irritable bowel syndrome and functional constipation of Guangzhou residents]. Zhonghua Nei Ke Za Zhi 2001;40:517–20 [in Chinese]. [55] Talley NJ, Weaver AL, Zinsmeister AR, et al. Self-reported diarrhea: what does it mean? Am J Gastroenterol 1994;89(8):1160–4. [56] Lynch AC, Dobbs BR, Keating J, et al. The prevalence of faecal incontinence and constipation in a general New Zealand population; a postal survey. N Z Med J 2001;114:474–7. [57] Rizk DE, Hassan MY, Shaheen H, et al. The prevalence and determinants of health careseeking behavior for fecal incontinence in multiparous United Arab Emirates females. Dis Colon Rectum 2001;44:1850–6. [58] Nelson R, Furner S, Jesudason V. Fecal incontinence in Wisconsin nursing homes: prevalence and associations. Dis Colon Rectum 1998;41:1226–9. [59] Edwards NI, Jones D. The prevalence of faecal incontinence in older people living at home. Age Ageing 2001;30:503–7. [60] Walter S, Hallbook O, Gotthard R, et al. A population-based study on bowel habits in a Swedish community: prevalence of faecal incontinence and constipation. Scand J Gastroenterol 2002;37:911–6. [61] Talley NJ, Weaver AL, Zinsmeister AR, et al. Functional constipation and outlet delay: a population-based study. Gastroenterology 1993;105:781–90. [62] Hyman PE,, Milla PJ, Benninga MA, et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 2006;130(5):1519–26.



Evolving Concepts in the Cellular Control of Gastrointestinal Motility: Neurogastroenterology and Enteric Sciences Amelia Mazzone, PhDa,b, Gianrico Farrugia, MDa,b,* a

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA b Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA

T

he function of the gastrointestinal tract is controlled by a dynamic interaction between different cell types that interact directly, or through a large number of signaling molecules. Enteric neural integrity is essential for normal gastrointestinal motility, as is a constant communication between the enteric and the central nervous system (CNS). Smooth muscle cells form an electrical syncytium within the gut and are innervated, directly or indirectly, by neurons. Not only are smooth muscle cells the final effector cells that result in gastrointestinal motility, but recently they have been found also to have an active role in the control of motility. The basic electrical rhythm of the gut, the slow waves, originates from a complex network of cells known as ‘‘interstitial cells of Cajal’’ (ICC). ICC not only generates the slow wave but is also involved in effective neurotransmission and in the control of smooth muscle membrane potential. Other cellular elements, such as the immune system and enteric glia, are now increasingly understood actively to be involved in the modulation of intestinal functions. The study of the complex interaction of different kind of cells is known as ‘‘neurogastroenterology,’’ a subspecialty of gastroenterology that focuses on understanding the control of the sensory and motor function of the gastrointestinal tract in health and disease. ENTERIC NERVOUS SYSTEM The enteric nervous system (ENS) regulates most of the physiologic and pathophysiologic processes in the gastrointestinal tract. These include control of This work was supported by grants DK17238, 57061, and 68055 from the National Institutes of Health.

*Corresponding author. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. E-mail address: farrugia. [email protected] (G. Farrugia). 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.003


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motor functions for the transport of luminal content, regulation of blood flow and of secretion and absorption, and modulation of the immune response against pathogens. The ENS consists of a network of enteric neurons organized in ganglia interconnected by nerve fiber bundles surrounded by support cells. These neural circuits are able to exchange and integrate information in a way similar to the CNS, including generation of reflexes; the ENS often is referred to as the ‘‘little brain.’’ The ENS is made up of two major components. The submucosal plexus is located between the inner layer of the circular muscle and the submucosa and is more developed in the small and large intestine. Its role is mainly in the regulation of mucosal and vascular functions in responses to nutrients. In large mammals, submucosal ganglia form two distinct, but interconnected, plexuses that are defined as inner and outer submucosal plexus [1]. The myenteric plexus lies between the inner circular and outer longitudinal smooth muscle layers along the entire gastrointestinal tract and it is mainly involved in the coordination of the activity of the muscle layers. In the small intestine a deep muscular plexus is also present, made up of nerve bundles (without cell bodies). The deep muscular plexus lies between the most inner circular smooth muscle cells and the rest of the circular muscle layer. Work on identification and classification of enteric neurons has been performed mostly in the guinea pig small intestine [2], but the overall organization and function of neurons is applicable to larger mammals, including humans. Based on morphology, electrophysiologic properties, function, and neurochemistry, enteric neurons can be classified in intrinsic primary afferent neurons (IPANs), interneurons, motor neurons, and intestinofugal neurons (Fig. 1). IPANs respond to mechanical and chemical stimuli and regulate the physiologic function of the gastrointestinal tract by transmitting information to other neurons. IPANs initiate intestinal reflexes. The somewhat laborious name given to these neurons rather than the more commonly used term ‘‘sensory neurons’’ is because of the fact that IPANS do not usually convey sensation from the intestine, as demonstrated by Kirchgessner and colleagues [3]. There are no nerve endings that directly reach the lumen of the gut; sensation occurs through enterochromaffin cells, located in the enteric epithelium, which work as sensory transducers [4]. IPANS are found in both plexi [5] and are cholinergic neurons [6]. Motor neurons are either excitatory or inhibitory and innervate the muscle layers of the digestive tract and blood vessels and glands. The cell bodies of motor neurons that supply the muscle layers are located in the myenteric ganglia, but there is evidence that there are a few cell bodies that innervate the muscle layers in submucosal ganglia [7]. The primary transmitters of the excitatory motor neurons are acetylcholine and tachykinins, such as substance P and neurokinin A. Inhibitory neurons use a larger spectrum of transmitters including nitric oxide, vasoactive intestinal polypeptide, c-aminobutyric acid, ATP, carbon monoxide, and pituitary adenyl cyclase–activating polypeptide [8]. Regulation of secretion of water and electrolytes and of blood flow in

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Fig. 1. Types of neurons in the enteric nervous system. 1. interneuron; 2. excitatory longitudinal muscle motor neuron; 3. myenteric intrinsic primary afferent neuron; 4. inhibitory longitudinal muscle motor neuron; 5. intestinofugal neuron; 6. myenteric plexus interstitial cell of Cajal; 7. excitatory circular muscle motor neuron; 8. inhibitory circular muscle motor neuron; 9. circular muscle interstitial cell of Cajal; 10. cholinergic secretomotor (nonvasodilator) neuron; 11. cholinergic secretomotor neuron; 12. noncholinergic vasomotor neuron; 13. submucosal intrinsic primary afferent neuron; 14. mucosal cell; 15. enterochromaffin cell. PVG, prevertebral ganglia. (Adapted from Furness JB. The enteric nervous system. Blackwell Publishing: Oxford, UK; 2006; p. 30; with permission.)

the gut occurs by secretomotor and vasomotor neurons, respectively. The cell bodies of these neurons reside in the submucosal plexus [9]. Interneurons are defined as ascending or descending based on whether their processes run orally or anally. They integrate information from IPANs and, in general, relay the information to enteric motor neurons. At least one type of ascending and three types of descending interneurons have been described in the small intestine of guinea pig [10]. Ascending interneurons are mainly cholinergic, whereas descending motor neurons have a varied and complex neurochemistry [11]. Ascending interneurons and the three types of the descending ones participate in local motility reflexes. A fourth type of descending interneuron conducts the migrating myenteric complexes (MMC). Ascending interneurons project to other myenteric neurons, whereas descending interneurons also innervate the submucosal plexus. A fourth class of enteric neurons, intestinofugal afferent neurons (IFANs), have their cell bodies within the myenteric plexus but send their processes out of the gut wall to form synapses with the inferior and superior mesenteric ganglia and the celiac ganglion (collectively known as ‘‘prevertebral ganglia’’) [12]. IFANs carry efferent signals from the gut and they work as mechanoreceptors that detect changes in gut volume [12]. Primary IFANs transmit directly to the prevertebral ganglia without synaptic interruption, whereas another

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population of intestinofugal neurons receives information arising from other enteric neurons [13]. MOTOR PATTERNS Coordinated activation of enteric neuronal circuits is responsible for the rhythmic and regular contraction of the gastrointestinal muscle and the aboral transport of the luminal content. Control of gastrointestinal motor function requires the coordinated function of several cell types. Four fundamental patterns of motility are present in the small intestine: (1) peristalsis, (2) segmentation, (3) the migratory motor complex, and (4) the postprandial motor pattern. Peristalsis consists of contraction waves that propagate along the gastrointestinal tract that mix and propel content distally. Peristalsis is initiated by mechanical and chemical stimuli triggered by the presence of a bolus in the gut lumen. These stimuli activate IPANs, which then activate ascending and descending interneurons, which activate excitatory and inhibitory motor neurons. Activation of excitatory motor neurons above the bolus results in contraction of smooth muscle above the bolus. Activation of inhibitory motor neurons results in relaxation of smooth muscle below the bolus. Shortening of the muscle immediately below the bolus also occurs as a result of descending excitation [14]. The rhythmicity of peristalsis is determined by the electrical activity of the ICC. Peristalsis is not affected by vagotomy or sympathetectomy, indicating it is mediated exclusively by the ENS. The ENS also initiates clusters of contractions that are nonpropulsive. These segmental contractions have the purpose of mixing chyme with digestive juices exposing it to the mucosa for absorption [15]. The MMC is a specific pattern of motor activity identified in the stomach and small intestine smooth muscle during fasting in most mammalian species, including human. The MMC clears the stomach and intestine of residual food and mucosal debris and prevents microorganism overgrowth [16]. The MMC is a periodic activity with a cycle time of about 1.5 to 2 hours in humans; it can be divided into four phases. Phase I is a quiescent phase of about 45 to 60 minutes during which there are only rare action potentials and contractions that progressively increase in frequency, followed by an irregular phase II of 30 minutes characterized by random activity. In phase III, also called the activity front, each slow wave is associated with spike potentials and resulting contractions, which consist of bands of quickly moving, evenly spaced contractions. This phase lasts for about 5 to 15 minutes. In contrast to the digestive period, the pylorus remains open during these peristaltic contractions, allowing many indigestible materials to pass into the small intestine. Phase IV is a brief cycle of irregular activity in between phase III and phase I. Extrinsic stimuli can modulate the MMC but are not required for its initiation or propagation. The progression of the activity front is a result of sequential activation of a specialized class of descending interneurons. Following the ingestion of a meal, the MMC is replaced by an irregular activity, similar to phase II, which in humans lasts for 1 to 2 hours.


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Colon motility is irregular and complex and the neuronal control of colonic patterns of motility is not yet well delineated. There are several distinct colonic motor patterns. The baseline pattern is one of seemingly chaotic, irregular contractile activity. Another pattern consists of high-amplitude propagated contractions. These often, but not always, propagate colonic content over long segments of the colon and can be associated with the urge to defecate [17]. The occurrence of these contractions is not regulated by slow waves and their duration in dogs is approximately 18 to 20 seconds [18]. Electrical activity that underlies motor activity in the colon is also not as well delineated as in the stomach and small bowel. Electrical activity recorded from the colonic myenteric plexus region is not in the form of electrical slow waves as in the small intestine and stomach but is in the form of frequent oscillations in membrane potential that originate near the myenteric border or within longitudinal muscle, and conduct through most of the circular muscle [18], defined as myenteric potential oscillations. Electrical slow waves do originate from submucosal plexus ICC but their role in regulating smooth muscle contractile activity is not yet established. EXTRINSIC CONTROL OF ENTERIC NERVOUS SYSTEM There is a close functional relationship between the ENS and the CNS in the control of gut function. Extrinsic afferent and efferent pathways transfer stimuli to and from the gut, respectively, providing a constant exchange of information between CNS and ENS. Afferent neurons signal information to the CNS about the chemical content of the gut lumen; about the mechanical status (tension or relaxation) of the gut wall; and about the condition of tissues (inflammation, pH, heat, cold). Efferent neurons transmit information from the CNS to the ENS. CNS neurons do not directly innervate smooth muscle cells. Both afferent and efferent nerves follow two major pathways (spinal and vagal) (see [19] for a review). Extrinsic Efferents The primary transmitter of sympathetic postganglionic neurons that supply the gastrointestinal tract is norepinephrine. Efferent neurons innervating the gut originate from prevertebral or paravertebral ganglia. Most cell bodies of sympathetic postganglionic neurons, located in paravertebral ganglia, control gastrointestinal blood vessels. Three other classes of neurons, whose cell bodies reside in the prevertebral ganglia, control motility and secretion. Several important roles of the upper gastrointestinal tract, such as gastric fundic relaxation and gastric and pancreatic secretion, are mediated through vagal neurons whose cell bodies lie within the brainstem. In contrast to the upper gut, the distal colon and rectum are innervated by pelvic nerves, not the vagus. In general, vagal stimulation causes inhibition of gastrointestinal secretion and motor activity, and contraction of gastrointestinal sphincters and blood vessels. Conversely, spinal stimuli typically stimulate these digestive activities.

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Extrinsic Primary Afferents Afferent innervation conveys sensory information from the gut to the CNS activating spinal and vagal-pelvic reflexes. Extrinsic primary afferent neurons (EPANs) are classified in vagal and spinal based on the physical location of their cell bodies. Vagal primary afferent neurons have cell bodies in the nodose and jugular ganglia and project centrally to the brainstem, whereas the cell bodies of the spinal EPANs are located in the dorsal root ganglia. Vagal afferent pathways carry information about the physiologic state of the digestive organs (eg, satiety and nausea) and regulate inflammatory responses, whereas spinal afferents primarily mediate pain impulses [20]. Similar to vagal efferents, vagal afferents are concentrated mainly in the upper gastrointestinal tract, whereas pelvic afferents innervate mostly the lower bowel; spinal afferents are distributed throughout the gut by splanchnic nerves [21]. SENSATION OF THE GUT Humans are usually not aware of the ongoing functions of the gastrointestinal tract, such as contractile activity, digestion, and absorption. In health, physiologic stimuli from the gut induce motor reflexes, but these remain largely unperceived, with the exception of those related to ingestion and excretion. Although these processes generally do not reach a level of sensation unless they go awry, they are closely monitored by specialized neurons in both the enteric and extrinsic nervous systems of the gastrointestinal tract. Food intake, contractile activity, and metabolic products of the enteric flora regulate digestive motility through the brain-gut axis mediated by extrinsic nerves, intrinsic neurons, and gastrointestinal hormones. These processes are also influenced by the environment and emotions. Disturbed digestive motility often contributes to the generation of gastrointestinal symptoms in various diseases. Two types of primary afferent neurons are involved in the detection of changes in the gastrointestinal environment: IPANs (whose cell bodies and processes never leave the gut) and vagal and spinal EPANs (whose cell bodies reside outside the gut). A third cell type, IFANs (whose cell body is within the gut but whose processes leave the gut), also participates in detecting gut stimuli. No nerve cell processes reach the enteric lumen. Sensation must be accomplished transepithelially by means of specialized cells, enteroendocrine cells. The best characterized of these sensory transducers are enterochromaffin cells that have been demonstrated to respond not only to mechanical pressure [22] but also to nutrients (eg, glucose or fatty acids) present in the intestinal lumen, by releasing chemical mediators into the wall of the gut and initiating responses [23,24]. Mechanosensation Mechanosensitivity, in particular that mediated by spinal afferents, can be transduced by a wide range of chemical mediators released following detection of mechanical stimuli inside the lumen of the gut. Paracrine mediators of distention include serotonin, cholecystokinin, gastrin, somatostatin, and peptide YY. Release of peptides activates intrinsic and extrinsic afferent neurons


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present in the submucosal plexus. The intrinsic afferents provide the basis for local reflexes that control and coordinate gastrointestinal function. Stretchsensitive IPANs also respond to tension in the muscle and to direct distortion of their processes [25] and communicate the information by the discharge of action potentials, through gating of mechanosensitive ion channels that are expressed in neurons [26]. Mechanical stimuli are also detected by EPANs and transferred to the CNS, to be processed and to evoke a reaction, through the combined action of vagal and spinal pathways. Vagal mechanosensitive EPANs are activated by low-intensity mechanical stimuli and can be classified based on localization of the terminal ending receiving the stimulus. Mucosal stroking, but not distention, stimulates one class of EPANs whose terminals innervate the gut mucosa. A second class responds to food intake by reacting to gut wall tension within the physiologic range (2 cm at inspiration. This is the HRM signature of hiatus hernia. Two subtypes were discernible, IIIa and IIIb, with the distinction being that the respiratory inversion point was proximal to the CD with IIIa (C) and proximal to the LES in IIIb (D). Minimal pressure increase reflecting CD contraction is observed during inspiration in type IIIb. (From Pandolfino JE, Kim H, Ghosh SK, et al. High-resolution manometry of the EGJ: an analysis of crural diaphragm function in GERD. Am J Gastroenterol, 2007;102(5):1056-63; with permission.)

of the EGJ and quantify the amount of time that the pressure across the EGJ was flow permissible. Although the paradigms described in these studies were the result of an iterative process of programming and then testing potential analytic algorithms unique to their institution, analogous measures can be made with the current commercially available Manoview software (Sierra Scientific). For instance, the isobaric contour tool on the Manoview analysis software can be set at various pressure values and the time at each pressure

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Fig. 7. An isobaric contour and a spatial pressure variation plot representation of a typical normal swallow. (A) Isobaric contour representation of the swallow. The upper esophageal sphincter (UES) briefly relaxes (at 0 seconds) to let the bolus through into the esophagus, which is then propelled in the antegrade direction by the peristaltic contraction wave. The proximal esophagus, the distal esophagus, and the transition zone that separated the striated from the smooth muscle esophagus are shown. (B) A series of spatial pressure variation plots of the swallow at 0.4-second intervals. The darkened plots show pressure scaling at 1.6 seconds. This provides a convenient method to visualize intraluminal pressure gradients responsible for esophageal emptying or retrograde escape. These plots allow a simultaneous illustration of peristaltic contraction, intrabolus pressure, and EGJ resistance pressure, and the pressure gradients for flow can be assessed. (Courtesy of S. Ghosh, MD and P. Kahrilas, MD, Chicago, IL.)

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Fig. 8. High-frequency, intraluminal ultrasonographic images of the LES and esophageal body in normal subjects; patients with high-amplitude esophageal contractions (nutcracker esophagus); diffuse esophageal spasm; and achalasia. Increased muscular thickness is appreciated in each of the spastic esophageal motility disorders. DES, diffuse esophageal spasm; HAEC, high-amplitude esophageal contractions.

can be calculated manually to provide a plot of the time in which the pressure is below the set relaxation pressure. The nadir pressure is easily determined for the entire deglutitive time period and the total time for a specific residual pressure can be calculated. Although this analysis can provide detailed information regarding EGJ relaxation and resistance through the EGJ, it is unclear whether these new measurements improve on existing technique. HRM does provide an opportunity, however, to explore the true physiologic pressure relationship underlying bolus transport by simultaneously measuring the relationship between intrabolus pressure and EGJ resistance. The authors have developed various paradigms to quantify this relationship and recently validated these techniques against fluoroscopy for predicting the time period were bolus transit is likely to occur [36]. Once again, it is unclear whether these techniques improve clinical management of patients with dysphagia and vigorous validation using objective end points is required. INTRALUMINAL ESOPHAGEAL ULTRASOUND Technical Aspects Although manometry is the primary tool available for the study of gastrointestinal motility disorders, conventional manometry only measures contractions of the circular muscle layer and ignores the activity of the longitudinal muscle and muscularis mucosa. In vitro studies using longitudinal muscle strips obtained from animals have demonstrated significant differences in the motor responses of the longitudinal muscle and circular muscle layers to enteric neurotransmitters. Additional physiologic studies in animals have used the relative

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Fig. 9. (A) Sustained esophageal contraction lasting for 2 minutes and associated with chest pain in the absence of either a corresponding significant perturbation on esophageal manometry or significant drop in esophageal pH. (B, C) Two phasic esophageal pressure waves are seen of normal amplitude [53].

movement of metal markers attached to the esophagus or strain gauges oriented along the longitudinal axis of the esophagus [37,38]. Human studies have used metal clips attached to esophageal mucosa with longitudinal contractions indirectly measured by relative clip movement under fluoroscopy and shown attenuated esophageal shortening in patients with hiatal hernias providing a possible mechanism for impaired bolus clearance [39,40]. Miller and Liu were the first to apply high-frequency, intraluminal ultrasonographic (HFIUS) probes to study esophageal motility [41,42]. The technology and images are similar to those obtained during endoscopic ultrasonography. Higher frequencies (20–30 MHz), however, are used to obtain detailed visualization of the muscularis layers and the probe size allows for transnasal


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intubation in unsedated patients and combination catheter assemblies that incorporate manometric sensors, impedance electrodes, and pH detection. An increase in thickness of the muscularis propria serves as a marker for longitudinal muscle contraction. Currently, the technique has been studied in two centers for investigative purposes. The analysis of images is very labor intensive and significant artifacts are created by the orientation of the HFIUS probe and the esophageal wall and even minute volumes of swallowed or refluxed air. Role in Studying Esophageal Function Early studies of longitudinal muscle function using fluoroscopic displacement of radiopaque markers on the esophagus and strain gauges in animal models concluded that the longitudinal muscle of the esophagus contracts before the circular muscle [37,40,43]. Using HFIUS, both Miller and Mittal demonstrated that longitudinal muscle precedes circular muscle contraction, whereas the maximum contractions of both muscle layers occurs simultaneously in healthy subjects [44–46]. The importance of the esophageal longitudinal muscle in disease has received little attention, largely because of technical difficulties in measurements of its function and the strong symptom correlation with circular muscle dysfunction in patients with achalasia, scleroderma, and esophageal spasm. The advent of ultrasonography has allowed novel insights into the pathogenesis of esophageal motility disorders. Several investigators using conventional endosonography and HFIUS have reported significant hypertrophy of both the circular and longitudinal muscular layers of the esophagus in achalasia and diffuse esophageal spasm, confirming earlier pathologic studies [47–49]. In patients with reflux esophagitis and scleroderma, increased echogenicity and thinning of muscular layers have been demonstrated [50,51]. It remains unclear whether these observations are primary to the disease pathogenesis or secondary phenomena. The opposing findings may reflect the neurogenic defect of achalasia and myogenic defect of scleroderma. Alternatively, Dogan and colleagues [52] hypothesized that the greater muscle thickness is a marker for esophageal outflow obstruction. An increase in muscle wall thickness was also noted in high-amplitude esophageal contractions or nutcracker esophagus patients [49]. Furthermore, the peak increase in muscle wall thickness occurred significantly earlier than the peak circular muscle contraction in contrast to the simultaneous circular and longitudinal muscle contractions measured in control subjects [44]. The investigators speculated that this asynchrony could lead to increased esophageal wall stress that could be responsible for the formation of esophageal diverticula. An increase in muscle thickness was also seen in subsets of patients with nonspecific esophageal motility disorders including hypertensive LES, impaired LES relaxation, and ineffective motility and patients with esophageal symptoms and normal manometry [52]. Although this suggests the potential use of HFIUS in defining clinically significant subgroups of patients with nonspecific disorders, it also implies a lack of specificity of the HFIUS characteristics. Further studies measuring intrabolus pressures or esophageal impedance will help substantiate this application of HFIUS.

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HFIUS has been applied to patients with noncardiac chest pain in a study of 20 subjects using prolonged HFIUS combined with manometry and pH monitoring [53]. Sustained esophageal contractions with increased thickness of both the circular and longitudinal muscle lasting a mean of 68 seconds were detected by HFIUS and associated with 75% of the episodes of chest pain. Of note, these episodes of chest pain did not generate simultaneous changes in intraluminal pressure that could be detected by simultaneous esophageal manometry. The study proposed a novel mechanism whereby the esophageal chest pain is induced by the sustained esophageal contractions. It should be noted, however, that 50% of the sustained esophageal contractions were associated with an acid reflux episode that typically preceded the contraction. This raises the important question as to whether the sustained esophageal contraction is a marker for transient LES relaxation with the pain generated by acid reflux or esophageal distention rather than the contraction itself. Further studies are needed to validate this important observation. SUMMARY The new technologies described in this article represent modifications of existing techniques and new methodologies that can improve accuracy and detail in describing esophageal function. These technologies should not be viewed as competing technologies because each method provides a valuable improvement over the existing technology. Instead, efforts should be focused on combining these techniques because they are largely complementary. For instance, wireless esophageal monitoring is less cumbersome, more comfortable, and allows for prolonged monitoring when compared with catheter-based systems. Efforts should be made to devise a wireless capsule system that can also measure impedance so that information on nonacid reflux can be obtained in a more comfortable and less restricting fashion. Similarly, HRM is the best method to analyze the pressure profile and certainly it should be combined with impedance and intraluminal ultrasound to provide a complete functional assessment of bolus transit and mechanics. Acknowledgments The authors acknowledge Dr. Sudip Ghosh for developing the HRM software programs and figures. References [1] Pandolfino JE, Kahrilas PJ. AGA technical review on the clinical use of esophageal manometry. Gastroenterology 2005;128:209–24. [2] Fass J, Silny J, Braun J, et al. Measuring esophageal motility with a new intraluminal impedance device: first clinical results in reflux patients. Scand J Gastroenterol 1994;29: 693–702. [3] Nguyen HN, Silny J, Albers D, et al. Dynamics of esophageal bolus transport in healthy subjects studied using multiple intraluminal impedancometry. Am J Physiol 1997;273: G958–64. [4] Srinivasan R, Vela MF, Katz PO, et al. Esophageal function testing using multichannel intraluminal impedance. Am J Physiol Gastrointest Liver Physiol 2001;280:G457–62.


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[5] Simren M, Silny J, Holloway R, et al. Relevance of ineffective oesophageal motility during oesophageal acid clearance. Gut 2003;52:784–90. [6] Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53: 1024–31. [7] Imam H, Shay S, Ali A, et al. Bolus transit patterns in healthy subjects: a study using simultaneous impedance monitoring, videoesophagram, and esophageal manometry. Am J Physiol Gastrointest Liver Physiol 2005;288:G1000–6. [8] Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology 1988;94:73–80. [9] Tutuian R, Castell DO. Clarification of the esophageal function defect in patients with manometric ineffective esophageal motility: studies using combined impedance-manometry. Clin Gastroenterol Hepatol 2004;2:230–6. [10] Tutuian R, Vela MF, Balaji NS, et al. Esophageal function testing with combined multichannel intraluminal impedance and manometry: multicenter study in healthy volunteers. Clin Gastroenterol Hepatol 2003;1(3):174–82. [11] Nguyen HN, Domingues GR, Winograd R, et al. Impedance characteristics of normal oesophageal motor function. Eur J Gastroenterol Hepatol 2003;15:773–80. [12] Nguyen NQ, Rigda R, Tippett M, et al. Assessment of oesophageal motor function using combined perfusion manometry and multi-channel intra-luminal impedance measurement in normal subjects. Neurogastroenterol Motil 2005;17:458–65. [13] Tutuian R, Castell DO. Combined multichannel intraluminal impedance and manometry clarifies esophageal function abnormalities: study in 350 patients. Am J Gastroenterol 2004;99:1011–9. [14] Conchillo JM, Selimah M, Bredenoord AJ, et al. Assessment of oesophageal emptying in achalasia patients by intraluminal impedance monitoring. Neurogastroenterol Motil 2006;18:971–7. [15] Tutuian R, Mainie I, Agrawal A, et al. Symptom and function heterogenicity among patients with distal esophageal spasm: studies using combined impedance-manometry. Am J Gastroenterol 2006;101:464–9. [16] Tutuian R, Castell DO. Rumination documented by using combined multichannel intraluminal impedance and manometry. Clin Gastroenterol Hepatol 2004;2:340–3. [17] Bredenoord AJ, Weusten BL, Sifrim D, et al. Aerophagia, gastric, and supragastric belching: a study using intraluminal electrical impedance monitoring. Gut 2004;53:1561–5. [18] Shay S, Tutuian R, Sifrim D, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004;99:1037–43. [19] Vela MF, Camacho-Lobato L, Srinivasan R, et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid astroesophageal reflux: effect of omeprazole. Gastroenterology 2001;120(7):1599–606. [20] Bredenoord AJ, Weusten BL, Timmer R, et al. Addition of esophageal impedance monitoring to pH monitoring increases the yield of symptom association analysis in patients off PPI therapy. Am J Gastroenterol 2006;101:453–9. [21] Kahrilas PJ, Quigley EM. Clinical esophageal pH recording: a technical review for practice guideline development. Gastroenterology 1996;110:1982–96. [22] Zerbib F, Roman S, Ropert A, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol 2006;101: 1956–63. [23] Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring. Gut 2006;55:1398–402. [24] Pandolfino JE, Shi G, Zhang Q, et al. Measuring EGJ opening patterns using high resolution intraluminal impedance. Neurogastroenterol Motil 2005;17:200–6.

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[25] Pandolfino JE, Zhang QG, Ghosh SK, et al. Transient lower esophageal sphincter relaxations and reflux: mechanistic analysis using concurrent fluoroscopy and high-resolution manometry. Gastroenterology 2006;131:1725–33. [26] McMahon BP, Frokaer JB, Drewes AM, et al. A new measurement of oesophago-gastric junction competence. Neurogastroenterol Motil 2004;16:543–6. [27] McMahon BP, Frokjaer JB, Liao D, et al. A new technique for evaluating sphincter function in visceral organs: application of the functional lumen imaging probe (FLIP) for the evaluation of the oesophago-gastric junction. Physiol Meas 2005;26:823–36. [28] Nayer DS, Khandwhalla F, Achkar EA, et al. Esophageal manometry: assessment of interpreter consistency. Clin Gastroenterol Hepatol 2005;3:218–24. [29] Clouse RE, Staiano A. Topography of the esophageal peristaltic pressure wave. Am J Physiol 1991;261:G677–84. [30] Li M, Brasseur JG, Dodds WJ. Analyses of normal and abnormal esophageal transport using computer simulations. Am J Physiol 1994;266:G525–43. [31] Orlowski J, Dodds WJ, Linehan JH, et al. Requirements for accurate manometric recording of pharyngeal and esophageal peristaltic pressure waves. Invest Radiol 1982;17: 567–72. [32] Clouse RE, Staiano A. Topography of normal and high-amplitude esophageal peristalsis. Am J Physiol 1993;265:G1098–107. [33] Clouse RE, Prakash C. Topographic esophageal manometry: an emerging clinical and investigative approach. Dig Dis 2000;18:64–74. [34] Pandolfino JE, Kim H, Ghosh SK, et al. High-resolution manometry of the EGJ: an analysis of crural diaphragm function in GERD. Am J Gastroenterol 2007;12(5):1056–63. [35] Pandolfino JE, Ghosh SK, Zhang Q, et al. Quantifying EGJ morphology and relaxation with high-resolution manometry: a study of 75 asymptomatic volunteers. Am J Physiol Gastrointest Liver Physiol 2006;290(5):1033–40. [36] Ghosh SK, Pandolfino JE, Zhang Q, et al. Quantifying esophageal peristalsis with highresolution manometry: a study of 75 asymptomatic volunteers. Am J Physiol Gastrointest Liver Physiol 2006;290:G988–97. [37] Dodds WJ, Stewart ET, Hodges D, et al. Movement of the feline esophagus associated with respiration and peristalsis: an evaluation using tantalum markers. J Clin Invest 1973;52: 1–13. [38] Sugarbaker DJ, Rattan S, Goyal RK. Swallowing induces sequential activation of esophageal longitudinal smooth muscle. Am J Physiol 1984;247:G515–9. [39] Kahrilas PJ, Wu S, Lin S, et al. Attenuation of esophageal shortening during peristalsis with hiatus hernia. Gastroenterology 1995;109:1818–25. [40] Pouderoux P, Lin S, Kahrilas PJ. Timing, propagation, coordination, and effect of esophageal shortening during peristalsis. Gastroenterology 1997;112:1147–54. [41] Liu JB, Miller LS, Goldberg BB, et al. Transnasal US of the esophagus: preliminary morphologic and function studies. Radiology 1992;184:721–7. [42] Miller LS, Liu JB, Klenn PJ, et al. High-frequency endoluminal ultrasonography of the esophagus in human autopsy specimens. J Ultrasound Med 1993;12:563–6. [43] Sugarbaker DJ, Rattan S, Goyal RK. Mechanical and electrical activity of esophageal smooth muscle during peristalsis. Am J Physiol 1984;246:G145–50. [44] Jung HY, Puckett JL, Bhalla V, et al. Asynchrony between the circular and the longitudinal muscle contraction in patients with nutcracker esophagus. Gastroenterology 2005;128: 1179–86. [45] Miller LS, Liu JB, Colizzo FP, et al. Correlation of high-frequency esophageal ultrasonography and manometry in the study of esophageal motility. Gastroenterology 1995;109: 832–7. [46] Nicosia MA, Brasseur JG, Liu JB, et al. Local longitudinal muscle shortening of the human esophagus from high-frequency ultrasonography. Am J Physiol Gastrointest Liver Physiol 2001;281:G1022–33.


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[47] Deviere J, Dunham F, Rickaert F, et al. Endoscopic ultrasonography in achalasia. Gastroenterology 1989;96:1210–3. [48] Miller LS, Liu JB, Barbarevech CA, et al. High-resolution endoluminal sonography in achalasia. Gastrointest Endosc 1995;42:545–9. [49] Mittal RK, Kassab G, Puckett JL, et al. Hypertrophy of the muscularis propria of the lower esophageal sphincter and the body of the esophagus in patients with primary motility disorders of the esophagus. Am J Gastroenterol 2003;98:1705–12. [50] Manabe N, Haruma K, Hata J, et al. Evaluation of esophageal motility by endosonography using a miniature ultrasonographic probe in patients with reflux esophagitis. Scand J Gastroenterol 2002;37:674–8. [51] Miller LS, Liu JB, Klenn PJ, et al. Endoluminal ultrasonography of the distal esophagus in systemic sclerosis. Gastroenterology 1993;105:31–9. [52] Dogan I, Puckett JL, Padda BS, et al. Prevalence of increased esophageal muscle thickness in patients with esophageal symptoms. Am J Gastroenterol 2007;102:137–45. [53] Balaban DH, Yamamoto Y, Liu J, et al. Sustained esophageal contraction: a marker of esophageal chest pain identified by intraluminal ultrasonography. Gastroenterology 1999;116: 29–37.



Esophageal Motor and Sensory Disorders: Presentation, Evaluation, and Treatment Benson T. Massey, MD, FACP GI Manometry Laboratory, Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA

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isorders of esophageal motility and sensation are relatively rare in the general population. Because their prevalence generally increases with age [1,2], more patients are expected to present with these disorders as the average age of the population increases. The rarity of these disorders, combined with the lack of specificity in their clinical presentation, makes early diagnosis a challenge. All of the currently available treatments are at best palliative, and their benefit may be offset by side effects and complications that require additional therapy. Despite treatment, progression of the underlying disorder occurs frequently, so that ongoing follow-up is necessary to manage symptom relapse and complications. Although rarely life-threatening, these disorders have substantial effects on the quality of life experienced by afflicted patients [3,4]. The magnitude of anxiety and suffering that these disorders engender is readily evident from Internet postings by members of disease-specific patient support groups. Quality care of these patients requires technical and cognitive mastery of the various diagnostic and treatment modalities, along with clinical acumen and compassion in helping patients cope with a chronic illness. This article develops an algorithmic approach to the evaluation of idiopathic and secondary esophageal motor and sensory disorders, with the exception of those related to gastroesophageal reflux disease (GERD). Readers are strongly encouraged to review the article on GERD elsewhere in this issue. This article also does not cover sensory and motor disorders of the oropharynx. Although the article title suggests that sensory and motor disorders are separate entities, a common clinical scenario is the conjoint manifestation of these problems in any single patient. Indeed, it is often hard to determine whether the sensory or the motor disturbance is the dominant agent for symptoms. A final introductory caveat is that although sensory and motor disorders comprise a wide

E-mail address: [email protected] 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.006


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spectrum, the condition with the greatest body of information and consensus on clinical approach is esophageal achalasia. Evaluation and management of achalasia of necessity dominates the article, as does the use of achalasia to exemplify important concepts in the general approach to all such disorders. ARE SYMPTOMS PRESENT THAT SUGGEST AN ESOPHAGEAL MOTOR OR SENSORY DISORDER? The first step in diagnosing an esophageal sensorimotor disorder is to recognize that the patient’s presentation is consistent with such a disorder (Fig. 1). The repertoire of presenting symptoms for esophageal sensorimotor disturbances is relatively limited. Symptomatic presentation of esophageal sensory and motor disorders is as follows: Primary symptoms of disorder Dysphagia for solids and liquids Chest pain or heartburn Regurgitation or vomiting Coughing or choking Hiccups, eructation Halitosis Globus Altered diet or eating behavior Secondary symptoms from complications Weight loss Fever Respiratory symptoms Hematemesis

Individual symptoms or constellations of symptoms are inconsistently present. For example, although the classic hallmark of motor disorders is dysphagia for both solids and liquids, dysphagia is an initial symptom in less than half of achalasia patients [5]. Certain features of the symptoms suggest the presence of a sensorimotor disorder. More difficulty is reported with cold or carbonated beverages, whereas warm drinks may improve symptoms. Patients may get up from the meal to walk around or arch their neck to move the swallowed material into the stomach [5]. Belching is not a spontaneous event that relieves a sense of gastric distention; instead, it is an event induced by air swallowing to try to remove air trapped in the top of the esophagus. Regurgitated food is not sour and has a taste similar to that when originally swallowed. Regurgitation of such food often occurs hours after it was consumed. Rather than food, the patient may bring up a bland foam-laden liquid, essentially the saliva that was swallowed throughout the day. Food particles are found on the bedclothes in the morning. Elicitation of these features often requires pointed questioning of the patient or family and at times direct observation of patient behavior during a challenge of eating and drinking. The symptoms typically begin insidiously and progress gradually over the course of weeks-to-months. The course of symptom progression is not always

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Are symptoms present that suggest an esophageal sensorimotor disorder?

Have more common caus for these symptoms been excluded?

Do test findings support the diagnosis of an esophageal sensorimotor disorder?

Is the sensorimotor disorder idiopathic, or does it result from another condition?

Are there additional disorders present to cause or modulate symptoms?

Are symptoms the result of complications from the disorder?

For secondary disorders, are symptoms manifestations of the underlying disorder?

Are significant psychosocial disorders or stressors present that are modulating the symptom presentation?

Fig. 1. Algorithm for the evaluation of patients with possible esophageal sensorimotor disorders.

relentless. For milder disorders, symptoms may only appear intermittently (but, to the patient’s consternation, often not predictably). Patient modification of eating habits and diet can give a false semblance of remission or reversal of the disorder. The dominant symptom can also change as the disorder progresses. For example, a common history in achalasia is that the major symptom early in the course is chest discomfort, to be replaced by dysphagia and eventually regurgitation, as the esophagus progressively dilates. Rarely, the patient has no primary symptom. This is more likely to be the case in patients with cognitive disturbances or developmental disorders, as with achalasia in patients

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with Down syndrome [6]. In such cases, presence of the disorder becomes recognized during the evaluation of a complication (eg, aspiration pneumonia), or by chance during evaluation of another condition (eg, dilated esophagus seen on a CT scan performed to rule out pulmonary embolism). Symptoms in patients may reflect complications of the disease. Respiratory symptoms can result from aspiration pneumonia or a piece of regurgitated food lodged in a bronchus. Rarely, achalasia presents with life-threatening acute respiratory distress from occlusion of the airway by the distended esophagus [7]. Hematemesis may be from a Mallory-Weiss tear from retching or a bleeding esophageal cancer. Weight loss would seem to be an obvious symptom of a condition that makes eating a challenge. As the prevalence of obesity has increased in the United States population, however, more patients with achalasia have been encountered who continue to gain weight despite the disorder to the point of warranting bariatric surgery [8]. One should not conclude that the patient with weight gain cannot have a major esophageal sensorimotor disorder. The standard physical examination is essentially unhelpful in determining the presence of a sensorimotor disorder per se. Physical findings may offer a clue to the presence of conditions causing secondary sensorimotor disturbances or the presence of complications from such disturbances. HAVE MORE COMMON CAUSES FOR THESE SYMPTOMS BEEN EXCLUDED? Two fundamental problems interact to impede attempts at making a presumptive diagnosis of an esophageal sensorimotor disorder based on symptoms. First, none of the individual symptoms are pathognomonic for a specific disorder or the general category of sensorimotor disorders. All of the primary and secondary symptoms listed previously have been reported in some fashion by patients with GERD. For example, in one series of patients studied manometrically for mixed solid-liquid dysphagia, GERD was over twice as prevalent as achalasia [9]. Second, sensorimotor disorders of the esophagus are extremely rare, especially when compared with the presence of GERD. As an example, the annual incidence of achalasia is about 1 per 200,000 population [10]. Given that about 1 out of 20 adults has daily symptoms caused by GERD, any given patient presenting with esophageal symptoms is about 10,000 times more likely to have GERD than achalasia. Even in a patient with multiple classic symptom features, the probability is still overwhelming that the patient has atypical GERD, not typical achalasia. More problematic still are the patients who initially have GERD and subsequently develop a separate disorder, such as achalasia [11,12]. The combination of rarity and symptom nonspecificity causes considerable delay between the onset of symptoms and the diagnosis of esophageal sensorimotor disorders. For achalasia, this diagnostic delay averages about 5 years [13,14]. Although it is frustrating for patients to be mistakenly diagnosed and treated initially as having GERD, most patients with similar symptoms are


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going to have GERD and are likely to respond to treatment. Even patients who fail to respond to such treatment are more likely to be patients with GERD who need a different treatment regimen than patients with a separate sensorimotor disorder. For patients with alarm symptoms, such as progressive dysphagia, the standard diagnostic test (endoscopy) can be nondiagnostic for both conditions. Most patients undergo endoscopy and unsuccessful courses of treatment for GERD before the diagnosis of an esophageal sensorimotor disorder is considered. GERD is the most common of a diverse range of other conditions that must be considered in the differential diagnosis of esophageal sensorimotor disorders, listed as follows: Structural esophageal disorders Rings, webs, caustic and inflammatory strictures Eosinophilic esophagitis Intrinsic neoplasm Extrinsic compression (neoplasm, vascular, inflammatory) Congenital atresia or fistula Inflammatory esophageal disorders Reflux esophagitis Infection (fungal, viral) Radiation Medication (pill injury) Nonesophageal functional and motor disorders Oropharyngeal motor disorders Bulimia Cyclic vomiting syndrome Rumination Gastroparesis Hyperemesis gravidarum Disorders of other organ systems Cardiovascular disease Pulmonary disease Musculoskeletal disorders of the chest Postherpetic and other sensory neuropathies Iatrogenic complications Dysfunctional antireflux procedure

The presence of many of these as the cause for symptoms becomes readily apparent after a careful history, physical examination, and evaluation by standard tests, such as endoscopy, barium esophagrams, and CT imaging of the chest and abdomen. Among this broad list, several conditions warrant specific discussion. In the patient whose dominant symptoms are chest discomfort rather than altered bolus transit, great care should be taken to ensure that the symptoms are not a result of underlying cardiovascular disease. Although a delay in the accurate diagnosis of an esophageal sensorimotor disorder can affect quality of life, a delay in the diagnosis of coronary artery disease can be fatal. Eosinophilic esophagitis is being diagnosed with increasing frequency

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[15]. Although certain characteristic features have been identified, these are not universally present, nor are the endoscopic, radiographic, and pathologic features always recognized when they are present. To avoid missing this diagnosis, the endoscopist needs to obtain esophageal biopsies from multiple sites and the pathologist needs to quantify the number of eosinophils per high-powered field. Patients with a tight fundoplication wrap may have a normal endoscopic and radiographic evaluation. The standard esophagram misses oropharyngeal motor disorders; if these are in the differential diagnosis, a videotaped fluoroscopic swallow study with a speech pathologist should be performed. DO TEST FINDINGS SUPPORT THE DIAGNOSIS OF AN ESOPHAGEAL SENSORIMOTOR DISORDER? Because the symptoms of esophageal sensorimotor disorders are nonspecific, once likely alternative causes for the symptoms are excluded, additional testing is required to support the clinical hypothesis that such a disorder is present. Testing for these disorders is imperfect and should serve as adjuncts to, not substitutes for, diagnostic reasoning. Testing for Esophageal Motor Disorders Testing for esophageal motor disorders is fraught with several conceptual and methodologic difficulties. First, the tests currently clinically available only provide information on the phenotype of the disorder. That is, they delineate alterations in esophageal morphology, muscle activity, and bolus transit without elucidating the underlying pathophysiologic disturbances contributing to the phenotype. Different disease processes may manifest an indistinguishable phenotype on a given test, the classic example being the similar manometric findings of idiopathic achalasia and pseudoachalasia from adenocarcinoma of the cardia [16]. Second, because the underlying pathophysiology is unknown, constellations of findings on the diagnostic test have been used as the gold standard for deciding that the disorder is present. Such gold standards have commonly been determined by expert consensus or statistical parameters (ie, a value on a given measurement that is outside the 95% confidence interval of a control group). In many cases, these gold standards lack rigorous evidence for validity (in terms of predicting natural disease course or response to therapy) or reproducibility. Diagnoses based on a finding being outside the normal range are particularly problematic because, by definition, 5% of normal subjects have this finding, and these normal ‘‘outliers’’ may be over 100 times more prevalent in the population than patients with true motor disorders who have similar outlying values. Because there can be considerable random variation in a parameter over time, a group of patients who are categorized as abnormal based on an outlier value on a single test have some members of that group revert to a normal value on repeat testing (regression to the mean), as has been demonstrated with hypertensive peristalsis [17]. Third, considerable functional variability can exist within a diagnosis. For example, by definition, diffuse esophageal spasm can range from a patient


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with infrequent (20%) normal amplitude simultaneous contractions but otherwise normal motility to a patient in whom nearly every swallow results in highamplitude, long-duration simultaneous contractions. Even in such a disorder as esophageal achalasia, which has considerable expert consensus about the diagnostic criteria, variant forms have been recognized [18]. Fourth, published diagnostic criteria for different disorders are inconsistently applied to manometric findings by different clinicians [19]. Fifth, there is little consensus for the testing apparatus used or the testing protocol followed among different motility centers. Normal values may vary greatly among manometry laboratories if they use different catheters and score pressure phenomena differently. Lack of uniformity in formatting of manometry data across different systems can make it nearly impossible for a person in one laboratory to interpret the raw data from a manometric study performed in another laboratory. Finally, one needs to distinguish between testing to document the presence of an esophageal sensorimotor disorder and testing to determine if the disorder is the cause of a particular symptom. This is especially true when motor disorders are identified, but the symptoms are more related to pain than abnormal bolus transport. Several tests are available to help establish the diagnosis of an esophageal motor disorder. Tests for motor dysfunction Endoscopy Barium radiography Esophageal scintigraphy Manometry Impedance testing Endosonography

Endoscopy is used more to exclude other causes for the symptoms than to diagnose a sensorimotor disorder. Certain findings on endoscopy can suggest the presence of some disorders. An obviously dilated esophageal lumen with substantial fluid retention and no obstructing structural lesion is highly suggestive of achalasia. Failure to observe peristaltic contractions with swallows on endoscopy, and abnormal opening patterns of the gastroesophageal junction with swallows, have been reported to be accurate in distinguishing the extreme motor disorders of achalasia and scleroderma esophagus from normal motility [20]. The use of endoscopy to detect more subtle motor disturbances remains untested. Both fluoroscopy and scintigraphy have been used in the evaluation of esophageal motor disorders. Both are excellent at detecting the gross disturbances in bolus transit through the esophagus that can be a consequence of some motor disorders. Abnormal temporal patterns of bolus deformation on radiology can suggest the presence of failed or weak contractions; simultaneous (spastic) contractions; or retrograde contractions. Neither modality can identify a contraction abnormality in a region of esophagus that has been cleared of bolus material, so that patients with hypertensive peristalsis are usually not detected by these

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techniques [21,22]. These tests are operator-dependent, and some radiologists fail to appreciate the characteristic features of even a standard motor disorder, such as achalasia [23]. Variant and early forms of achalasia are even less well recognized, so that the sensitivity for radiology and scintigraphy in the detection of achalasia is suboptimal [24]. This is becoming more of a problem as radiologists in training in the United States devote less time and enthusiasm to mastery of these techniques. This author’s clinical perception is that unseasoned radiologists are often overcalling motor disturbances, because of a failure to appreciate the effects of normal physiologic processes on bolus transport, such as deglutitive inhibition and refractory periods with closely spaced swallows, the normal degree of retrograde bolus escape seen in the transition zone region between the striated and smooth muscle in the proximal esophagus, and the normal inefficient clearance of solid boluses with single swallows [25,26]. The risks of radiation exposure limit the duration of these studies. Manometric studies of esophageal motor function have traditionally been used as the gold standard for determining the presence and classification of an esophageal motor disorder. Clear advantages for manometry over radiology and scintigraphy are the ability to perform prolonged studies and detect motor abnormalities in regions of the esophagus not occupied by a bolus at the time of observation. Methodologic limitations for manometry until recently have been a lack of adequate spatial resolution for most systems. This can result in two problems. One is the likelihood of missing focal abnormalities (uncoordinated or weak contractions) that occur between two widely spaced sensors. The other is the axial dislocation of a high-pressure zone off of a point sensor, resulting in the spurious finding of relaxation. The manometric sleeve device was developed to allow continuous recording of high-pressure zones, such as the lower esophageal sphincter (LES), during axial movement [27], identifying the failed relaxation of the LES with deglutition in achalasia. Accurate interpretation of sleeve findings requires careful positioning of the sleeve relative to the sphincter. If the sphincter is located too close to the proximal end of the sleeve, the sphincter moves off of the sleeve with deglutition, imparting a false sense of relaxation. Although the customary position of the top of the sleeve is 2 cm above the top of the sphincter high-pressure zone, it is clear that in some circumstances more vigorous axial displacement is possible [28]. Such displacement may well account for the unexpectedly frequent occurrence of LES relaxations in conjunction with vigorous esophageal body contractions during ambulatory sleeve recordings in achalasia patients [29]. As a practical rule, if the sleeve seems to record LES relaxations that are simultaneous with vigorous proximal esophageal body contractions, recordings should be repeated with the sleeve repositioned at least 2 cm more proximally. Like radiographic methods, esophageal manometry is exceedingly dependent on the expertise of the operator. Few trainees in gastroenterology devote sufficient time and concentration in the technique. Failure to appreciate the limitations of the manometric recording apparatus, and a lack of knowledge about esophageal anatomy and physiology, are the major reasons for the need to


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repeat studies performed elsewhere. In this author’s experience, the most common errors are a failure to identify incomplete LES relaxations because of use of a single point sensor, misdiagnosis of ineffective motility by recording from a hiatal hernia instead of the distal esophagus, misinterpretation of intrabolus pressures as esophageal contractions, and failure to appreciate the effect of dry swallows and upright body position on peristaltic amplitude and velocity [30–32]. Because atypical features are inconsistently interpreted and consensus criteria for diagnosis are not uniformly applied, diagnostic agreement on study interpretation, even at expert centers, can be poor for certain disorders [19]. Given these difficulties in assigning diagnostic labels to manometric findings, a reasonable approach may be instead to report the component abnormalities in sphincter and esophageal body motor function [33,34]. Newer techniques of high-resolution solid-state manometry, esophageal impedance, and endosonography may revolutionize the assessment of these patients in the future. The performance characteristics of these tests are covered in more detail elsewhere in this issue. Testing for Esophageal Sensory Disorders Positive diagnosis of esophageal sensory disorders remains problematic. Sensory disorders tend to be considered only after nonesophageal disorders (eg, cardiac disease), GERD, and esophageal motor disorders have been ruled-out by testing. Evidence against this approach comes from studies indicating that these different disorders may occur together in groups of patients with chest pain [35–37]. Ideally, a diagnostic test for esophageal sensory disturbances has reproducibility and clinical validity even when other disorders are present. Diagnostic tests for esophageal sensory and motor disorders include the following: Tests for sensory dysfunction Esophageal distension Esophageal electrical stimulation Pharmacologic provocation Esophageal acid perfusion

A variety of stimuli have been applied to the esophagus to demonstrate that selected groups of patients with chest symptoms have reduced thresholds for discomfort or higher perceptions of pain, when compared with normal subjects. Some of these stimuli could potentially cause symptomatic motor responses; however, response to noxious stimuli after blockade of motor responses supports the presence of visceral hypersensitivity [38]. Several factors have limited the clinical use of provocative sensory testing for diagnosing esophageal sensory disorders. First, the techniques for stimulus production vary considerably among laboratories, with accompanying variation in normal values. The manner in which the stimulus is applied can significantly affect the threshold for symptom induction [39]. Second, there is a high risk of response bias, requiring blinding of the test administrator and the patient to the stimulus [40]. Third, studies have shown significant age and gender differences in sensory thresholds [41,42].

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Fourth, although studies have shown significant differences between patients with chest symptoms and asymptomatic controls, the range of responses between the two groups often overlaps. Some otherwise normal subjects have been identified as having esophageal hypersensitivity, based on their outlier responses to testing [43]. For most tests, data on sensitivity and specificity are either not available or inadequate because of a lack of sufficient sample size or performance of a receiver operating characteristic curve analysis to determine the optimal test threshold for diagnosis. Fifth, patients may have a positive response to one stimulus but not another. Use of multiple stimuli is likely to improve sensitivity at the expense of specificity. Use of multiple sequential stimuli at the same test setting also runs the risk of inducing altered responses because of central sensitization [44]. From these considerations, it is evident that any laboratory proposing to perform a diagnostic test battery for abnormal esophageal sensitivity cannot assume that its protocol precisely matches those from published studies. This means that each laboratory needs to develop its own set of normal data for its specific protocol. Such a data set needs to include subjects rigorously tested for the presence of other symptomatic disorders and report normal value ranges adjusted for age and gender. Although the usual clinical emphasis is on hypersensitive disorders, some patients may have reduced esophageal sensitivity. Reduced sensitivity has been demonstrated in patients with achalasia [45] and Chagas’ disease [46]. Abnormal sensory pathways may result in a failure to elicit normal clearing peristaltic contractions in response to a retained esophageal bolus [47]. Despite its potential importance, testing for esophageal hyposensitivity is almost never performed clinically. IS THE SENSORIMOTOR DISORDER IDIOPATHIC, OR DOES IT RESULT FROM ANOTHER CONDITION? When esophageal sensorimotor abnormalities have been identified, the clinician needs to determine whether they are primary (idiopathic) or are a secondary manifestation of another disorder. Secondary etiologies for esophageal sensory and motor disorders include the following: Neoplastic Adenocarcinoma of the cardia Small cell carcinoma (anti-Hu) Amyloidosis Neurologic disorders Parkinson’s disease Multiple sclerosis Autonomic or sensory neuropathies Inflammatory or autoimmune disorders Chagas’ disease Connective tissue disorders Eosinophilic esophagitis


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Metabolic Diabetes mellitus Hypothyroidism Alcoholism Hereditary or genetic disorders Allgrove’s (AAAS) syndrome Down syndrome Fabry’s disease Neurofibromatosis Iatrogenic Anticholinergic medication Vagotomy Tight fundoplication wrap Myotomy Mediastinal radiation Miscellaneous Idiopathic intestinal pseudo-obstruction

For some conditions, the medical history, examination findings, and other laboratory tests may have already confirmed the presence of the underlying disorder, and the role of esophageal function testing is to confirm that this organ is also affected and causing symptoms. The esophageal manifestations, however, can sometimes be the presenting feature of the disease. An important example of this is the development of an achalasia phenotype as a paraneoplastic response months before the underlying small cell carcinoma can be detected [48]. In patients with Allgrove’s syndrome, the esophageal motor disturbance can develop before the life-threatening adrenal insufficiency [49]. The entity of pseudoachalasia arising from adenocarcinoma of the gastric cardia requires specific mention, because this condition can on manometry be indistinguishable from idiopathic achalasia. Although frequently identified at endoscopy, at times CT scanning or endosonography is required to identify the lesion. Pseudoachalasia should be suspected in patients presenting at an older age, with a rapid symptom course and substantial weight loss [50]. Rare cases of eosinophilic esophagitis presenting as secondary motor rather than mucosal disorders can be extremely difficult to diagnose [51]. ARE THERE ADDITIONAL DISORDERS PRESENT TO CAUSE OR MODULATE SYMPTOMS? At times, one is fortunate to identify an esophageal sensorimotor disorder relatively early in the presentation and diagnostic work-up. In such cases, one has to be cognizant of the potential for a more common disorder to be present also and contributing to the clinical picture. The 65-year-old hyperlipidemic smoker with dysphagia and chest pain may have both achalasia and unstable angina. Abnormal esophageal acid exposure is a common finding in hypertensive peristalsis. Symptoms may result from a complication of the disorder, rather than the inherent pathophysiology of the disorder. An example is odynophagia from an ulcer caused by a retained caustic medication. For secondary

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disorders, symptoms may be another manifestation of the underlying disorder, such as chest pain resulting from diabetic sensory neuropathy. Since the classic studies of Wolf and Almy [52], it has been known that psychologic stressors can modulate esophageal sensorimotor disorders. Psychiatric disorders are common among patients with esophageal motor disorders referred for diagnostic testing [53], although patients with similar symptoms and no motor disorders are also found to have evidence for depression, anxiety, and somatization [54]. In such patient groups, psychiatric disturbance is more closely associated with symptoms of chest pain than dysphagia [54]. Acute stress can modify esophageal contractions [55] and perception thresholds for heartburn [56]. Often unappreciated is the effect of stress on diaphragmatic crural function [57], contraction of which can impair esophageal emptying [58]. One has to be wary of this phenomenon in anxious patients, to avoid misdiagnosis of a disorder of smooth muscle LES relaxation. WHAT THERAPIES SHOULD BE USED IN PATIENTS WITH SENSORIMOTOR ESOPHAGEAL DISORDERS? When devising a treatment plan for esophageal sensorimotor disorders, several issues must be considered. The first issue is whether the severity of the disturbance and its effect on the patient’s overall health and quality of life are severe enough to warrant treatment. A patient with isolated episodes of brief chest discomfort or bolus hesitancy every few days or weeks from a focal and intermittent discoordination of contractions in the esophageal body may require no treatment other than an explanation and reassurance. Studies have suggested that following confirmation of an esophageal disorder by testing, patients have less hospital use and fewer absences from work and social functions [59]. Many patients who are found to have less severe motor disorders exhibit improvement in symptoms over time [60]. At the other extreme, the patient with substantial weight loss and dehydration from near daily regurgitation and vomiting or with recurrent aspiration pneumonia is going to require more definitive therapy. The second issue when considering treatment is that none of the therapies available at present correct the underlying disorder. These treatments are at best palliative for the dominant symptoms of the patient. All available treatments have the potential for side effects and complications, which need to be considered carefully in the context of the patient’s overall health, comorbid illnesses, and life expectancy. Treatments often lack a durable response or lose their benefit as the underlying disease progresses. The evidence for many treatments is anecdotal at best, with few controlled clinical trails to support efficacy. When competing treatments are available for a disorder, few have undergone comparisons in appropriately designed clinical trials of adequate length. If symptoms are severe enough to warrant active treatment, one then has to decide which pathophysiologic processes are responsible for the symptoms. Although the dichotomy is not perfect, motor disturbances are more likely to


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have symptoms of bolus transport (eg, dysphagia, regurgitation), whereas hypersensitivity is more likely to result in symptoms of pain. Treatment of Motor Disorders Motor disorders from a functional standpoint can be divided into two broad categories: disorders of outflow obstruction from an inadequately relaxing LES and disorders of peristaltic bolus transport in the esophageal body. Esophageal body disorders can be divided into disorders of inadequate peristaltic propulsive strength and disorders of abnormal contraction sequencing (spasm). Interactions between LES and esophageal body dysfunction determine the pattern of abnormal bolus transport and the therapeutic approach (Fig. 2). Findings on manometric and radiographic studies can help identify the disturbances of bolus transport.

Selection of Therapeutic Options for Motor Disorders Based on Pattern of Motor Disturbances

Motor Disturbance Weak/absent peristaltic contractions and no outflow obstruction

Motor Disturbance Disordered (spastic) esophageal contractions and no outflow obstruction

Motor Disturbance Outflow obstruction < driving force from peristaltic/spastic esophageal body contractions

Motor Disturbance Outflow obstruction < driving force from peristaltic/spastic esophageal body contractions

Dietary/Behavioral Eat upright Liberal use of liquids Carbonated drinks Thorough chewing Avoid gummy foods

Dietary/Behavioral Eat upright Hot beverages Avoid provocative foods Peppermint

Dietary/Behavioral Eat upright Hot beverages Avoid provocative foods

Dietary/Behavioral Eat upright Frequent smaller meals

Medical Therapy Contraction stimulants

Medical Therapy Contraction/tone inhibitors Botulinum toxin: body

Medical Therapy Contraction/tone inhibitors Botulinum toxin: LES Pneumatic dilation

Medical Therapy Botulinum toxin: LES Pneumatic dilation

Surgical Therapy Esophageal replacement

Surgical Therapy Long myotomy of esophageal body

Surgical Therapy Myotomy of LES Long myotomy of esophageal body

Surgical Therapy Myotomy of LES

Fig. 2. Algorithm for selecting therapies for esophageal motor disorders. LES, lower esophageal sphincter.

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Isolated disorders of inadequate propulsive strength leave bolus residue in the esophageal body. In the upright position the combined effects of gravity and the feeble propulsive force are usually sufficient to overcome resistance at the gastroesophageal junction and intragastric pressure, so that liquid boluses are almost completely cleared into the stomach. Nondeforming boluses that adhere to the esophageal wall may not clear at all until dissolved. The goal of therapy is to improve the strength of contractions, when possible. Isolated disorders of contraction sequencing are commonly accompanied by a failure of descending inhibition [61,62]. Contractions distal to the bolus impair its entry into the stomach and can move the bolus retrograde. In the absence of outflow obstruction and with the benefit of gravity, however, there is no progressive retention of bolus with repeated swallows. The goal of currently available therapy is to diminish or abolish these abnormal contractions. When outflow obstruction is present from abnormal LES relaxation, this needs to be reduced or eliminated to facilitate esophageal emptying. If peristaltic or spastic contractions can raise the pressure in the bolus sufficiently to propel it into the stomach, then significant esophageal retention is usually not observed. Symptoms may result from activation of pain receptors in regions where higher intrabolus pressures result in increased intramural tension. In this situation, reduction of both LES tone and esophageal body contractions may be beneficial. When esophageal body contractions are insufficiently vigorous to generate an adequate pressure gradient to force the bolus through the LES, however, then esophageal retention occurs and esophageal contractions cannot occlude the lumen (Fig. 3). On manometry isobaric pressure waves are observed [63]. In this situation, pharmacologic agents that relax all smooth muscle are not helpful, because the reduction in LES pressure is offset by the reduction in esophageal body contractility that serves to move the bolus into the stomach. In this situation, targeted reduction of the outflow resistance is required. Modifications of diet and lifestyle are the first line of treatment for motor disorders. Patients should eat and drink in an upright position and remain that way postprandially, so that gravity can facilitate esophageal clearance. Swallowing hot (60 C) water with meals may aid in bolus passage [64]. Peppermint may decrease spastic contractions [65]. Foods the patient identifies as provoking spasm should be avoided [66]. Patients with poor esophageal propulsive ability need to wash down food with liberal use of liquids. Carbonated beverages can also be helpful if significant outflow obstruction is absent. A limited number of pharmacologic agents are available to alter tonic and phasic contractions of the LES and esophageal body. For increasing contractions, the only pathway available at present is through agents that mimic acetylcholine or enhance the availability of acetylcholine. Bethanechol has been shown acutely to increase esophageal contractions and improve bolus clearance in patients with GERD and severe ineffective motility [67,68]. This has not been evaluated in chronic studies in patients with disorders of ineffective motility. More agents are available to inhibit contractions and tone. The major classes are nitrates, calcium channel blockers, anticholinergics, and phosphodiesterase


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Fig. 3. Progression from nonisobaric to isobaric waves in an achalasia patient. Manometric tracing shows a sequence of one dry swallow followed by five wet (5 mL water) swallows. The top seven channels show pressure data from recording sites in the esophageal body (E1–6) placed 3 cm apart and from the LES (recorded with a sleeve device). Channel E1-LES is the difference between these two channels, with a positive value being favorable for bolus passage from the esophagus through the LES. Pressure scales are 0 to 100 mm Hg, except for the bottom channel (50–þ50 mm Hg.) Note that the periods of favorable pressure differential for esophageal emptying are of short duration and low magnitude, insufficient to allow complete esophageal emptying. The first few swallows show pressure waveforms that are different throughout the esophagus (nonisobaric). As the esophagus fills with retained fluid, however, the basal pressure rises, and the contractions are no longer able to occlude the esophageal lumen. The pressure they generate is transmitted uniformly throughout the retained fluid, resulting in the same pressure waveform being recorded on all of the sensors in the esophageal body (isobaric waves) by the third wet swallow. DS, dry swallow; LES, lower esophageal sphincter; WS, wet swallow.

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inhibitors. Essentially, they serve to inhibit muscle tone directly or block the excitatory actions of acetylcholine. None work specifically on the LES or esophageal body. This may explain why nifedipine is reported to be beneficial in early achalasia [69], but does not improve esophageal emptying in most patients with established achalasia [70]. Symptomatic improvement in patients with spastic esophageal disorders has also been reported in patients with nitrates [71], and injection of botulinum toxin into the esophageal body [72,73]. With sildenafil, changes in motility were not accompanied by consistent improvement in symptoms [74]. All of these studies are unblinded and lack appropriate controls. Selective reduction in LES pressure can be achieved currently by injection of botulinum toxin into the LES, pneumatic dilation of the LES, or myotomy of the LES. The published trials of these therapies are largely confined to patients with the diagnosis of achalasia. Of the three, botulinum toxin has the least risk for complications. The treatments must be repeated, however, and some patients develop resistance, likely from the development of antibodies to the toxin. Comparative trials of botulinum toxin to pneumatic dilation have shown similar initial results but more durable results long term with pneumatic dilation [75]. Botulinum toxin should be reserved for patients who are too frail to undergo pneumatic dilation or myotomy, have a life expectancy of less than 6 months, or require a short-term intervention until more definitive therapy can be arranged. Pneumatic dilation is usually performed as an outpatient endoscopic procedure, with the patient able to return to usual activities the following day. The major immediate risk of the procedure is esophageal perforation, which occurs in about 2% and may require surgical repair. The risk for perforation increases with use of balloon pressures above 10 psi [76]. Patients often require one or two additional dilations to achieve a satisfactory clinical response in 80% to 90% of patients [77,78]. Younger patients, especially young men, are less likely to have a successful response [78,79]. Surgical myotomy has evolved to a laparoscopic abdominal procedure for most patients. The success with a single operation is in the range of 90% [78]. Although the need to add an antireflux to the myotomy is controversial [80], a recent randomized trial showed a benefit of a Dor antireflux procedure on esophageal acid exposure in the early postoperative period [81]. In patients with dysphagic symptoms from spastic esophageal contractions, extension of the myotomy up through the smooth muscle portion of the esophageal body can be considered, but the outcomes are not as uniformly beneficial as those for achalasia [82,83]. Rarely, patients with a dilated, completely dysfunctional esophagus require esophagectomy. Patients too frail to undergo esophagectomy may require feeding by placement of a percutaneous endoscopic gastrostomy. Treatment of Sensory Disorders Diet and lifestyle modifications for patients with a hypersensitive esophagus are mostly a matter of avoiding foods and drinks that reproducibly cause


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symptoms. Patients with a hyposensitive esophagus require counseling to avoid scalding liquids and pills that could injure the esophagus if their failed passage was not recognized. Such patients are also at risk for damage from unperceived acid reflux. Medical treatment for the hypersensitive esophagus has largely been with the use of low-doses of tricyclic antidepressants and trazodone [84,85]. Acute or short-term studies of the antidepressant citalopram [43], the 5-hydroxytryptamine4 receptor agonist tegaserod [86], and the phosphodiesterase inhibitor theophylline [87] have shown reduction in symptoms or elevation of experimental pain thresholds. Their potential for long-term benefit is unclear. Patients with an acid-sensitive esophagus may benefit from acid-suppression therapy. Anticonvulsive agents are being used for other pain disorders, but there are no reported trials of their use in patients with esophageal sensory disorders to date. Because patients can have both motor and sensory disorders of the esophagus, concurrent treatment for both may be indicated. The usual clinical practice is first to identify and treat motor disorders, with treatment for sensory disorders initiated on an empiric basis when symptoms persist and studies indicate that the motor disturbance has been reasonably palliated. Care must be taken, however, to avoid overly aggressive treatment of a motor disturbance when the symptoms are likely sensory in origin. For example, chest pain in patients with nutcracker esophagus responds poorly to myotomy [82]. WHAT ARE THE CAUSES OF PERSISTENT OR RECURRENT SYMPTOMS AFTER TREATMENT? A fairly long list of conditions needs to be considered when the patient has symptoms after treatment (Table 1). When symptoms persist early after

Table 1 Etiologies for symptoms after treatment of esophageal sensory and motor disorders Category

Specific Causes

Timeframe

Primary treatment failure Complication of treatment

Incomplete myotomy GERD, peptic ulcer, stricture Myotomy site scarring Postoperative hematoma Paraesophageal herniation Neuroma in operative field Refeeding edema Obesity Pill injury Cardiovascular disease Psychiatric disorder or stress Second sensory or motor disorder Dilated, sigmoid esophagus Aspiration pneumonia Esophageal cancer

Early Early–late Early–late Early Early–late Early–late Early Late Early–late Early–late Early–late Early–late Late Early–late Late

Iatrogenic injury Comorbid condition

Progression of disease Complication of disease

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treatment, the most likely problem is that the treatment simply failed to work. The reason for failure is often not evident, and the patient may need to be tried on a different therapy. A specific identifiable and remediable cause for treatment failure in achalasia is an incomplete myotomy, which could be treated with surgical completion of the myotomy or pneumatic dilation. The two most common reasons for patients with achalasia to develop symptoms after an initially successful course of therapy are the development of GERD and progression of the underlying disease. Although GERD can develop following pneumatic dilation, it is much more common after a myotomy [88] and becomes more prevalent with time even when an antireflux procedure has been performed [89]. Disease progression can result from redevelopment of esophageal outflow obstruction, further deterioration in the contractile ability of the esophageal body, or a combination of the two. With sufficient follow-up, nearly half of achalasia patients treated by pneumatic dilation or surgery develop recurrent or new symptoms that require additional treatment [88,90]. For this reason, patients with achalasia should remain in on-going follow-up after therapy to monitor for symptoms of disease progression or complications [91]. Diagnostic testing of persistent or recurring symptoms usually starts with endoscopy to look for the presence of esophagitis, stricture, neoplasm, and disrupted antireflux procedures. A timed barium esophagram can assess the functional impairment in esophageal emptying [92], and a solid bolus challenge may help detect a subtle stenosis. Manometry may be necessary to identify an incomplete myotomy, tight antireflux wrap, or inadequate reduction in LES pressure after pneumatic dilation. Esophageal pH-impedance monitoring can document symptomatic reflux. Rarely, CT scans of the chest are needed to identify seromas or hematomas that are causing outflow obstruction. There are two additional points worth making for motor disorders when the posttreatment symptom is primarily pain, rather than dysphagia or regurgitation. First, another disorder may be present: the patient who develops new chest pain years after stable symptom remission may have angina. Second, the patient may have visceral hypersensitivity compounded by the coexistence of a psychiatric disorder or psychosocial stressors. This constellation of problems is unlikely to be solved by ever more aggressive attempts at improving motor function. The depressed achalasia patient, whose dominant problem of chest pain persists after an esophagectomy for same, is the epitome an unacceptable clinical outcome. SUMMARY Despite advances in pharmacologic, endoscopic, and surgical treatment, esophageal motor and sensory disorders remain a challenging problem for management, especially when complicated by the additional problems of psychiatric disease and psychosocial stressors. Although symptoms from minor disorders may respond to reassurance, patients with more significant disorders require a lifetime of follow-up. Patients require counseling about the nature and prognosis of their disease and instruction on dietary and lifestyle modifications.


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[45] Brackbill S, Shi G, Hirano I. Diminished mechanosensitivity and chemosensitivity in patients with achalasia. Am J Physiol Gastrointest Liver Physiol 2003;285(6):G1198–203. [46] Ejima FH, Dantas RO, Simoes MV, et al. Intraesophageal balloon distension test in Chagas’ disease patients with noncardiac chest pain. Dig Dis Sci 1998;43(11):2567–71. [47] Schoeman MN, Holloway RH. Secondary oesophageal peristalsis in patients with nonobstructive dysphagia. Gut 1994;35(11):1523–8. [48] Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 1998;50(3): 652–7. [49] Pedreira CC, Zacharin MR. Allgrove syndrome: when a recognisable paediatric disorder occurs in adulthood. Med J Aust 2004;180(2):74–5. [50] Rozman RW, Achkar E. Features distinguishing secondary achalasia from primary achalasia. Am J Gastroenterol 1990;85(10):1327–30. [51] Evrard S, Louis H, Kahaleh M, et al. Idiopathic eosinophilic oesophagitis: atypical presentation of a rare disease. Acta Gastroenterol Belg 2004;67(2):232–5. [52] Wolf S, Almy TP. Experimental observations on cardiospasm in man. Gastroenterology 1949;13:401–21. [53] Clouse RE, Lustman PJ. Psychiatric illness and contraction abnormalities of the esophagus. N Engl J Med 1983;309(22):1337–42. [54] Song CW, Lee SJ, Jeen YT, et al. Inconsistent association of esophageal symptoms, psychometric abnormalities and dysmotility. Am J Gastroenterol 2001;96(8):2312–6. [55] Anderson KO, Dalton CB, Bradley LA, et al. Stress induces alteration of esophageal pressures in healthy volunteers and non-cardiac chest pain patients. Dig Dis Sci 1989;34(1): 83–91. [56] Bradley LA, Richter JE, Pulliam TJ, et al. The relationship between stress and symptoms of gastroesophageal reflux: the influence of psychological factors. Am J Gastroenterol 1993;88(1):11–9. [57] Mittal RK, Stewart WR, Ramahi M, et al. The effects of psychological stress on the esophagogastric junction pressure and swallow-induced relaxation. Gastroenterology 1994; 106(6):1477–84. [58] Mittal RK, Shaffer HA, Parollisi S, et al. Influence of breathing pattern on the esophagogastric junction pressure and esophageal transit. Am J Physiol 1995;269(4 Pt 1): G577–83. [59] Rose S, Achkar E, Easley KA. Follow-up of patients with noncardiac chest pain: value of esophageal testing. Dig Dis Sci 1994;39(10):2063–8. [60] Spencer HL, Smilth L, Riley SA. A questionnaire study to assess long-term outcome in patients with abnormal esophageal manometry. Dysphagia 2006;21:149–55. [61] O’Hanrahan T, Bancewicz J, Thompson D, et al. Oesophageal reflex responses: abnormalities of the enteric nervous system in patients with oesophageal symptoms. Br J Surg 1992;79(9):938–41. [62] Behar J, Biancani P. Pathogenesis of simultaneous esophageal contractions in patients with motility disorders. Gastroenterology 1993;105(1):111–8. [63] Massey BT, Dodds WJ, Hogan WJ, et al. Abnormal esophageal motility: an analysis of concurrent radiographic and manometric findings. Gastroenterology 1991;101(2):344–54. [64] Triadafilopoulos G, Tsang HP, Segall GM. Hot water swallows improve symptoms and accelerate esophageal clearance in esophageal motility disorders. J Clin Gastroenterol 1998;26(4):239–44. [65] Pimentel M, Bonorris GG, Chow EJ, et al. Peppermint oil improves the manometric findings in diffuse esophageal spasm [see comments]. J Clin Gastroenterol 2001;33(1):27–31. [66] Bajaj JS, Shaker R, Hogan WJ. Esophageal veggie spasms: a food-specific cause of chest distress. Am J Gastroenterol 2004;99(7):1396–8. [67] Phaosawasdi K, Malmud LS, Tolin RD, et al. Cholinergic effects on esophageal transit and clearance. Gastroenterology 1981;81(5):915–20.

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The Many Manifestations of Gastroesophageal Reflux Disease: Presentation, Evaluation, and Treatment Joel E. Richter, MD, FACP, MACG The Richard L. Evans Chair, Department of Medicine, Temple University School of Medicine, 3401 North Broad Street, 801 Parkinson Pavilion, Philadelphia, PA 19140, USA

G

astroesophageal reflux disease (GERD) is a common problem that is expensive to diagnose and treat in primary and specialty care settings. The annual direct and indirect cost for managing this disease is estimated to be more than $14 billion in the United States, of which 60% is spent on drugs [1]. There have been major advances in understanding and improving the diagnosis and treatment of GERD over the last 5 years, which are summarized in this article. DEFINITION Unfortunately there is no gold standard test for GERD. Because the reflux of acid, particularly after meals, is a physiologic process, the simple presence of gastroesophageal reflux (GER) or occasional symptoms of heartburn or acid regurgitation cannot be defined as a disease. Recently a group of 44 experts from 18 countries used a modified Delphi process to develop a globally acceptable definition and classification of GERD that can be applied in clinical practice and in research (Fig. 1) [2]. This international group defined GERD as ‘‘a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.’’ Troublesome symptoms are defined by the patient to affect their quality of life. Mild symptoms occurring 2 or more days per week or moderate to severe symptoms occurring more than 1 day per week are often considered troublesome by patients. Patients may be diagnosed based on typical symptoms alone or on tests demonstrating reflux of stomach contents (eg, pH testing, impedance monitoring) or the injurious effects of the refluxate (endoscopy, histology, electron microscopy), in the presence of typical or atypical symptoms or complications. This new definition also recognizes that the refluxate causing symptoms may be weakly acidic or gaseous. E-mail address: [email protected] 0889-8553/07/$ – see front matter doi:10.1016/j.gtc.2007.07.014


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Fig. 1. The overall Montreal definition of GERD and its constituent syndromes. (From Vakil N, Van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence based consensus. Am J Gastroenterol 2006;101:1900–20; with permission.)

The group further divided the manifestations of GERD into esophageal and extraesophageal syndromes, with extraesophageal syndromes divided into established and proposed associations. In primary care, most patients are initially uninvestigated and present with symptomatic syndromes, either typical reflux complaints of heartburn and regurgitation or reflux-related chest pain. After investigation, usually endoscopy with histology, patients can be further classified as having the ‘‘syndromes with mucosal injury’’ to include reflux esophagitis, stricture, Barrett esophagus, or esophageal adenocarcinoma. The proposed consensus definition thus allows symptoms to define the disease but permits further characterization if mucosal injury is found. This group also recognized laryngitis, cough, asthma, and dental erosions as possible extraesophageal syndromes of GERD. The statement was restrained in defining a causal relationship, however, because of the lack of high-level evidence, especially showing a beneficial effect of reflux treatments on the extraesophageal syndromes and the reality that these syndromes are usually multifactorial, with GERD as one of several potential aggravating cofactors. EPIDEMIOLOGY Prevalence and Incidence The prevalence and incidence of GERD was recently estimated in two systematic reviews that defined GERD as at least weekly heartburn and/or acid regurgitation and met criteria concerning sample size, response rate, and recall period [3,4]. The prevalence in the Western world generally ranges between

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15% and 25%, whereas in Asia the prevalence is reported to be less than 5% (Fig. 2). Time trends confirm a significant increase in the prevalence of reflux symptoms averaging 5% annually in North America, 27% annually in Europe, and only 1% in Asia [4]. The disease is a relapsing and remitting disorder, but in contrast to the data for period prevalence, there are few longitudinal studies that describe the incidence of heartburn in the population. Based on only two studies from the Western world, the incidence of GERD can be estimated at 5 per 1000 person-years or an adjusted yearly incidence of weekly heartburn of approximately 1.5% to 3%. Even less is known about the prevalence of reflux esophagitis. A recent population-based endoscopic study suggests that asymptomatic esophagitis is common. In a random sample of a Swedish adult population, reflux symptoms were reported by 40% and esophagitis was diagnosed in nearly 16%. One third of those who had esophagitis, however, had no symptoms of GERD [5]. Two other population-based studies found the prevalence of esophagitis to be nearly 12% in Italy but only 7% in Japan [4]. Risk Factors The effect of increasing age on the prevalence of GERD symptoms is unclear. European studies report a slight but significant association, but the relationship

Fig. 2. Prevalence of at least weekly heartburn or acid regurgitation in various regions of the world. Time trends suggest an increase in the prevalence of reflux symptoms in North America and Europe but not Asia. (From El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol 2007;5:17–26; with permission.)

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was not observed for heartburn with or without acid regurgitation in Olmstead County, Minnesota [6]. A recent study suggested an association between advancing age and milder reflux symptoms but more severe esophagitis [7]. All studies report a similar prevalence of heartburn in men and women [5]. On the other hand, endoscopy database studies find male sex a significant risk factor for reflux esophagitis [8]. Cross-sectional studies and systematic reviews consistently find that obesity is associated with a statistically significant increase in the risk for reflux symptoms, erosive esophagitis, Barrett esophagus, and esophageal adenocarcinoma [9–11]. In these studies, obesity (BMI >25) was associated with 2.5- to 3.0-fold increase in these presentations of GERD. The causative mechanism for this relationship is unknown. Helicobacter pylori infection is an environmental factor that has declined as GERD, Barrett esophagus, and esophageal adenocarcinoma have increased in developed countries [12]. A systematic review of observational studies has confirmed that there is a negative association between H pylori and GERD, although this finding is most apparent in Asian countries [13]. The causative mechanism for this protective effect is the H pylori-induced gastritis, involving the antrum and corpus, which decreases the parietal cell mass, reduces acid secretion, and elevates gastric pH [14]. Along with environmental factors, the epidemiology of GERD may be affected by genetics. There have been two studies [15,16] assessing the prevalence of reflux symptoms in monozygotic versus dizygotic twins. Data from the Swedish Twin Registry [15] suggested that 31% (95% CI, 23%–39%) of GERD is caused by additive genetic factors, whereas a United Kingdom Twin Registry study [16] reported that this value was 43% (32%–55%). Although one group defined a locus on chromosome 13 associated with severe pediatric GERD [17], this has not been confirmed in adults. The genetic mechanisms are unknown but may be related to a smooth muscle disorder associated with hiatal hernia, low LES pressure, and impaired esophageal motility. CLINICAL PRESENTATIONS Heartburn and acid regurgitation are the classic symptoms of GERD. Heartburn describes a burning feeling, rising from the stomach or lower chest and radiating toward the neck, throat, and occasionally, the back [18]. It occurs postprandially, particularly after large meals or after eating spicy foods, citrus products, fats, chocolates, or drinking alcohol. The supine position or bending over may exacerbate heartburn. Nighttime heartburn may cause sleeping difficulties and impair next-day function [19]. The frequency and severity of heartburn does not predict the degree of esophageal damage [7]. The effortless regurgitation of acidic fluid, especially after meals and worsened by stooping or the supine position, is suggestive of GERD. Among patients who have daily regurgitation, LES pressure is usually low, many have associated gastroparesis, and esophagitis is common, making this symptom more difficult to treat than


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classic heartburn. Symptoms such as dysphagia, odynophagia, globus sensation, burping, water brash, and cough are other possible presentations of GERD, but their diagnostic yield is uncertain. Odynophagia may be seen with severe reflux esophagitis, but usually suggests an infection or pill-related esophagitis. Water brash is the sudden appearance in the mouth of a salty fluid. It is not regurgitated fluid, but rather secretions from the salivary glands in response to acid reflux [20]. The clinical accuracy of heartburn or regurgitation in diagnosing GERD is difficult to define. A recent systematic review [21] identified seven studies that assessed the accuracy of these reflux symptoms in diagnosing GERD in more than 5000 patients. Endoscopy with the presence of esophagitis has excellent specificity; thus, it was used as the gold standard to assess the sensitivity of heartburn and regurgitation. Unfortunately the sensitivity of these classic reflux symptoms was poor, with a range of 30% to 76% and a pooled sensitivity of 55% (95% CI, 45%–68%). Many patients who have atypical upper gastrointestinal (GI) symptoms thus may have GERD. Some patients who have GERD are asymptomatic. This is particularly true in elderly patients, perhaps because of reduced gastric acidity from chronic H pylori infection or decreased pain perception. Many elderly patients present first with complications of GERD because of long-standing disease with minimal complaints. For example, up to one third of patients who have Barrett esophagus are insensitive to acid at the time of presentation [22]. DIAGNOSTIC TESTS A large number of tests are available for evaluating patients who have suspected GERD. Many times these tests are unnecessary, because the presence of frequent heartburn and acid regurgitation are sufficiently accurate to identify the disease and begin medical treatment. This is not always the case, however, and clinicians must decide which tests to choose so as to make the diagnosis in a reliable, timely, and cost-effective manner, depending on the information desired (Table 1) [23]. Upper Endoscopy The identification of esophagitis at the time of endoscopy is highly specific (90%–95%) for GERD [24], but has a sensitivity of only approximately 50%. Multiple classification systems for esophagitis have been proposed, some are confusing, and none have worldwide acceptance [25]. The most thoroughly evaluated esophagitis classification is the Los Angeles (LA) system, which is gaining acceptance in the United States and Europe (Fig. 3) [26]. In referral centers, approximately 50% of patients have esophagitis, but in primary care and the general population, the rate of esophagitis is more in the range of 10% to 30% [4]. Most patients who have esophagitis have mild LA grade A-B disease and only 10% have the more severe LA grade C-D esophagitis [27]. Endoscopy can also evaluate complications of GERD, such as peptic strictures and Barrett

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Table 1 Diagnostic tests for gastroesophageal reflux disease Tests for reflux Intraesophageal pH monitoring Ambulatory bilirubin monitoring (bile reflux) Ambulatory impedance and pH monitoring (non-acid reflux) Barium esophagram Tests to assess symptoms Empirical trial of PPIs Intraesophageal pH monitoring with symptom analysis

Tests to assess esophageal mucosal damage Endoscopy Esophageal mucosal biopsy Barium esophagram

Tests to assess esophageal function Esophageal manometry Esophageal impedance Barium esophagram with fluoroscopy

esophagus and is recommended if patients have alarm symptoms, such as progressive dysphagia, weight loss, or iron deficiency anemia [28]. In routine clinical practice, endoscopy is reserved for evaluating patients who have alarm symptoms, for suspected GERD complications, and for surveillance for Barrett esophagus in patients who have chronic reflux complaints [29]. Over the years esophageal biopsies have had a varying role in the evaluation of GERD. The presence of eosinophils (20 eosinophils per HPF). The current primary indication for esophageal biopsies is to determine the presence of Barrett epithelium [29]. When this diagnosis is suspected, biopsies are mandatory and best done when esophagitis is healed. Esophageal pH Monitoring Ambulatory intraesophageal pH monitoring is the standard for establishing pathologic reflux [23]. Traditionally the pH probe is passed nasally, positioned 5 cm above the manometrically determined LES, and connected to a batterypowered data logger capable of collecting pH values every 4 to 6 seconds for 24 hours. Patients record meals, sleeping, and when symptoms are experienced. Acid reflux episodes are defined as a pH drop of less than 4. The total percent of time the pH is less than 4 is the most reproducible measure of GERD, with the reported upper limits of normal ranging from 4% to 5.5% [33]. The sensitivity of 24-hour pH monitoring in patients who have esophagitis approaches 90% with a specificity of 85% to 100%. In patients who have normal endoscopy in which pH testing may be most needed, the sensitivity is only 60% and the specificity from 85% to 90% [34]. Clinical indications for ambulatory pH monitoring include (1) before fundoplication to insure the presence of pathologic reflux in patients who have a normal endoscopy, (2) after antireflux surgery if heartburn symptoms persist, (3) patients who have reflux symptoms

Fig. 4. Intercellular spaces in esophageal mucosa from A) healthy subjects without reflux symptoms and B) GERD patients without esophagitis identified by transmission electron microscopy. (From Calabrese C, Fabbri A, Bortolotti M, et al. Dilated intercellular spaces as a marker of oesophageal damage: comparative results in gastro-oesophageal reflux disease with or without bile reflux. Aliment Pharmacol Ther 2003;18:525–32; with permission.)

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and a normal endoscopy not responding to PPI treatment, and (4) patients who have suspected extraesophageal symptoms of GERD [34]. Two new advances are improving the role of pH testing in evaluating GERD. The first is a wireless device (Bravo pH probe, Medtronics, Minneapolis, MN) the size of a vitamin pill attached, usually by endoscopy, 6 cm above the Z-line (Fig. 5) [35]. This decreases patient discomfort, allows for longer (48 hours or more) monitoring, and may increase test sensitivity by allowing patients to more comfortably carry out their usual activities [36]. The capsule detaches and passes spontaneously within 2 weeks. Rare patients may note severe pain after attachment, which resolves spontaneously with endoscopic removal. Two significant complications have occurred with this device—one report of esophageal bleeding requiring transfusion and one esophageal perforation [37]. The second technologic advancement combines multichannel intraluminal impedance monitoring with pH sensors to detect acid, weak acid, and non-acid reflux using a transnasal catheter over 24 hours [38]. The number of respective reflux episodes, rather than percentage of exposure time, is the critical measurement, with normal values established from United States and European studies [38]. The results of several studies suggest that impedance-pH monitoring is useful in the evaluation of patients who have PPI-resistant typical reflux symptoms, especially regurgitation complaints, and chronic unexplained cough [39–41]. Barium Esophagram The barium esophagram is inexpensive and less invasive than endoscopy. It is most useful in demonstrating strictures, rings, hiatus hernias, and major

Fig. 5. Wireless pH capsule attached to the esophagus 6 cm above the squamocolumnar junction.


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abnormalities in peristalsis. The barium esophagram’s ability to detect esophagitis varies, with sensitivities of 79% to 100% for moderate to severe esophagitis, whereas mild esophagitis is usually missed [23]. It is also not reliable for detecting Barrett esophagus. Esophageal Manometry Esophageal manometry allows assessment of LES pressure and relaxation and peristaltic activity, including contraction amplitude, duration, and velocity. It is generally not indicated in the evaluation of patients who have uncomplicated GERD, however, because most have normal resting LES pressure [42]. Esophageal manometry to document adequate esophageal peristalsis is traditionally recommended before antireflux surgery. If the study identifies ineffective peristalsis (low amplitude or frequent failed peristalsis), then a complete fundoplication may be contraindicated. This assumption has recently been challenged, however, by several studies finding that reflux control was better and dysphagia no more common in patients who had weak peristalsis after a complete as opposed to partial fundoplication [43]. An improvement of traditional manometry, combining it with impedance testing, is helping to clarify this controversy. Using this technology, a recent study found that less than 50% of patients who had ineffective peristalsis had a significant delay in esophageal bolus transit measured by impedance [44]. Proton Pump Inhibitor Test An empiric trial of acid suppression is the simplest method for diagnosing GERD and assessing its relationship to symptoms. With the advent of PPIs, this test has become the first diagnostic study used in patients who have classic or atypical reflux symptoms without alarming complaints. Symptoms usually respond to a PPI test in 1 to 2 weeks. If symptoms disappear with therapy and then return when medication is discontinued, GERD is established. A systematic review [45] identified 15 studies that assessed the accuracy of normal or high dose PPIs for 1 to 4 weeks in the diagnosis of GERD. The pooled sensitivity was good at 78% (95% CI, 66%–86%), but the specificity was poor at 54% (95% CI, 44%–65%) when 24-hour ambulatory pH was used as a gold standard. Nevertheless an empiric PPI trial for diagnosing GERD offers many advantages: the test is office-based, easily done, inexpensive (especially with over-the-counter PPIs), available to all physicians, and may avoid needless procedures. For example, one study showed a savings of greater than $570 per average patient because of a 59% reduction in the number of diagnostic tests (upper endoscopy, pH tests) [46]. Disadvantages are few, but include a placebo response and uncertain symptomatic endpoint if symptoms do not totally resolve with extended treatment. COMPLICATIONS There are few data on the long-term outcome of patients who have varying severities of GERD. Severity and duration of symptoms seem to have a poor correlation with the presence or severity of esophagitis [7]. Furthermore, there is

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some controversy whether GERD exists as a spectrum of disease severity or as a categoric disease in three distinct groups: nonerosive and erosive reflux disease and Barrett esophagus [24,47]. The recent European ProGERD study involving nearly 4000 patients sheds some light on the progression or regression of GERD over 2 years [47]. After endoscopy to assess the presence or absence of esophagitis, all patients were treated with 4 to 8 weeks of esomeprazole then returned to their primary care physician. Two years later all patients underwent a second endoscopy with biopsies. As shown in Fig. 6, after 2 years 25% of patients who had nonerosive GERD progressed to LA grade A-B esophagitis but severe LA grade C-D esophagitis was rare (

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