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Esophageal body motility disorders
Chapter 13
Esophageal body motility disorders Herit Vachhani, Zubair Malik Gastroenterology Section, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, United States
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Esophageal motility disorders can present with dysphagia, uncontrolled reflux, heartburn, nausea/vomiting, and chest pain. Chicago classification can be utilized to categorize esophageal disorders using high resolution esophageal manometry, however other pathologies can also be identified. Symptoms may or may not correlate with manometric findings. Diagnostic and treatment approaches can be tailored to specific esophageal disorders.
Introduction Esophageal body disorders refer to the abnormalities that restrict or inhibit food transport from the mouth to the stomach after they clear the oropharynx. Extrinsic or intrinsic factors can contribute to these disorders. They could be anatomic, autonomic, autoimmune, toxin-mediated, drug-induced, or infectious. There is also an association with body mass index, cholesterol levels, and glucose levels that may act as predictors for esophageal contractility and lower esophageal sphincter function [1]. They should be suspected in patients presenting with dysphagia, non-cardiac chest pain, heartburn, gastroesophageal reflux disease (GERD), regurgitation, nausea/vomiting, epigastric pain, or odynophagia [2]. High resolution esophageal manometry (HREM) is the diagnostic modality of choice and considered the gold standard for diagnosis of esophageal motility disorders. The following chapter will review each of the esophageal body disorders based on the Chicago classification (CC) version 3.0 and furthermore, explain miscellaneous abnormalities topographically seen on HREM with known and unclear clinical significance.
Symptoms Patients with esophageal motility disorders can present with a wide spectrum of symptoms, hence a good history is crucial. These symptoms commonly include dysphagia, chest pain, regurgitation, heartburn, and bloating. They can be mild or severe, intermittent or persistent, acute or chronic [3]. Dysphagia can begin with solids and progress to liquids making patient's quality of life abysmal. Long term consequences of uncontrolled symptoms can lead to weight loss, malnutrition, or in severe cases, malignancy. Certain symptoms are more prevalent with specific disorders of the esophagus and can aid in optimizing treatment options as will be discussed later.
Diagnostic approach The diagnostic approach in general for patients with esophageal body disorders include esophagogastroduodenoscopy (EGD), computed tomography (CT) scan of Chest, barium esophagram, and HREM. In patients presenting with solid and/or liquid dysphagia, EGD with mucosal biopsies can rule out eosinophilic esophagitis (EoE), candidiasis, reflux disease, structural lesions, and malignancy. Suspicion should be raised for esophageal motility disorder if there is food impaction, dilated or tortuous esophagus, and/or increased resistance when intubating the esophagogastric junction (EGJ). CT chest imaging can be a beneficial initial step in the evaluation, such as in esophagogastric junction outflow obstruction (EGJOO) or achalasia, to exclude a compressing structural lesions or infiltrating disease. Timed barium esophagram can demonstrate the dynamic function of the esophagus, quantitatively and qualitatively, showing how well the esophagus empties [4]. If there is stagnation of contrast suggesting a motility defect in functional patients, they may benefit from lower esophageal sphincter (LES) pressure lowering therapies [5]. Certain findings on barium imaging Clinical and Basic Neurogastroenterology and Motility. https://doi.org/10.1016/B978-0-12-813037-7.00013-3 © 2020 Elsevier Inc. All rights reserved.
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such as “birds-beak,” “corkscrew,” or “beaded” appearance may suggest abnormal motility and should warrant further workup. In cases of achalasia, barium testing and EGD have low sensitivity for differentiating the subtypes [6]. This is one condition where HREM holds advantage, where it can not only help in diagnosing achalasia, but also differentiate phenotypes and its clinical relevance with associated treatment outcomes [7]. With that being said, it is important to note that no manometric pattern is absolutely sensitive or specific for achalasia [8]. Endoscopic functional luminal imaging probe (Endoflip) is another novel modality that can be utilized as an adjunct to endoscopy to further evaluate the EGJ. It differs from HREM in that it also provides the EGJ luminal compliance and distensibility explaining the radial force, but is done while the patient is sedated during endoscopy [9]. This can separate a relaxed state from a contracted state of EGJ, a variable that HREM does not provide [10,11]. Furthermore, it can aid in risk stratification of patients that may develop achalasia [5,12]. Version 2 of EndoFLIP also has the ability to show esophageal contractility. Endoscopic ultrasound can also be utilized to detect subtle obstructions of the EGJ. Since HREM is considered the gold standard for diagnostic testing of esophageal body disorders, this procedure will be explained in greater detail.
HREM procedure HREM is a procedure that involves intranasal intubation of a calibrated solid-state catheter with 32 circumferentially placed sensors [13]. Typically, the patient is asked to swallow liquid and/or solids in the supine position. The collected data is then transcribed using computer software to map high resolution pressure topography. The metrics are then analyzed in a stepwise method using the Chicago classification system [14]. This procedure is not recommended for patients with known or suspected anatomical obstructions of the nose, pharynx and esophagus, significant bleeding disorders, or those unable to tolerate a prolonged supine position [13].
HREM analysis HREM analysis begins by evaluating a landmark frame by appropriately marking the upper esophageal sphincter (UES), LES borders, and pressure inversion point (PIP). Individual swallows are then predominantly assessed for LES pressure, peristalsis, and contraction vigor. Contraction is included in analysis for pressures >20 mm Hg on topography. LES pressure in the CC is expressed in the form of integrated relaxation pressure (IRP). It refers to the 4-s window of lowest LES pressures in relation to the gastric pressure during a 10-s timeframe. Peristalsis can be objectively evaluated by distal latency (DL), defined at the point of UES relaxation to the contractile deceleration point (CDP), present by the abrupt reduction in propagation velocity during peristalsis [15]. Contraction vigor is measured by the distal contractile integral (DCI), which is a product of time, amplitude, and length. It is calculated from the transition zone to upper border of LES and can be utilized to classify strength of the distal esophageal waves [16]. The transition zone refers to the area where the proximal third of the esophagus changes from striated muscle to the smooth muscle of the distal two thirds of the esophagus. In addition to HREM, bolus transit and clearance from the upper esophagus to stomach could also be analyzed by superimposing impedance onto swallow topography. Impaired bolus clearance could suggest a potential abnormality in the involved segment of the esophagus. Fig. 1 shows normal bolus transit and Fig. 2 shows impaired bolus transit using the impedance tracing on HREM.
Normal interpretation of HREM It is important to understand the normal findings of esophageal motility prior to discussing the abnormal findings. Once food enters the oral cavity and is chewed, a bolus is formed. The rhythmic, unidirectional, propelling force that drives the bolus from oropharynx to the stomach is called peristalsis. During a normal voluntary swallow, primary peristalsis is initiated by (UES) relaxation with a simultaneous transient LES relaxation, called deglutitive inhibition, followed by a coordinated contraction of the circular and longitudinal muscles along the esophagus to aid bolus propulsion [17,18]. Fig. 3 shows normal esophageal motility on HREM and normal metrics used to quantify a swallow.
Esophageal body disorders The Chicago classification version 3.0 in analysis of HREM has been an invaluable tool to systematically evaluate esophageal disorders as it logically categorizes esophageal motility disorders based on HREM metrics. It was developed by the International HRM Working Group, who first introduced the classification in 2009, and then further revised it in 2011 and 2014. Its internationally standardized hierarchical method divides it into four parts with sequential priority: (1) EGJ outflow
FIG. 1 Normal bolus transit during a swallow on HREM superimposed with impedance. The pink tracing represents bolus movement. After peristalsis there is no pink on topography showing normal clearance. Courtesy of Temple University Hospital GI Motility Lab.
FIG. 2 Impaired bolus transit on HREM superimposed with impedance. Here there is significant bolus retention after peristalsis. Courtesy of Temple University Hospital GI Motility Lab.
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FIG. 3 A normal recording using HREM. The topographic representations of the upper esophageal sphincter (VES), the striated, transition and smooth muscle zones, the lower esophageal sphincter (LES), the crural diaphragm (CD) are shown. Additionally, the recording shows HREM measurements such as the integrated relaxation pressure (IRP), distal latency (DL), and distal contractile integral (DCI) and how they are calculated. Courtesy of Temple University Hospital GI Motility Lab.
disorders, (2) major disorders of peristalsis, (3) minor disorders of peristalsis, and (4) normal esophageal motility. Though impedance analysis on HREM is not a part of CC, it can be still used to show bolus transit during peristalsis. When there is retention of the bolus in any segment of the esophagus that is not cleared by primary peristalsis, the esophageal distention can trigger a secondary peristalsis that is involuntary and independent of swallow initiation [19] (Fig. 4). Occasionally, a tertiary, or rarely, a quaternary peristalsis can also be present that may be initiated by a swallow or occur spontaneously. Both would be considered abnormal [20].
Disorders of outlet obstruction Disorders of the EGJ, including achalasia subtypes and EGJ outflow obstruction (EGJOO), suggest a defect in relaxation of the lower esophageal sphincter (LES).
Achalasia Achalasia subtypes are divided into Type 1 (classic), Type 2 (compressive), and Type 3 (spastic). Manometrically, all three subtypes relay impairment in relaxation of the LES with median IRP >15 mmHg, however, differ by their topographic presence of pressurization and contraction patterns [21]. According to the CC, achalasia type 1 refers to absence of peristalsis or esophageal pressurization. Achalasia type 2 denotes absence of peristalsis and pan-esophageal pressurization in greater than or equal to 20% of the swallows. Achalasia type 3, shows premature contractions defined by a DL of less than 4.5 s in greater than or equal to 20% of the swallows. Fig. 5 shows different types of achalasia. Achalasia is the best understood and most studied esophageal motility disorder and will be addressed in a separate chapter.
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FIG. 4 Secondary peristalsis on HREM. Courtesy of Temple University Hospital GI Motility Lab.
EGJ outflow obstruction EGJ outflow obstruction is characterized by intact peristalsis present on HREM with incomplete relaxation of the LES (median IRP greater than 15 mmHg) [14] (Fig. 6). It's a challenging topic in a sense that its clinical significance is not definitive, and it is unclear as to taking the next steps to evaluate after manometric diagnosis. It can be an isolated event or be present with other esophageal abnormalities. EGJOO findings can be functional, incidental, or as a result of an anatomic abnormality caused by a stricture or neoplasm. It can also be an incompletely expressed or early achalasia [22]. One study has shown that despite preserved esophageal peristalsis in EGJOO, abnormal bolus transit can still result suggesting presence of additional factors contributing to the disorder. The three most common symptoms that were reported to have association with EGJOO and abnormal bolus transit were dysphagia, heartburn, and regurgitation. Conversely, symptomatic correlation to bolus clearance alone remains unclear and a substantial number of patients have spontaneous symptomatic alleviation or no bolus stagnation [23]. It is often logical for patients with this abnormal manometric finding to undergo barium swallow for evaluation for delayed emptying to delineate the result from a true correlation to a false positive or an artifact. Of note, the CC currently does not include the analysis of esophageal impedance on HREM for bolus clearance as part of the criteria. As mentioned previously, other advanced procedures such as EUS or Endoflip can aid to find a relationship. In cases with incidental findings with asymptomatic patients undergoing HREM (i.e., Pre-lung transplant evaluation, Pre-bariatric surgical evaluation, or undergoing HREM for LES localization for 24 h pH testing), it's reasonable to observe them. In patients with concomitant symptoms to findings of EGJOO on manometry and/or other studies, botulinum toxin injection, pneumatic dilation, and/or Heller myotomy may be effective [24]. It is important to note that many different factors can falsely display elevation of IRP on HREM suggesting impaired LES relaxation and may give a diagnosis of EGJOO. Such factors include opioid use, tachypnea, and misplaced catheter position into a large hiatal hernia [25]. Rapid respirations, such as in patients with underlying respiratory disorders or experiencing distress during the procedure, can shorten the duration between crural diaphragmatic contractions on topography not allowing for proper calculation of the IRP when present in close proximity to each other. To improve the diagnostic yield of a true impairment of LES relaxation, provocative or adjunctive testing can be utilized [8], though no set criteria exist for analysis. Multiple rapid swallow (MRS) continues to be an emerging topic of further
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(C) FIG. 5 (A) Achalasia Type 1 on HREM. (B) Achalasia type 2 on HREM. (C) Achalasia type 3 on HREM. Courtesy of Temple University Hospital GI Motility Lab.
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FIG. 6 EGJ outflow obstruction with IRP of 19.1 on HREM. Courtesy of Temple University Hospital GI Motility Lab.
interest and its clinical relevance is evolving. It is simple, quick, and entails drinking small volumes of liquid in 4–6 consecutive swallows, triggering a profound deglutitive inhibition of the LES pressures without esophageal contractions during the swallows, followed by a strong peristaltic reserve of the distal esophageal body. The rationale for MRS is that increasing the volume and viscosity of the bolus may trigger a more vigorous esophageal contraction and thereby pressurization on topography. It can help in differentiating functional EGJ obstruction from an achalasia variant [26].
Major disorders of peristalsis Major disorders are characterized into diffuse esophageal spasm (DES), jackhammer esophagus (JE), and absent contractility (AC). These disorders of peristalsis refer to abnormalities that are rarely found in healthy individuals [8,27].
Diffuse esophageal spasm Diffuse esophageal spasm (DES) is characterized by contractions that are normal in amplitude, but that lack coordination, and result in rapid velocity simultaneous contractions, impairing bolus transit from the mouth to the stomach. It is predominantly associated with dysphagia and non-cardiac chest pain [28]. The pathophysiology of DES is not entirely understood, but is theorized that deficiency of nitric oxide in the body of esophagus and increase in acetylcholine release may play a role in causing premature contractions in the distal muscularis propria [29]. Other etiologies include increased acid reflux or with presence of other nerve or motor disorders [30]. Classically, on a barium swallow and EGD, a “corkscrew” appearance can be demonstrated [31]. EUS may display thickening of circular and longitudinal muscles. HREM shows a normal IRP with a distal latency less than 4.5 s in greater than or equal to 20% of the swallows, suggesting premature (spastic) contractions along with rapid and simultaneous contractions that may be present [14] (Fig. 7). Tertiary contractions could also be evident. Since DES and JE share similar concepts of suspected pathophysiology, treatment option will be discussed together in the next section.
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FIG. 7 Diffuse esophageal spasm on HREM. Courtesy of Temple University Hospital GI Motility Lab.
Jackhammer esophagus Jackhammer esophagus (JE) is a rare condition that is characterized on HREM as hypercontractile distal esophagus with a DCI greater than 8000 mmHg in greater than or equal to 20% of the swallows with preserved peristalsis [14] (Fig. 8). Previously categorized into nutcracker esophagus and JE, it now exists as one entity in the CC. Dysphagia is a common presenting symptom, though GERD may play a role in provocation of hypercontractile contractions. Little is known about the correlation between symptoms and contraction vigor [32]. A recent study suggests that different phenotypes of JE exist and have been linked to associated symptomology such as chest pain, but further studies are needed to solidify the relationship [33]. Its pathophysiology is similar to DES in that little is known about the exact mechanism; however neurochemical pathways and hypersensitivity may play a role. A small percentage of these patients may progress to achalasia [34]. Therapy overall has yielded disappointing results, however can be tried. The primary goal of treatment for both DES and JE should focus on symptomatic control. Initial steps include lifestyle modifications to reduce stress, improve dietary intake, acid suppression, and assessment of psychosocial factors. After which, pharmacological treatments can be considered. The mainstay of medical therapy is to enhance nitric oxide availability and relax the smooth muscle of the esophagus. These include calcium channel blockers (i.e., verapamil and nifedipine), nitrates (short acting and long acting), and 5-phosphodiesterase inhibitors (sildenafil). Peppermint oil has also been shown to have some benefit. Low dose tricyclic antidepressants such as imipramine have shown some success as well [34,35]. If symptoms persist despite medical intervention, botulinum treatment can be considered. Botulinum toxin can inhibit the excitatory acetylcholine release [36–38] and in theory should weaken spastic esophageal contractions allowing for symptoms to improve. Although considered relatively safe, treatments with repeated botulinum toxin injections carry unclear long term safety and efficacy. It is recommended to inject 100 units of botulinum toxin diluted in 10 mL of saline in four quadrants at 2 cm and 7 cm above the EGJ. Should this fail, endoscopic intervention with per-oral endoscopic myotomy (POEM) can be performed. POEM involves severing the musculature of the esophagus to prevent contractions and is performed endoscopically without requiring any surgical incisions. The technique requires mucosal incision to gain entry into the submucosa and creating a tunnel that extends into the gastric cardia, then performing a myotomy, followed by closure of mucosal incision leading to the tunnel [39]. POEM is an emerging and promising technique that can be an alternative to Heller myotomy in treatment of spastic esophageal disorders [40]. Its advantage holds from the ability to perform the procedure per orally
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FIG. 8 Jackhammer esophagus on HREM. Courtesy of Temple University Hospital GI Motility Lab.
with an intraluminal approach and can be performed for both the circular and longitudinal muscles at any length within the esophagus. Short term clinical success for achalasia based on a study by Inoue et al. utilized the post-POEM Eckardt's score and suggested this technique was highly effective [41]. Other studies that used standardized questionnaires from patients showed significant improvement in quality of life [42]. Long term efficacy data is lacking, though accumulating as more studies are being conducted and longer term follow up is being done [43]. A systematic review and meta-analysis by Khan MA et al. showed POEM is an effective and safe therapeutic modality for treatment of spastic esophageal disorders. They also revealed clinical success based on Eckardt's score was 87% for all spastic esophageal disorders; 92% for achalasia type III, 88% for DES, and 72% for JE [40]. In summary, POEM appears to show good success in patients suffering from these spastic disorders that have been resistant to other more conservative therapies. DES and JE often result in functional limitations for patients, but generally are not life-threatening.
Absent contractility Absent contractility is described by the presence of normal LES relaxation (IRP <15 mmHg) without a scorable contraction (absence of peristalsis) (Fig. 9). The general pathophysiology involves muscles of the esophagus undergoing atrophy, whether it's by fibrotic changes or by having abnormalities in the neuronal innervation. Unfortunately, it affects both the LES and the esophageal body, predisposing subjects to increased reflux associated complications, such as esophagitis, peptic strictures, and Barrett's esophagus. Hence, a strong attention to adequate acid suppression is recommended. It is associated with interstitial lung disease and mixed connective tissue disease such as scleroderma, though patients in these cohorts may present with normal motility or ineffective esophageal motility. Other contributors to absent esophageal contractility include sjögren syndrome, systemic lupus erythematosus, multiple sclerosis, Type 1 diabetes mellitus, myotonic dystrophy, chest radiation therapy, and sarcoidosis. It is also important to consider achalasia in the manometric diagnosis of absent
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FIG. 9 Absent contractility on HREM. Courtesy of Temple University Hospital GI Motility Lab.
contractility, as challenges with LES calculations may mislead diagnosis. Patients with this major peristaltic disorder also suffer from a longer duration of symptoms that negatively impacts their quality of life. In particular, presence of interstitial lung disease and scleroderma predict greater severity in esophageal dysfunction [44]. Furthermore, it is also clinically relevant in patients being evaluated for bariatric surgery, fundoplication, and lung transplant as there is a relative contraindication given the risk of developing post-surgical dysphagia and/or graft loss [45]. It is unclear if provocation testing such as multiple rapid swallows may be beneficial alongside standard esophageal manometry testing. Given the pathology of the disease process, treatment can be difficult for restoring peristalsis, and damage is often permanent. Medication therapy has not proven to be effective either, though some will try bethanechol to improve esophageal motility. A small subset of patients with uncontrolled GERD may present to surgeons for evaluation of anti-reflux surgery [46] and have absent peristalsis on esophageal manometry. Often, these patients are at risk for poor outcome, and hence surgery is best avoided. In patients general, surgery is not recommended, though there are some studies looking at the benefit of partial fundoplication in those with GERD and absent peristalsis [47].
Minor disorders of peristalsis Minor disorders of peristalsis include ineffective motility and fragmented peristalsis. These disorders have a poor correlation with symptoms, have unclear clinical significance, the majority do not progress in severity, and they can be seen in healthy asymptomatic volunteers [8].
Ineffective esophageal motility Ineffective esophageal motility (IEM) is characterized on HREM by normal LES relaxation (IRP <15 mmHg) and ≥50% ineffective swallows that is failed or weak (DCI < 450 mmHg × s × cm) [14] (Fig. 10). Though the pathophysiology is unclear,
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FIG. 10 Ineffective esophageal motility on HREM. Courtesy of Temple University Hospital GI Motility Lab.
it is theorized that inflammatory mediators may play a role in causing an intermittent defect in normal muscle contraction. Other etiologies that are hypothesized to cause ineffective motility are rapid food intake, advanced age, and vagal hyperreactivity [48–52]. It has a known association with acid exposure to the esophagus, particularly in the supine position [53,54]. For these patients, acid suppression tends to be beneficial. In the opposite spectrum with cases of normal acid exposure and persistence of symptoms, treatment options remain limited. As the motility field continues to evolve, novel therapies continue to arise. One of them is buspirone, a serotonin receptor agonist, which has shown some efficacy in improving esophageal peristalsis and LES function making this therapy an option for patients with treatment resistant IEM [55].
Fragmented peristalsis Fragmented peristalsis is defined on HREM as large breaks in intact peristalsis >5 cm in >50% of the swallows [14] (Fig. 11). In theory, it's reasonable to consider that breaks in peristalsis would correlate with stagnation of bolus and dysphagia; however studies have found that this is not the case. Breaks in peristalsis on topography are often noted in healthy subjects, poorly correlate to bolus stagnation, and weakly associated with symptoms [56,57]. This knowledge questions the significance of this minor disorder. Its long-term implications are also unclear, though it may be a marker of esophageal hypomotility [58], and in the future, could be used as a prognostic factor as more research continues to shed light.
Miscellaneous pathologies There are several other etiologies that can impair esophageal motility. These include infections, autoimmune disorders, pharmacologic agents, toxins such as opioids and alcohol. Each can present with its own characteristic manometric pattern or it can have findings of unclear significance.
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FIG. 11 Fragmented peristalsis on HREM. Courtesy of Temple University Hospital GI Motility Lab.
Mixed connective tissue disease (MTCD) MTCD is an autoimmune process that is a common cause of secondary esophageal motility disorders. The most common symptoms are acid reflux, heartburn, and regurgitation [59]. Few patients may experience dysphagia or odynophagia. The proximal one-third of the esophagus is striated muscle and is typically involved with polymyositis (PM) and dermatomyositis (DM), whereas the distal two-thirds of the esophagus encompasses smooth muscle and is involved in scleroderma/systemic sclerosis. Systemic sclerosis can cause smooth muscle atrophy and fibrosis of the esophagus. Complications can lead to esophagitis, Barrett's esophagus, strictures, and candidiasis. It is suspected that microvascular damage to the esophagus may lead to hypo-perfusion and ischemia, further leading to neuronal damage by compression and/or inflammation ultimately resulting in fibrosis [60]. Manometrically, the disease may progress from weak peristaltic contractions (IEM) to lack of peristalsis with diminished EGJ integrity (absent contractility). An autoimmune workup is recommended for these patients, as they could potentially benefit from rheumatic therapy, however as mentioned earlier, it is unlikely to restore lost motility as fibrosis is often a permanent. In theory, any skeletal muscle disorder can impair the process of swallowing and cause dysphagia. However, polymyositis and dermatomyositis have been linked with involvement of the esophagus, often causing dysphagia [61]. It has been theorized to caused by the inflammation and dysfunction of the skeletal muscles. Cricopharyngeal muscles and other muscles that initiate swallowing could also be involved [62]. These patients present with an increased risk of aspiration events that can lead to pneumonia. Treatment modalities focus on symptomatic control and management of the inflammatory disorders. There is also often an overlap between PM/DM and systemic sclerosis/scleroderma, which can guide better immunosuppressive therapy. It is important to note that many of these mechanisms are speculative, and knowledge is limited on detailed aspects of the pathophysiology of MCTD in the esophagus.
Opioid-induced esophageal dysfunction Opioids have been known to cause adverse effects on various parts of the gastrointestinal tract, such as the colon, however its effects on the esophagus are not clearly understood [63–66]. A study from 1983 by Rattan S et al. identified and localized opioid receptors in an animal model and concluded that both inhibitory and excitatory opioid receptors
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exist in the LES [67]. Since then there have been only few studies that have looked at conventional esophageal manometry and its correlative metrics, but have yielded conflicting data. However, the evolution of HREM has found a link in chronic opioid users. Though the mechanism is unclear, it has been widely documented that opioids can contribute to abnormal metrics on HREM supporting esophageal dysfunction. It can cause one or more of the following: impaired LES relaxation, simultaneous contractions, and high amplitude/velocity peristalsis [68] (Fig. 12). Ratuapli SK et al. showed based on the CC, the predominant disorders observed were EGJOO, achalasia type II, achalasia type III, and JE for those using opioids within at least 24 h of manometry testing [69,70]. They theorized that imbalance in nitric oxide and cholinergic neuronal response resulted in excitatory output with spastic and hypertensive esophageal contractions. Hence, it is of value to suggest cessation of opioids for at least 24 h prior to performing HREM to achieve higher diagnostic yield and recommend complete cessation for those having symptomatic association with abnormal manometry readings. If cessation is not possible as this is often the case, it is recommended that the dosage be reduced to the lowest effective dosage. Botulinum toxin injections may be considered as a temporary option until opioids can be tapered off. Calcium channel blockers have provided very little help and pneumatic dilations have shown poor results. Heller myotomy or POEM can be considered, particularly in patients that don't improve after stopping opioids or will be remaining on opioids long term.
Infection related dysmotility Post infectious parasitic or viral illnesses can directly affect the neuronal innervation and musculature of the esophagus. There have been implications in neuronal innervation from human immunodeficiency virus (HIV), infectious mononucleosis [71], and polio virus leading to dysphagia. Chagas disease caused by Trypanosoma cruzi is also a well-known culprit in neuronal damage to the smooth muscles of the esophagus and may lead to achalasia or mega-esophagus. HIV can cause a plethora of opportunistic esophageal infections, such as candida, cytomegalovirus, and herpes simplex virus; however can
FIG. 12 An example of opioid induced esophageal dysfunction on HREM. Courtesy of Temple University Hospital GI Motility Lab.
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also independently cause esophageal dysmotility [72]. Hypercontractile contractions, incomplete LES relaxation, and/or non-specific dysmotility can been seen on HREM.
Pharmacologic agents and toxin induced esophageal dysfunction Pharmacologic agents that can affect both the skeletal muscle and smooth muscle are anticholinergics, antimuscarinics, neuromuscular blocking agents, antineoplastics, immunosuppressants, antiemetics, benzodiazepines, narcotics, skeletal muscle relaxants, antibiotics, anti-arrhythmics, aspirin, bisphosphonates, NSAIDs, iron products, potassium chloride, vitamin C, anti-Parkinson agents, antiretroviral agents, botulinum toxin, tetanus toxoid, and anti-viral agents [73–75]. Long-term use of high-dose corticosteroids can also induce proximal esophageal striated skeletal muscle atrophy causing dysphagia [73]. When evaluating for esophageal disorders, careful history and medication reconciliation is suggested as immunosuppressive therapy can disrupt the esophageal mucosa allowing for opportunistic infections resulting in dysphagia. Among many harmful effects of alcohol, both acute and chronic ingestion can cause esophageal dysmotility by impairing LES relaxation and lowering contraction vigor [76,77].
Vascular artifacts on HREM Some of the artifacts that can be present on HREM can be clinically significant or can be considered irrelevant. Cardiovascular structures compressing the esophagus can produce analytical disturbance on topography by the presence of horizontal pulsatile pressure system bands on HREM [78] (Fig. 13). This can be present in normal healthy volunteers and often bear no pathological implication. In contrast, some have known associations such as dysphagia lusoria, which
FIG. 13 An example of a vascular band on HREM. Courtesy of Temple University Hospital GI Motility Lab.
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is an anatomic abnormality that is caused by an aberrant right subclavian artery that is often responsible for dysphagia [79,80]. Treatment is usually surgical with repair/reconstruction if functional limitation is present. There is also a relationship with atherosclerosis and calcification of the distal thoracic aorta in elderly and its compressive effects causing difficulty swallowing, known as dysphagia aortica [81,82]. Left atrial enlargement with mitral valve disease and congestive heart failure can also compress the distal esophagus leading to dysphagia [83,84]. Vascular structural artifacts are a common phenomenon noted on HREM that are not routinely evaluated and it has been poorly studied in the literature in terms of its significance and prevalence.
Conclusions Disorder that affect esophageal body are important because they can diminish the quality of life for many patients. HREM and the CC have been invaluable for evaluating esophageal function and classifying these disorders [85]. Advances in diagnostic modalities, treatment options, and deeper understanding of the pathophysiology of esophageal disorders have revolutionized patient care, though there is still a large unmet need. A myriad of research studies are underway that hopefully will answer questions yet unanswered. Further studies are needed to better understand the pathophysiology of different disorders. Including evaluation of diagnostic modalities such as Endoflip, and treatment modalities such as new medications that can affect GI motility and POEM procedures.
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Peroral endoscopic myotomy for treating achalasia and esophageal motility disorders. J Neurogastroenterol Motil 2016;22(1):14–24. [40] Khan M, Kumbhari V, Ngamruengphong S, Ismail A, Chen Y, Chavez Y, et al. Is POEM the answer for management of spastic esophageal disorders? A systematic review and meta-analysis. Dig Dis Sci 2017;62(1):35–44. [41] Inoue H, Sato H, Ikeda H, Onimaru M, Sato C, Minami H, et al. Per-oral endoscopic myotomy: a series of 500 patients. J Am Coll Surg 2015;221(2):256–64. [42] Ujiki MB, Yetasook AK, Zapf M, Linn JG, Carbray JM, Denham W. Peroral endoscopic myotomy: a short-term comparison with the standard laparoscopic approach. Surgery 2013;154(4):900. [43] Chiu PWY, Wu JCY, Teoh AYB, Chan Y, Wong SKH, Liu SYW, et al. Peroral endoscopic myotomy for treatment of achalasia: from bench to bedside (with video). Gastrointest Endosc 2013;77(1):29–38. [44] Crowell MD, Umar SB, Griffing WL, DiBaise JK, Lacy BE, Vela MF. 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Is esophageal dysphagia in the extreme elderly (> or = 80 years) different to dysphagia younger adults? A clinical motility service audit, Dis Esophagus 2008;21(7):656–9. [50] Li K, Chen J, Zhang Q, Huizinga JD, Vadakepeedika S, Zhao Y, et al. Habitual rapid food intake and ineffective esophageal motility. World J Gastroenterol 2013;19(14):2270–7. [51] Hiestand M, Abdel Jalil A, Castell DO. Manometric subtypes of ineffective esophageal motility. Clin Transl Gastroenterol 2017;8(3):e78. [52] Chen J. Ineffective esophageal motility and the vagus: current challenges and future prospects. Clin Exp Gastroenterol 2016;9:291–9. [53] Shetler KP, Bikhtii S, Triadafilopoulos G. Ineffective esophageal motility: clinical, manometric, and outcome characteristics in patients with and without abnormal esophageal acid exposure. Dis Esophagus 2017;30(6):1–8. [54] Botoman VA. How effective are we at understanding ineffective esophageal motility? Gastrointest Endosc 2008;68(3):432–3. 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Esophageal body motility disorders Herit Vachhani, Zubair Malik Gastroenterology Section, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, United States
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Esophageal motility disorders can present with dysphagia, uncontrolled reflux, heartburn, nausea/vomiting, and chest pain. Chicago classification can be utilized to categorize esophageal disorders using high resolution esophageal manometry, however other pathologies can also be identified. Symptoms may or may not correlate with manometric findings. Diagnostic and treatment approaches can be tailored to specific esophageal disorders.
Introduction Esophageal body disorders refer to the abnormalities that restrict or inhibit food transport from the mouth to the stomach after they clear the oropharynx. Extrinsic or intrinsic factors can contribute to these disorders. They could be anatomic, autonomic, autoimmune, toxin-mediated, drug-induced, or infectious. There is also an association with body mass index, cholesterol levels, and glucose levels that may act as predictors for esophageal contractility and lower esophageal sphincter function [1]. They should be suspected in patients presenting with dysphagia, non-cardiac chest pain, heartburn, gastroesophageal reflux disease (GERD), regurgitation, nausea/vomiting, epigastric pain, or odynophagia [2]. High resolution esophageal manometry (HREM) is the diagnostic modality of choice and considered the gold standard for diagnosis of esophageal motility disorders. The following chapter will review each of the esophageal body disorders based on the Chicago classification (CC) version 3.0 and furthermore, explain miscellaneous abnormalities topographically seen on HREM with known and unclear clinical significance.
Symptoms Patients with esophageal motility disorders can present with a wide spectrum of symptoms, hence a good history is crucial. These symptoms commonly include dysphagia, chest pain, regurgitation, heartburn, and bloating. They can be mild or severe, intermittent or persistent, acute or chronic [3]. Dysphagia can begin with solids and progress to liquids making patient's quality of life abysmal. Long term consequences of uncontrolled symptoms can lead to weight loss, malnutrition, or in severe cases, malignancy. Certain symptoms are more prevalent with specific disorders of the esophagus and can aid in optimizing treatment options as will be discussed later.
Diagnostic approach The diagnostic approach in general for patients with esophageal body disorders include esophagogastroduodenoscopy (EGD), computed tomography (CT) scan of Chest, barium esophagram, and HREM. In patients presenting with solid and/or liquid dysphagia, EGD with mucosal biopsies can rule out eosinophilic esophagitis (EoE), candidiasis, reflux disease, structural lesions, and malignancy. Suspicion should be raised for esophageal motility disorder if there is food impaction, dilated or tortuous esophagus, and/or increased resistance when intubating the esophagogastric junction (EGJ). CT chest imaging can be a beneficial initial step in the evaluation, such as in esophagogastric junction outflow obstruction (EGJOO) or achalasia, to exclude a compressing structural lesions or infiltrating disease. Timed barium esophagram can demonstrate the dynamic function of the esophagus, quantitatively and qualitatively, showing how well the esophagus empties [4]. If there is stagnation of contrast suggesting a motility defect in functional patients, they may benefit from lower esophageal sphincter (LES) pressure lowering therapies [5]. Certain findings on barium imaging Clinical and Basic Neurogastroenterology and Motility. https://doi.org/10.1016/B978-0-12-813037-7.00013-3 © 2020 Elsevier Inc. All rights reserved.
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such as “birds-beak,” “corkscrew,” or “beaded” appearance may suggest abnormal motility and should warrant further workup. In cases of achalasia, barium testing and EGD have low sensitivity for differentiating the subtypes [6]. This is one condition where HREM holds advantage, where it can not only help in diagnosing achalasia, but also differentiate phenotypes and its clinical relevance with associated treatment outcomes [7]. With that being said, it is important to note that no manometric pattern is absolutely sensitive or specific for achalasia [8]. Endoscopic functional luminal imaging probe (Endoflip) is another novel modality that can be utilized as an adjunct to endoscopy to further evaluate the EGJ. It differs from HREM in that it also provides the EGJ luminal compliance and distensibility explaining the radial force, but is done while the patient is sedated during endoscopy [9]. This can separate a relaxed state from a contracted state of EGJ, a variable that HREM does not provide [10,11]. Furthermore, it can aid in risk stratification of patients that may develop achalasia [5,12]. Version 2 of EndoFLIP also has the ability to show esophageal contractility. Endoscopic ultrasound can also be utilized to detect subtle obstructions of the EGJ. Since HREM is considered the gold standard for diagnostic testing of esophageal body disorders, this procedure will be explained in greater detail.
HREM procedure HREM is a procedure that involves intranasal intubation of a calibrated solid-state catheter with 32 circumferentially placed sensors [13]. Typically, the patient is asked to swallow liquid and/or solids in the supine position. The collected data is then transcribed using computer software to map high resolution pressure topography. The metrics are then analyzed in a stepwise method using the Chicago classification system [14]. This procedure is not recommended for patients with known or suspected anatomical obstructions of the nose, pharynx and esophagus, significant bleeding disorders, or those unable to tolerate a prolonged supine position [13].
HREM analysis HREM analysis begins by evaluating a landmark frame by appropriately marking the upper esophageal sphincter (UES), LES borders, and pressure inversion point (PIP). Individual swallows are then predominantly assessed for LES pressure, peristalsis, and contraction vigor. Contraction is included in analysis for pressures >20 mm Hg on topography. LES pressure in the CC is expressed in the form of integrated relaxation pressure (IRP). It refers to the 4-s window of lowest LES pressures in relation to the gastric pressure during a 10-s timeframe. Peristalsis can be objectively evaluated by distal latency (DL), defined at the point of UES relaxation to the contractile deceleration point (CDP), present by the abrupt reduction in propagation velocity during peristalsis [15]. Contraction vigor is measured by the distal contractile integral (DCI), which is a product of time, amplitude, and length. It is calculated from the transition zone to upper border of LES and can be utilized to classify strength of the distal esophageal waves [16]. The transition zone refers to the area where the proximal third of the esophagus changes from striated muscle to the smooth muscle of the distal two thirds of the esophagus. In addition to HREM, bolus transit and clearance from the upper esophagus to stomach could also be analyzed by superimposing impedance onto swallow topography. Impaired bolus clearance could suggest a potential abnormality in the involved segment of the esophagus. Fig. 1 shows normal bolus transit and Fig. 2 shows impaired bolus transit using the impedance tracing on HREM.
Normal interpretation of HREM It is important to understand the normal findings of esophageal motility prior to discussing the abnormal findings. Once food enters the oral cavity and is chewed, a bolus is formed. The rhythmic, unidirectional, propelling force that drives the bolus from oropharynx to the stomach is called peristalsis. During a normal voluntary swallow, primary peristalsis is initiated by (UES) relaxation with a simultaneous transient LES relaxation, called deglutitive inhibition, followed by a coordinated contraction of the circular and longitudinal muscles along the esophagus to aid bolus propulsion [17,18]. Fig. 3 shows normal esophageal motility on HREM and normal metrics used to quantify a swallow.
Esophageal body disorders The Chicago classification version 3.0 in analysis of HREM has been an invaluable tool to systematically evaluate esophageal disorders as it logically categorizes esophageal motility disorders based on HREM metrics. It was developed by the International HRM Working Group, who first introduced the classification in 2009, and then further revised it in 2011 and 2014. Its internationally standardized hierarchical method divides it into four parts with sequential priority: (1) EGJ outflow
FIG. 1 Normal bolus transit during a swallow on HREM superimposed with impedance. The pink tracing represents bolus movement. After peristalsis there is no pink on topography showing normal clearance. Courtesy of Temple University Hospital GI Motility Lab.
FIG. 2 Impaired bolus transit on HREM superimposed with impedance. Here there is significant bolus retention after peristalsis. Courtesy of Temple University Hospital GI Motility Lab.
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FIG. 3 A normal recording using HREM. The topographic representations of the upper esophageal sphincter (VES), the striated, transition and smooth muscle zones, the lower esophageal sphincter (LES), the crural diaphragm (CD) are shown. Additionally, the recording shows HREM measurements such as the integrated relaxation pressure (IRP), distal latency (DL), and distal contractile integral (DCI) and how they are calculated. Courtesy of Temple University Hospital GI Motility Lab.
disorders, (2) major disorders of peristalsis, (3) minor disorders of peristalsis, and (4) normal esophageal motility. Though impedance analysis on HREM is not a part of CC, it can be still used to show bolus transit during peristalsis. When there is retention of the bolus in any segment of the esophagus that is not cleared by primary peristalsis, the esophageal distention can trigger a secondary peristalsis that is involuntary and independent of swallow initiation [19] (Fig. 4). Occasionally, a tertiary, or rarely, a quaternary peristalsis can also be present that may be initiated by a swallow or occur spontaneously. Both would be considered abnormal [20].
Disorders of outlet obstruction Disorders of the EGJ, including achalasia subtypes and EGJ outflow obstruction (EGJOO), suggest a defect in relaxation of the lower esophageal sphincter (LES).
Achalasia Achalasia subtypes are divided into Type 1 (classic), Type 2 (compressive), and Type 3 (spastic). Manometrically, all three subtypes relay impairment in relaxation of the LES with median IRP >15 mmHg, however, differ by their topographic presence of pressurization and contraction patterns [21]. According to the CC, achalasia type 1 refers to absence of peristalsis or esophageal pressurization. Achalasia type 2 denotes absence of peristalsis and pan-esophageal pressurization in greater than or equal to 20% of the swallows. Achalasia type 3, shows premature contractions defined by a DL of less than 4.5 s in greater than or equal to 20% of the swallows. Fig. 5 shows different types of achalasia. Achalasia is the best understood and most studied esophageal motility disorder and will be addressed in a separate chapter.
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FIG. 4 Secondary peristalsis on HREM. Courtesy of Temple University Hospital GI Motility Lab.
EGJ outflow obstruction EGJ outflow obstruction is characterized by intact peristalsis present on HREM with incomplete relaxation of the LES (median IRP greater than 15 mmHg) [14] (Fig. 6). It's a challenging topic in a sense that its clinical significance is not definitive, and it is unclear as to taking the next steps to evaluate after manometric diagnosis. It can be an isolated event or be present with other esophageal abnormalities. EGJOO findings can be functional, incidental, or as a result of an anatomic abnormality caused by a stricture or neoplasm. It can also be an incompletely expressed or early achalasia [22]. One study has shown that despite preserved esophageal peristalsis in EGJOO, abnormal bolus transit can still result suggesting presence of additional factors contributing to the disorder. The three most common symptoms that were reported to have association with EGJOO and abnormal bolus transit were dysphagia, heartburn, and regurgitation. Conversely, symptomatic correlation to bolus clearance alone remains unclear and a substantial number of patients have spontaneous symptomatic alleviation or no bolus stagnation [23]. It is often logical for patients with this abnormal manometric finding to undergo barium swallow for evaluation for delayed emptying to delineate the result from a true correlation to a false positive or an artifact. Of note, the CC currently does not include the analysis of esophageal impedance on HREM for bolus clearance as part of the criteria. As mentioned previously, other advanced procedures such as EUS or Endoflip can aid to find a relationship. In cases with incidental findings with asymptomatic patients undergoing HREM (i.e., Pre-lung transplant evaluation, Pre-bariatric surgical evaluation, or undergoing HREM for LES localization for 24 h pH testing), it's reasonable to observe them. In patients with concomitant symptoms to findings of EGJOO on manometry and/or other studies, botulinum toxin injection, pneumatic dilation, and/or Heller myotomy may be effective [24]. It is important to note that many different factors can falsely display elevation of IRP on HREM suggesting impaired LES relaxation and may give a diagnosis of EGJOO. Such factors include opioid use, tachypnea, and misplaced catheter position into a large hiatal hernia [25]. Rapid respirations, such as in patients with underlying respiratory disorders or experiencing distress during the procedure, can shorten the duration between crural diaphragmatic contractions on topography not allowing for proper calculation of the IRP when present in close proximity to each other. To improve the diagnostic yield of a true impairment of LES relaxation, provocative or adjunctive testing can be utilized [8], though no set criteria exist for analysis. Multiple rapid swallow (MRS) continues to be an emerging topic of further
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(A)
(B)
(C) FIG. 5 (A) Achalasia Type 1 on HREM. (B) Achalasia type 2 on HREM. (C) Achalasia type 3 on HREM. Courtesy of Temple University Hospital GI Motility Lab.
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FIG. 6 EGJ outflow obstruction with IRP of 19.1 on HREM. Courtesy of Temple University Hospital GI Motility Lab.
interest and its clinical relevance is evolving. It is simple, quick, and entails drinking small volumes of liquid in 4–6 consecutive swallows, triggering a profound deglutitive inhibition of the LES pressures without esophageal contractions during the swallows, followed by a strong peristaltic reserve of the distal esophageal body. The rationale for MRS is that increasing the volume and viscosity of the bolus may trigger a more vigorous esophageal contraction and thereby pressurization on topography. It can help in differentiating functional EGJ obstruction from an achalasia variant [26].
Major disorders of peristalsis Major disorders are characterized into diffuse esophageal spasm (DES), jackhammer esophagus (JE), and absent contractility (AC). These disorders of peristalsis refer to abnormalities that are rarely found in healthy individuals [8,27].
Diffuse esophageal spasm Diffuse esophageal spasm (DES) is characterized by contractions that are normal in amplitude, but that lack coordination, and result in rapid velocity simultaneous contractions, impairing bolus transit from the mouth to the stomach. It is predominantly associated with dysphagia and non-cardiac chest pain [28]. The pathophysiology of DES is not entirely understood, but is theorized that deficiency of nitric oxide in the body of esophagus and increase in acetylcholine release may play a role in causing premature contractions in the distal muscularis propria [29]. Other etiologies include increased acid reflux or with presence of other nerve or motor disorders [30]. Classically, on a barium swallow and EGD, a “corkscrew” appearance can be demonstrated [31]. EUS may display thickening of circular and longitudinal muscles. HREM shows a normal IRP with a distal latency less than 4.5 s in greater than or equal to 20% of the swallows, suggesting premature (spastic) contractions along with rapid and simultaneous contractions that may be present [14] (Fig. 7). Tertiary contractions could also be evident. Since DES and JE share similar concepts of suspected pathophysiology, treatment option will be discussed together in the next section.
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FIG. 7 Diffuse esophageal spasm on HREM. Courtesy of Temple University Hospital GI Motility Lab.
Jackhammer esophagus Jackhammer esophagus (JE) is a rare condition that is characterized on HREM as hypercontractile distal esophagus with a DCI greater than 8000 mmHg in greater than or equal to 20% of the swallows with preserved peristalsis [14] (Fig. 8). Previously categorized into nutcracker esophagus and JE, it now exists as one entity in the CC. Dysphagia is a common presenting symptom, though GERD may play a role in provocation of hypercontractile contractions. Little is known about the correlation between symptoms and contraction vigor [32]. A recent study suggests that different phenotypes of JE exist and have been linked to associated symptomology such as chest pain, but further studies are needed to solidify the relationship [33]. Its pathophysiology is similar to DES in that little is known about the exact mechanism; however neurochemical pathways and hypersensitivity may play a role. A small percentage of these patients may progress to achalasia [34]. Therapy overall has yielded disappointing results, however can be tried. The primary goal of treatment for both DES and JE should focus on symptomatic control. Initial steps include lifestyle modifications to reduce stress, improve dietary intake, acid suppression, and assessment of psychosocial factors. After which, pharmacological treatments can be considered. The mainstay of medical therapy is to enhance nitric oxide availability and relax the smooth muscle of the esophagus. These include calcium channel blockers (i.e., verapamil and nifedipine), nitrates (short acting and long acting), and 5-phosphodiesterase inhibitors (sildenafil). Peppermint oil has also been shown to have some benefit. Low dose tricyclic antidepressants such as imipramine have shown some success as well [34,35]. If symptoms persist despite medical intervention, botulinum treatment can be considered. Botulinum toxin can inhibit the excitatory acetylcholine release [36–38] and in theory should weaken spastic esophageal contractions allowing for symptoms to improve. Although considered relatively safe, treatments with repeated botulinum toxin injections carry unclear long term safety and efficacy. It is recommended to inject 100 units of botulinum toxin diluted in 10 mL of saline in four quadrants at 2 cm and 7 cm above the EGJ. Should this fail, endoscopic intervention with per-oral endoscopic myotomy (POEM) can be performed. POEM involves severing the musculature of the esophagus to prevent contractions and is performed endoscopically without requiring any surgical incisions. The technique requires mucosal incision to gain entry into the submucosa and creating a tunnel that extends into the gastric cardia, then performing a myotomy, followed by closure of mucosal incision leading to the tunnel [39]. POEM is an emerging and promising technique that can be an alternative to Heller myotomy in treatment of spastic esophageal disorders [40]. Its advantage holds from the ability to perform the procedure per orally
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FIG. 8 Jackhammer esophagus on HREM. Courtesy of Temple University Hospital GI Motility Lab.
with an intraluminal approach and can be performed for both the circular and longitudinal muscles at any length within the esophagus. Short term clinical success for achalasia based on a study by Inoue et al. utilized the post-POEM Eckardt's score and suggested this technique was highly effective [41]. Other studies that used standardized questionnaires from patients showed significant improvement in quality of life [42]. Long term efficacy data is lacking, though accumulating as more studies are being conducted and longer term follow up is being done [43]. A systematic review and meta-analysis by Khan MA et al. showed POEM is an effective and safe therapeutic modality for treatment of spastic esophageal disorders. They also revealed clinical success based on Eckardt's score was 87% for all spastic esophageal disorders; 92% for achalasia type III, 88% for DES, and 72% for JE [40]. In summary, POEM appears to show good success in patients suffering from these spastic disorders that have been resistant to other more conservative therapies. DES and JE often result in functional limitations for patients, but generally are not life-threatening.
Absent contractility Absent contractility is described by the presence of normal LES relaxation (IRP <15 mmHg) without a scorable contraction (absence of peristalsis) (Fig. 9). The general pathophysiology involves muscles of the esophagus undergoing atrophy, whether it's by fibrotic changes or by having abnormalities in the neuronal innervation. Unfortunately, it affects both the LES and the esophageal body, predisposing subjects to increased reflux associated complications, such as esophagitis, peptic strictures, and Barrett's esophagus. Hence, a strong attention to adequate acid suppression is recommended. It is associated with interstitial lung disease and mixed connective tissue disease such as scleroderma, though patients in these cohorts may present with normal motility or ineffective esophageal motility. Other contributors to absent esophageal contractility include sjögren syndrome, systemic lupus erythematosus, multiple sclerosis, Type 1 diabetes mellitus, myotonic dystrophy, chest radiation therapy, and sarcoidosis. It is also important to consider achalasia in the manometric diagnosis of absent
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FIG. 9 Absent contractility on HREM. Courtesy of Temple University Hospital GI Motility Lab.
contractility, as challenges with LES calculations may mislead diagnosis. Patients with this major peristaltic disorder also suffer from a longer duration of symptoms that negatively impacts their quality of life. In particular, presence of interstitial lung disease and scleroderma predict greater severity in esophageal dysfunction [44]. Furthermore, it is also clinically relevant in patients being evaluated for bariatric surgery, fundoplication, and lung transplant as there is a relative contraindication given the risk of developing post-surgical dysphagia and/or graft loss [45]. It is unclear if provocation testing such as multiple rapid swallows may be beneficial alongside standard esophageal manometry testing. Given the pathology of the disease process, treatment can be difficult for restoring peristalsis, and damage is often permanent. Medication therapy has not proven to be effective either, though some will try bethanechol to improve esophageal motility. A small subset of patients with uncontrolled GERD may present to surgeons for evaluation of anti-reflux surgery [46] and have absent peristalsis on esophageal manometry. Often, these patients are at risk for poor outcome, and hence surgery is best avoided. In patients general, surgery is not recommended, though there are some studies looking at the benefit of partial fundoplication in those with GERD and absent peristalsis [47].
Minor disorders of peristalsis Minor disorders of peristalsis include ineffective motility and fragmented peristalsis. These disorders have a poor correlation with symptoms, have unclear clinical significance, the majority do not progress in severity, and they can be seen in healthy asymptomatic volunteers [8].
Ineffective esophageal motility Ineffective esophageal motility (IEM) is characterized on HREM by normal LES relaxation (IRP <15 mmHg) and ≥50% ineffective swallows that is failed or weak (DCI < 450 mmHg × s × cm) [14] (Fig. 10). Though the pathophysiology is unclear,
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FIG. 10 Ineffective esophageal motility on HREM. Courtesy of Temple University Hospital GI Motility Lab.
it is theorized that inflammatory mediators may play a role in causing an intermittent defect in normal muscle contraction. Other etiologies that are hypothesized to cause ineffective motility are rapid food intake, advanced age, and vagal hyperreactivity [48–52]. It has a known association with acid exposure to the esophagus, particularly in the supine position [53,54]. For these patients, acid suppression tends to be beneficial. In the opposite spectrum with cases of normal acid exposure and persistence of symptoms, treatment options remain limited. As the motility field continues to evolve, novel therapies continue to arise. One of them is buspirone, a serotonin receptor agonist, which has shown some efficacy in improving esophageal peristalsis and LES function making this therapy an option for patients with treatment resistant IEM [55].
Fragmented peristalsis Fragmented peristalsis is defined on HREM as large breaks in intact peristalsis >5 cm in >50% of the swallows [14] (Fig. 11). In theory, it's reasonable to consider that breaks in peristalsis would correlate with stagnation of bolus and dysphagia; however studies have found that this is not the case. Breaks in peristalsis on topography are often noted in healthy subjects, poorly correlate to bolus stagnation, and weakly associated with symptoms [56,57]. This knowledge questions the significance of this minor disorder. Its long-term implications are also unclear, though it may be a marker of esophageal hypomotility [58], and in the future, could be used as a prognostic factor as more research continues to shed light.
Miscellaneous pathologies There are several other etiologies that can impair esophageal motility. These include infections, autoimmune disorders, pharmacologic agents, toxins such as opioids and alcohol. Each can present with its own characteristic manometric pattern or it can have findings of unclear significance.
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FIG. 11 Fragmented peristalsis on HREM. Courtesy of Temple University Hospital GI Motility Lab.
Mixed connective tissue disease (MTCD) MTCD is an autoimmune process that is a common cause of secondary esophageal motility disorders. The most common symptoms are acid reflux, heartburn, and regurgitation [59]. Few patients may experience dysphagia or odynophagia. The proximal one-third of the esophagus is striated muscle and is typically involved with polymyositis (PM) and dermatomyositis (DM), whereas the distal two-thirds of the esophagus encompasses smooth muscle and is involved in scleroderma/systemic sclerosis. Systemic sclerosis can cause smooth muscle atrophy and fibrosis of the esophagus. Complications can lead to esophagitis, Barrett's esophagus, strictures, and candidiasis. It is suspected that microvascular damage to the esophagus may lead to hypo-perfusion and ischemia, further leading to neuronal damage by compression and/or inflammation ultimately resulting in fibrosis [60]. Manometrically, the disease may progress from weak peristaltic contractions (IEM) to lack of peristalsis with diminished EGJ integrity (absent contractility). An autoimmune workup is recommended for these patients, as they could potentially benefit from rheumatic therapy, however as mentioned earlier, it is unlikely to restore lost motility as fibrosis is often a permanent. In theory, any skeletal muscle disorder can impair the process of swallowing and cause dysphagia. However, polymyositis and dermatomyositis have been linked with involvement of the esophagus, often causing dysphagia [61]. It has been theorized to caused by the inflammation and dysfunction of the skeletal muscles. Cricopharyngeal muscles and other muscles that initiate swallowing could also be involved [62]. These patients present with an increased risk of aspiration events that can lead to pneumonia. Treatment modalities focus on symptomatic control and management of the inflammatory disorders. There is also often an overlap between PM/DM and systemic sclerosis/scleroderma, which can guide better immunosuppressive therapy. It is important to note that many of these mechanisms are speculative, and knowledge is limited on detailed aspects of the pathophysiology of MCTD in the esophagus.
Opioid-induced esophageal dysfunction Opioids have been known to cause adverse effects on various parts of the gastrointestinal tract, such as the colon, however its effects on the esophagus are not clearly understood [63–66]. A study from 1983 by Rattan S et al. identified and localized opioid receptors in an animal model and concluded that both inhibitory and excitatory opioid receptors
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exist in the LES [67]. Since then there have been only few studies that have looked at conventional esophageal manometry and its correlative metrics, but have yielded conflicting data. However, the evolution of HREM has found a link in chronic opioid users. Though the mechanism is unclear, it has been widely documented that opioids can contribute to abnormal metrics on HREM supporting esophageal dysfunction. It can cause one or more of the following: impaired LES relaxation, simultaneous contractions, and high amplitude/velocity peristalsis [68] (Fig. 12). Ratuapli SK et al. showed based on the CC, the predominant disorders observed were EGJOO, achalasia type II, achalasia type III, and JE for those using opioids within at least 24 h of manometry testing [69,70]. They theorized that imbalance in nitric oxide and cholinergic neuronal response resulted in excitatory output with spastic and hypertensive esophageal contractions. Hence, it is of value to suggest cessation of opioids for at least 24 h prior to performing HREM to achieve higher diagnostic yield and recommend complete cessation for those having symptomatic association with abnormal manometry readings. If cessation is not possible as this is often the case, it is recommended that the dosage be reduced to the lowest effective dosage. Botulinum toxin injections may be considered as a temporary option until opioids can be tapered off. Calcium channel blockers have provided very little help and pneumatic dilations have shown poor results. Heller myotomy or POEM can be considered, particularly in patients that don't improve after stopping opioids or will be remaining on opioids long term.
Infection related dysmotility Post infectious parasitic or viral illnesses can directly affect the neuronal innervation and musculature of the esophagus. There have been implications in neuronal innervation from human immunodeficiency virus (HIV), infectious mononucleosis [71], and polio virus leading to dysphagia. Chagas disease caused by Trypanosoma cruzi is also a well-known culprit in neuronal damage to the smooth muscles of the esophagus and may lead to achalasia or mega-esophagus. HIV can cause a plethora of opportunistic esophageal infections, such as candida, cytomegalovirus, and herpes simplex virus; however can
FIG. 12 An example of opioid induced esophageal dysfunction on HREM. Courtesy of Temple University Hospital GI Motility Lab.
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also independently cause esophageal dysmotility [72]. Hypercontractile contractions, incomplete LES relaxation, and/or non-specific dysmotility can been seen on HREM.
Pharmacologic agents and toxin induced esophageal dysfunction Pharmacologic agents that can affect both the skeletal muscle and smooth muscle are anticholinergics, antimuscarinics, neuromuscular blocking agents, antineoplastics, immunosuppressants, antiemetics, benzodiazepines, narcotics, skeletal muscle relaxants, antibiotics, anti-arrhythmics, aspirin, bisphosphonates, NSAIDs, iron products, potassium chloride, vitamin C, anti-Parkinson agents, antiretroviral agents, botulinum toxin, tetanus toxoid, and anti-viral agents [73–75]. Long-term use of high-dose corticosteroids can also induce proximal esophageal striated skeletal muscle atrophy causing dysphagia [73]. When evaluating for esophageal disorders, careful history and medication reconciliation is suggested as immunosuppressive therapy can disrupt the esophageal mucosa allowing for opportunistic infections resulting in dysphagia. Among many harmful effects of alcohol, both acute and chronic ingestion can cause esophageal dysmotility by impairing LES relaxation and lowering contraction vigor [76,77].
Vascular artifacts on HREM Some of the artifacts that can be present on HREM can be clinically significant or can be considered irrelevant. Cardiovascular structures compressing the esophagus can produce analytical disturbance on topography by the presence of horizontal pulsatile pressure system bands on HREM [78] (Fig. 13). This can be present in normal healthy volunteers and often bear no pathological implication. In contrast, some have known associations such as dysphagia lusoria, which
FIG. 13 An example of a vascular band on HREM. Courtesy of Temple University Hospital GI Motility Lab.
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is an anatomic abnormality that is caused by an aberrant right subclavian artery that is often responsible for dysphagia [79,80]. Treatment is usually surgical with repair/reconstruction if functional limitation is present. There is also a relationship with atherosclerosis and calcification of the distal thoracic aorta in elderly and its compressive effects causing difficulty swallowing, known as dysphagia aortica [81,82]. Left atrial enlargement with mitral valve disease and congestive heart failure can also compress the distal esophagus leading to dysphagia [83,84]. Vascular structural artifacts are a common phenomenon noted on HREM that are not routinely evaluated and it has been poorly studied in the literature in terms of its significance and prevalence.
Conclusions Disorder that affect esophageal body are important because they can diminish the quality of life for many patients. HREM and the CC have been invaluable for evaluating esophageal function and classifying these disorders [85]. Advances in diagnostic modalities, treatment options, and deeper understanding of the pathophysiology of esophageal disorders have revolutionized patient care, though there is still a large unmet need. A myriad of research studies are underway that hopefully will answer questions yet unanswered. Further studies are needed to better understand the pathophysiology of different disorders. Including evaluation of diagnostic modalities such as Endoflip, and treatment modalities such as new medications that can affect GI motility and POEM procedures.
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