Lower Esophageal Sphincter Relaxation Research Articles

Na+ /Ca2+ exchanger 1 is a key mechanosensitive molecule of the esophageal myenteric neurons.

Our earlier studies showed that mechanical stretch activates inhibitory motor neurons of the oesophagus; however, the underlying molecular mechanisms are unclear. Here, we sought to examine if Na+ /Ca2+ exchanger 1 (NCX1) is responsible for the mechanosensitivity in the esophageal myenteric neurons (EMN) of rats and humans. The function of NCX1 in primary culture of neurons was determined using calcium imaging, and mechanosensitivity was tested using osmotic stretch and direct mechanical stretch. Axial stretch-induced relaxation of the lower esophageal sphincter (LES) was also studied in vivo in rats. The expression and co-localization of NCX1 with nNOS were identified in the EMN from both rats and humans. The extracellular Ca2+ entry caused by ATP through purinergic signalling in the rat EMN was significantly inhibited by selective NCX blockers. Removal of extracellular Na+ to activate the Ca2+ entry mode of NCX1 induced an increase in the cytoplasmic calcium ([Ca2+ ]cyt ), which was attenuated by NCX blockers. Osmotic stretch and mechanical stretch-induced [Ca2+ ]cyt signalling in the rat and human EMN were attenuated by NCX blockers as well as specific NCX1 knockdown. Osmotic stretch and mechanical stretch also induced [Ca2+ ]cyt signalling in the Chinese hamster ovary (CHO) cells with NCX1 over-expression, which was attenuated by NCX blockers. Finally, NCX blockade inhibited axial stretch-activated LES relaxation in vivo experiments in the rats. We demonstrate a novel NCX1/Ca2+ pathway in the mechanosensitive neurons of rat and human oesophagus, which may provide a potential therapeutic target for the treatment of oesophageal motility disorders.

Upper Esophageal Sphincter (UES) Abnormalities Are a Frequent Finding on High Resolution Manometry (HREM) and Associated With Esophageal Motility Disorders (EMD)

Introduction: While there has been an increased frequency of UES abnormalities noted among patients with esophageal motility disorders (EMD), the Chicago Classification for manometric disorders does not comment on UES findings. Here, we assess the frequency and type of UES abnormalities among patients referred for HREM; the frequency of UES abnormalities among patients with EMD (achalasia and esophagogastric junction outflow obstruction (EGJOO)); bolus clearance, lower esophageal sphincter (LES) and UES residual pressures to determine the severity of disease in patients with both EMD and a UES abnormality and; if presence of UES abnormalities in patients with EMD is associated with poor treatment response. Methods: This retrospective study at 3 tertiary care hospitals identified 136 consecutive patients referred for HREM to assess for a suspected motility disorder from 10/2016-10/2017. UES pressures were measured before 10 wet swallows. HREM reports were analyzed for UES, LES and bolus transit abnormalities. Medical records were reviewed for demographic data. Results: UES abnormalities were present in 38% (n=51) of all patients referred for HREM (n=136) and in 43% of 54 patients with EMD. Of those with UES abnormalities present, 45% (n=23) had an EMD. Of these individuals, 61% (n=14) were diagnosed with EGJOO and 39% (n=9) with achalasia (predominantly Type II (n=7/9)). There was a significant correlation between impaired LES residual pressure and UES residual pressure (r=0.238, P=0.005) in patients with EMD. Incomplete bolus clearance was not significantly associated with UES pressure abnormalities (p=0.48, CI: 0.5699 to 3.3019). Data on treatment response was captured in 35 patients with EMD (57% had pharmacological treatment, 1 had fundoplication, and 46% had combined pharmacological and procedural treatment). There was a trend towards presence of UES abnormalities in EMD with poorer outcomes but was not statistically significant (p=0.37). Botox therapy was performed more commonly in the treatment of EMD with normal UES (62%) compared to those with abnormal UES (24%). Conclusion: There appears to be a significant correlation between impairment in UES and LES relaxation, suggesting a shared pathophysiological mechanism. A stratification scheme, based on pathophysiological defect, and inclusion of UES findings while evaluating EMD patients may help in understanding this increasingly common but undoubtedly heterogeneous syndrome and facilitate the development of targeted therapies.

Return of Peristalsis After Heller Myotomy: A Rare Case

Achalasia is characterized by esophageal aperistalsis and failure of lower esophageal sphincter (LES) relaxation. Anatomical abnormalities lead to dysphagia, heartburn, regurgitation, epigastric or noncardiac chest pain. We present a case of a patient with achalasia II who had return of peristalsis after Heller myotomy. A 48-year-old female presented with dysphagia, regurgitation and a 40 lbs weight loss in 3 months. Significant past medical history of acid reflux disease, H. Pylori and a 9.5 pack year smoking history. On upper endoscopy (EGD) the gastroesophageal junction was tight and therapeutically dilated. High-resolution esophageal manometry (HRM) confirmed achalasia II with high-integrated relaxation pressure, and panesophageal pressurization. (Image 1) One month later, she underwent Heller myotomy with Dor fundoplication. Over the next 8 months her symptoms recurred requiring 3 dilations. Repeat HRM showed LES relaxation with a high normal IRP. There was esophageal compartmentalized pressurization, esophageal foreshortening and evidence of peristaltic contractions not seen on the prior HRM (Image 2). We believe her recurrent symptoms were due to the fundoplication. HRM increased understanding of achalasia and led to the Chicago Classification currently in version 3.0. Chicago Classification has 3 subgroups with achalasia under the first group. Literature review revealed a handful of patients with return of peristalsis after intervention. Ponce et al.1 and Parrilla et al.2 reported return of peristalsis in patients after Heller's myotomy. The subset of achalasia patients that regain peristalsis after correcting LES obstruction could be explained by three scenarios. First, HRM may inadequately differentiate EGJ outflow obstruction and achalasia. Second, this may be a very early diagnosis of achalasia. Third, this may be a new phenotype that becomes apparent after intervention. Functional lumen imaging probe (FLIP) topography may have an adjunct role for clear classification of phenotypes. Carlson et al.3 reported a 31% variability in achalasia II patients using FLIP topography compared to HRM. Further research and continued monitoring is required to properly diagnose and classify patients with return of peristalsis after therapeutic intervention.1706_A Figure 1 No Caption available.1706_B Figure 2 No Caption available.

Successful Treatment of a Severe Case of Corkscrew Esophagus With Sildenafil

This report presents an interesting case of progressive esophageal dysmotility and highlights the successful use of sildenafil in a patient with severe corkscrew esophagus. A 55-year-old female presented with dysphagia over the course of three years, which progressively worsened over the past 6 months. She reported feeling the food “sitting in her chest” and she would subsequently develop squeezing chest pain. She denied nausea, vomiting, or pyrosis. Multiple subsequent endoscopies noted tortuous esophagus. A high-resolution manometry study was performed and was normal except for rapid swallows. A 24-hour pH impedance study showed no reflux. An esophagram was normal, except for smooth tapering of the distal esophagus with delayed passage of 13 mm barium tablet. Two years after her initial workup, she was referred to our center due to progressively worsening symptoms for a repeat manometry, which showed esophagogastric outflow obstruction with elevated basal LES pressure at 55 mmHg. LES relaxation was also abnormal, with a residual pressure of 28.8 mmHg. The majority of swallows failed, and the remaining were peristaltic but rapid with a repetitive spasm pattern. This raised suspicion for an achalasia variant. A repeat esophagram was performed, which then revealed a corkscrew esophagus. (Fig. 1) Patient did not respond to a botulinum toxin injection in the LES and failed other treatments including PPI, diltiazem, and neuromodulators. Patient was then prescribed sildenafil 25 mg PO BID but was rejected by her insurance, citing insignificant evidence for treatment of corkscrew esophagus, but the decision was reversed after detailed discussion with the medical director. Patient then reported complete resolution of her chest pain and dysphagia, noting “this is the first time I felt normal in three years.” After one year, patient continues to have symptoms under control. This report shows that motility disorders of the esophagus can be progressive. It also shows the need for combining clinical, endoscopic, and radiological findings, and not solely depending on motility testing, which did not show features of classic type III achalasia, or distal esophageal spasm. Additionally, sildenafil caused a dramatic improvement in the patient's symptoms. Further publications should be encouraged evaluating sildenafil in the treatment of spastic and hypercontractile esophageal disorders, as many insurance companies reject it for this treatment.1792 Figure 1. Esophagram demonstrating corkscrew esophagus

Esophageal dysmotility: An intrinsic feature of megacystis, microcolon, hypoperistalsis syndrome (MMIHS)

ObjectivesMegacystis–microcolon–hypoperistalsis syndrome (MMIHS) also called Berdon's Syndrome, is a smooth muscle myopathy that results in an enlarged bladder, microcolon, and small bowel hypoperistalsis. In our series of six patients with this disorder, all had disordered swallowing. Therefore, we prospectively characterized esophageal structure and function in all. MethodsDiagnoses had been established by contrast radiography, small bowel manometry, and urodynamic studies. To investigate the esophagus, we endoscoped and biopsied the esophagus of each patient on multiple occasions. All patients also underwent water soluble contrast esophagography and esophageal manometry. ResultsUpon careful questioning, all patients had swallowing dysfunction, and the majority of their enteral intake was via gastrostomy or gastrojejunostomy. All took some oral alimentation, but eating was slow and none could aliment themselves completely by the oral route, receiving 50% or less of their calories by mouth. Four had megaesophagus whereas the esophagus of the two youngest was of normal caliber. All had eosinophilic esophagitis and/or esophageal Candidiasis from time to time, but successful treatment of these findings failed to improve their symptoms. Manometry revealed normal lower esophageal sphincter (LES) resting tone and normal LES relaxation, but for all, peristalsis was absent in the esophageal body. ConclusionsThis series expands the spectrum of findings in MMIHS, to include a primary motility disorder of the esophageal body. As patients age, the esophageal caliber appears to increase. Successful treatment of neither esophageal eosinophilia nor Candidiasis is effective in ameliorating the motility disorder. If our findings are confirmed in more patients with MMIHS, this disorder should be renamed, megacystis–microcolon–intestinal-and esophageal hypoperistalsis syndrome. Type of studyPrognosis study, Level IV (case series).

RA06.01: PATHOLOGICAL IMPLICATIONS OF SWALLOW-ASSOCIATED TRANSIENT LOWER ESOPHAGEAL SPHINCTER ELEVATION

Abstract Background We have previously reported that swallow-induced transient hiatal hernia (tHH) is associated with pathological gastroesophageal reflux. In this study, we built upon our previous study of tHH, assessing the pathological implications of swallow-induced tHH in a new, larger cohort. Methods We queried a prospectively maintained database to identify patients who underwent both 24-hour pH monitoring and high-resolution manometry (HRM) between January 2017 and December 2017. We excluded patients with end-stage lung disease, inadequate LES relaxation, major esophageal motility disorders, or manometric hiatal hernia. Significant swallow-induced LES–CD separation was defined as ≥ 1 cm separation in ≥ 30% swallows or ≥ 2 cm separation in ≥ 10% swallows. We used HRM to separate patients into 3 groups, as follows: 1. Persistent tHH (p-tHH): Significant LES–CD separation at the 2nd inspiration after the conclusion of swallow-induced esophageal peristalsis. 2. Incident tHH (i-tHH): Significant LES–CD separation at the 1st inspiration after the conclusion of peristalsis without meeting p-tHH criterion. 3. Non-tHH: Neither p-tHH nor i-tHH was observed. Results In total, 472 patients underwent both HRM and a 24-hour pH study during the study period. Of these, 74 patients met inclusion criteria. The mean age was 51.6 years, and 45 patients (60.8%) were women. Forty-two patients (56.8%) had an abnormal DeMeester score (ie, > 14.72). Fourteen patients (18.9%) were categorized into the p-tHH group, 36 (48.6%) were in the i-tHH group, and 24 (32.4%) were in the non-tHH group. LES pressure, LES pressure integral, esophageal peristaltic vigor, and prevalence of dysmotility were similar among the groups. No significant differences were observed in the pH studies for patients with i-tHH and non-tHH; however, patients in the p-tHH group had a higher prevalence of abnormal DeMeester score and longer total acid reflux time than patients in the non-tHH cohort (78.6 vs 45.8%, P < 0.05; 8.0 vs 3.8%, P = 0.016, respectively). Conclusion We confirm that p-tHH is associated with pathological distal esophageal acid exposure and appears to be an early indicator of LES dysfunction. Disclosure All authors have declared no conflicts of interest.

Risk factors for gastroesophageal reflux disease and analysis of genetic contributors.

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder with an increasing prevalence. GERD develops when the reflux of stomach contents causes troublesome typical and atypical symptoms and/or complications. Several risk factors of GERD have been identified and evaluated over the years, including a considerable amount of genetic factors. Multiple mechanisms are involved in the pathogenesis of GERD including: (1) motor abnormalities, such as impaired lower esophageal sphincter (LES) resting tone, transient LES relaxations, impaired esophageal acid clearance and delayed gastric emptying; and (2) anatomical factors, such as hiatal hernia and obesity. Genetic contribution seems to play a major role in GERD and GERD- related disorders development such Barrett’s esophagus and esophageal adenocarcinoma. Twin and family studies have revealed an about 31% heritability of the disease. Numerous single-nucleotide polymorphisms in various genes like FOXF1, MHC, CCND1, anti-inflammatory cytokine and DNA repair genes have been strongly associated with increased GERD risk. GERD, Barrett’s esophagus and esophageal adenocarcinoma share several genetic loci. Despite GERD polygenic basis, specific genetic loci such as rs10419226 on chromosome 19, rs2687201 on chromosome 3, rs10852151 on chromosome 15 and rs520525 on the paired related homeobox 1 gene have been mentioned as potential risk factors. Further investigation on the risk genes may elucidate their exact function and role and demonstrate new therapeutic approaches to this increasingly common disease.

Effects of bariatric surgery on the esophagus.

Bariatric surgery is the best therapeutic approach to patients with morbid obesity, but there is mounting evidence that it is associated with esophageal dysfunctions, including gastroesophageal reflux disease (GERD) and motor disorders. In the present review, we summarize the existing information on the complex link between bariatric surgery and esophageal disorders. Although high-quality studies on these effects are lacking, because of evident methodological flaws and retrospective nature, the review of published investigations show that pure restrictive procedures, such as laparoscopic adjustable gastric banding (LAPG) and laparoscopic sleeve gastrectomy (LSG), are associated with de novo development or worsening of GERD. Moreover, LAGB is the procedure with the greatest frequency of esophageal motor disorders, including impairment of LES relaxation and ineffective esophageal peristalsis associated with esophageal dilation. LSG seems to be less associated with esophageal dysmotility, although evidence derived from studies with objective measurements of esophageal dysfunction is limited. Finally, RYGB seems to be the best procedure for improvement of GERD symptoms and preservation of esophageal function. Overall, the restrictive-malabsorptive approach represented by RYGB must be preferred to pure restrictive operations in order to avoid the negative consequences of bariatric surgery on esophageal functions.

Periprocedurálne komplikácie POEM

Introduction : Achalasia is a primary rare esophageal motility disorder characterized by the aperistalsis with concomitant abscence of relaxation of lower esophageal sphincter. A significant advance in treatment was the introduction of a new technique -peroral endoscopic myotomy (POEM). In this work, we decided to focus on the periprocedural complications of POEM in our patients. Methods: Retrospectively, we evaluated the incidence of periprocedural complications in patients with esophageal achalasia who had undergone POEM. Results: Of the total number of 136 patients, 132 patients received POEM successfully. In most patients was performed POEM anterior (n = 109), POEM posterior was performed in 23 patients. A total of 50 patients (38%) experienced some type of complication during surgery. The most frequent complication was thermal damage of the mucosa (27.3%). The second most common complication was capnoperitoneum (14%). Severe capnoperitoneum was present in 5 patients (3.8%). Subcutaneous emphysema was observed in 6 patients (4.5%). Seven patients (6%) experienced periprocedural perforation. Of all the complications, two required subsequent surggical treatment. There was no performance-related death in our patient population. Conclusion and discussion: POEM is a worldwide accepted therapy for achalasia. It is generally considered to be a safe method with low incidence of serious adverse complications. Data on the incidence of peroperative complications vary, particularly in what is considered to be a complication and what is a normal part of surgery. However, the important fact remains that severe life-threatening complications are rare.

Cholecystokinin induces esophageal longitudinal muscle contraction and transient lower esophageal sphincter relaxation in healthy humans.

Cholecystokinin (CCK) is known to cause lower esophageal sphincter (LES) relaxation through the activation of inhibitory motor neurons. CCK receptor agonists increase the frequency of transient LES relaxation through a peripheral mechanism. Recent studies show that the longitudinal muscle contraction (LMC)-related axial stretch might play a role in the LES relaxation by activating the mechanosensitive inhibitory motor neurons. The aim of our study was to determine whether the CCK-induced LES relaxation and the characteristics of LMC resemble those seen with spontaneous transient LES relaxation in humans. Nine healthy volunteers (5 Fr, 40 ± 12 yr) received escalating doses of CCK-octapeptide (CCK-8) (5, 10, 20, and 40 ng/kg). All subjects demonstrated a monophasic response to 5 ng/kg of CCK-8. In the majority of subjects, this response consisted of partial LES relaxation. All subjects showed a biphasic response to 40 ng/kg of CCK-8. The latter in most subjects consisted of 1) a period of partial relaxation followed by 2) complete LES relaxation along with crural diaphragm inhibition. The length of the esophagus decreased by 0.9 ± 0.4 cm, and muscle thickness increased by 40 ± 14% to 1.4 ± 0.2 mm ( P < 0.05) during initial partial LES relaxation. During complete LES relaxation there was greater LMC, as demonstrated by an esophageal shortening of 1.9 ± 0.5 cm and an increase in muscle thickness of 100 ± 16% ( P < 0.01). The complete phase 2 LES relaxation typically terminated with a robust after-contraction. Atropine significantly attenuated the CCK-induced esophageal LMC, prevented crural diaphragm inhibition, and abolished the phase 2 complete LES relaxation. NEW & NOTEWORTHY The phenotypic features of CCK-induced longitudinal muscle contraction (LMC), complete lower esophageal sphincter (LES) relaxation, and crural diaphragm inhibition, followed by a robust after-contraction, resemble those seen during spontaneous transient LES relaxation. A strong temporal relationship between the LMC and complete transient LES relaxation supports our hypothesis that the LMC plays an important role in the LES relaxation and crural diaphragmatic inhibition.

Estradiol mediates relaxation of porcine lower esophageal sphincter

Most pregnant women have symptoms of gastroesophageal reflux disease (GERD) during pregnancy. Postmenopausal hormone replacement therapy is associated with GERD. The effects of estradiol on lower esophageal sphincter (LES) motility and GERD are not clearly known. The purpose of this study is to investigate the effects of estradiol on the motility of the porcine LES. Relaxations of clasp and sling strips of porcine LES caused by estradiol were measured using isometric transducers. We investigated the mechanism of estradiol-induced relaxation of the porcine LES using tetraethylammonium, apamine, iberiotoxin, glibenclamide, KT5720, KT5823, NG-nitro-l-arginine, tetrodotoxin, and ω-conotoxin GVIA. Reverse transcription polymerase chain reaction (PCR) analysis and immunohistochemistry (IHC) were performed to determine the existence of the G protein-coupled estrogen receptor (GPER) in the porcine LES. In endothelin-1-precontracted porcine LES strips, estradiol caused marked relaxations in a concentration-dependent manner. The mechanism of estradiol-induced relaxation on the porcine LES was associated with the potassium channel. Reverse transcription PCR analysis and IHC revealed that GPER was expressed in the sling and clasp fibers of the porcine LES. This finding suggests that GPER mediates the relaxation of the porcine LES. Estradiol may play a role in LES motility.

Sa1091 - Effect of Citalopram on Esophageal Motility in Healthy Subjects. Implications for Transient Lower Esophageal Sphincter Relaxations, Dysphagia and Globus Pharyngeus

Sa1091 - Effect of Citalopram on Esophageal Motility in Healthy Subjects. Implications for Transient Lower Esophageal Sphincter Relaxations, Dysphagia and Globus Pharyngeus

Mo1538 - Both Incomplete Les Relaxation and Premature Contraction of Esophageal Body are Characteristics of Dry Swallow

Mo1538 - Both Incomplete Les Relaxation and Premature Contraction of Esophageal Body are Characteristics of Dry Swallow

Preliminary study of 1940 nm thulium laser usage in peroral endoscopic myotomy for achalasia.

Esophageal achalasia is a type of motility disorder characterized by incomplete relaxation of lower esophageal sphincter (LES) and absence of esophageal peristalsis. Peroral endoscopic myotomy (POEM) is a new treatment option for achalasia that is less invasive, more effective, and safe as compared to surgery. High-frequency electrotome is commonly used in POEM, but takes longer time to make the tunnel in the esophagus and causes many complications. The thulium laser decreases the risk of bleeding and perforation in endoscopy but has not been reported in digestive diseases, especially in POEM. Therefore, the aim of this study is to evaluate the feasibility of the 1940 nm thulium laser in POEM. From March 2015 to August 2015, five patients with achalasia at the Digestive department, Beijing Friendship Hospital, Capital Medical University, Beijing, China were included. Before the procedure, the patients' gender, age, and duration of symptoms were recorded. Eckardt symptom score and LES thickness, which measured by endoscopic ultrasonography, were recorded. While the subtypes of achalasia (according to the Chicago classification), lower esophagus sphincter resting pressure (LESRP) and integrated relaxation pressure (IRP) were measured by HRM for all patients. Barium esophagram was also used to rule out anatomical lesions, esophageal varices, or neoplasia, which may cause similar symptoms. All examinations were performed one week before POEM. POEM was performed with the 1940 nm thulium laser under general anesthesia. Eckardt score, procedure duration, myotomy length, and complications were recorded one week after POEM. All the patients were followed-up at two weeks and four weeks after POEM. POEM was successfully performed in all five patients. The mean age of the patients was 38.8 years (24-54 years). Achalasia subtypes were type I (n=1), II (n=2), and III (n=2). The operation duration was 186, 180, 111, 75, and 126 minutes for the five cases. Pre/postprocedure Eckardt scores were 3/0, 7/0, 5/1, 6/0, and 9/0. Pre/postprocedure LESRP (mmHg) were 45.3/26.4, 18.0/1.1, 25.8/10.4, 16.5/11.2, and 24.2/20.8. Pre/postprocedure IRP (mmHg) were 27.3/15.5, 15.4/4.2, 5.7/6.8, 15.5/10.1, and 13.1/14, respectively. No adverse events occurred during the procedure. After POEM, subcutaneous emphysema occurred in case 1 on the first day, which relieved spontaneously after two days without special intervention. Infection occurred in case 5 on the day of POEM was healed with antibiotics three days later. The 1940 nm thulium laser is feasible for POEM procedure. Further studies are needed to determine whether the 1940 nm thulium laser is better than high-frequency electrotome.

A Randomized Double-Blind, Placebo-Controlled, Cross-Over Study Using Baclofen in the Treatment of Rumination Syndrome.

Both rumination syndrome and supra-gastric belching (SGB) have limited treatment options. We demonstrated (open-label) that baclofen reduces pressure flow events in these patients. We aimed to study the effect of baclofen in a placebo-controlled, double-blind, cross-over study in patients with clinically suspected rumination and/or SGB. Twenty tertiary-care patients (mean age 42 years (range 18-61), 13f) with clinically suspected rumination and/or SGB were randomized to receive baclofen (10 mg, t.i.d) or placebo for 2 weeks with cross-over to the alternative intervention after a 1 week wash-out period. At the end of each treatment period, patients underwent a solid-state high-resolution impedance manometry measurement, during which they registered symptoms. Patients received a solid meal and recordings continued for 1 h. They scored overall treatment evaluation (OTE) on a -3 to +3 scale. Both the number of regurgitation event markers and rumination episodes were significantly decreased after baclofen (6 (0-19) vs. 4 (0-14), P=0.04; 13 (8-22) vs. 8 (3-11), P=0.004). The number of SGB episodes was similar in both groups. Lower esophageal sphincter (LES) pressure was significantly higher and the number of transient LES relaxations was significantly lower after baclofen (17.8 (12.7-22.7) vs. 13.1 (7.2-16.9) mm Hg, P=0.0002; 4(1-8) vs. 7(3-12), P=0.17). The number of reflux events decreased in the baclofen condition (4 (1-9) vs. 3 (0-6), P=0.03). Straining episodes were similar in both arms, but the rumination/straining ratio was significantly lower in the baclofen arm (0.06 (0-0.32) vs. 0.33 (0-0.51), P=0.0012). OTE was superior after baclofen compared to placebo (P=0.03). Baclofen is an effective treatment option for patients with rumination syndrome, probably through its effect on LES pressure.

Management of Functional Esophagogastric Junction Outflow Obstruction: A Systematic Review

Introduction: Esophagogastric Junction Outflow Obstruction (EGJOO) is an increasingly recognized disorder of incomplete lower esophageal sphincter (LES) relaxation with intact peristalsis and was first incorporated into the Chicago Classification (CC) for high resolution manometry in 2012. EGJOO may be idiopathic or related to a mechanical obstruction, the former being functional EGJOO. Although awareness of this diagnosis has increased, there is no consensus on its appropriate management. Methods: We performed a systematic review of the literature to examine the optimal treatment strategy for functional EGJOO. The Pubmed/MEDLINE, Embase and the Cochrane library electronic databases were searched through February 2017 for all studies including adult patients describing a treatment strategy for EGJOO or incomplete LES relaxation. The search strategy yielded 1,568 studies and 7 (0.4%) met inclusion criteria (Figure 1).Figure: PRISMA flow diagram of article search and identification.Results: All included studies were retrospective and comprised a total of 143 patients. Of these, one study was completed prior to the CC but satisfied criteria for EGJOO and was therefore included in the analysis. There were a total of 5 interventions described, with botulinum toxin (Botox) injection (N=61) and expectant management (N=57) the most frequently reported (Table 1). Treatments were not directly compared in any study and there was variability in how treatment success was defined. Reported successful resolution of symptoms was similar among all interventions, although the most robust evidence for therapeutic response was to both Botox injection (56%) and expectant management (54%). The mean follow-up time for the included studies was 21 months.Table: Table. Management Strategies and Treatment Response for Esophagogastric Junction Outflow ObstructionConclusion: Functional EGJOO is a heterogeneous disorder but may represent early or atypical achalasia. Overall, there are limited data on the optimal management strategy for EGJOO with some studies suggesting no treatment is needed. However, we identified 4 potential approaches aimed at disrupting LES hypertonicity. As a review of retrospective studies, these findings are limited by reporting and publication bias. Given that over half of patients with EGJOO resolve with expectant management alone, a reasonable approach may be to perform Botox injection as a diagnostic challenge or to provide definitive treatment only once an EGJOO diagnosis has been confirmed over time. Ultimately, these data support the need for a large randomized controlled trial to identify a definitive approach.

Paraneoplastic Pseudoachalasia: An Uncommon Presentation of Malignancy

Achalasia is an idiopathic disorder characterized by absent esophageal contractility and failure of lower esophageal sphincter relaxation. An identical clinical picture, termed pseudoachalasia, can be caused by benign or malignant disease processes at the gastroesophageal (GE) junction, including peptic strictures, post-surgical changes, and tumors. Less commonly, pseudoachalasia can be a result of a paraneoplastic phenomenon. Here, we present a case of small cell lung cancer (SCLC) presenting as dysphagia secondary to paraneoplastic pseudoachalasia. A 64-year-old female with a 40 pack-year smoking history presented with 5 months of progressive dysphagia to both solids and liquids, associated with regurgitation and a 45-kg weight loss. She also noted upper and lower extremity weakness and paresthesias. A barium esophagram demonstrated a dilated esophagus with a ‘bird beak' appearance of the GE junction. Subsequent esophagogastroduodenoscopy (EGD) confirmed that the narrowing was functional and not from obstruction. High resolution impedance manometry showed impaired LES relaxation and panesophageal pressurization consistent with type 2 achalasia. A CT scan of the chest revealed a left hilar mass, and pathology obtained via transbronchial needle aspiration was consistent with SCLC. A paraneoplastic panel was positive for Anti-Neuronal Nuclear Antibody-1 (ANNA-1), as well as N- and P/Q-type voltage gated calcium channel (VGCC) antibodies. Neurologic investigation with electromyography showed both a peripheral neuropathy and myelopathy. She underwent EGD with botulinum toxin injection of the LES, with moderate improvement in her dysphagia, after which definitive therapy for SCLC with chemoradiation was initiated. Pseudoachalasia secondary to a paraneoplastic syndrome is a rare diagnosis. It has been associated with a wide range of malignancies including esophageal, gastric, prostate, and lung cancers, with non-SCLC more commonly seen than SCLC. Multiple auto-antibodies have been implicated, including ANNA-1 and N- and P/Q-type VGCC antibodies, but to our knowledge, the presence of all three antibodies simultaneously is a novel finding. While neurologic symptoms are most common, a minority of patients will initially present with gastrointestinal dysmotility, including achalasia. In these patients, testing for paraneoplastic auto-antibodies should be considered, and investigation for an underlying malignancy should be pursued.Figure: Barium esophagram demonstrating a dilated esophagus with a ‘bird beak' appearance of the GE junction.

Laparoscopic esophageal myotomy versus pneumatic dilation in the treatment of idiopathic achalasia: a meta-analysis of randomized controlled trials.

BackgroundAchalasia is a primary esophageal motility disorder of unknown etiology associated with abnormalities in peristalsis and lower esophageal sphincter relaxation. The disease is incurable; however, definitive treatment procedures like pneumatic dilation (PD)/balloon dilation and laparoscopic esophageal myotomy (LEM) are performed to relieve dysphagia and related symptoms. Currently, there is paucity of data comparing the outcomes of these procedures. The aim of this meta-analysis is to compare the short- and long-term success rates of PD and LEM.MethodsA thorough systematic search of PubMed, Scopus, clinicaltrials.gov, and Cochrane library was conducted for randomized controlled trials (RCTs) comparing the outcomes of PD versus LEM in the treatment of achalasia. The Mantel-Haenszel method and random effect model were used to analyze the data. RCTs with outcome data at 3-month, 1-year, and 5-year intervals were analyzed.ResultsA total of 437,378 and 254 patients at 3-month, 1-year, and 5-year intervals were analyzed for outcome data. At 3 months and 1 year, PD was not as effective as LEM (odds ratio [OR]: 0.50; confidence interval [CI] 0.31–0.82; P = 0.009 and OR: 0.47; CI 0.22–0.99; P = 0.21) but at 5 years, one procedure was non-inferior to the other (OR: 0.62; 0.33–1.19; P = 0.34).ConclusionPD was as effective as LEM in relieving symptoms of achalasia in the long-term.

Subtle lower esophageal sphincter relaxation abnormalities in patients with unexplained esophageal dysphagia.

Esophageal dysphagia is a relatively common symptom. We aimed to evaluate whether subtle, presently not acknowledged forms of dysfunction of the lower esophageal sphincter (LES) could explain dysphagia in a subset of patients with normal findings at high-resolution manometry (HRM) according to the Chicago classification v3.0. We used HRM to compare LES relaxation characteristics in 97 patients with unexplained dysphagia with those in 44 healthy subjects. In addition, normative values for time to LES relaxation and completeness of LES relaxation were calculated. Patients with delayed or incomplete LES relaxation were compared with patients with normal relaxation. Dysphagia patients had a higher nadir LES pressure (P=.001) and a longer time to LES relaxation (P=.012) than healthy subjects. Based on the findings in healthy subjects, normal values of LES relaxation were defined as: ≥50% of swallows with normal LES relaxation time (<5seconds) and ≤20% of swallows with incomplete LES relaxation (not reaching a value below 10mm Hg). Dysphagia patients had significantly more often >50% swallows with delayed and/or incomplete LES relaxation than healthy controls (25% vs 4.5%; P=.004). Dysphagia patients with >50% delayed and/or incomplete LES relaxation had a significantly higher LES resting pressure (P<.001) and a significantly higher intrabolus pressure (P<.001) than dysphagia patients who did not fulfill the criteria. Subtle LES relaxation abnormalities, such as a delayed relaxation of the LES and/or incomplete LES relaxation, could be a cause of dysphagia in approximately one quarter of the patients with otherwise unexplained esophageal dysphagia.

Mechanisms underlying excessive esophageal acid exposure in patients with gastroesophageal reflux disease

The cause of reflux esophagitis (RE) is excessive esophageal acid exposure. Acid reflux and acid clearance after acid reflux are important factors related to excessive esophageal acid exposure. The main mechanism responsible for acid reflux is transient lower esophageal sphincter relaxation (TLESR), which is LES relaxation not associated with swallowing, and acid reflux caused by low LES pressure is rare. The frequency of TLESR in the postprandial period does not significantly differ between healthy subjects and gastroesophageal reflux disease (GERD) patients; however, the proportion of acid reflux episodes during TLESR is significantly higher in GERD patients. The layer of acid that appears above the dietary layer immediately below the esophagogastric junction (acid pocket) is attracting increasing attention as a cause of the difference in the proportion of acid reflux episodes during TLESR. The proportion of acid reflux episodes during TLESR is significantly higher when the acid pocket is present in the hernia sac than when it is located below the diaphragm. The acid pocket also shows upward migration and reaches the esophageal side of the esophagogastric junction, and the acid pocket itself has been suggested to cause mucosal damage in the lower esophagus. The amplitude and success rate of primary peristalsis decreases with increases in the severity of RE, leading to excessive esophageal acid exposure. Furthermore, the success rate of secondary peristalsis is lower in GERD patients than in healthy subjects.