FMRP regulation of aggrecan mRNA translation controls perineuronal net development.

Perineuronal nets (PNNs) are mesh-like structures on the surfaces of parvalbumin-expressing inhibitory and other neurons, and consist of proteoglycans such as aggrecan, brevican, and neurocan. PNNs regulate the Excitatory/Inhibitory (E/I) balance in the brain and are formed at the closure of critical periods of plasticity during development. PNN formation is disrupted in Fragile X Syndrome, which is caused by silencing of the fragile X messenger ribonucleoprotein 1 (Fmr1) gene and loss of its protein product FMRP. FXS is characterized by impaired synaptic plasticity resulting in neuronal hyperexcitability and E/I imbalance. Here, we investigate how PNN formation is altered in FXS. PNNs are reduced in Fmr1 KO mouse brain when examined by staining for the lectin Wisteria floribunda agglutin (WFA) and aggrecan. Examination of PNNs by WFA staining at P14 and P42 in the hippocampus, somatosensory cortex, and retrosplenial cortex shows that they were reduced in these brain regions at P14 but mostly less so at P42 in Fmr1 KO mice. However, some differential FMRP regulation of PNN development in these brain regions persists, perhaps caused by asynchrony in PNN development between brain regions in wild-type animals. During development, aggrecan PNN levels in the brain were reduced in all brain regions in Fmr1 KO mice. Aggrecan mRNA levels were unchanged at these times, suggesting that FMRP is normally an activator of aggrecan mRNA translation. This hypothesis is buttressed by the observations that FMRP binds aggrecan mRNA and that ribosome profiling data show that aggrecan mRNA is associated with reduced numbers of ribosomes in Fmr1 KO mouse brain, indicating reduced translational efficiency. Moreover, aggrecan mRNA poly(A) tail length is also reduced in Fmr1 KO mouse brain, suggesting a relationship between polyadenylation and translational control. We propose a model where FMRP modulates PNN formation through translational up-regulation of aggrecan mRNA polyadenylation and translation.

FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is often modeled in Fmr1 knockout mice where the RNA-binding protein FMRP is absent. Here, we show that in Fmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of splicing mis-regulation, we employed N2A cells depleted of Fmr1. In the absence of FMRP, RNA-specific exon skipping events are linked to the splicing factors hnRNPF, PTBP1, and MBNL1. FMRP regulates the translation of Mbnl1 mRNA as well as Mbnl1 RNA auto-splicing. Elevated Mbnl1 auto-splicing in FMRP-deficient cells results in the loss of a nuclear localization signal (NLS)-containing exon. This in turn alters the nucleus-to-cytoplasm ratio of MBNL1. This redistribution of MBNL1 isoforms in Fmr1-deficient cells could result in downstream splicing changes in other RNAs. Indeed, further investigation revealed that splicing disruptions resulting from Fmr1 depletion could be rescued by overexpression of nuclear MBNL1. Altered Mbnl1 auto-splicing also occurs in human FXS postmortem brain. These data suggest that FMRP-controlled translation and RNA processing may cascade into a general dys-regulation of splicing in Fmr1-deficient cells.

Antisense oligonucleotide rescue of CGG expansion-dependent FMR1 mis-splicing in fragile X syndrome restores FMRP.

Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here, we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissues of individuals with fragile X syndrome (FXS). Surprisingly, the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene is transcribed in >70% of the FXS tissues. In all FMR1-expressing FXS tissues, FMR1 RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-known FMR1-217 RNA isoform, which is comprised of FMR1 exon 1 and a pseudo-exon in intron 1. FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissues. We show that in cells aberrantly expressing mis-spliced FMR1, antisense oligonucleotide (ASO) treatment reduces FMR1-217, rescues full-length FMR1 RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably, FMR1 gene reactivation in transcriptionally silent FXS cells using 5-aza-2'-deoxycytidine (5-AzadC), which prevents DNA methylation, increases FMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length FMR1 expression and restores FMRP. These findings indicate that misregulated RNA-processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing FMR1-217, ASO treatment may offer a therapeutic approach to mitigate the disorder.

CPEB and translational control by cytoplasmic polyadenylation: impact on synaptic plasticity, learning, and memory.

The late 1990s were banner years in molecular neuroscience; seminal studies demonstrated that local protein synthesis, at or near synapses, was necessary for synaptic plasticity, the underlying cellular basis of learning and memory [1, 2]. The newly made proteins were proposed to "tag" the stimulated synapse, distinguishing it from naive synapses, thereby forming a cellular memory [3]. Subsequent studies demonstrated that the transport of mRNAs from soma to dendrite was linked with translational unmasking at synapses upon synaptic stimulation. It soon became apparent that one prevalent mechanism governing these events is cytoplasmic polyadenylation, and that among the proteins that control this process, CPEB, plays a central role in synaptic plasticity, and learning and memory. In vertebrates, CPEB is a family of four proteins, all of which regulate translation in the brain, that have partially overlapping functions, but also have unique characteristics and RNA binding properties that make them control different aspects of higher cognitive function. Biochemical analysis of the vertebrate CPEBs demonstrate them to respond to different signaling pathways whose output leads to specific cellular responses. In addition, the different CPEBs, when their functions go awry, result in pathophysiological phenotypes resembling specific human neurological disorders. In this essay, we review key aspects of the vertebrate CPEB proteins and cytoplasmic polyadenylation within the context of brain function.

The Modified Barium Swallow Study and Esophageal Screening: A Survey of Clinical Practice Patterns.

PURPOSE: Modified barium swallow study (MBSS) is a videofluoroscopic evaluation of oropharyngeal swallowing. Views of esophageal bolus flow during MBSS are permitted under speech-language pathology practice guidelines. However, controversy exists over its implementation. Poor consensus and limited practice guidance may lead to clinical practice variations. Aims of the investigation were to (a) describe current practice patterns of speech-language pathologist visualizing bolus flow through the esophagus during the MBSS, (b) understand areas of variation when incorporating esophageal visualization during the MBSS, and (c) determine clinicians' willingness to modify MBSS procedures to include esophageal imaging. METHOD: A web-based survey (Qualtrics XM) consisting of 26 questions was distributed via web posting and e-mail to members of the American Speech-Language-Hearing Association Special Interest Group 13 and Dysphagia Café. The survey was open for 3 months. Descriptive and associative statistics were completed. Field-testing was performed prior to dissemination of the survey to address content validity. RESULTS: A total of 321 individuals participated; 265 responses were used for analysis. Ninety-three percent of respondents viewed the esophagus during the MBSS. Twelve percent followed to the proximal esophagus, 15% to the mid esophagus, 66% to the lower esophagus, and 6% to varied levels. Variability was also reported in contrast type, volume administered, and nomenclature used. Interestingly, few people (3.61%) disagreed that esophageal visualization should be performed during MBSS. CONCLUSIONS: Speech-language pathology respondents in this study visualize contrast flow through the esophagus and are enthusiastic about expanding the standard MBSS. However, results of the survey demonstrate a lack of uniformity in assessment practices. Unfortunately, this may impact the diagnostic accuracy and clinical utility when adding esophageal visualization to the MBSS. This study highlights the need for a standardized protocol and identifies current barriers and controversies that may prevent expanding the MBSS to more comprehensively evaluate individuals with dysphagia.

Impact of opioids on treatment response among idiopathic esophagogastric junction outflow obstruction patients: A retrospective cohort study.

BACKGROUND: Esophageal dysmotility has been attributed to opioid use. The goal was to assess the differences in pre- and post-treatment timed-barium esophagram (TBE) barium heights at 1 and 5 minutes and symptomatic response to treatment in esophagogastric junction outflow obstruction (EGJOO) patients according to opioid use status. METHODS: We performed a retrospective cohort study. Consecutive patients with EGJOO were eligible for inclusion. Data were collected on demographics, pre and post-treatment 1 and 5 minutes TBE barium heights and symptom outcomes. Groups were compared according to opioid use. RESULTS: Thirty-one EGJOO patients met the inclusion criteria. All patients were treated with pneumatic dilation. Of the 31 patients, 11 (35%) had opioid exposure and 20 (65%) did not. The median follow-up post-treatment was two months (range 1-47 months). There was no statistically significant difference in post-treatment outcomes for opioid exposed vs. unexposed groups. The median per cent decrease in the TBE barium height at 1 minute was 100% for the opioid exposed vs. 71% for the unexposed group (p = 0.92). The median per cent decrease in the TBE barium height at 5 minutes was zero % for the opioid exposed and unexposed groups (p = 0.67). The incidence of symptomatic improvement was 82% (9/11) for the opioid exposed group vs 95% (19/20) for the unexposed group (p = 0.28). CONCLUSIONS: Patients with EGJOO seem to respond to treatment similarly regardless of being on opioids.

Voice Hoarseness with Reflux as a Suspected Etiology: Incidence, Evaluation, Treatment, and Symptom Outcomes.

PURPOSE: To describe the clinical evaluation course, treatments, and outcomes of patients with a primary complaint of hoarseness due to suspected laryngopharyngeal reflux (LPR). METHODS: A retrospective chart review was conducted of patients with a primary complaint of hoarseness with acid reflux as the suspected cause at a single institution between October 2011 and March 2020 who underwent clinical evaluation, treatment, and follow-up. Data collected included diagnostic procedures and treatments received, subjective symptom outcomes, and final diagnosis as determined by the treating physician. RESULTS: A total of 134 patients met the inclusion criteria. Videostroboscopy was the most performed procedure (n = 59, 44%) followed by endoscopy (n = 38, 28%) and pH monitoring (n = 28, 21%). Three patients were removed for statistical analysis of treatment differences and outcomes due to variant treatment plans. Most patients received sole medical management (n = 86, 66%), 7 patients received only voice therapy (5%), and 10 patients underwent surgical management (8%). Several patients received combined medical management and voice therapy (n = 21, 16%). Final diagnoses included gastroesophageal reflux disease (GERD) (25%), followed by multifactorial causes (17%) and dysphonia with unclear etiology (13%). Among all patients, 82 (61%) reported symptom improvement. Twenty-eight patients were diagnosed with LPR or LPR with GERD (21%), and 22 reported symptom improvement (79%). There was a statistically significant relationship between a final diagnosis with a reflux component and symptom improvement (p = .038). There was no statistically significant difference between treatment types and symptom outcomes both within the total patient population (p = .051) and patients diagnosed with a reflux condition (p = .572). CONCLUSION: LPR remains a difficult diagnosis to establish and represents a minority of patients with voice complaints. Despite varying evaluation and treatment modalities, most patients with LPR improved during their treatment and evaluation period without a clear association with any specific type of treatment. Further studies should explore diagnostic criteria for LPR, the necessary and efficient clinical evaluation to establish a diagnosis, and possible beneficial treatments.

Update on the Diagnosis and Treatment of Achalasia.

Achalasia is a rare disease of the esophagus with impaired relaxation of the lower esophageal sphincter and aperistalsis. The etiology is unknown but speculations include a viral or autoimmune etiology. All specialists dealing with swallowing and esophageal diseases should recognize the classic symptoms of dysphagia for solids/liquids, regurgitation, and choking, especially at night. High-resolution manometry is critical for the diagnosis with endoscopy and barium esophagram having a supportive role. The disease cannot be cured but most can return to near normal swallowing and a regular diet with appropriate therapy. Treatment includes smooth muscle relaxants, botulinum toxin injections to the lower sphincter, pneumatic dilation, Heller myotomy, and peroral endoscopic myotomy. One treatment does not fit all and a tailored approach through a multidiscipline team will give the best long-term outcomes.

Inter- and intra-rater agreement of interpretation of functional lumen imaging probe in healthy subjects.

BACKGROUND: The functional lumen imaging probe (FLIP) evaluates esophagogastric junction (EGJ) opening and esophageal contractility. Both post hoc and real-time analyses are possible, but reproducibility and reliability of analysis remain undefined. This study assesses inter- and intra-rater agreement of normative FLIP measurements among novice and experienced users. METHODS: Eight motility experts from different institutions independently evaluated de-identified video recordings from 27 asymptomatic healthy subjects using FLIP. Interpretation methods simulating a post-procedure and a live procedure setting were tested. Novice FLIP users (n = 3) received training prior to post-procedure interpretation. Experienced FLIP users (n = 5) interpreted using both methods. Users recorded maximum EGJ and distal esophageal body diameter, distensive pressure, and EGJ distensibility index (EGJ-DI), at balloon fill volumes of 50-, 60-, and 70 ml, as well as repetitive antegrade contractions (RACs). Inter- and intra-rater agreements of diameters, distensive pressure and EGJ-DI were assessed by intra-class correlation coefficient (ICC) and Pearson's correlation coefficient (PCC). Percentage agreement evaluated inter- and intra-rater reliability for RACs. KEY RESULTS: Novice and experienced users acquired normative FLIP metrics. Good-to-excellent inter- and intra-rater reliability were achieved for all variables at 60 ml balloon fill volumes. Median parameters at 60 ml balloon fill volume were as follows: EGJ-DI 5.5 mm2 /mmHg, maximum EGJ diameter 18.6 mm, distensive pressure at maximum EGJ diameter 48.1 mmHg, and distal esophageal body diameter 19.5 mm. CONCLUSIONS AND INFERENCES: Normative FLIP parameters can be reliably extracted from FLIP videos using both real-time and post hoc analyses, with high reliability between experienced and novice users.

Resource utilization and variation among practitioners for evaluating voice hoarseness secondary to suspected reflux disease: A retrospective chart review.

The purpose of this study was to assess the variation in resource utilization for the diagnosis and treatment of dysphonia or hoarseness in patients with suspected laryngopharyngeal reflux (LPRD) and/or gastroesophageal reflux (GERD). Secondary data was collected from a single-institution database of charts from patients evaluated between October 1, 2011 and March 31, 2020. This study was conducted as a retrospective chart review. Key outcome variables included demographic data, initial specialty visit, date of first symptom evaluation to final follow-up visit, additional procedural evaluation, and final diagnosis as attributed by the diagnosing physician. Inclusion criteria included patients ≥18 older referred to providers for suspected LPRD/GERD with a primary complaint of voice changes or hoarseness and appeared for follow-up. A total of 134 subjects were included for analysis. Data analysis included descriptive and univariate analysis, chi-square test of independence, independent means t test, and 1-way analysis of variance. Most patients (88) received some form of procedural evaluation in addition to clinical evaluation. The most frequent was videostroboscopy (59). Patients who first visited a gastroenterologist were more likely to undergo esophageal pH-monitoring (n = 14, P < .001) and manometry (n = 10, P < .001). Patients referred to speech-language pathology were very likely to undergo videostroboscopic evaluation (n = 7, P < .001). The prevailing final diagnosis as attributed by the diagnosing physician was confirmed to be of non-reflux etiology (49) or due to GERD alone (34). LPRD only was the least frequent diagnosis (10). Our results demonstrate that there is significant variation in the number and type of diagnostic tests based on the type of practitioner initially seen by the patient. Additionally, of patients thought to have voice change or hoarseness because of LPRD and/or GERD, more than a third had a non-reflux cause of their symptoms. Further research should identify beneficial patterns in resource utilization and further diagnostic utility of diagnostic procedures for more accurate diagnosis.

Endoscopic approach to eosinophilic esophagitis: American Society for Gastrointestinal Endoscopy Consensus Conference.

Endoscopy plays a critical role in caring for and evaluating the patient with eosinophilic esophagitis (EoE). Endoscopy is essential for diagnosis, assessment of response to therapy, treatment of esophageal strictures, and ongoing monitoring of patients in histologic remission. To date, less-invasive testing for identifying or grading EoE severity has not been established, whereas diagnostic endoscopy as integral to both remains the criterion standard. Therapeutic endoscopy in patients with adverse events of EoE may also be required. In particular, dilation may be essential to treat and attenuate progression of the disease in select patients to minimize further fibrosis and stricture formation. Using a modified Delphi consensus process, a group of 20 expert clinicians and investigators in EoE were assembled to provide guidance for the use of endoscopy in EoE. Through an iterative process, the group achieved consensus on 20 statements yielding comprehensive advice on tissue-sampling standards, gross assessment of disease activity, use and performance of endoscopic dilation, and monitoring of disease, despite an absence of high-quality evidence. Key areas of controversy were identified when discussions yielded an inability to reach agreement on the merit of a statement. We expect that with ongoing research, higher-quality evidence will be obtained to enable creation of a guideline for these issues. We further anticipate that forthcoming expert-generated and agreed-on statements will provide valuable practice advice on the role and use of endoscopy in patients with EoE.

Clinical role of ambulatory reflux monitoring in PPI non-responders: recommendation statements.

BACKGROUND: Optimal ambulatory reflux monitoring methodology in symptomatic reflux patients continues to be debated. AIMS: To utilise published literature and expert opinion to develop recommendation statements addressing use of ambulatory reflux monitoring in clinical practice METHODS: The RAND Appropriateness Method (RAM) was utilised among 17 experts with discussion, revision and two rounds of ranking of recommendation statements. Ambulatory reflux monitoring protocol, methodology and thresholds ranked as appropriate by ≥80% of panellists met the criteria for appropriateness. RESULTS: Prolonged (96-h recommended) wireless pH monitoring off proton pump inhibitor (PPI) was identified as the appropriate diagnostic tool to assess the need for acid suppression in patients with unproven gastro-oesophageal reflux disease (GERD) and persisting typical reflux symptoms despite once-daily PPI. Acid exposure time (AET) <4.0% on all days of monitoring with negative reflux-symptom association excludes GERD and does not support ongoing PPI treatment. Conversely, AET >6.0% across ≥2 days is conclusive evidence for GERD and supports treatment for GERD, while AET >10% across ≥2 days identifies severe acid burden that supports escalation of anti-reflux treatment. In previously proven GERD, impedance-pH monitoring on PPI is helpful in defining refractory GERD and mechanisms of continued symptoms; the presence of <40 reflux events, AET <2.0% and a negative reflux-symptom association does not support escalation of anti-reflux treatment. In contrast, AET > 4.0% and positive reflux-symptom association support escalation of anti-reflux treatment, including use of invasive therapeutics. CONCLUSIONS: Statements meeting appropriateness for average clinical care have been identified when utilising reflux monitoring in patients with typical reflux symptoms and PPI non-response.

CPEB1 regulates the inflammatory immune response, phagocytosis, and alternative polyadenylation in microglia.

Microglia are myeloid cells of the central nervous system that perform tasks essential for brain development, neural circuit homeostasis, and neural disease. Microglia react to inflammatory stimuli by upregulating inflammatory signaling through several different immune cell receptors such as the Toll-like receptor 4 (TLR4), which signals to several downstream effectors including transforming growth factor beta-activated kinase 1 (TAK1). Here, we show that TAK1 levels are regulated by CPEB1, a sequence-specific RNA binding protein that controls translation as well as RNA splicing and alternative poly(A) site selection in microglia. Lipopolysaccharide (LPS) binds the TLR4 receptor, which in CPEB1-deficient mice leads to elevated expression of ionized calcium binding adaptor molecule 1 (Iba1), a microglial protein that increases with inflammation, and increased levels of the cytokine IL6. This LPS-induced IL6 response is blocked by inhibitors of JNK, p38, ERK, NFκB, and TAK1. In contrast, phagocytosis, which is elevated in CPEB1-deficient microglia, is unaffected by LPS treatment or ERK inhibition, but is blocked by TAK1 inhibition. These data indicate that CPEB1 regulates microglial inflammatory responses and phagocytosis. RNA-seq indicates that these changes in inflammation and phagocytosis are accompanied by changes in RNA levels, splicing, and alternative poly(A) site selection. Thus, CPEB1 regulation of RNA expression plays a role in microglial function.

Oppositional poly(A) tail length regulation by FMRP and CPEB1.

Poly(A) tail length is regulated in both the nucleus and cytoplasm. One factor that controls polyadenylation in the cytoplasm is CPEB1, an RNA binding protein that associates with specific mRNA 3'UTR sequences to tether enzymes that add and remove poly(A). Two of these enzymes, the noncanonical poly(A) polymerases GLD2 (TENT2, PAPD4, Wispy) and GLD4 (TENT4B, PAPD5, TRF4, TUT3), interact with CPEB1 to extend poly(A). To identify additional RNA binding proteins that might anchor GLD4 to RNA, we expressed double tagged GLD4 in U87MG cells, which was used for sequential immunoprecipitation and elution followed by mass spectrometry. We identified several RNA binding proteins that coprecipitated with GLD4, among which was FMRP. To assess whether FMRP regulates polyadenylation, we performed TAIL-seq from WT and FMRP-deficient HEK293 cells. Surprisingly, loss of FMRP resulted in an overall increase in poly(A), which was also observed for several specific mRNAs. Conversely, loss of CPEB1 elicited an expected decrease in poly(A), which was examined in cultured neurons. We also examined polyadenylation in wild type (WT) and FMRP-deficient mouse brain cortex by direct RNA nanopore sequencing, which identified RNAs with both increased and decreased poly(A). Our data show that FMRP has a role in mediating poly(A) tail length, which adds to its repertoire of RNA regulation.

Ribosome profiling reveals novel regulation of C9ORF72 GGGGCC repeat-containing RNA translation.

GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-containing RNA is translated into dipeptide repeat (DPR) proteins, some of which are neurotoxic. Using dynamic ribosome profiling, we identified three translation initiation sites in the intron upstream of (G4C2) repeats; these sites are detected irrespective of the presence or absence of the repeats. During translocation, ribosomes appear to be stalled on the repeats. An AUG in the preceding C9ORF72 exon initiates a uORF that inhibits downstream translation. Polysome isolation indicates that unspliced (G4C2) repeat-containing RNA is a substrate for DPR protein synthesis. (G4C2) repeat-containing RNA translation is 5' cap-independent but inhibited by the initiation factor DAP5, suggesting an interplay with uORF function. These results define novel translational mechanisms of expanded (G4C2) repeat-containing RNA in disease.

Demystifying Esophageal Lichen Planus: A Comprehensive Review of a Rare Disease You Will See in Practice.

Lichen planus (LP) is a chronic inflammatory disorder that often affects the skin, hair, nails, and mucus membranes. Although esophageal involvement has traditionally been felt to be rare, recent reports suggest that it is often unrecognized or misdiagnosed. The diagnoses of esophageal lichen planus can be challenging and is suspected based on patients' endoscopic and histologic findings and in the context of their clinical history and physical examination. Physicians must have an index of suspicion, particularly in older white women and in those patients with an atypical esophagitis or stricturing disease, which do not respond to traditional treatment. Currently, there are limited data on esophageal lichen planus patients, and no formal management guidelines for this disease, which all gastroenterologists will see in practice. This article reviews the etiology and histopathology of LP and provides a comprehensive discussion of the clinical features, diagnosis, and management of esophageal disease from the gastroenterologist's perspective. Finally, we address the esophageal complications of LP.

Do Fragile X Syndrome and Other Intellectual Disorders Converge at Aberrant Pre-mRNA Splicing?

Fragile X Syndrome is a neuro-developmental disorder caused by the silencing of the FMR1 gene, resulting in the loss of its protein product, FMRP. FMRP binds mRNA and represses general translation in the brain. Transcriptome analysis of the Fmr1-deficient mouse hippocampus reveals widespread dysregulation of alternative splicing of pre-mRNAs. Many of these aberrant splicing changes coincide with those found in post-mortem brain tissue from individuals with autism spectrum disorders (ASDs) as well as in mouse models of intellectual disability such as PTEN hamartoma syndrome (PHTS) and Rett Syndrome (RTT). These splicing changes could result from chromatin modifications (e.g., in FXS, RTT) and/or splicing factor alterations (e.g., PTEN, autism). Based on the identities of the RNAs that are mis-spliced in these disorders, it may be that they are at least partly responsible for some shared pathophysiological conditions. The convergence of splicing aberrations among these autism spectrum disorders might be crucial to understanding their underlying cognitive impairments.

Esophagogastric junction outflow obstruction.

In the Chicago Classification version 4.0 (CCv4), esophagogastric junction outflow obstruction (EGJOO) is manometrically defined as an elevated median integrated relaxation pressure (IRP) and elevated intrabolus pressure (IBP) during supine wet swallows, and persistently elevated median IRP in the upright position. A clinically relevant conclusive diagnosis of EGJOO requires a manometric diagnosis of EGJOO and associated symptoms such as dysphagia and/or chest pain with at least one of the following supportive investigations (pharmacologic provocation, timed barium esophagogram, and/or endoflip). The Chicago Classification is intended for diagnosis of primary esophageal motor disorders, and thus history and endoscopic evaluation are important to exclude conditions (eg, previous surgery, strictures, or masses) that can secondarily generate the EGJOO pattern on HRM. While a manometric finding of EGJOO is often made and can be an early sign of achalasia, more often it is a manometric finding without clinical implications. The proposed changes in CC4.0 have attempted to make the diagnosis more specific, in order to reduce the number of clinically irrelevant diagnoses and avoid confusion by patients and physicians alike.