Peroral endoscopic myotomy: a two-center retrospective study of practice and adverse events.

Background and study aims: Peroral endoscopic myotomy (POEM) is the preferred technique for the treatment of esophageal motility disorders and is less invasive than surgery. This study was performed to compare two university centers in the practice of POEM, in terms of efficacy and adverse events, for the treatment of esophageal motility disorder. Patients and methods: Retrospective comparative study of patients undergoing a POEM between September 2020 and December 2022 from the University Hospital of Liège (Belgium) and Besançon (France). The clinical success was defined by an Eckardt score ≤ 3 after the procedure. Results: Fifty-five patients were included. In both centers, 87,3% of the patients had achalasia (mostly type II), and 12,7% had another esophageal motility disorder. The use of antibiotic prophylaxis was systematic in Liège center but not in Besançon center (100% and 9.1% respectively). The mean value of the post-operative Eckardt score was 1.55± 2.48 in both center with 93.2% of patients with a score ≤ 3 (92% in Besançon and 94.74% in Liège). The rate of adverse event was generally low. There were two minor adverse events more frequent in Liège, clinical capnomediastinum and pain at day one, but they were managed with conservative treatment. Only 7.3% of the total patients had an infectious phenomenon that did not correlate with the use of antibiotic prophylaxis. Conclusion: The post-operative Eckardt score and the adverse event rate were comparable between the university centers. This study confirmed that POEM is a safe and effective technique. It also showed that using an antibiotic prophylaxis does not influence the development of infectious adverse events.

Artificial Intelligence Tools for Improving Manometric Diagnosis of Esophageal Dysmotility.

PURPOSE OF REVIEW: Artificial intelligence (AI) is a broad term that pertains to a computer's ability to mimic and sometimes surpass human intelligence in interpretation of large datasets. The adoption of AI in gastrointestinal motility has been slower compared to other areas such as polyp detection and interpretation of histopathology. RECENT FINDINGS: Within esophageal physiologic testing, AI can automate interpretation of image-based tests, especially high resolution manometry (HRM) and functional luminal imaging probe (FLIP) studies. Basic tasks such as identification of landmarks, determining adequacy of the HRM study and identification from achalasia from non-achalasia patterns are achieved with good accuracy. However, existing AI systems compare AI interpretation to expert analysis rather than to clinical outcome from management based on AI diagnosis. The use of AI methods is much less advanced within the field of ambulatory reflux monitoring, where challenges exist in assimilation of data from multiple impedance and pH channels. There remains potential for replication of the AI successes within esophageal physiologic testing to HRM of the anorectum, and to innovative and novel methods of evaluating gastric electrical activity and motor function. The use of AI has tremendous potential to improve detection of dysmotility within the esophagus using esophageal physiologic testing, as well as in other regions of the gastrointestinal tract. Eventually, integration of patient presentation, demographics and alternate test results to individual motility test interpretation will improve diagnostic precision and prognostication using AI tools.

Fifteen-year symptomatic outcome of patients with nonactionable motor findings on high-resolution manometry.

BACKGROUND: High-resolution manometry (HRM) is performed for evaluation of esophageal symptoms, but patient outcome is unclear when no actionable motor disorder is identified. We evaluated long-term symptomatic outcome of patients with nonactionable HRM findings. METHODS: Patients who underwent (HRM) studies in 2006-2008 were tracked. Patients with achalasia spectrum disorders, foregut surgery before or after HRM, and incomplete symptom documentation were excluded. Symptom questionnaires assessing dominant symptom intensity (DSI, product of symptom severity and frequency recorded on 5-point Likert scales) and global symptom severity (GSS, from 10 cm visual analog scale) were repeated. Change in symptom burden was compared against HRM motor findings using Chicago Classification 4.0 (CCv4.0), applied retroactively to 2006-2008 data. KEY RESULTS: Overall, 134 patients (median age 68 years, 64.5% female) could be contacted. The majority (73.1%) had normal motility; others had ineffective esophageal motility (8.2%), esophagogastric junction outflow obstruction (13.4%), hypercontractile esophagus (3.0%), or absent contractility (2.2%), none managed invasively. Over 15 years of follow-up, DSI decreased from 8.0 (4.0-16.0) to 1.0 (0.0-6.0) (p < 0.001) and GSS improved from 5.5 (3.3-7.7) to 2.0 (0.0-4.0) (p < 0.001); improvement was consistent across CCv4.0 diagnoses and subgroups. The majority (82.8%) reported improvement over time, and antisecretory medication was the most effective intervention (83.0% improvement). There was no difference in medication efficacy (p = 0.75) or improvement in symptoms (p = 0.20) based on CCv4 diagnosis. CONCLUSIONS AND INFERENCES: Esophageal symptoms improve with conservative symptomatic management over long-term follow-up when no conclusive obstructive motor disorders or achalasia spectrum disorders are found on HRM.

Surgical and per-oral endoscopic myotomy (POEM) for the treatment of primary esophageal motility disorders: A systematic analysis of current trends in Germany between 2011 and 2019.

BACKGROUND/AIMS: While surgery remains a standard treatment for primary esophageal motility disorders (PEMDs), per-oral endoscopic myotomy (POEM) has recently evolved as an alternative. Systematic data on current trends of invasive procedures for PEMDs in Germany are missing. METHODS: Hospital discharge data were used to evaluate trends and mortality of invasive treatment options for PEMDs in Germany between 2011 and 2019. RESULTS: 4543 cases of PEMDs (achalasia: n = 4349, dyskinesia of the esophagus: n = 194) receiving open surgery (n = 200), minimal invasive surgery (n = 2366), or POEM (n = 1977) were identified. The relative proportion of POEM significantly increased from 10.9% (2011) to 65.7% (2019). Hospital mortality was 0.2%. The median duration of mechanical ventilation was significantly lower in POEM patients (29.4 hours) compared to open (274.0 hours) or minimal invasive (91.9 hours) surgery. The duration of hospitalization was lowest among POEM patients (5.7 days) compared to surgical procedures (13.7 and 7.7 days). CONCLUSION: While the low in-hospital mortality of all procedures combined confirms the solid safety profile of invasive procedures in general, our findings show that POEM has the lowest duration of mechanical ventilation and hospitalization compared to invasive surgical options.

Achalasia alters physiological networks depending on sex.

Achalasia is a rare esophageal motility disorder for which the etiology is not fully understood. Evidence suggests that autoimmune inflammatory infiltrates, possibly triggered by a viral infection, may lead to a degeneration of neurons within the myenteric plexus. While the infection is eventually resolved, genetically susceptible individuals may still be at risk of developing achalasia. This study aimed to determine whether immunological and physiological networks differ between male and female patients with achalasia. This cross-sectional study included 189 preoperative achalasia patients and 500 healthy blood donor volunteers. Demographic, clinical, laboratory, immunological, and tissue biomarkers were collected. Male and female participants were evaluated separately to determine the role of sex. Correlation matrices were constructed using bivariate relationships to generate complex inferential networks. These matrices were filtered based on their statistical significance to identify the most relevant relationships between variables. Network topology and node centrality were calculated using tools available in the R programming language. Previous occurrences of chickenpox, measles, and mumps infections have been proposed as potential risk factors for achalasia, with a stronger association observed in females. Principal component analysis (PCA) identified IL-22, Th2, and regulatory B lymphocytes as key variables contributing to the disease. The physiological network topology has the potential to inform whether a localized injury or illness is likely to produce systemic consequences and the resulting clinical presentation. Here we show that immunological involvement in achalasia appears localized in men because of their highly modular physiological network. In contrast, in women the disease becomes systemic because of their robust network with a larger number of inter-cluster linkages.

Dysphagia associated with esophageal wall thickening in patients with nonspecific high-resolution manometry findings: Understanding motility beyond the Chicago classification version 4.0.

BACKGROUND: Previous studies have demonstrated that 50% of patients with normal high-resolution manometry (HRM) findings or ineffective esophageal motility (IEM) may have abnormal functional luminal imaging probe (FLIP) results. However, the specific HRM findings associated with abnormal FLIP results are unknown. Herein, we investigated the relationship between nonspecific manometry findings and abnormal FLIP results. METHODS: We retrospectively analyzed 684 patients who underwent HRM at a tertiary care center in Seoul, Korea, based on the Chicago Classification version 4.0 protocol. KEY RESULTS: Among the 684 patients, 398 had normal HRM findings or IEM. Of these 398 patients, eight showed esophageal wall thickening on endoscopic ultrasonography or computed tomography; however, no abnormalities were seen during esophagogastroduodenoscopy. Among these eight patients, seven showed repetitive simultaneous contractions (RSCs) in at least one of the two positions: 61% (±29%) in 10 swallows in the supine position and 51% (±30%) in five swallows in the upright position. Four patients who underwent FLIP had a significantly decreased esophagogastric junction distensibility index (1.0 ± 0.5 m m 2 mmHg - 1 at 60 mL). Two of these patients underwent per-oral endoscopic myotomy (POEM) due to a lack of response to medication. Esophageal muscle biopsy revealed hypertrophic muscle with marginal eosinophil infiltration. CONCLUSIONS & INFERENCES: A subset of patients (2%) with normal HRM findings or IEM and RSCs experienced dysphagia associated with poor distensibility of the thickened esophageal wall. FLIP assessment or combined HRM and impedance protocols may help better define these patients who may respond well to POEM.

Role of mechanoregulation in mast cell-mediated immune inflammation of the smooth muscle in the pathophysiology of esophageal motility disorders.

Major esophageal disorders involve obstructive transport of bolus to the stomach, causing symptoms of dysphagia and impaired clearing of the refluxed gastric contents. These may occur due to mechanical constriction of the esophageal lumen or loss of relaxation associated with deglutitive inhibition, as in achalasia-like disorders. Recently, immune inflammation has been identified as an important cause of esophageal strictures and the loss of inhibitory neurotransmission. These disorders are also associated with smooth muscle hypertrophy and hypercontractility, whose cause is unknown. This review investigated immune inflammation in the causation of smooth muscle changes in obstructive esophageal bolus transport. Findings suggest that smooth muscle hypertrophy occurs above the obstruction and is due to mechanical stress on the smooth muscles. The mechanostressed smooth muscles release cytokines and other molecules that may recruit and microlocalize mast cells to smooth muscle bundles, so that their products may have a close bidirectional effect on each other. Acting in a paracrine fashion, the inflammatory cytokines induce genetic and epigenetic changes in the smooth muscles, leading to smooth muscle hypercontractility, hypertrophy, and impaired relaxation. These changes may worsen difficulty in the esophageal transport. Immune processes differ in the first phase of obstructive bolus transport, and the second phase of muscle hypertrophy and hypercontractility. Moreover, changes in the type of mechanical stress may change immune response and effect on smooth muscles. Understanding immune signaling in causes of obstructive bolus transport, type of mechanical stress, and associated smooth muscle changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.NEW & NOTEWORTHY Esophageal disorders such as esophageal stricture or achalasia, and diffuse esophageal spasm are associated with smooth muscle hypertrophy and hypercontractility, above the obstruction, yet the cause of such changes is unknown. This review suggests that smooth muscle obstructive disorders may cause mechanical stress on smooth muscle, which then secretes chemicals that recruit, microlocalize, and activate mast cells to initiate immune inflammation, producing functional and structural changes in smooth muscles. Understanding the immune signaling in these changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.

[A Case of Type II Achalasia Occurring in a Nonagenarian Diagnosed with Acute Food Impaction].

Achalasia is an esophageal motility disorder characterized by loss of esophageal peristalsis and impaired relaxation of the lower esophageal sphincter. Patients with achalasia often complain of persistent symptoms for several years before diagnosis. On the other hand, achalasia diagnosed as a sudden esophageal food impaction is uncommon, and no report has been issued on the diagnosis and successful treatment of achalasia in a 95-year-old patient. We report a case of achalasia diagnosed by high-resolution esophageal manometry and timed barium esophagography after food material removal by endoscopy in a 95-year-old woman who visited the hospital due to sudden esophageal food impaction and was successfully treated by endoscopic balloon dilatation.

Characteristics of Esophageal Motility and Associated Symptom Profiles in Patients with Esophageal Diverticulum: A Study Based on High-Resolution Impedance Manometry.

BACKGROUND: Esophageal diverticulum (ED) is an uncommon structural disorder with heterogenous manifestations and elusive pathophysiology. Our aim was to investigate esophageal motility and associated symptom profiles in patients with ED based on high-resolution impedance manometry (HRIM). METHODS: Consecutive patients with ED referred to our motility laboratory between 2015 to 2022 were identified in our electronic database. All patients were evaluated based on an upper endoscopy, HRIM, and standardized symptom questionnaires. Patients with ED were further stratified into upper, middle, and lower (epiphrenic) cases. Esophageal motility was evaluated with HRIM and the updated Chicago Classification v4.0. RESULTS: Twenty-four patients with ED (9 upper, 4 middle, and 11 epiphrenic) were analyzed. Patients with ED were generally older (mean: 65 ± 13.3 years) and predominantly women (58.3%). Most ED cases were unilaterally located (95.8%) and left-side predominant (62.5%). Mean symptom duration was 20 months (range: 1-120) and the most common symptoms were dysphagia (70.8%) and regurgitation (37.5%). Erosive esophagitis was noted in 16 patients (69.6%), while barium stasis was noted in 5 patients (20.8%). Fourteen patients (58.3%) were diagnosed with esophageal motility disorders using HRIM, with achalasia being the most common diagnosis (n = 5, 20.8%). Patients with epiphrenic diverticulum had significantly higher symptom scores and achalasia prevalence. CONCLUSION: Patients with ED tended to be older and was associated with a high prevalence of EMD. A multi-disciplinary evaluation, including complete anatomical and motility surveys, may help clarify the underlying pathophysiology and tailor further treatment strategies.

Impedance planimetry during per-oral endoscopic myotomy is associated with decreased inadvertent capnoperitoneum.

BACKGROUND: Per-oral endoscopic myotomy (POEM) has become an accepted minimally invasive alternative to Heller myotomy for the treatment of achalasia and other disorders of esophageal dysmotility. One associated adverse event is the inadvertent creation of capnoperitoneum. A proposed mechanism is that extension of the submucosal tunnel below the esophageal hiatus and onto the gastric wall leads to transmural perforation. We hypothesized that the use of impedance planimetry with the endoscopic functional luminal imaging probe (EndoFLIP) more accurately identifies the esophagogastric junction and helps to better define the myotomy's ideal limits, thus lowering the incidence of inadvertent capnoperitoneum. METHODS: This is a single-center, retrospective review of consecutive POEM cases from 06/11/2011 to 08/08/2022, with EndoFLIP introduced in 2017. Patient and procedural characteristics, including the incidence of clinically significant capnoperitoneum and decompression, were analyzed using univariate and multivariable linear regression statistics. RESULTS: There were 140 POEM cases identified, 74 (52.9%) of which used EndoFLIP. Clinically significant capnoperitoneum was encountered in 26 (18.6%) cases, with no differences in patient characteristics between those who had capnoperitoneum and those who did not. There was a decreased incidence of capnoperitoneum in cases using EndoFLIP compared to those without (n = 6, 23% vs n = 20, 77%, p = 0.001), with zero instances in the final 56 cases. After adjusting for potentially confounding factors, EndoFLIP use was associated with a - 15.93% (95% confidence interval - 30.68%, - 1.18%) decrease in procedure duration. CONCLUSIONS: The routine use of EndoFLIP during POEM was associated with decreased incidence of clinically significant capnoperitoneum, potentially due to improved myotomy tailoring and decreased duration of insufflation with shorter procedure times.

Compartmentalized pressurization is a novel prognostic factor for hypercontractile esophagus.

BACKGROUND: Hypercontractile esophagus (HE) is a disorder of increased esophageal body contractile strength on high-resolution esophageal manometry (HREM). Compartmentalized pressurization (CP) is a pattern with an isobaric contour of >30 mmHg extending from the contractile front to the lower esophageal sphincter on HREM. The relevance of CP to HE has yet to be explored. METHODS: A retrospective review was performed on 830 HREM studies of patients to identify HE. HE patients' CP status and symptoms by Eckardt score (ES) were reviewed. Diagnoses were made using Chicago Classification (CC) v4.0. KEY RESULTS: Forty-seven patients (5.6%) were identified as having HE by CCv3, 30 (3.6%) of which had HE by CCv4. 11/30 HE patients had CP, and 19/30 did not. CP was associated with chronic opioid use (36.4% vs. 5.3% p = 0.047). Presenting ES was greater for HE patients with CP (7 vs. 4). Seven HE patients with CP and 11 without CP were managed medically. ES after medical therapy was higher in HE patients with CP compared to those without CP (9 vs. 0). No HE patients with CP responded to medical therapy. Kaplan-Meier analysis demonstrated significance of this association over time. 83% of all HE patients had all-cause symptom remission. CONCLUSIONS & INFERENCES: HE patients with CP are associated with a higher presenting ES. HE patients with CP do not respond to medical therapy, while HE patients without CP frequently do respond. CP in HE may have prognostic value in determination of treatment strategy for patients with HE.

Esophageal anatomy and physiology vary across spastic and non-spastic phenotypes of disorders of esophagogastric junction outflow.

BACKGROUND: Pathophysiologic mechanisms of disorders of esophagogastric junction (EGJ) outflow are poorly understood. We aimed to compare anatomic and physiologic characteristics among patients with disorders of EGJ outflow and normal motility. METHODS: We retrospectively evaluated adult patients with achalasia types 1, 2, 3, EGJ outflow obstruction (EGJOO) or normal motility on high-resolution manometry who underwent endoscopic ultrasound (EUS) from January 2019 to August 2022. Thickened circular muscle was defined as ≥1.6 mm. Characteristics from barium esophagram (BE) and functional lumen imaging probe (FLIP) were additionally assessed. KEY RESULTS: Of 71 patients (mean age 56.2 years; 49% male), there were 8 (11%) normal motility, 58 (82%) had achalasia (5 (7%) type 1, 32 (45%) classic type 2, 21 (30%) type 3 [including 12 type 2 with FEPs]), and 7 (7%) had EGJOO. A significantly greater proportion of type 3 achalasia had thickened distal circular muscle (76.2%) versus normal motility (0%; p < 0.001) or type 2 achalasia (25%; p < 0.001). Type 1 achalasia had significantly wider mean maximum esophageal diameter on BE (57.8 mm) compared to type 2 achalasia (32.8 mm), type 3 achalasia (23.4 mm), EGJOO (15.9 mm), and normal motility (13.5 mm). 100% type 3 achalasia versus 0% type 1 achalasia/normal motility had tertiary contractions on BE. Mean EGJ distensibility index on FLIP was lower for type 3 achalasia (1.2 mmHg/mm2 ) and EGJOO (1.2 mmHg/mm2 ) versus type 2 (2.3 mmHg/mm2 ) and type 1 achalasia (2.9 mmHg/mm2 ). CONCLUSIONS: Our findings suggest distinct pathologic pathways may exist: type 3 achalasia and EGJOO may represent a spastic outflow phenotype consisting of a thickened, spastic circular muscle, which is distinct from type 1 and 2 achalasia consisting of a thin caliber circular muscle layer with more prominent esophageal dilation.

Optimizing the Management Algorithm for Esophageal Dysphagia After Index Endoscopy: Cost-Effectiveness and Cost-Minimization Analysis.

INTRODUCTION: Guidelines advise esophageal motility testing for dysphagia when structural disorders are ruled out, but cost concerns impede adoption. We evaluated cost-effective positioning of esophageal motility testing in the algorithm to evaluate esophageal dysphagia. METHODS: We developed a decision analytic model comparing 3 strategies: (i) esophageal manometry, (ii) screening impedance planimetry followed by esophageal manometry if needed, or (iii) nonalgorithmic usual care. Diagnostic test accuracy was adapted to expected rates of esophageal motility disorders in general gastroenterology populations. We modeled routine testing for all patients with nonstructural/mechanical dysphagia compared with selective testing with strong suspicion for achalasia. Cost outcomes were defined on national commercial and Medicare datasets stratified on age and sex. Health outcomes were modeled on populations with achalasia. The time horizon was 1 year. RESULTS: Motility testing was preferred over nonalgorithmic usual care due to cost savings rather than health gains. To commercial insurers, routine esophageal manometry for nonstructural/mechanical dysphagia would be cost-saving below a reimbursed cost of $2,415. Screening impedance planimetry would be cost saving below a reimbursed cost of $1,130. The limit for reimbursed costs would be lower for patients older than 65 years to achieve cost savings mainly due to insurance. Sex did not significantly influence cost-effectiveness. Patients and insurers preferred routine screening impedance planimetry before manometry when the index of suspicion for achalasia was below 6%. DISCUSSION: Aligning with practice guidelines, routine esophageal motility testing seems cost saving to patients and insurers compared with nonalgorithmic usual care to evaluate nonstructural/mechanical dysphagia. Choice of testing should be guided by index of suspicion.

Association of esophageal motility disorder symptoms with Chicago classification versions 3.0 and 4.0 using high-resolution esophageal manometry: A single-center experience from Saudi Arabia.

BACKGROUND: Esophageal motility disorders (EMDs) can significantly impact patients' quality of life. The Chicago Classification (CC) was developed as a robust framework to enable clinicians to better understand and classify the nature of motility disorders. Previous studies have primarily focused on the CC version 3.0 (CCv3.0), and data regarding the correlation between symptoms and CC version 4.0 (CCv4.0) in the Saudi Arabian population are lacking. This study aimed to assess the correlation between symptoms and CCv3.0 and CCv4.0 using high-resolution esophageal manometry (HRM) in Saudi Arabia, to evaluate the diagnostic performance of both classifications. METHODS: A total of 182 patients presenting with esophageal symptoms were included in this study. HRM was performed to assess esophageal motility, and patients' reported symptoms were recorded. The association between HRM findings and symptomatic variables was analyzed using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Variability was observed in the diagnostic performance of symptomatic variables for major EMDs. CCv4.0 demonstrated a higher sensitivity for dysphagia than CCv3.0; however, it exhibited lower sensitivity to atypical gastroesophageal reflux disease (GERD) symptoms. Noncardiac chest pain (NCCP) exhibited the highest specificity and PPV, whereas typical GERD symptoms showed lower specificity. CONCLUSION: CCv4.0 demonstrated potential improvements in sensitivity for dysphagia, but lower sensitivity for atypical GERD symptoms, compared with CCv3.0. These insights provide guidance for clinicians in Saudi Arabia and contribute to understanding the diagnostic performance of CCv3.0 and CCv4.0.

Chicago Classification v4.0 Stratifies Acid Burden and Abnormal Impedance-pH Variables Better Than Chicago Classification v3.0 Chicago Classification v4.0 and GERD.

INTRODUCTION: Gastroesophageal reflux disease (GERD) severity increases with esophageal body hypomotility, but the impact of Chicago Classification (CC) v4.0 criteria on GERD diagnosis is incompletely understood. METHODS: In patients with GERD evaluated with high-resolution manometry and pH-impedance monitoring, CCv3.0 and CCv4.0 diagnoses were compared. RESULTS: In 247 patients, hypomotility diagnosis decreased from 45.3% (CCv3.0) to 30.0% (CCv4.0, P < 0.001). In contrast, within patients with ineffective esophageal motility, proportions with pathological acid exposure increased from 38% (CCv3.0) to 88% (CCv4.0); baseline impedance and esophageal clearance demonstrated similar findings ( P < 0.05 for each comparison). DISCUSSION: CCv4.0 hypomotility criteria are more specific in supporting GERD evidence compared with CCv3.0.

Esophageal Motility Disorders: Diagnosis and Treatment Strategies.

BACKGROUND: Esophageal motility disorders (EMDs) are caused by the impaired relaxation of the upper/lower esophageal sphincter and/or defective esophageal peristaltic contractions, resulting in dysphagia and noncardiac chest pain. High-resolution manometry (HRM) is essential for the diagnosis of primary EMD; however, the recognition of EMD and HRM by general practitioners in Japan is limited. This review summarizes the diagnosis of and treatment strategies for EMD. SUMMARY: HRM is a specific test for the diagnosis of EMD, whereas endoscopy and barium swallow as screening tests provide characteristic findings (i.e., esophageal rosette and bird's beak sign) in some cases. It is important to note that manometric diagnoses apart from achalasia are often clinically irrelevant; therefore, the recently updated guidelines suggest additional manometric maneuvers, such as the rapid drink challenge, and further testing, including functional lumen imaging, for a more accurate diagnosis before invasive treatment. Endoscopic/surgical myotomy, pneumatic dilation, and botulinum toxin injections need to be considered for patients with achalasia and clinically relevant esophagogastric junction outflow obstruction. KEY MESSAGE: Since the detailed pathophysiology of EMD remains unclear, their diagnosis needs to be cautiously established prior to the initiation of invasive treatment.