Etiopathological aspects of achalasia: lessons learned with Hirschsprung's disease.

The etiology of primary esophageal achalasia is largely unknown. There is increasing evidence that genetic alterations might play an important but underestimated role. Current knowledge of the genetic base of Hirschsprung's disease in contrast is far more detailed. The two enteric neuropathies have several clinical features in common. This association may also exist on a cellular and molecular level. The aim of this review is to enlighten those etiopathogenetic concepts of Hirschsprung's disease that seem to be useful in uncovering the pathological processes causing achalasia. Three aspects are looked at: (i) the genetic base of Hirschsprung's disease, particularly its major susceptibility gene rearranged during transfection and its potential reference to achalasia; (ii) the altered motor functions in both conditions with loss of inhibitory innervation and interstitial cell pathology; and (iii) the involvement of these motility disorders in genetic syndromes.

Appropriateness of colonoscopy in Europe (EPAGE II). Screening for colorectal cancer.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for screening for colorectal cancer (CRC) in asymptomatic individuals without personal history of CRC or polyps, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews, and primary studies regarding colonoscopy for screening for colorectal cancer was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy in these circumstances. RESULTS: Available evidence for CRC screening comes from small case-controlled studies, with heterogeneous results, and from indirect evidence from randomized controlled trials (RCTs) on fecal occult blood test (FOBT) screening and studies on flexible sigmoidoscopy screening. Most guidelines recommend screening colonoscopy every 10 years starting at age 50 in average-risk individuals. In individuals with a higher risk of CRC due to family history, there is a consensus that it is appropriate to offer screening colonoscopy at < 50 years. EPAGE II considered screening colonoscopy appropriate above 50 years in average-risk individuals. Panelists deemed screening colonoscopy appropriate for younger patients, with shorter surveillance intervals, where family or personal risk of colorectal cancer is higher. A positive FOBT or the discovery of adenomas at sigmoidoscopy are considered appropriate indications. CONCLUSIONS: Despite the lack of evidence based on randomized controlled trials (RCTs), colonoscopy is recommended by most published guidelines and EPAGE II criteria available online (http://www.epage.ch), as a screening option for CRC in individuals at average risk of CRC, and undisputedly as the main screening tool for CRC in individuals at moderate and high risk of CRC.

[Achalasia or pseudoachalasia? Problems of diagnostic and treatment decisions in two cases]. / Achalasie oder Pseudoachalasie? Fallstricke der Diagnostik und Therapieentscheidung.

HISTORY: Patient 1 (female, aged 55 years) had for some time complained of morning nausea. She reported symptoms of reflux with regurgitation of food for two-and-a-half years and also dysphagia with retrosternal bolus obstruction for the last eighteen months. Patient 2 (male, aged 84 years) complained of restrosternal dysphagia with each intake of food for one year, weight loss of 12 kg and occasional regurgitation of food. INVESTIGATIONS: The general condition of patient 1 was only slightly impaired but that of patient 2 markedly reduced. Routine laboratory tests were unremarkable in both. Barium meal in patient 1 revealed fixed narrowing in the region of the esophageal hiatus. The inferior esophageal sphincter was closed but opened under pressure during esophagogastroscopy. At computed tomography (CT) of the thorax and abdomen an esophageal fistula was detected and bronchoscopy confirmed its opening into the esophagus. Barium meal in patient 2 (done at another hospital) demonstrated a spastic esophagus. Manometry of the esophagus revealed at rest an abnormal increase in the inferior esophageal sphincter without relaxation. DIAGNOSIS, TREATMENT AND COURSE: Patient 1 had an achalasia and an esophagogastric fistula with recurrent aspiration pneumonia, bronchial carcinoma being excluded. The fistula was closed by suture, followed by cardiomyotomy and anterior partial gastric fundectomy. In patient 2 an isolated achalasia had at first been suspected and botulinum toxin injected into the inferior esophageal sphincter. This caused a progressively worse dysphagia. CT of the thorax and abdomen established the diagnosis of a pseudoachalasia due to an adenoma of the cardia, proven by biopsy at an exploratory laparotomy. A stent was implanted in the esophagus: the postoperative course was without complication. CONCLUSION: Patient 2 with the pseudoachalasia had a relatively short history of dysphagia, marked weight loss and was elderly. This compares with the history in patient 1: shorter period of dysphagia, no weight loss and a younger age. The differential diagnosis between the two conditions may be difficult with routine methods and other imaging modalities: exploratory surgery may be necessary for a definitive diagnosis.

[Achalasia in circumscribed scleroderma]. / Achalasie bei zirkumskripter Sklerodermie.

HISTORY: A 38-year-old man had been suffering from circumscribed scleroderma for 12 years. Dysphagia had been diagnosed 5 years ago and for the last 2 years he had retrosternal dysphagia for solid and liquid food. His symptoms had increased markedly 6 months before presenting at our hospital and the patient had lost 15 kg of weight. 2 months ago, a percutaneous endoscopic gastrostomy (PEG) had been inserted at another hospital. INVESTIGATIONS: The patient presented in a reduced general and nutritional state. The routine laboratory tests and tumor markers were within normal range. Endoscopy showed a moderately dilated esophagus with food remnants. It was not possible to pass the cardia without exerting pressure. Esophageal manometry and barium upper gastrointestinal series revealed the classical findings of achalasia. THERAPY AND COURSE: An extramucosal Heller myotomy with anterior semifundoplication (Dor's procedure) was performed. The postoperative course was uneventful and the patient was able to take solid and liquid food without any dysphagia. CONCLUSION: The association of achalasia and circumscribed scleroderma has not been described in medical publications yet. The entity could possibly be based on common autoimmune mechanisms and an analogous pathogenesis with resulting fibrosis.

Image cytometric DNA analysis of mucosal biopsies in patients with primary achalasia.

AIM: To determine DNA aneuploidy in mucosal biopsies of achalasia patients for subsequent rapid diagnosis. METHODS: Biopsies from the middle third of the esophagus were obtained in 15 patients with achalasia. Immunohistochemical staining was carried out with monoclonal antibodies MIB-1 for Ki67 and PAb 1801 for p53, in addition to the conventional histologic examination for dysplasia. Nuclei of fresh biopsy material were enzymatically and mechanically isolated, and the DNA content was determined with image cytometry after Feulgen staining. DNA grading of malignancy was assessed according to Boecking to determine the variability of DNA values noted around the normal diploid peak. Further indices measured included the aneuploid rate, and the 5c-, 7c- and 9c-exceeding rate. RESULTS: The histological examination did not demonstrate dysplasia; while MIB-1 (basal) showed a positive reaction in 8/15 achalasia specimens, p53 was negative in all specimens. Image cytometric DNA analysis detected aneuploidy in 4/15 (26.7%) specimens. Samples from 15 patients with squamous cell carcinoma as well as specimens obtained exclusively 2 cm proximal to the tumor served as reference tests. All carcinomas (15/15) as well as 9 of the peritumoral samples (9/15) were aneuploid. The comparison of biopsies from achalasia patients with peritumoral and carcinoma specimens revealed statistically significant differences regarding the aneuploid rate (diploid: P < 0.0001; tetraploid: P = 0.001), grading of malignancy according to Boecking (P < 0.0001) and the 5c- (P < 0.0001), 7c- (P < 0.0001), and 9c- (P = 0.0001) exceeding rate with progredient DNA alterations in the respective order. CONCLUSION: The finding that DNA aneuploidy was identified by image cytometry in esophageal specimens of patients with achalasia, which may be due to specific chromosomal alterations presenting as precancerous lesions in 27% of patients, leads us to conclude that image cytometry represents a valuable screening tool.

[Esophageal resection for non-specific esophageal motility disorder]. / Osophagusresektion bei unspezifischer Motilitätsstörung der Speiseröhre -- Bedeutung der neuropathologischen Befunde.

A 47-year-old patient presented with a history of dysphagia for solid food for almost 10 years and weight loss of more than 50 kg. Non-resecting surgical as well as endoscopic procedures (laparoscopic cardiomyotomy with secondary antireflux operations, balloon dilation, Botulinum-toxin injection) were without success. A barium esophagogram showed a confinement of the distal esophagus with a filiform passage of the contrast medium and undigested food in the prestenotic dilated esophageal corpus. Manometry displayed a hypertensive lower esophageal sphincter with a resting pressure of 43.8 mmHg - although completely relaxing. The tubular esophagus was aperistaltic with 100 % simultaneous and repetitive contractions. As all attempts of previous therapy had failed, a transhiatal esophagectomy with gastric pull-up and cervical esophagogastrostomy ensued. Neuropathological examination of the esophagus showed that degeneration of the myenteric plexus was not severely involved, whereas inflammatory and fibrotic changes were obvious. Esophageal resection provided the only chance of a long-term benefit for our patient with relief of dysphagia.

[Epiphrenic diverticulum: possible causes and surgical therapy]. / Epiphrenisches Divertikel. Mögliche Ursachen und chirurgische Therapie.

INTRODUCTION: In the majority of patients suffering from epiphrenic diverticula, functional disorders of the esophagus are evident. The significance of surgical therapy is unclear, especially in case of nonspecific esophageal motility disorders. Besides "triple therapy" with diverticulectomy, myotomy, and semifundoplication, myotomy alone is also applied. Based on our own long-term results, we intended to prove if a treatment concept modeled on the motility disorder is justified. PATIENTS AND METHODS: Between July 1989 and December 2002, 12 patients with symptomatic epiphrenic diverticula underwent surgery at our clinic. Myotomy was carried out with diverticulectomy (and semifundoplication) only if achalasia had been proven, and an antireflux procedure was done only in case of gastroesophageal reflux. Surgery was performed openly in ten patients, and laparoscopically in two. RESULTS: After a median follow-up of 46 months (range 9-169), all patients regarded the operative results as good to very good (11 follow-up investigations). CONCLUSION: To alleviate symptoms in patients with epiphrenic diverticula, myotomy is only rarely indicated. As with diverticulectomy, it is only necessary, if achalasia has been proven. Our long-term results do not suggest performing myotomy as a rule for underlying unspecific motility disorders of the esophagus.

[Long-term results for Heller-myotomy with anterior semifundoplication in achalasia]. / Langzeitergebnisse nach Heller-Myotomie mit anteriorer Semifundoplikatio bei Achalasie.

INTRODUCTION: The positive success rate of cardiomyotomy in the treatment of achalasia has recently - especially in young patients - resulted in a primary operative treatment concept. Few studies of long-term effects of myotomy concerning the removal of dysphagia and the development of gastroesophageal reflux have been submitted. PATIENTS AND METHODS: In the period between September 1985 and March 2003, an open, transabdominal Heller-myotomy combined with a Dor-semifundoplication was carried out in 93 patients with achalasia. 77 patients were followed for more than 6 months postoperatively (median follow-up: 70 months). The procedure was prospectively observed, and patients were questioned concerning their clinical symptoms by means of structured interviews. X-ray examinations of the esophagus were pre- and postoperatively available of 47 patients, manometrical findings before and after myotomy of 26 patients. RESULTS: The pre-operatively existing symptoms dysphagia, regurgitation, retrosternal pain and weight-loss could be improved by myotomy in 97 % of the patients with good to excellent long-term results. Post-operatively, a significant reduction of the median maximum diameter of the esophagus of 50 mm to 30 mm was evident (p < 0.001), whereas the diameter of the cardia increased from 3 mm to 10 mm (p < 0.001). The pre-operative resting pressure of the lower esophageal sphincter (LES) of 29.3 mmHg was reduced to 7.9 mmHg (p < 0.001). Patients suffering from reflux esophagitis showed a significant lower resting pressure of the LES (4 mmHg) in comparison with patients without reflux esophagitis (8.5 mmHg) after myotomy (p=0.045). The clinical long-term results of patients with preceding pneumatic dilation did not differ significantly from those with primary myotomy. CONCLUSION: Conventional Heller-myotomy with anterior semifundoplication can in the long run remove the symptoms existent in achalasia with high efficiency. If the decrease of the post-operative resting pressure of the LES is too intense (< 5 mmHg), a possible gastroesophageal reflux has to be taken into account. The results of open cardiomyotomy have to be regarded as standard for assessing the minimal-invasive procedure.

Transabdominal ultrasonography in achalasia.

BACKGROUND: The aim of this study was to investigate whether transabdominal ultrasonography can differentiate between achalasia and neoplasms involving the oesophagogastric junction. METHODS: Ultrasonography was performed in 28 patients with achalasia, 28 sex- and age-matched controls and 13 patients with neoplasms. All studies were done with a 3.5 MHz real time curved array scanner and using an electronic caliper to measure oesophageal wall thickness and the maximum oesophageal diameter. Specificity and sensitivity in making a diagnosis of achalasia and tumours were determined by having unmarked images interpreted by a blinded observer. RESULTS: Patients with achalasia were identified by recognition of a dilated oesophagus without the presence of a neoplastic lesion (maximum oesophageal diameter (median)=achalasia: 20.0 (14; 25)mm; controls 10.1 (9; 11) mm; P < 0.001). Oesophageal wall thickness was similar in the two groups (achalasia: 3.2 (2.5; 3.4) mm; controls: 2.9 (2.5; 3.4)). In patients with neoplasms, a hypoechoic lesion was identified at the level of the gastric cardia. The sensitivity of making a tumour diagnosis was 100% and the specificity 82%. CONCLUSION: Transabdominal ultrasonography is a useful, non-invasive diagnostic aid in differentiating patients with primary achalasia from those with neoplastic lesions at the gastric cardia.

Pneumatic dilation for achalasia: late results of a prospective follow up investigation.

BACKGROUND: and aims: In this prospective study, we determined the long term clinical course of patients with achalasia who were treated by pneumatic dilation using the Browne-McHardy dilator, and determined whether previously described predictors of outcome remain significant after prolonged follow up. METHODS: Between 1981 and 1991, 54 consecutive patients were treated by pneumatic dilation and followed up at regular intervals for a median of 13.8 years. Remission was determined with the use of a structured interview and a previously described symptom score. Duration of remission was evaluated by Kaplan-Meier estimates of time to recurrence. Predictors of outcome were determined using the log rank test. RESULTS: Complete follow up until 2002 was obtained in 98% of all patients. Seven patients had died and were censored. A single pneumatic dilation resulted in a five year remission rate of 40% and a 10 year remission rate of 36%. Repeated dilations only mildly improved the clinical response. Patients who were older than 40 years had a significantly better outcome than younger patients (log rank test, p = 0.0014). However, the most significant predictive factor for a favourable long term outcome was a post-dilation lower oesophageal sphincter pressure of less than 10 mm Hg (log rank test, p = 0.0001). CONCLUSIONS: Long term results of pneumatic dilation are less favourable than previously thought. Young patients and those not responding to a single pneumatic dilation should be offered alternative therapy. Patients who remain in remission for five years are likely to benefit from the longlasting treatment effect of pneumatic dilation.

[Dolichomegaesophagus in achalasia. Therapy by esophogectomy in an aged patient]. / Dolichomegaösophagus bei Achalasie. Therapie durch Osophagusresektion bei einer alten Patientin.

HISTORY AND CLINICAL FINDINGS: A 78-year-old woman suffered from achalasia since 63 years with a progressive decompensation over the last year. 53 years ago, treatment with the Stark Dilator and 24 years ago, pneumatic dilation had been carried out. Currently, the patient presented with dysphagia for liquid and solid food, with permanent retrosternal pain and regurgitation for every meal, leading to a weight loss of 10 kg. INVESTIGATIONS: The barium esophagogram showed a marked dilation of the esophagus with retinated secretions and food. The cardia had a maximum width of 15 mm. On endoscopy, reflux esophagitis and an insufficient lower esophageal sphincter were evident. TREATMENT AND COURSE: Transhiatal esophageal resection with gastric pull-up and cervical esophagogastrostomy was performed. The postoperative course was without complications and normal alimentation could be restored with a marked improvement of preoperative symptoms. CONCLUSION: Esophageal resection and gastric pull up is the more favourable treatment option in elderly patients with decompensated achalasia and dolichomegaesophagus compared to a gastric tube for alimentation--adjusted to the individual surgical risk.

[Long-term outcome of myotomy and semi-fundoplication in achalasia]. / Langzeitergebnisse nach Myotomie und Semifundoplicatio bei Achalasie.

The basic principle behind the treatment of achalasia consists of alleviating swallowing disorders by reducing resistance in the lower esophageal sphincter without inducing gastroesophageal reflux. Only a few studies are available on long-term results after operative treatment. Fifty-one patients were studied with regard to long-term results after open transabdominal extramucosal myotomy of the distal esophagus along with partial anterior fundoplication (Dor procedure). Clinical data were collected by standardized interviews, and symptoms were assigned a score ranging from 0 to 3 according to severity and frequency. The pre- and postoperative symptoms were comparable in 50 patients. The median duration of follow-up was 88 months (range: 12-160 months). Operative time was a median of 80 min. Two esophageal mucosal tears were recognized intraoperatively and promptly repaired. Postoperative morbidity occurred in two patients (3.9%). Very good or good long-term results after surgical therapy were achieved in 49 patients (96.1%). Forty-seven patients (92.2%) have no or rare dysphagia. The frequency of regurgitation as well as chest pain was also significantly reduced after surgery. Forty-nine patients (96.1%) either maintained or gained weight. Preoperative duration of symptoms, follow-up, age, and gender had no influence on the results (p > 0.05). Two patients (3.9%) mentioned occasional heartburn. Five patients (9.8%) took or still take proton pump inhibitors postoperatively. Severe stage IV symptoms due to peptic stricture and dolichomegaesophagus required reoperation in one patient (2%). The results show that myotomy and the antireflux procedure (semifundoplication) lead to long-term relief of dysphagia without inducing reflux at a low operative risk. Since long-term results are as yet not available for minimally invasive surgery, it remains to be seen if this operative technique will become the primary surgical procedure for this disease.

Does scant hematochezia necessitate the performance of total colonoscopy?

BACKGROUND AND STUDY AIMS: Controversy exists as to whether all patients with lower intestinal bleeding need to undergo total colonoscopy. This study compares the prevalence of colonic neoplasms in patients reporting scant hematochezia with the prevalence in controls. PATIENTS AND METHODS: Structured interviews were carried out with 4265 consecutive patients referred for colonoscopy. Of these, 468 patients had scant hematochezia, 299 had occult rectal bleeding and 57 reported dark rectal bleeding. Patients with scant hematochezia were matched for age and sex with those having no risk factors for colorectal neoplasms. For all groups, we determined the prevalence of adenomas and cancers below and above 50 cm. RESULTS: Colonic neoplasms were found in 18 % of patients with scant hematochezia and in 7.5 % of controls. However, most of these tumors were located within the reach of a sigmoidoscope. Compared with controls, patients with scant hematochezia had no increased risk for proximal neoplasms (odds ratio [OR] = 1.2), while this risk was significantly increased in patients with occult rectal bleeding (OR = 3.1) and patients who had observed maroon-colored blood in their stool (OR = 4.8). CONCLUSIONS: Flexible sigmoidoscopy appears to be a sufficient work-up for young patients who have observed trace amounts of bright red blood on the surface of their stool.

[Esophageal resection in treatment of achalasia. 4 case reports and review of the literature]. / Osophagusresektion zur Behandlung der Achalasie. Vier Fallberichte und Ubersicht über die Literatur.

In the time period between 1985 and June 2001, four of 81 patients diagnosed with achalasia were surgically treated by means of transhiatal esophageal resection. Replacement with stomach and cervical anastomosis was performed in three patients aged 8, 19, and 27 years, respectively, after initial myotomy. In one case, the esophagus resection was the primary surgical measure and the colon was used as the replacement. The preoperative symptoms of the four patients showed improvement 51, 34, 15, and 8 months after the operation, respectively. Dysphagia and regurgitation no longer occurred. One patient died 4.5 years after esophageal resection due to ulcerous bleeding of the distal redundant colon interposition. In accordance with other studies investigating serious swallowing disorders, it could be shown that transhiatal resection with esophagus-replacement through stomach pull-up can lead to symptom-relief as well as an improvement in the quality of living.

Life expectancy and cancer risk in patients with Barrett's esophagus: a prospective controlled investigation.

BACKGROUND: It has been suggested that patients with Barrett's esophagus have a substantially increased risk of esophageal and possibly extra-esophageal cancers. We compared the incidence of cancer and the survival rates of patients with Barrett's esophagus with those observed in patients with achalasia, with Schatzki's ring, and in the general population. PATIENTS AND METHODS: From 1980 through 1994, 60 consecutive patients with newly diagnosed long-segment Barrett's esophagus without dysplasia were seen in a single gastroenterology consultation office and followed until the Fall of 1999. Cancer incidence and survival rates were compared with age- and sex-matched patients with symptomatic Schatzki's ring (n = 60) and achalasia (n = 60). Survival data were also compared with those of the German population. RESULTS: During a mean (+/-SD) observation period of 10 +/- 5 years, 2 patients with Barrett's esophagus (3%; 95% confidence interval [CI]: 0% to 11%) developed esophageal cancer, and 9 (15%; 95% CI: 7% to 27%) developed extra-esophageal cancers. These data differed only slightly from those of patients with Schatzki's ring (esophageal cancer: n = 1, 2%; 95% CI: 0% to 9%; extra-esophageal cancers: n = 9, 15%; 95% CI: 7%-27%) and achalasia (no esophageal cancers, extra-esophageal cancers: n = 3, 5%; 95% CI: 1% to 4%). Estimated 10-year survival was similar in patients with Barrett's esophagus (83%), patients with symptomatic Schatzki's ring (80%), patients with achalasia (87%), and in the general population (82%). CONCLUSIONS: The cancer risk in patients with Barrett's esophagus has been overestimated. If patients with nondysplastic epithelium are followed, the risk of esophageal cancer is about 1 per 300 patient-years.

Clinical presentations and complications of achalasia.

Patients with achalasia often present with atypical symptoms. If these occur in the context of "normal" morphological findings, the diagnosis may be delayed for several years. However, a careful interview and the use of modern methods that concentrate on pathophysiologic aspects always allow an early diagnosis and the initiation of therapy that affects most but rarely all symptoms. Finally, regardless of whether this therapy remains partially or totally effective, patients require some follow-up since serious and late complications may occur.

[Are screening programs in Barrett esophagus meaningful?]. / Sind Uberwachungsprogramme beim Barrett-Osophagus sinnvoll?

This review analyses whether the assumption is justified that endoscopic screening in patients with Barrett's syndrome facilitates early recognition of cancer and leads to prolongation of life. It is shown that no reliable data exist that would support the latter conclusion. Although there is scant information that some patients may benefit from close surveillance, it appears unlikely that an all too ambitious surveillance program will either be cost effective or acceptable for patients and/or endoscopy centers.