Triple A (Allgrove) syndrome due to AAAS gene mutation with a rare association of amyotrophy.

INTRODUCTION: Triple A (Allgrove) syndrome is a rare autosomal recessive disorder characterized by cardinal features of primary adrenal insufficiency (AI) due to adrenocorticotropic hormone (ACTH) resistance, achalasia, and alacrima. It is frequently associated with neurological manifestations such as autonomic dysfunction, cognitive dysfunction, cranial nerve, or motor involvement. Amyotrophy/motor neuron disease is a rare association. CASE PRESENTATION: We herein report a 19-year-old boy diagnosed with triple A syndrome (TAS), with the classic triad of ACTH-resistant adrenal insufficiency, achalasia, and alacrima. Additionally, he had distal spinal muscle amyotrophy. Alacrima was the earliest feature evident in early childhood, followed by achalasia at 12 years of age. He was diagnosed with AI at the age of 19 years, with involvement of the mineralocorticoid axis. Further evaluation showed a neurogenic pattern on electromyography, consistent with a diagnosis of motor neuron disease. A nerve conduction study revealed no significant neuropathy. Genetic analysis confirmed a pathogenic homozygous mutation in the AAAS gene c.43C>A, p.Gln15Lys. He improved with glucocorticoid and mineralocorticoid supplements for AI, and nifedipine for achalasia and artificial tears. He is planned for esophagomyotomy. CONCLUSION: In any young patient with AI not due to congenital adrenal hyperplasia, Allgrove syndrome should be ruled out. Though mineralocorticoid sparing pattern is classical, it can rarely be involved, as seen in the index case. Various components of the syndrome, as well as amyotrophy and other neurologic features, may present in a metachronous fashion. Hence, a high index of clinical suspicion can aid in early diagnosis and management.

A case of vomiting in an anorexic achalasic patient.

Wernicke's encephalopathy is a neurological disorder caused by thiamine (vitamin B1) deficiency characterized by vertigo, ataxia, and mental confusion. Wernicke's encephalopathy has a causative association with alcoholism but recently there has been an increased prevalence also in other clinical conditions. In literature potentially fatal Wernicke's encephalopathy onset in an advanced achalasia has been previously reported only once. We describe for the first time an improvement of achalasic symptoms in a young patient affected by end-stage achalasia and anorexia nervosa (coming from ineffective Heller-Dor myotomy) after vitamin B1 supplementation. This case report suggest a potential positive impact of B1 supplementation on end-stage achalasic patients and requires systematic studies to confirm this observation.

Laparoscopic esophagogastrostomy: an alternative minimally invasive treatment for achalasia stage III.

BACKGROUND: The surgical treatment for stage III achalasia with markedly dilated and sigmoid-shaped esophagus is a matter of controversy. Some authors recommend esophagectomy as the primary treatment because they believe that Heller myotomy cannot improve dysphagia in such cases. We present a patient with achalasia stage III in whom we successfully performed a laparoscopic esophagogastrostomy with posterior semifundoplication. METHODS: Using a five-trocar technique, the esophagogastric junction and the distal esophagus up to the tracheal bifurcation were dissected. An endoscopic stapler (Endo-GIA II) was inserted through a small gastrotomy at the cardia, with one branch placed in the gastric fundus and the other, under esophagoscopic control, in the esophagus. By two consecutive stapler applications, a wide side-to-side esophagogastrostomy was created. To prevent gastroesophageal reflux, a posterior semifundoplication was performed. RESULTS: The operation time was 170 min. Oral food intake was started after radiologic control on postoperative day 7. Radiologic study showed rapid passage of the barium meal and no reflux through the gastroesophageal junction. CONCLUSIONS: Laparoscopic esophagogastrostomy with posterior semifundoplication represents an alternative to esophagectomy and laparoscopic Heller-Dor surgery. Because of the wide side-to-side anastomoses, there is no risk of persisting stenosis such as that reported for the Heller operation, and the procedure certainly is less invasive than esophagectomy. As compared with laparoscopic extramucosal myotomy using anterior Dor fundoplication, it presents about the same technical difficulties.

Medical therapy of achalasia: A benefit reserved for few.

BACKGROUND: The rationale for medical therapy of initial achalasia and the results obtained over the last 20 years in our laboratory are presented. METHODS: Achalasic patients were selected as candidates for medical therapy on the basis of the presence of a slight esophageal dilation (<5 cm) on X-rays and a good manometric response to nifedipine administration. These patients were asked to take 10-20 mg of nifedipine sublingually 30-45 min before each meal for 2 weeks. Chronic medical therapy was continued only in those with an 'excellent' or 'good' clinical response to nifedipine and a lack of severe side effects. X-ray controls were planned every 6 months and manometric examination after the first 6 months. RESULTS: Of the 56 patients selected in the above-mentioned manner, 17 had an insufficient clinical response or severe side effects during the initial trial and did not continue medical therapy. Of the 39 patients who started chronic medical treatment, 13 are still on therapy and 26 stopped after an average of 2.8 years: 17 because they underwent dilation or myotomy; 4 for unknown reasons, and 5 apparently recovered. Esophageal manometry was carried out in 4 of the latter patients and revealed that the achalasic motor pattern had been replaced by a near-normal pattern. CONCLUSIONS: We believe that medical treatment of achalasia should be carried out not only in those patients who cannot undergo invasive procedures or do not respond well to them, but also in patients with initial achalasia selected using the above-mentioned criteria, because regression of the disease could take place in some of them.

Treating achalasia: from whalebone to laparoscope.

OBJECTIVE: To review the pathophysiology and management of achalasia. DATA SOURCES: Peer-reviewed publications located via MEDLINE using the search term esophageal achalasia (subheadings: complications, drug therapy, epidemiology, etiology, physiopathology, surgery, and therapy) published in English from 1966 to December 1997. STUDY SELECTION: Of 2632 citations identified, 4.5% were selected for inclusion by authors' blinded review of the abstracts. New developments in the understanding of achalasia or reports of therapeutic efficacy in either controlled trials or uncontrolled consecutive series involving 10 patients or more observed for a year or longer were reviewed in detail. DATA EXTRACTION: All 6 controlled therapeutic trials were included, and therapeutic efficacy in uncontrolled series was assessed by the authors extracting the patients with a good-to-excellent response from each study and calculating a pooled estimate of response rate with individual studies weighted proportionally to sample size. DATA SYNTHESIS: Achalasia results from irreversible destruction of esophageal myenteric plexus neurons causing aperistalsis and failed lower sphincter relaxation. The only therapies that adequately compensate for this dysfunction for a sustained time are pneumatic dilation and Heller myotomy. The single controlled trial comparing these treatments found surgery superior to dilation (95% vs 51% nearly complete symptom resolution, P<.01). In uncontrolled trials pneumatic dilation (weighted mean [SD]) is 72% (26%) effective vs 84% (20%) for Heller myotomy. The limitation of dilation is a 3% risk of perforation; thoracotomy morbidity has been the major limitation of myotomy. Surgical morbidity has been sharply reduced by laparoscopic techniques. CONCLUSIONS: Both pneumatic dilation and surgical myotomy are effective therapies for achalasia; laparoscopic Heller myotomy is emerging as the optimal surgical therapy.

Isosorbide dinitrate or nifedipine: which is preferable in the medical therapy of achalasia?

Oesophageal motor activity was recorded manometrically with a low compliance system in 16 patients with achalasia and a slightly dilated oesophagus. After a basal recording period, nifedipine 20 mg was given sublingually to 9 patients and isosorbide dinitrate 5 mg to another 7 patients. Lower oesophageal sphincter pressure (LESp) and oesophageal body pressure wave amplitude were measured for 60 min after drug administration. Both drugs decreased LESp and pressure wave amplitude, but the effect of isosorbide dinitrate was faster and more intense than that of nifedipine. There was a lower inhibitory effect of nifedipine on the amplitude of pressure waves than on LESp, while isosorbide dinitrate inhibited with a similar intensity both LESp and pressure waves.

Return of esophageal peristalsis after nifedipine therapy in patients with idiopathic esophageal achalasia.

This study was carried out to demonstrate the possible return of esophageal peristalsis in patients affected by esophageal achalasia chronically treated with sublingual nifedipine and to investigate which parameters are correlated with the return of peristalsis. Thirty-two patients were treated with sublingual nifedipine 10-20 mg taken 30 min before meals. A clinical and manometric evaluation was performed before and after 6 months of therapy. Before treatment, in no patient was peristaltic activity recorded. After 6 months, peristalsis was observed in six patients. In this group, no pretreatment manometric parameter was different from that of the remaining achalasic patients; only the clinical history of dysphagia was significantly shorter (p < 0.001) and the esophageal diameter significantly less (p < 0.001). In conclusion, chronic treatment with sublingual nifedipine can induce a return of esophageal peristalsis in patients with a short clinical history of disease and slightly dilated esophagus.

Short report: comparison of the effects of sublingual nifedipine and isosorbide dinitrate on oesophageal emptying in patients with Chagasic achalasia.

The effects of sublingual nifedipine and isosorbide dinitrate on oesophageal emptying were compared in 11 patients with Chagasic achalasia. The oesophageal emptying of a radiolabelled test meal was assessed three times in each patient by a scintigraphic technique. No treatment preceded one of the studies (basal study). Nifedipine (20 mg) by the sublingual route 30 min before the meal, preceded one study. Isosorbide dinitrate, 5 mg by the sublingual route 5 min before the meal, preceded the third study. The order of the studies was allocated randomly for each patient. Oesophageal retention at the completion of the meal was significantly less (P less than 0.01) after isosorbide dinitrate (median: 54%, range: 5-87%) than after sublingual nifedipine (median: 78%, range: 7-99%) or after the control study (median: 83%, range: 5-100%). This difference persisted up to 20 min after the meal. Values measured in the control study and after sublingual nifedipine were not different (P greater than 0.10). These results show that isosorbide dinitrate, but not sublingual nifedipine, enhances oesophageal emptying in Chagasic achalasia.

Medical treatment of esophageal achalasia. Double-blind crossover study with oral nifedipine, verapamil, and placebo.

Calcium channel blockers have been previously shown to decrease lower esophageal sphincter (LES) pressure and improve symptoms in achalasia. We performed a placebo-controlled, double-blind, crossover study to assess the effects of oral nifedipine and verapamil on LES pressure, amplitude of esophageal body contraction, and clinical symptomatology in eight patients with symptomatic achalasia diagnosed by endoscopy, barium swallow, and manometry. Patients were randomized to receive up to 20 mg nifedipine, 160 mg verapamil, or placebo and underwent esophageal manometry before (baseline) and after four weeks on each drug. Diary cards were kept to record and grade symptoms and drug plasma level determinations were correlated with manometric and clinical findings. Both nifedipine and verapamil caused a statistically significant decrease in mean LES pressure, but only nifedipine caused a significant decrease in the amplitude of contractions of the smooth muscle portion of the esophagus. No statistically significant differences in the overall clinical symptomatology were noted with any of the drugs, although some individual improvements in dysphagia and chest pain were noted. We conclude that, despite the reduction in LES pressure and contraction amplitude of the distal esophageal body, oral nifedipine and verapamil do not significantly alter the clinical symptomatology of patients with achalasia.

The role of nifedipine therapy in achalasia: results of a randomized, double-blind, placebo-controlled study.

Utilizing the rationale that the calcium channel blocker nifedipine decreases lower esophageal sphincter pressure, we performed a double-blind, placebo-controlled, crossover trial of sublingual nifedipine in achalasia, a disorder whose treatment depends on reduction in lower esophageal sphincter pressure. Ten patients participated in this trial, completed diaries, underwent manometric determinations of lower esophageal sphincter pressure, and had testing of esophageal emptying rates by a solid-meal radionuclide method. Nifedipine, titrated to a dose of 10-30 mg before meals, was well tolerated. Compared with placebo, nifedipine significantly reduced the frequency of dysphagia, but some symptoms of dysphagia, regurgitation, or nocturnal cough were still present most days. Nifedipine significantly reduced lower esophageal sphincter pressure by 28%, a value approximately one-half that achieved by successful pneumatic dilatation or myotomy. Esophageal emptying rates, as determined by the radionuclide method, were unchanged by nifedipine. We concluded that 1) nifedipine reduces symptoms of achalasia, but substantial symptoms do remain during such therapy; 2) the suboptimal effect results from the limited, although statistically significant, effect of nifedipine on reduction of lower esophageal sphincter pressure; and 3) although we believe that nifedipine may be recommended as treatment for achalasia in the subset of patients whose overall medical condition places them at high risk for forceful dilatation or surgery, it cannot be recommended as a standard alternative to these other modalities.

Quantitative assessment of the response to therapy in achalasia of the cardia.

Radionuclide oesophageal transit studies and manometry have been carried out in 15 patients with achalasia of the cardia, before treatment, after a course of nifedipine and after pneumatic bag dilatation. Transit studies were also done in 10 patients after cardiomyotomy and in 10 normal subjects. Images were recorded with the subjects seated in front of a gamma camera while swallowing a 10 ml bolus of 99Tcm-tin colloid and then after a further drink of 50 ml water. There was marked retention of tracer in the oesophagus in patients with achalasia compared with rapid clearance in control subjects. Bag dilatation significantly reduced lower oesophageal sphincter pressure but there was no significant difference in the 50% clearance time or percentage dose retained at 100s before and after the treatments. Oesophageal clearance of tracer after the additional drink of water, was improved by bag dilatation. Oesophageal transit in the patients after cardiomyotomy was similar to that in patients who had undergone bag dilatation. There was considerable retention of the tracer in the oesophagus overnight, but this did not result in pulmonary aspiration. Radionuclide oesophageal transit studies provided a quantitative assessment of therapy in achalasia and the proportion of tracer retained after the additional drink proved to be a sensitive measure of response to treatment. Nifedipine proved ineffective as a treatment for achalasia. Bag dilatation and cardiomyotomy were of similar value.

[Calcium antagonists: accounts on new perspectives of their use and an update on side effects]. / I farmaci calcioantagonisti. Cenni su nuove prospettive di impiego e aggiornamento sugli effetti collaterali.

Although calcium antagonists are drugs which have been introduced relatively recently, their use is already so widespread, at least in the treatment of cardiovascular diseases as to represent one of the main therapies for diseases such as ischaemic cardiopathy, arterial hypertension, and, to a lesser extent, arrhythmias. Together with the development of clinical applications, deeper insight has been gained into the clinical and experimental pharmacology of these drugs. The authors of this review concentrate their attention on some of the less frequently discussed aspects of calcium antagonists. On the one hand, they describe some "nonprimary" uses of these drugs, both in the cardiovascular and in other therapeutic fields, which already receive confirmation from relatively solid experimental data. On the other hand, they review the side effects and some pharmacological interactions of calcium antagonists, both of which should be held in due consideration, seeing that these drugs are widely employed in clinical practice and their use often requires prolonged, intensive treatment. The most common side effects are described, together with others relatively less well known ones, and outline is given of potential undesirable effects on the cardiovascular as well as on other systems.

The use of nifedipine for the treatment of achalasia in children.

Four adolescents with achalasia were treated with nifedipine. All the patients' symptoms improved dramatically. On manometric evaluation, following oral nifedipine, the lower esophageal sphincter pressure decreased approximately 50%. No change in esophageal peristaltic activity was noted. Side effects were minimal; two patients had mild headache initially. Nifedipine, which is commonly used in adult patients with achalasia, may be beneficial for short-term symptomatic relief in children until more definitive therapy can be performed.

Primary oesophageal motility disorders. Current therapeutic concepts.

Various oesophageal manometric disorders have been associated with chest pain or dysphagia. The classic motility disorders are achalasia and diffuse oesophageal spasm. In achalasia, a disorder of aperistalsis in the oesophageal body and incomplete relaxation of the lower oesophageal sphincter, either surgical myotomy or pneumatic dilatation is an effective approach, although some investigators have suggested a role for pharmacological therapy. For the treatment of diffuse oesophageal spasm, a disorder of non-peristaltic motor activity in the oesophagus, various pharmacological approaches with nitrates, anticholinergics, and calcium antagonists have been used. In the presence of associated lower oesophageal sphincter dysfunction, bouginage or pneumatic dilatation may be indicated. Long oesophagomyotomy should be considered for those patients who fail to respond to these measures. Recent manometric techniques have led to the identification of patients with chest pain or dysphagia who have abnormalities of increased contractile amplitude ('nutcracker' oesophagus) or duration. An association with gastro-oesophageal reflux or with psychiatric disturbance has been suggested. Treatment directed towards these factors is indicated and may be supplemented by pharmacological intervention, e.g. by calcium antagonists or anticholinergics.