Achalasia: A review of therapeutic options and outcomes

Advances in achalasia has led to the development of new therapeutic options. This review will focus on methodology and outcomes of two established techniques; pneumatic dilation and surgical myotomy; and one new technique, LES injection of botulinum A toxin.     

Peroral endoscopic myotomy for management of gastrointestinal motility disorder

Achalasia is a type of esophageal motility disorder, consisting of relaxation dysfunction of the lower esophagus and disturbed esophageal peristalsis. Related clinical symptoms include dysphagia, regurgitation, chest pain, and weight loss. Traditional treatment options include endoscopic botulinum toxin injection, endoscopic pneumatic dilation, and laparoscopic Heller’s myotomy. These therapies mainly relieve symptoms by reducing the pressure on the lower esophageal sphincter and reducing blood flow resistance at the esophagogastric junction. Based on endoscopic submucosal dissection and natural orifice transluminal endoscopic surgery, peroral endoscopic myotomy (POEM) is a purely endoscopic method of myotomy with minimal invasiveness and a low rate of adverse events when performed by experienced operators. Since then, numerous studies have shown the significant clinical efficacy and safety of POEM. The purpose of this article is to introduce different modified POEMs, special indications for different POEMs, and their advantages as well as disadvantages.     

Etiology and treatment of achalasia in the pediatric age group

Achalasia in children bears many similarities to the disorder in adults, both in terms of clinical features and in terms of the approach to therapy. Pharmacologic management is of limited temporary benefit until more definitive therapy is undertaken. Intrasphincteric injections of botulinum toxin provides safe but short-term relief from symptoms. Based on our review of the safety and effectiveness of pneumatic dilation, we advocate this procedure as the primary form of definitive therapy for achalasia in children. In patients who do not achieve satisfactory results from a series of graduated pneumatic dilations, Heller myotomy provides safe and effective surgical treatment.     

Long-term results and prognostic factors in the treatment of achalasia with botulinum toxin

BACKGROUND AND STUDY AIMS: Endoscopic therapy of achalasia by injection of botulinum toxin into the lower esophageal sphincter has very limited adverse effects and is initially successful in 70 % of patients. However, this result only lasts for 6 - 9 months on average in most patients and only half of them benefit for more than 1 year. The aim of this study was to find out which factors are predictive for a good long-term success. PATIENTS AND METHODS: We retrospectively studied 25 patients with achalasia. The diagnosis had been proven by barium swallow and esophageal manometry. Therapy was carried out endoscopically between June 1996 and December 1998 by injection of 25 mouse units (MU) botulinum toxin into each of the four quadrants of the lower esophageal sphincter (LES). Lower esophageal sphincter pressure (LESP) was measured prior to and 1 week after endoscopic therapy. A standardized questionnaire was used for symptom assessment, at the initial presentation, at 1 week and at 2.5 +/- 0.8 years after treatment. RESULTS: The LESP was significantly reduced (pre-treatment 62.1 +/- 15.2 mmHg vs. post-treatment 43.1 +/- 12.5 mmHg; P < 0.01). Symptoms improved in 16 patients (pre-treatment symptom score 9.5 +/- 2.9 vs. post-treatment symptom score 4.7 +/- 1.8; P < 0.01). Nine patients showed no relevant improvement. From the 16 patients with a good initial response, two were lost to follow-up. In nine patients the outcome was still satisfactory after a mean of 2.5 years (1.5 - 4 years) (pre-treatment symptom score 9.5 +/- 2.9 vs. symptom score at 2.5 years after Botox 5.1 +/- 1.5; P < 0.05). These patients were on average 67.7 +/- 12.5 years old. The remaining five patients received a second or third injection of botulinum toxin, but none improved substantially for more than 6 months. One of them eventually underwent pneumatic dilation, and three laparoscopic myotomy. Thus, botulinum toxin treatment was unsuccessful in 14 patients in all. These 14 patients were, on average, significantly younger than the nine successfully treated patients (46.1 +/- 12.6 years vs. 67.7 +/- 12.5 years; P < 0.01) and had significantly higher LESP values prior to botulinum toxin therapy (72.8 +/- 8.9 mmHg vs. 47.8 +/- 9.2 mmHg; P < 0.01). CONCLUSIONS: The long-term success of botulinum toxin injection into the LES in patients with achalasia is highest in elderly patients and in patients with an LESP not exceeding the upper normal level prior to treatment by 50 % or more. On the basis of our results, younger patients (< 55 years) with a severe increase in LESP do not seem to benefit from botulinum toxin injection and pneumatic dilation or myotomy may be more advantageous to them.     

Successful treatment of long-standing post-stroke dysphagia with botulinum toxin and rehabilitation.

Cricopharyngeal myotomy is the most common treatment used to restore normal swallowing in patients with persistent (>6 months) cricopharyngeal muscle dysfunction post-stroke. We describe 2 patients whose dysphagia was due to cricopharyngeal muscle over-activity and who significantly improved after a percutaneous botulinum toxin injection in the cricopharyngeal muscle in combination with a rehabilitation treatment (dietary modifications, postural techniques, airflow protection manoeuvres). Swallowing was assessed clinically and by fibreoptic endoscopic evaluation of swallowing and videofluoroscopy; the degree of dysphagia was scored using the penetration-aspiration scale. Two months after the botulinum toxin injection the patients, who were previously fed via percutaneous endoscopic gastrostomy, returned to independent oral feeding and at 6, 12 and 24 months follow-up, both were still able to maintain an adequate oral intake with no signs of aspiration (by videofluoroscopy) or clinical complications. No further botulinum toxin injections or rehabilitation treatments were required. Our findings strongly suggest that even long-standing dysphagia can improve dramatically in selected patients. To the best of our knowledge, there are no other reports with such a long follow-up.     

Diagnosis and treatment of esophageal motility disorders

Apart from gastroesophageal reflux disease, achalasia, non-cardiac chest pain and functional dysphagia are the most important manifestations of disturbed esophageal motility. Achalasia is characterized by esophageal aperistalsis and impaired deglutitive relaxation of the lower esophageal sphincter. The morphological correlate is a degeneration of nitrergic neurons in the myenteric plexus. Diagnosis is based on barium esophagram or esophageal manometry with the latter setting the gold standard. Endoscopic exclusion of a tumor at the gastroesophageal junction is mandatory. Appropriate therapeutic interventions are pneumatic dilatation or (laparoscopic myotomy) of lower esophageal sphincter. In patients unfit for these procedures endoscopic injection of botulinum toxin into the lower esophageal sphincter is appropriate. Non-cardiac chest pain may be of esophageal origin. Gastroesophageal reflux, spastic motility disorders and visceral hypersensitivity are arguable underlying mechanisms. The most important diagnostic procedure is 24 h esophageal pH metry correlating symptoms and reflux episodes. Proton pump inhibitors and tricyclic antidepressants serving as visceral analgesics are appropriate therapeutic approaches. Functional dysphagia defines the sensation of impaired passage without mechanical obstruction or a neuromuscular disease with known pathology, e.g. scleroderma. Impaired transit is proven by esophageal scintigraphy or radiogram both using solid boluses. Manometry assesses the underlying mechanisms.     

Traitement endoscopique de l’achalasie : dilatation pneumatique, chirurgie ou myotomie pérorale endoscopique ?

Achalasia is an esophageal motility disorder defined by the absence of propagated contractions (aperistalsis) in the body of the esophagus and failure of relaxation of the lower esophageal sphincter. Thanks to high resolution manometry and study of the esophageal pressure topography, three subtypes, according to the classification of Chicago, have a direct interest in the choice of treatment to use: type I of achalasia presents the same result with pneumatic dilatation (81%) and surgery (85%); type II of achalasia presents the best result with pneumatic dilatation (100%); type III of achalasia called “spastic”, which is the more resistant, have the best result with Heller-Dor myotomy (86%). More recently appeared the peroral endoscopic myotomy, which remains to study in France, but with the preliminary results, this technic could become the treatment of choice for achalasia, particularly in the type III which is the most resistant.     

Adjuvant treatments associated with botulinum toxin injection for managing spasticity: An overview of the literature

Background and objectiveA wide range of adjunct therapies after botulinum toxin administration have been proposed. The aim of the present paper is to provide an overview of major writings dealing with adjuvant (non-pharmacological) treatments associated with botulinum toxin for managing spasticity in order to provide some up-to-date information about the usefulness of the most commonly used procedures.MethodsThe literature in PubMed was searched with the MeSH terms botulinum toxins, muscle spasticity, physical therapy modalities, and rehabilitation. The results were limited to studies focusing on adjuvant treatments associated with botulinum toxin for managing spasticity. We excluded papers on the use of non-drug treatments for spasticity not associated with botulinum toxin serotype A (BoNT-A) injection. Relevant literature known to the authors along with this complementary search represented the basis for this overview of the literature.ResultsAdhesive taping and casting effectively improved the botulinum toxin effect in patients with upper- and lower-limb spasticity. There is level 1 evidence that casting is better than taping for outcomes including spasticity, range of motion and gait. However, consensus about their most appropriate timing, duration, target and material is lacking. In terms of physical modalities combined with botulinum toxin injection, we found level 1 evidence that extracorporeal shock wave therapy is better than electrical stimulation for some post-injection outcomes including spasticity and pain. Furthermore, electrical stimulation of injected muscles might be useful to boost the toxin effect. However, the best stimulation protocol has not been defined. In addition, we found level 2b evidence that whole-body vibration therapy might reduce spasticity with cerebral palsy.ConclusionFuture research in this field should focus on investigating the most appropriate post-injection treatment protocol for each goal to achieve.     

Behandlung der Achalasie

Achalasia is a condition of unknown etiology. It represents a motor disorder of the esophagus characterized by absent or incomplete relaxation of the lower esophageal sphincter upon swallowing and by non-propulsive swallow-induced contraction waves or amotility of the esophageal body. Dysphagia and regurgitation of ingesta are the most frequent symptoms. Medical treatment, i.e. by calcium-channel blockers and nitric oxide donors, may be tried in patients with mild dysphagia or in elderly patients but rarely yields adequate symptom relief. Mechanical dilatation of the achalasic sphincter may be performed as an initial treatment option. Intrasphincteric injections of botulinum toxin seemed to be a promising alternative, but it has become obvious that, in most cases, repeated applications of the toxin are required to maintain patients symptom-free. Myotomy of the achalasic sphincter with or without fundoplication to prevent gastroesophageal reflux, is employed mainly in patients in whom dilatations have failed, but since the introduction of minimally invasive surgery, myotomy has become the primary treatment at many centers. This article aims to provide an overview of the development of the conservative and surgical treatment of achalasia.     

Esophageal achalasia: intrasphincteric injection of botulinum toxin A versus balloon dilation.

BACKGROUND AND STUDY AIMS: In patients with esophageal achalasia, pneumatic dilation is the treatment of choice, but it bears the risk of perforation in about 4% of cases. A new nonsurgical method, intrasphincteric injection of botulinum toxin A, has shown promising initial results, and we thus undertook this study to compare the long-term outcome of these two methods. PATIENTS AND METHODS: In a prospective randomized study, 24 patients with definitive esophageal achalasia were divided into two equal groups and underwent either balloon dilation or injection of botulinum toxin (20 U injected into each of the four quadrants in the lower esophageal sphincter). The outcome was assessed on the basis of a symptom score documented before treatment and at regular intervals for two and a half years thereafter. Complications associated with the two techniques were also documented. RESULTS: No relevant complication occurred in either of the treatment groups. Initially, dilation was successful in 10 of 12 patients (83%), and botulinum toxin injection in 9 of 12 patients (75%). The symptom scores showed no significant differences between the two groups before and one month after treatment. Over the two and a half year follow-up, however, all nine successfully treated patients in the botulinum toxin group experienced recurrence of symptoms, but only four of the ten patients (40%) in the dilation group. CONCLUSIONS: The two treatment methods initially had equal success rates, but in the long term the effect of the botulinum toxin injection was statistically significantly shorter than that of balloon dilation. As fewer risks are associated with the injection treatment, studies should be undertaken either to identify patient subgroups in whom botulinum toxin can be effective long-term or to test substances with longer-lasting effects.     

Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy

OBJECTIVES: To determine the effect of botulinum toxin type A on calcitonin gene-related peptide secretion from cultured trigeminal ganglia neurons. BACKGROUND: The ability of botulinum toxins to cause muscle paralysis by blocking acetylcholine release at the neuromuscular junction is well known. Previous studies and clinical observations have failed to demonstrate sensory changes related to botulinum toxins or the disease of botulism. Recent studies, however, have suggested that botulinum toxin type A injected into pericranial muscles may have a prophylactic benefit in migraine. This observation has renewed the debate of a mechanism of sensory inhibition mediated by botulinum toxin type A. METHODS: Primary cultures of rat trigeminal ganglia were utilized to determine whether botulinum toxin type A could directly decrease the release of calcitonin gene-related peptide, a neuropeptide involved in the underlying pathophysiology of migraine. Untreated cultures or cultures stimulated with a depolarizing stimulus (potassium chloride) or capsaicin, an agent known to activate sensory C fibers, were treated for 3, 6, or 24 hours with clinically effective doses of botulinum toxin type A or a control vehicle. The amount of calcitonin gene-related peptide secreted into the culture media following the various treatments was determined using a specific radioimmunoassay. RESULTS: A high percentage (greater than 90%) of the trigeminal ganglia neurons present in 1- to 3-day-old cultures was shown to express calcitonin gene-related peptide. Treatment with depolarizing stimuli (potassium chloride), a mixture of inflammatory agents, or capsaicin caused a marked increase (4- to 5-fold) in calcitonin gene-related peptide released from the trigeminal neurons. Interestingly, overnight treatment of trigeminal ganglia cultures with therapeutic concentrations of botulinum toxin type A (1.6 or 3.1 units) did not affect the amount of calcitonin gene-related peptide released from these neurons. The stimulated release of calcitonin gene-related peptide following chemical depolarization with potassium chloride or activation with capsaicin, however, was greatly repressed by the botulinum toxin, but not by the control vehicle. A similar inhibitory effect of overnight treatment with botulinum toxin type A was observed with 1.6 and 3.1 units. These concentrations of botulinum toxin type A are well within or below the range of tissue concentration easily achieved with a local injection. Incubation of the cultures with toxin for 24, 6, or even 3 hours was very effective at repressing stimulated calcitonin gene-related peptide secretion when compared to control values. CONCLUSIONS: These data provide the first evidence that botulinum toxin type A can directly decrease the amount of calcitonin gene-related peptide released from trigeminal neurons. The results suggest that the effectiveness of botulinum toxin type A in the treatment of migraine may be due, in part, to its ability to repress calcitonin gene-related peptide release from activated sensory neurons.     

The role of botulinum toxin injections in the management of muscle overactivity of the lower limb

Muscle overactivity is common in patients with adult onset central nervous system damage. It can produce significant disablement in conjunction with other impairments such as adaptive soft tissue shortening and loss of muscle strength. Muscle overactivity is not evenly distributed throughout the body; across joints there is frequently imbalance between agonist and antagonist, producing abnormal joint postures and movement patterns. Due to the asymmetric nature of the abnormal activity across joints, in general we recommend local treatment targeting the more overactive of the two agonists, rather than systemic treatment. Considerable experience with the use of botulinum toxin, both serotypes A and B, in the treatment of muscle overactivity has been accumulated in the last two decades through pragmatic clinical practice and open label studies, supported by an increasing number of randomized controlled trials. In most cases, it is important to use botulinum toxin injection for treatment of muscle overactivity in the setting of wider rehabilitation goals and interventions. Focal and partial blocks with botulinum toxin should be used as a component of a general neurorehabilitation programme rather than as an alternative to other treatments. We review the evidence supporting the use of botulinum toxin to treat muscle overactivity in the lower limb, present practical guidelines on when and how to use botulinum toxin and provide direction for future research.     

Subcutaneous Botulinum Toxin for Chronic Post‐Thoracotomy Pain

Objective: Botulinum toxin is a neurotoxin that has been widely used in chronic pain for the treatment of multiple conditions with a component of localized muscle spasm. Recent studies suggest that botulinum toxin is effective in the treatment of neuropathic pain syndromes such as post‐herpetic neuralgia. Case Report: We report the case of a 67‐year‐old man who underwent atypical segmentectomy of a right lower lobe lung nodule. The patient was referred to our pain management department with a of 2‐year history persistent pain along the thoracotomy scar having a predominantly neuropathic component, refractory to standard treatments. He was successfully treated with subcutaneous botulinum toxin type A. Discussion: On the basics of our own experience and on the analysis of the reports published in the literature, fractioned subcutaneous injections of botulinum toxin may be useful for the treatment of various chronic localized pain conditions including chronic post‐thoracotomy pain.     

The role of botulinum toxin injections in the management of muscle overactivity of the lower limb

Muscle overactivity is common in patients with adult onset central nervous system damage. It can produce significant disablement in conjunction with other impairments such as adaptive soft tissue shortening and loss of muscle strength. Muscle overactivity is not evenly distributed throughout the body; across joints there is frequently imbalance between agonist and antagonist, producing abnormal joint postures and movement patterns. Due to the asymmetric nature of the abnormal activity across joints, in general we recommend local treatment targeting the more overactive of the two agonists, rather than systemic treatment. Considerable experience with the use of botulinum toxin, both serotypes A and B, in the treatment of muscle overactivity has been accumulated in the last two decades through pragmatic clinical practice and open label studies, supported by an increasing number of randomized controlled trials. In most cases, it is important to use botulinum toxin injection for treatment of muscle overactivity in the setting of wider rehabilitation goals and interventions. Focal and partial blocks with botulinum toxin should be used as a component of a general neurorehabilitation programme rather than as an alternative to other treatments. We review the evidence supporting the use of botulinum toxin to treat muscle overactivity in the lower limb, present practical guidelines on when and how to use botulinum toxin and provide direction for future research.     

Radiographic evaluation of achalasia immediately after pneumatic dilatation with the Rigiflex dilator

Radiographic evaluation of the lower esophagus was done immediately after pneumatic dilatation using the Rigiflex dilator in 34 patients (24 men, 10 women; mean age, 55 years) with achalasia. The dilator was positioned across the esophagogastic junction using fluoroscopy and the balloon was inflated for 1 min. The esophagus was intubated and injected sequentially with water-soluble and barium contrast materials. Radiographic analysis included changes in the appearance of the caliber and contour of the esophagogastric junction, rate of esophageal emptying, and presence of complications. In 23 patients with predilatation esophagrams, the mean esophagogastric junction caliber increased from 4.7–7.6 mm following dilatation. The postdilatation esophagrams in 33 patients showed a smooth contour in 22 (67%) and immediate esophageal emptying in 26 (79%). Esophageal perforation occurred in one (3%) patient and intramural hematoma in one (3%). Clinical follow-up (mean, 7 months) was available in 29 patients and 23 (79%) had symptomatic improvement. Five of the six patients who did not improve clinically all had previous Heller myotomy, pneumatic dilatation, or both.     

Botulinum Toxin Treatment of Myofascial Pain: A Critical Review of the Literature

This is a review of literature relevant to the treatment of myofascial pain syndrome by botulinum injections. The objective is to critically review the studies to see if they are appropriately designed, conducted, and interpreted to provide guidance in the management of myofascial pain. The intent is to better understand the mixed results that these studies have provided. A search was made utilizing PubMed for literature relevant to the use of botulinum toxin in the treatment of myofascial pain. All identifiable series were reviewed, including open label, single-blinded and double-blinded studies, randomized and controlled, or not. In general, small case series of only a few patients were not included unless they made a relevant point and there were no available randomized studies or larger studies. Single case reports were not included. This is not a meta-analysis. The studies were evaluated according to their design and the selection of outcome measurements, and the interpretation of results. The studies were individually critiqued, and an overall assessment and commentary was made of the studies in the field as a whole. Problems that were common to the studies were robust placebo responders, incomplete treatment of a regional myofascial pain syndrome, inappropriate or confounding control populations or treatments, and inappropriate time periods for assessment of outcomes, or misinterpretation of the time-frame of action of botulinum toxin. The studies of the effect of botulinum toxin treatment of myofascial trigger points have had mixed results. However, few studies have been designed to avoid many of the pitfalls associated with a trial of botulinum toxin treatment of trigger points. Better-designed studies may give results that can be used to guide practice based on reliable evidence. At the present time, one must conclude that the available evidence is insufficient to guide clinical practice.     

Strategies for treating severe refractory dysphagia

Traditional treatment of achalasia, pneumatic dilatation or surgical myotomy, results in satisfactory relief of dysphagia in 85% to 90% of patients. Unfortunately, a small percentage of patients do not respond to these therapies or remain refractory, often because of a severely dilated or sigmoid esophagus. Esophagectomy, with gastric pull up or color interposition, is the procedure of choice in these patients, which can result in satisfactory relief of dysphagia with minimal mortality. This article reviews the strategies for management of achalasia patients with refractory dysphagia.     

Is there a role for botulinum toxin in the treatment of migraine?

In this review, the studies and case reports that are available from reference systems and published congress contributions on the treatment of migraine with botulinum toxin are evaluated. The studies and reports were analyzed with respect to the study design, the efficacy parameters, and the significance of results. One double-blind, placebocontrolled, randomized study with negative (for a 75 U dose of botulinum toxin) and positive (for a 25 U dose of botulinum toxin) evidence of efficacy, one that was a partly positive controlled study (pain intensity, but not attack-frequency improved), and four positive open studies were available. For the acute treatment of migraine with botulinum toxin, only positive case reports were published. As a result of this analysis, there is no sufficient scientific evidence for a treatment recommendation of migraine with botulinum toxin. Further studies are needed for a definite evaluation of subgroups with probable benefit from such a treatment and for the comparison of botulinum toxin with other migraine prophylactic drugs.     

内镜下气囊扩张治疗贲门失弛缓症的系统评价

目的系统评价内镜下气囊扩张治疗贲门失弛缓症的有效性和安全性。方法计算机检索Cochrane图书馆临床对照试验数据库(2007年第1期)、MEDLINE(1978～2007年)、EMbase(1978～2007年)、OVID数据库(1978~2007年)、中国生物医学文献数据库(1978～2007年)、维普中文期刊数据库(1989～2007年)、中国期刊全文数据库(1979～2007年)和万方学位论文数据库(1978～2007年),手工检索相关会议论文集及所获文献的参考文献,全面收集全世界关于内镜下气囊扩张治疗贲门失弛缓症的随机对照试验。按Cochrane协作网推荐的方法进行系统评价。结果共纳入24个RCT,包括1045例患者。Meta分析结果显示:①短期总有效率:内镜下气囊扩张治疗优于内镜下注射肉毒杆菌毒素治疗[OR0.47,95%CI(0.30,0.73);P=0.0007]。②长期总有效率:内镜下气囊扩张治疗优于内镜下注射肉毒杆菌毒素治疗[OR0.31,95%CI(0.13,0.70);P=0.005]。③临床复发率:内镜下注射肉毒杆菌毒素治疗高于内镜下气囊扩张治疗[OR8.88,95%CI(3.31,23.79);P<0.0001]。④副作用及并发症发生率:内镜下气囊扩张治疗高于内镜下注射肉毒杆菌毒素治疗[OR0.14,95%CI(0.04,0.44);P=0.0008];经腹开放性括约肌切开治疗高于内镜下气囊扩张治疗[OR0.15,95%CI(0.05,0.44);P=0.0006]。结论目前的证据表明,内镜下气囊扩张治疗具有较好的长短期疗效,且操作简单方便,不良反应少,建议在临床实践中依患者病情选用。