Treatment of symptomatic nonachalasia esophageal motor disorders with botulinum toxin injection at the lower esophageal sphincter

The purpose of this study was to determine if botulinum toxin injection at the lower esophageal sphincter improves symptoms in patients with nonachalasia spastic esophageal motility disorders. Fifteen patients with nonachalasia spastic esophageal motility disorders (diffuse esophageal spasm, nonspecific esophageal motility disorders, and lower esophageal sphincter dysfunction) unresponsive to medical therapy underwent endoscopic injection of botulinum toxin at the level of the gastroesophageal junction. Symptoms were scored (0=no symptoms, 1=mild, 2=moderate, 3=severe and 4=very severe) before treatment, at seven days and every 30 days after treatment. There was significant improvement in chest pain, dysphagia, and regurgitation at 7, 30, 60 and 90 days after treatment. At one month after treatment, 11 of 15 (73%) patients had a good or excellent response to treatment. At the last patient interview (mean follow-up of 10.6 months), five (33%) patients continued to have a good to excellent response, whereas 10 (67%) underwent subsequent treatment with repeat botulinum toxin, pneumatic dilation, or bougienage. We conclude that botulinum toxin injection at the gastroesophageal junction leads to significant symptom improvement in patients with nonachalasia esophageal motility disorders. These results suggest that botulinum toxin may be an effective treatment option in some of these patients not responsive to conventional medical therapy.     

Case Report: Botulinum Toxin in Hypertensive Lower Esophageal Sphincter: A Manometric Case Study

The hypertensive lower esophageal sphincter (HLES) is a disorder of esophageal motility associated with dysphagia and chest pain. Although well characterized manometrically, opinions differ greatly with regard to its pathophysiology and its management. Therapy is limited to a few medications, esophageal dilatation, and even surgery, although none of these options are consistently successful. In this case report we describe a 54-year-old woman with HLES and dysphagia who was successfully treated with botulinum toxin injection of the lower esophageal sphincter (LES). Esophageal manometry after botulinum toxin therapy revealed normalization of LES pressures. Three months after therapy, symptoms returned and repeat esophageal manometry demonstrated the return of elevated LES pressures. This report is the only published case of botulinum toxin injection into the LES with both pre- and post-treatment esophageal manometric data. This case report is evidence that LES dysfunction produces symptoms in patients with HLES, and that reduction in LES pressure improves symptoms. Current pathophysiologic hypotheses for HLES-associated dysphagia and its treatment are briefly reviewed in this report.     

Endoscopic dilation for treatment of esophageal motility disorders

Esophageal dilation is an important therapeutic strategy in patients with esophageal motility disorders. Patients with achalasia have for many years benefited from pneumatic dilation as a definitive form of therapy, which is superior to botulinum toxin injection and equivalent in efficacy to surgical myotomy. Optimal performance of pneumatic dilation ensures maximum efficacy and reduced complication of perforation. Esophageal dilation also plays a crucial role in esophagogastric junction outflow obstruction due to strictures or prior surgical interventions as well as in esophageal hypercontractile states such as spastic disorders or in those with nonobstructive dysphagia. In this section, we will review the clinical evidence of esophageal dilation in achalasia, esophagogastric junction outflow obstruction, esophageal spastic disorders and in patients with dysphagia and nonobstructive dysphagia. We will outline specific techniques currently recommended and employed in esophageal dilations for these disorders and provide relative efficacy to other forms of therapy.     

Symptomatic improvement of diffuse esophageal spasm after botulinum toxin injection

Diffuse esophageal spasm, an uncommon esophageal motility disorder, has recently been defined using high-resolution manometry. Patients with distal esophageal spasm usually complain of chest pain or dysphagia. The etiology and pathophysiology of this disorder are poorly known, and treatment options are limited. However, some options to improve symptoms are available, including endoscopic injection of botulinum toxin. Nevertheless, few reports have described the effects of endoscopic injection of botulinum toxin in patients with symptomatic diffuse esophageal spasm with clear endoscopic and high-resolution manometry images. Here, we report a case of diffuse esophageal spasm diagnosed with high-resolution manometry and treated by endoscopic injection of botulinum toxin with good results at the 7-month follow-up.     

The Role of Botulinum Toxin Injections for Esophageal Motility Disorders

Purpose of review

The advancement of high-resolution esophageal manometry has led to improvement in the diagnosis of esophageal motility disorders. We reviewed the recent medical literature regarding the use of botulinum toxin (BTx) injections in the esophagus and the indications, current outcomes, and reported complications of this therapy.

Recent findings

The response rates of BTx injection therapy vary depending on the esophageal motility disorder. Studies have shown that response is transient in achalasia patients and given the more effective therapies available, it is only recommended in patients who are not surgical candidates. In nonachalasia patients, studies of BTx injections have demonstrated improvement in dysphagia symptoms in patients with spastic disorders, though studies are small and largely retrospective. The available literature showed a variable response to BTx in esophagogastric junction outlet obstruction (EGJOO) and non-cardiac chest pain patients. Despite advances in diagnosing esophageal motility disorders, there is a need for further research in patient selection for esophageal BTx, dose and injection location, and disease-specific outcomes. Placebo-controlled trials are crucial to evaluate BTx efficacy and duration of response.

Summary

Esophageal-directed BTx injections are beneficial in improving dysphagia in spastic motility disorders and in achalasia patients who are elderly or have multiple co-morbidities. There is a lack of evidence to support use in patients with EGJOO and non-cardiac chest pain, or for young or healthy achalasia patients.

     

Distal Esophageal Spasm

Distal esophageal spasm (DES) is an uncommon esophageal motility disorder associated with dysphagia and/or chest pain. Its pathophysiology implies an impairment of esophageal inhibitory neural function. Using conventional manometry, DES was defined by the presence of simultaneous esophageal contractions. With the introduction of high-resolution manometry and esophageal pressure topography (EPT) in clinical practice, rapidly propagated contractions are nonspecific of esophageal spasm. Hence, a more physiological and clinically relevant definition was proposed. Distal latency (DL) measures the period of inhibition that precedes contraction in the distal esophagus immediately proximal to the esophagogastric junction (EGJ). Premature contractions, defined as reduced DL, appeared to be much more specific for DES in EPT. Premature contractions with normal EGJ relaxation constitute DES, while premature contractions with impaired EGJ relaxation are diagnostic of spastic achalasia. Because of the interaction between DES and gastroesophageal reflux disease, 24-h esophageal pH monitoring should also be considered in patient evaluation. Medical treatment of DES aims to compensate for the deficient inhibitory neural function. Sildenafil, which blocks nitric oxide degradation and thus prolongs esophageal muscle relaxation, is a promising treatment. Endoscopic injection of botulinum toxin in the esophageal muscle is also an interesting therapeutic option. Finally, extended surgical myotomy might be discussed in extreme cases after failure of other therapeutic options.     

New Therapies for Non-cardiac Chest Pain

After excluding a cardiac cause, potent anti-reflux therapy should be administered to patients with non-cardiac chest pain since gastroesophageal reflux disease (GERD) is the most common underlying mechanism of this disorder. If GERD is an unlikely cause of patient’s symptoms, an esophageal motor disorder should be excluded. Spastic motility disorders can be treated with a smooth muscle relaxant (such as calcium channel blocker, nitrate, or phosphodiesterase 5 inhibitors). Alternatively, spastic motility disorders may respond to anti-spasmodics, pain modulators, botulinum toxin injection into the distal esophagus, and/or surgery. Patients with functional chest pain have recently seen an expanded treatment armamentarium including medications such as trazadone, tricyclic anti-depressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, pregabalin, and/or ramelteon.     

Botulinum toxin injection for hypercontractile or spastic esophageal motility disorders: may high‐resolution manometry help to select cases?

Endoscopic injections of botulinum toxin in the cardia or distal esophagus have been advocated to treat achalasia and spastic esophageal motility disorders. We conducted a retrospective study to evaluate whether manometric diagnosis using the Chicago classification in high‐resolution manometry (HRM) would be predictive of the clinical response. Charts of patients with spastic and hypertensive motility disorders diagnosed with HRM and treated with botulinum toxin were retrospectively reviewed at two centers. HRM recordings were systematically reanalyzed, and a patient's phone survey was conducted. Forty‐five patients treated between 2008 and 2013 were included. Most patients had achalasia type 3 (22 cases). Other diagnoses were jackhammer esophagus (8 cases), distal esophageal spasm (7 cases), esophagogastric junction outflow obstruction (5 cases), nutcracker esophagus (1 case), and 2 unclassified cases. Botulinum toxin injections were performed into the cardia only in 9 cases, into the wall of the distal esophagus in 19 cases, and in both locations (cardia and distal esophagus) in 17 cases. No complication occurred in 31 cases. Chest pain was noticed for less than 7 days in 13 cases. One death related to mediastinitis occurred 3 weeks after botulinum toxin injection. Efficacy was assessed in 42 patients: 71% were significantly improved 2 months after botulinum toxin, and 57% remained satisfied for more than 6 months. No clear difference was observed in terms of response according to manometric diagnosis; however, type 3 achalasia previously dilated and with normal integrated relaxation pressure (4s‐integrated relaxation pressure < 15 mmHg) had the worst outcome: none of these patients responded to the endoscopic injection of botulinum toxin. Endoscopic injections of botulinum toxin may be effective in some patients with spastic or hypercontractile esophageal motility disorders. The manometric Chicago classification diagnosis does not seem to predict the results. Prospective randomized trials are required to identify patients most likely to benefit from esophageal botulinum toxin treatment.     

Treatment of symptomatic diffuse esophageal spasm by endoscopic injections of botulinum toxin: a prospective study with long-term follow-up.

BACKGROUND: Diffuse esophageal spasm is a rare esophageal motility disorder for which there are no satisfactory pharmacologic alternatives for treatment. The aim of this study was to investigate whether botulinum toxin (BTX) injection is an effective short- and long-term treatment for patients with symptoms caused by diffuse esophageal spasm. Whether recurrence of clinical symptoms can be successfully retreated by BTX injection was also studied. METHODS: Nine symptomatic patients (6 women, 3 men; 57-86 years) with manometrically proven diffuse esophageal spasm underwent BTX injection. One hundred IU BTX were diluted in l0 mL of saline solution and injected endoscopically at multiple sites along the esophageal wall beginning in the region of the lower esophageal sphincter and moving proximally in 1- to 1.5-cm intervals, and into endoscopically visible contraction rings. Symptom scores based on an analogue scale for dysphagia, regurgitation, and noncardiac chest pain were assessed before and after therapy, 1 day thereafter, and at 1 and 6 months. RESULTS: Symptoms improved immediately in 7 (78%) patients after 1 injection session. After 4 weeks 8 (89%) patients were in remission with a decrease in total symptom score. The total symptom score decreased from a median 8.0 (interquartile range: 6.75; 9.0) before treatment to 2.0 (1.5; 3.75) after 1 day (p < 0.01) and to 2.0 (interquartile range: 0.75; 3.0) after 1 month (p < 0.01). After 6 months all 8 patients with a response at 1 month still had a symptom score of 3 or less without further treatment. Subsequently 4 patients required reinjection 8, 12, 15, or 24 months after the initial treatment with similarly good results. No serious adverse effects were observed. CONCLUSIONS: BTX injection at several levels of the tubular esophagus is an effective treatment for patients with symptoms caused by diffuse esophageal spasm. Symptom relapse can be effectively treated by repeated BTX injection.     

Noncardiac chest pain

Noncardiac chest pain (NCCP) affects approximately 1 quarter of the adult population in the United States. The pathophysiology of the disorder remains to be fully elucidated. Identified underlying mechanisms for esophageal pain include gastroesophageal reflux disease (GERD), esophageal dysmotility, and visceral hypersensitivity. Aggressive antireflux treatment has been the main therapeutic strategy for GERD-related NCCP. NCCP patients with or without spastic esophageal motor disorders are responsive to pain modulators. The value of botulinum toxin injection, endoscopic treatment for GERD, and antireflux surgery in alleviating NCCP symptoms is limited.     

Noncardiac chest pain

Opinion statement Noncardiac chest pain (NCCP) is a common condition with significant morbidity and economic implications. Psychological factors, gastroesophageal reflux disease (GERD), alteration in pain perception, and esophageal dysmotility play an important role in the pathogenesis of the disorder. Proton pump inhibitor (PPI) therapy is the most effective medical intervention for the treatment of GERD-related NCCP, as well as the most costeffective diagnostic strategy for this condition. Pain modulators such as tricyclic antidepressants, trazodone, and selective serotonin reuptake inhibitors infer a visceral analgesic effect and consequently are the treatment of choice for patients with non-GERD-related NCCP. Furthermore, cognitive behavioral therapy has also been shown to be useful in the management of subset of patients with non-GERD-related NCCP. Newer therapeutic modalities and interventions such as lower esophageal sphincter injection of botulinum toxin in NCCP patients with spastic esophageal motility disorders, theophylline, and 5-HT4 receptor agonists may supplement or replace current treatment for non-GERD-related NCCP. Future compounds may include new visceral analgesics or medications that interfere with the development of peripheral or central sensitization.     

The spectrum of the symptoms and presentations of gastroesophageal reflux disease

The symptoms and presentations of gastroesophageal reflux disease are rather numerous. These include the typical symptoms, such as heartburn, regurgitation, water brash, or dysphagia. However, reflux may also be responsible for such symptoms as hoarseness, pulmonary aspiration, or asthma. It may also be an important cause of noncardiac chest pain. Thus, gastroesophageal reflux disease may be considered a disease with more than just "esophageal" symptoms.     

Esophageal pharmacology and treatment of primary motility disorders

Swallowing is a complex mechanism based on the coordinated collaboration of tongue, pharynx and esophagus. Disturbances of this interplay or disorders of one or several of these components lead to dysphagia, non-cardiac chest pain or regurgitation. The major primary esophageal motility disorders--achalasia, diffuse esophageal spasm, hypercontractile esophagus ('nutcracker esophagus') and non-specific motility disorder--are of unknown etiology. Other esophageal diseases, such as cervical diverticula or gastroesophageal reflux disease, might also be caused by a primary esophageal motility disorder. Medical treatment of esophageal disorders with esophageal hyper- or dysmotility requires agents that reduce esophageal contractile force (anticholinergic agents, nitrates, calcium antagonists). Despite the beneficial effect of the various drugs on esophageal motility parameters, the clinical benefit of medical treatment of esophageal motility disorders is rather disappointing. Calcium channel antagonist, alone or in combination with anticholinergics or nitrates, can be used as a medical trial, especially in mild achalasia. However, medical therapy is clearly inferior to pneumatic balloon dilation therapy. Recently, botulinum toxin injection was suggested as a therapeutic option in achalasia patients with good results on lower esophageal sphincter pressure (LESP) and symptom scores that were similar to the results achieved by pneumatic balloon dilation. Hypercontractile esophagus shows a good manometric response to calcium channel antagonists, but only little clinical effect in terms of improvement of symptoms. Diffuse esophageal spasm is a relatively rare disease and few clinical studies are available. The use of calcium channel antagonists can be beneficial, at least in some patients with diffuse esophageal spasm. From clinical and epidemiological studies, there is some evidence of a 'psychological' component in the pathogenesis or perception of esophageal symptoms. There is some clinical benefit from centrally acting drugs such as benzodiazepines or antidepressants. With the exception of botulinum toxin for achalasia, medical therapy of primary esophageal motility disorders is rather limited and the clinical results are poor. Further understanding of esophageal pathophysiology as well as development of new receptor-selective drugs might increase our chances of a successful treatment of primary esophageal motility disorders.     

Nutcracker esophagus: clinical evaluation of 97 patients]

Nutcracker esophagus is a manometric abnormality classified as a primary esophageal motor disorder, characterized by high pressure peristaltic waves in distal esophagus and related to non-cardiac chest pain. Further studies observed nutcracker esophagus in dysphagic patients and recently in gastroesophageal reflux disease. However, there is controversy about the meaning of this motor disorder and there are few clinical studies involving a great number of patients. A retrospective study involving 97 patients with manometric criteria of nutcracker esophagus according a control group was undertaken. Most of the patients were female (63.9%), mean age 54.3 years. The chief complaint was chest pain, followed by dysphagia and heartburn. Clinical findings, as a whole were chest pain (53.6%), dysphagia (52.6%), heartburn (52.6%), regurgitation (21.6%), otorhinolaryngologic symptoms (15.4%), dyspepsia (15.4%) and odynophagia (4.1%). The majority of patients had multiple symptoms, however in 28% just a single one was observed. Endoscopic examination observed erosive esophagitis in 8% of the patients, while signs of esophageal motor disorders were showed by esophagogram in 16.4%. Esophageal pH recordings indicated abnormal gastroesophageal reflux in 41.2% of the cases reported. We concluded that there are other symptoms in nutcracker esophagus patients besides chest pain and dysphagia and the use of esophageal pH recordings is helpful to establish its association with acid reflux and guide the appropriate therapy.     

Esophageal testing of patients with noncardiac chest pain or dysphagia. Results of three years' experience with 1161 patients

Records from 910 patients referred to our clinical esophageal manometry laboratory for evaluation of noncardiac chest pain between January 1983 and December 1985 were reviewed and compared with records from 251 patients referred for dysphagia. Evaluation included baseline esophageal manometry, acid perfusion test, and edrophonium provocation. In the chest-pain group, 655 patients (72%) had normal esophageal motility and 255 (28%) had abnormal motility. Nutcracker esophagus was present in 48% of abnormal tracings, suggesting that it is a manometric marker for noncardiac chest pain. Of the total chest-pain group, 243 patients (27%) had their pain reproduced during provocative testing ("definite" esophageal pain); 192 patients (21%) had baseline manometric abnormalities but no pain during provocative testing ("probable" esophageal chest pain). The highest percentage of positive provocative responses (34%) occurred in patients with nutcracker esophagus on baseline manometry. Manometric abnormalities were statistically commoner (p less than 0.001) in patients with dysphagia, occurring in 53%. Achalasia (36%) and nonspecific esophageal motility disorders (38%) were the commonest abnormalities in this group, with nutcracker esophagus being infrequent (10%).     

Spontaneous noncardiac chest pain: Value of ambulatory esophageal pH and motility monitoring

We performed esophageal investigations in 20 patients suffering from noncardiac chest pain in order to assess the diagnostic value of short- versus long-term manometric and pH studies. Patients had baseline esophageal manometry with two provocative tests: a Bernstein test and an intravenous injection of edrophonium. On a separate occasion they had a 24-hr ambulatory esophageal pH and motility recording. The Bernstein test provoked chest pain in two patients, while edrophonium injection did not elicit pain in any of the patients. The ambulatory pH study helped to establish the esophagus as the likely source of pain in one patient, and the ambulatory motility one in another. In our experience, ambulatory pH and motility recordings have a low diagnostic yield in the evaluation of patients with noncardiac chest pain.     

Botulinum toxin in the treatment of diffuse esophageal spasm

Diffuse esophageal spasm is a primary esophageal motility disorder. The prevalence is 3–10% in patients with dysphagia and treatment options are limited. This review summarizes the treatment of diffuse esophageal spasm, including pharmacotherapy, endoscopic treatment, and surgical treatment with a special focus on botulinum toxin injection. A PubMed search was performed to identify the literature using the search items diffuse esophageal spasm and treatment. Pharmacotherapy with smooth muscle relaxants, proton pump inhibitors, and antidepressants was suggested from small case series and uncontrolled clinical trials. Endoscopic injection of botulinum toxin is a well‐studied treatment option and results in good symptomatic benefit in patients with diffuse esophageal spasm. Surgical treatment was reported in patients with very severe symptoms refractory to pharmacologic treatment. This article summarizes the present knowledge on the treatment of diffuse esophageal spasm with a special emphasis on botulinum toxin injection. Endoscopic injection of botulinum toxin is presently the best studied treatment option but many questions remain unanswered.     

Achalasia: current treatment options

Achalasia is a rare esophageal motility disorder, characterized by impaired swallow-induced, lower esophageal sphincter (LES) relaxation and defective esophageal peristalsis. Unfortunately, there are no etiological therapies for achalasia. Patients present with dysphagia, chest pain and regurgitation of undigested food, often leading to weight loss. The currently available treatments have the common aim of relieving symptoms by decreasing the pressure of the LES. This can be achieved with some medications, by inhibiting the cholinergic innervation (botulinum toxin), by stretching (endoscopic dilation) or cutting (surgery) the LES. Recently, other therapeutic options, including per-oral endoscopic myotomy have been developed and are gaining international consensus. The authors report on the benefits and weaknesses of the different therapies and provide an updated approach to the management of achalasia.     

The Pathogenesis and Management of Achalasia: Current Status and Future Directions

Achalasia is an esophageal motility disorder that is commonly misdiagnosed initially as gastroesophageal reflux disease. Patients with achalasia often complain of dysphagia with solids and liquids but may focus on regurgitation as the primary symptom, leading to initial misdiagnosis. Diagnostic tests for achalasia include esophageal motility testing, esophagogastroduodenoscopy and barium swallow. These tests play a complimentary role in establishing the diagnosis of suspected achalasia. High-resolution manometry has now identified three subtypes of achalasia, with therapeutic implications. Pneumatic dilation and surgical myotomy are the only definitive treatment options for patients with achalasia who can undergo surgery. Botulinum toxin injection into the lower esophageal sphincter should be reserved for those who cannot undergo definitive therapy. Close follow-up is paramount because many patients will have a recurrence of symptoms and require repeat treatment.     

Controlled trial of botulinum toxin injection versus placebo and pneumatic dilation in achalasia

BACKGROUND & AIMS: Intrasphincteric injection of botulinum toxin has been suggested as an alternative treatment modality in esophageal achalasia. A controlled trial comparing botulinum toxin, placebo, and pneumatic dilation is reported. METHODS: Sixteen patients received random intrasphincteric injections of either botulinum toxin or saline. The efficacy of treatment was assessed by symptom score, esophageal manometry, and scintigraphy. In case of failure, pneumatic dilation was performed. RESULTS: One month after injection, symptoms had improved in all patients treated with botulinum toxin (symptom score, 0.9 +/- 0.6 vs. 5.5 +/- 1.4; P < 0.02). In the placebo group, symptoms were unchanged in all patients, who were all dilated. Lower esophageal sphincter pressure decreased by 49% after treatment with botulinum toxin (P < 0.03) and by 72% after dilation (P < 0.01). Similarly, esophageal retention decreased by 47% after treatment with botulinum toxin (P < 0.02) and by 59% after dilation (P < 0.02). No significant difference in symptom score and esophageal function test results was found between patients treated with botulinum toxin injections and those undergoing dilation. However, 7 of the 8 patients in the botulinum toxin group required a second injection because of recurrent dysphagia. CONCLUSIONS: Treatment of achalasia with botulinum toxin was as effective as pneumatic dilation in relieving symptoms and improving esophageal function. The effect of the first injection was temporary, but the effect of the second injection lasted longer. (Gastroenterology 1996 Dec;111(6):1418-24)