Endoscopic botulinum toxin injection: Benefit and limitation

Effects of intervention

BTI was first introduced as a viable treatment for achalasia nearly two decades ago. In their report, Pasricha et al4 demonstrated symptomatic improvement in 82% of the patients after BTI, compared with 10% of those who received placebo. This trial was followed by a prospective, long-term follow-up study, which showed that two-thirds of patients who received BTI have an improved symptom response, at a mean follow-up of 2.4 years.14

In general, a total dose of 100 IU is endoscopically injected in the LES, using a sclerotherapy needle. A large multicenter study reported that a dose of 100 IU, followed 1 month later by a second 100-IU injection in responders, was more efficacious than either 50 IU or 200 IU administered in a single dose.13 At a mean follow-up of 12 months, relapse was seen in 19% of patients treated with the double injections of 100 IU, compared with 47% and 43% of the patients receiving 50 IU and 200 IU doses, respectively. Increasing the dose to 200 IU does not improve the rate of success, whereas repeating a 100-IU injection after 1 month may improve its efficacy.9

Fifteen prospective studies in the literature have examined the efficacy of botulinum toxin. The response rates at 1 month following administration average 82% (range, 69–90%). By 6 months, the clinical response rate drops to 57% (range, 33–77%), and by 12 months to 48% (range, 15–76%; Table 1).3,4,9,11,14–25 It is apparent that with repeated injections, the response rates reported are similar or lower to that achieved with the initial injection. The diminishing effect may be attributable to the development of protective antibodies against the botulinum toxin molecule.13,14,25,26 The use of a different serotype of botulinum toxin may be a way of prolonging response rates, although this approach remains to be proven.

Predictors for long-term success of BTI

Interestingly, the therapeutic response differs between the manometric subtypes—panesophageal pressurization is found to be a predictor of a positive treatment response, whereas spastic achalasia is associated with a negative treatment response.

Pandolfino and colleagues27,28 proposed classifications into three different subtypes: type I, classic achalasia with no evidence of pressurization; type II, panesophageal pressurization; and type III, vigorous achalasia, or two or more spastic contractions of the distal esophageal segment. Older age, moderate LES pressure, and “vigorous” achalasia (type III) have been identified by some researchers as factors predicting a favorable response to botox injection.14

Predictors of response to BTI include age greater than 50 years and the presence of vigorous achalasia, defined by the finding of esophageal contractile waves, with amplitudes in excess of 40 mmHg.14 The duration of illness, baseline radiographic features, initial symptom severity, and sex have not been shown to be predictive of response.

Patients older than 50 years of age had nearly double the response rate, compared with younger patients (82% vs. 43%; P = 0.03). This difference in response rates caused by age was further exaggerated in patients with classic achalasia (75% vs. 27%; P = 0.04). However, in the presence of vigorous achalasia, the response to BTI was uniformly favorable regardless of age.14

Because local BTI is less invasive than pneumatic dilation or surgical myotomy, it may be the procedure of choice for the treatment of achalasia. However, the long-term results are less favorable than those of dilation or myotomy.20,26 One study analyzed the outcome in 25 patients with achalasia, after a median of 2.5 years, in order to define the parameters that predict a good long-term outcome.29 In this study,29 patients with a lower esophageal sphincter pressure (LESP) prior to treatment were particularly likely to benefit from the BTI. In patients who responded manometrically to the treatment, the average LESP reduction was 30%. The degree of pressure reduction was independent of the initial LESP; furthermore, there was no difference between long- and short-term responders with respect to initial pressure reduction.29

In all studies, long-term responders have been found to be significantly older than short-term responders.4,14,15,30,31 Botulinum toxin relieves LESP through reduction of the excitatory cholinergic innervation of the sphincter. It leads to an irreversible decline of end-phase potentials. The recovery of neurotransmission and subsequent muscle activity requires the sprouting of new nerve endings, and formation of new synaptic contacts to the adjacent muscle fibers.32,33 It is highly possible that in elderly patients, the capability of this regenerative process is reduced, thus leading to a longer-lasting response.

Predictors for the long-term success of botulinum toxin are the presence of vigorous achalasia, an LESP not exceeding the upper normal limit by more than 50% in patients without vigorous achalasia, age greater than 55 years, and mode of treatment (repeat injection after 4 weeks).29

Possible complications

BTI for achalasia has an excellent safety profile. Transient chest pain is usually mild and has been reported in approximately 20% of patients. Significant heartburn is reported in approximately 5–10% of patients.11 Isolated case reports of potential adverse events have included heart block, urinary retention, and pneumothorax. Case reports have noted mediastinitis, gastroparesis, and fatal arrhythmia; however, these may relate to a suboptimal technique.34 Concerns regarding the potential for systemic neuromuscular paralysis have not been realized in gastrointestinal or neurologic applications, because the doses used in practice are 20–30-fold lower than the lethal doses reported in previous studies.11

Benefit and limitation

Most studies show that BTI is inferior, in terms of therapeutic efficacy, to both pneumatic dilation and myotomy.35,36 A recent study demonstrated that pneumatic dilation may remain an effective treatment if administered in an on-demand fashion.37 A total of 150 patients were treated with pneumatic dilation until remission was achieved, which occurred in 90% of the patients. Patients were then dilated only if their symptoms returned, and the probability of the patients achieving remission at 5 years and 10 years was 97% and 93%, respectively.37 Previous studies have suggested that the remission rates for open Heller myotomy deteriorate over time.38,39 In one study, 95% success rates at 1 year fell to 77% at 5 years, 68% at 10 years, and 67% at 20 years.39 Short-term data with laparoscopic Heller myotomy demonstrated excellent results, with 98% of patients reporting symptomatic improvement at 5.3 years.40 But the most compelling aspects of BTI for achalasia are the ease of technique, and the low rate as well as the mild degree of complications. It is for these reasons that botulinum injection is commonly used in most centers worldwide. Indeed, one American survey found that BTI is the most common initial therapy, despite its known inferior efficacy.41

BTI has also been used as second-line salvage therapy, following unsuccessful pneumatic dilation and surgical myotomy.31 Additionally, BTI prior to pneumatic dilation has been shown to have benefits.42 However, after BTI, there is an increased risk for pneumatic dilation perforation.43 One study showed that having prior endoscopic treatment was more strongly associated with intra-operative complications, especially esophageal perforation, and persistent and recurrent symptoms requiring additional therapy, after myotomy. However, other studies showed no difference in intraoperative complications, degree of surgical difficulty, or symptom improvement with prior endoscopic treatment.44 Botulinum toxin should be preferentially reserved for patients with significant comorbidity, and is not adequate for conventional treatment with laparoscopic Heller’s myotomy or pneumatic dilation, or for patients who are on a waiting list for surgery or who are refusing other forms of treatment.

Studies comparing the cost-effectiveness of botulinum toxin, pneumatic dilation, and surgical myotomy are rare. The cost of treatment of botulinum toxin and pneumatic dilation are less than that of surgical myotomy. Studies comparing the cost-effectiveness of pneumatic dilation and Heller myotomy have in the past favored dilation; however, the laparoscopic surgical approach has decreased the length of hospitalization as well as additional surgical costs.45 This fact, in combination with long-term pneumatic dilation data suggesting a less than 40% remission rate, will likely shift the cost analysis in favor of laparoscopic Heller myotomy.

The selection of pneumatic dilation or surgery as primary therapy is still debated. Although surgery is more effective at achieving a durable response, recurrent dysphagia occurs in a significant proportion of surgical patients. By contrast, pneumatic dilation commonly requires repeated dilations, to sustain remission. Currently, the choice of therapy remains an individualized decision that weighs factors that include available expertise, the patient’s acceptance of possible risks, and factors such as age and comorbidities.