Reply to the Letter of Dr. Madaliński

Dear Sir,

We are very grateful for the comments by Dr. Madaliński concerning our study [1]. As can be seen from the discussion in our paper, we also view the use of botulinum toxin in achalasia critically and believe its clinical value to be clearly limited. Compared with the gold standard of balloon dilation, BTX injection has a time-limited effect but comparable efficacy [2] [3]. Thus, as indicated in our study, the indications will be very restricted [1] [3] [4] [5] [6].

We also agree that the mode of action has still not been completely elucidated, and blockage of the release of acetylcholine or another excitatory neurotransmitter is probably just one possible mechanism. Further proof is awaited concerning whether induction of nitric oxide synthase (NOS) really takes place in gastrointestinal neurons in vivo. An increase of NADPH staining has been shown in a study in facial nerves of rats; however, the type and form of NOS isoenzyme induced was not investigated [7]. This effect most likely occurs as a consequence of axonal damage in the cholinergic motoneurons. Whether this effect also occurs in enteric neurons is a matter of conjecture and has not been demonstrated. However, such a mode of action could be an interesting but so far very speculative hypothesis. According to most available data, the NOS-positive neurons degenerate in achalasia and thus the pathophysiological situation is completely different from the use of BTX in striated muscle, where no inhibitory motoneurons exist.

The use of topical nitrates is beneficial in chronic anal fissure, but the use of systemic nitrates in achalasia is of limited use mostly because of their systemic side effects (headache, hypotension). There is not a single controlled study which demonstrates the long-term effects of long-acting nitrates in achalasia, but there is good evidence for the use of short-acting nitrates for diagnostic purposes or short symptomatic relief in achalasia. In comparison with nitrates, calcium-channel antagonists can be used and show some beneficial effect. Our patients all had long-standing achalasia which was not resolved by these medical alternatives.

Concerning the variations in concentration and dose used, with regard to different botulinum toxin preparations, it is well known that Botox and Dysport do show differing biological activity for a given amount of toxin [8]. This is probably due to different methods of isolation and preparation of the toxin and has nothing to do with concentration or diffusion effects. Even when tested in vitro in isolated muscle strips, Botox is approximately three times as biologically effective on a mg basis (personal communication: H. D. Allescher). An increase in concentration could influence the diffusion of the toxin but, as shown, the clinical effect appears to be similar when this difference in biological activity is accounted for. In most clinical studies published so far on the use of BTX in achalasia, BTX has been diluted to a concentration of 20 - 25 U/ml, and in our experience this was also the most suitable way to inject it during endoscopy, as smaller amounts are difficult to handle and control and active peptide could get lost. For the moment, 20 U/ml of Botox is the optimal dilution. Whether the effect could be increased with higher concentrations and lower volumes is doubtful and in fact seems questionable.

Regarding the use of botulinum toxin in other esophageal and gastric diseases, we have published a report of a series of patients with diffuse esophageal spasm who were successfully treated by BTX injection and we have since greatly extended this series with similar results [9]. We also have good experience with the use of BTX in certain types of gastroparesis or gastric emptying problems in suspected forms of pylorospasm. Therefore we do think that there could be other even more effective applications for the use of BTX, as for these disorders there is no real therapeutic alternative. However, larger numbers must first be studied with regard to these rare disorders. Thus, BTX is most probably only the second or third treatment of choice in achalasia but could be the first-line treatment in other disorders.

References

• 1 Allescher H D, Storr M, Seige M. et al . Treatment of achalasia: botulinum toxin injection vs. pneumatic balloon dilation. A prospective study with long-term follow-up.  Endoscopy. 2001;  33 1007-1017
• 2 Annese V, Basciani M, Perri F. et al . Controlled trial of botulinum toxin injection versus placebo and pneumatic dilation in achalasia.  Gastroenterology. 1996;  111 1418-1424
• 3 Pasricha P J, Rai R, Ravich W J. et al . Botulinum toxin for achalasia: long-term outcome and predictors of response.  Gastroenterology. 1996;  110 1410-1415
• 4 Eaker E Y, Gordon J M. Esophageal botulinum toxin injection in high risk achalasia patients: a prospective trial.  Gastroenterology. 1996;  110 A99
• 5 Dufour J F, Fawaz K A, Libby E D. Botulinum toxin injection for secondary achalasia with esophageal varices.  Gastrointest Endosc. 1997;  45 191-193
• 6 Boyce H W, Robinson B E, Hones J. Botulinum toxin A (Botox) therapy for classical and variant achalasia: results in 59 patients.  Gastrointest Endosc. 1996;  43 292
• 7 Mariotti R, Bentivoglio M. Botulinum toxin induces nitric oxide synthase activity in motoneurons.  Neurosci Lett. 1996;  219 25-28
• 8 Dressler D. Botulinum-Toxin-Therapie. Stuttgart; Georg Thieme Verlag 1995
• 9 Storr M, Allescher H D, Rösch T. et al . Treatment of symptomatic diffuse esophageal spasm by endoscopic injection of botulinum toxin: a prospective study with long term follow-up.  Gastrointest Endosc. 2001;  54 18A