UroToday – Botulinum toxin (BTX) is used therapeutically for several disorders associated with excessive muscular contractions including focal dystonias. Recently BTX has been successfully used for the treatment of disorders of the gastrointestinal and urinary tracts. Nevertheless, controversy exists regarding safety of this treatment.
Several studies reported autonomic effects of BTX, particularly of BTX B used to treat cervical dystonia, including dry mouth, blurred vision, lightheadedness and constipation.(1,2,3)

In the present study intraprostatic injection of BTX A has been successfully used to reduce voiding dysfunction in 77 patients with Benign Prostatic Hyperplasia (BPH).

In another clinical experience, seven patients, all of whom reported no symptomatic improvement with BTX A treatment, have been treated using intraprostatic injection of BTX B (NeuroBloc, Elan, Ireland) with the same technique, in order to avoid the risk of resistance to BTX A and to obtain long-lasting results. The NeuroBloc equivalent was determined by multiplying by 50 the dose as Botox units, so 10000 U of BTX B were used.

Two months after injections, AUA score decreased from 23.6 В±1.7 to 12.3 В±2 points (P =0.00001), serum PSA from 4.1 В±0.6 to 2.0 В±0.8 ng per ml (P =0.0004), prostatic volume from 47.8 В±9.8 to 26.1 В±6.0 ml (P =0.0009), and residual volume from 76 В±26 to 47 В±7.6 ml (P =0.02). At the same time, mean peak urinary flow rate increased from 9.4 В±3.0 to 14.4 В±0.7 ml per second (P =0.002). Two of the seven patients (40%) experienced erectile dysfunction and dry mouth.

Furthermore, to investigate cardiovascular autonomic effects of BTX A, we have studied six patients, from 22 to 62 years old, without detectable cardiovascular or autonomic diseases, treated with 150 units (0.75 ml) of BTX A (Dysport, Ipsen SpA, Milan, Italy) for chronic anal fissure. We have utilized the Ewing protocol at baseline (before treatment) and repeated the tests within 96 hours and within 30 days after treatment with BTX. The Ewing protocol, including measurement of heart rate changes during deep breathing, Valsalva maneuver and standing up; blood-pressure measurement during handgrip and during standing up, have been developed to assess the autonomic control of cardiovascular system and to diagnose autonomic neuropathy. To class the severity of damage of ANS, a score (0 = normal response; 1 = borderline; 2 = abnormal) is given to each test. The final score can change from 0/10-1/10 (normal pattern), to 2/10-4/10 (borderline pattern), to 5/10-10/10 (abnormal pattern). None of the patients had worsening of test scores after toxin injections. In particular, before treatment a borderline pattern (2/10 score) was found in 4 patients. At 96-hour evaluation, a borderline pattern (2/10 score) was found in 1 patient. At 30 days evaluation, all patients who had previously reported abnormal score no longer had such scores, and a normal pattern (0/10) was found in all treated patients.

In these clinical trials BTX did not produce any serious cardiovascular adverse events. Besides, BTX B caused significant decrease of saliva production and erectile dysfunction in 40% of patients. According to our results, in a recent double blind randomized trial BTX A and B were compared in the treatment of 20 patients with cervical dystonia; patients treated with BTX B showed dry mouth and greater severity of chronic constipation in absence of severe autonomic dysfunctions in each group of patients. (3)

Although BTX B affects neuromuscular cholinergic synapses, its clinical effects on autonomic cholinergic synapses are considerably stronger, as reflected by the adverse events reported. It is unclear whether this reflects either a relatively higher affinity of BTX B, as compared to BTX A, for autonomic synapses, or the observation that doses of BTX B for production of neuromuscular effects in humans are several-fold higher than those of toxin A, such that at therapeutic neuromuscular doses, autonomic synapses are stimulated by BTX B. However, in our patients it seems conceivable that erectile dysfunction and dry mouth may represent, respectively, a local diffusion to autonomic targets and a systemic effect. Therefore, given its side effect profile, BTX B should be used carefully in patients with pre-existing autonomic dysfunction, other anticholinergic treatment, or conditions in which anticholinergics are contraindicated.

References:

1. Tintner R, Gross R, Winzer UF, Smalky KA, Jankovic J. Autonomic function after botulinum toxin type A or B: A double blind, randomized trial. Neurology 2005; 65: 765-767
2. Jankovich J. Treatment of cervical dystonia with botulinum toxin. Mov Disord 2004;19: S109-115
3. DresslerD, Benecke R. Autonomic side effects of botulinum toxin type B treatment of cervical dystonia and hyperidrosis. Eur Neurol 2003; 49: 34-38

Giuseppe Brisinda, MD, Federica Cadeddu, MD, and Giorgio Maria MD as part of Beyond the Abstract on UroToday

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Corresponding Author
Giuseppe Brisinda
Department of Surgery
Catholic School of Medicine
University Hospital “Agostino Gemelli”
Largo Agostino Gemelli 8
00168 Rome (Italy)

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