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Official Journal of the
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ISSN: 1983-991X
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| Original Article « PDF file » |
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Use of Botulinum Toxin Type A (Botox®) Through Transcystoscopic Vesical Insertion for Overactive Bladder Syndrome Non-Responsive to Oral Medication or for Parasympatholytic Drugs use Severe Side Effects
Lessandro Curcio*; Fabicio Costa; Marcos Augusto Marinho; Antonio Claudio Cunha; Juan Renteria; Geraldo Dibiase Filho
* Department of micturition dysfunction - Urology Service at Hospital Geral de Ipanema.
ABSTRACT
The botulinum toxin type A (Botox®) has been used in several specialties, and has showed to be efficient in the
improvement of urodynamics parameters and the quality of life of patients with overactive bladder symptoms. We present in this
study our initial case series of intradetrusor injection. The patient was placed in lithotomy position and through a rigid
cystoscope an endoscopic needle was inserted and injected in 20 sites. We injected 100 U of BTX-A for idiopathic patients and
200 U of BTX-A for neurogenic patients. Ambulatory follow-up was performed at 2, 4, 6, 12 and 24 weeks after BTX-A injection.
Eleven applications were done in 9 patients. The voiding diary parameters emphasized the good results in terms
of nocturia and frequency (nocturia decreased 64,2% and daily frequency decreased 50,8%). Urodynamics
parameters showed an improvement in maximum cystometric capacity and a reduction in the detrusor pressure of
uninhibited contraction (76%). The quality of life parameter improved 74,8%. No serious complication had occurred. We had an
initial experience of eleven cases of BTX-A injection, where no significant side effects were observed, with good
results concerning quality of life and urodynamics parameters. The botulinum toxin type A has been emerging in urology as
a great ally to fight against voiding dysfunction; however, its substantial costs and the necessity of reapplication are
still factors that hinder the widespread use of this approach.
Key words: Botulinum toxin; overactive bladder, neurogenic bladder.
Braz. J. Video-Sur, 2008, v. 1, n. 3: 097-103
| Accepted after revision: June, 10, 2008. |
INTRODUCTION
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veractive bladder syndrome (OAB) is a public health issue with severe physical and
financial consequences to the population with greater
incidence in the elderly. It is the fourth chronic disease
in prevalence behind cardiopathies and
sinusites1 and with annual incidence of 16% in Brazil and 19%
in the USA2. The estimated annual economic cost
of OAB is of $ 26 billions in the USA including
diagnosis and treatment3.
The method of choice to treat OAB syndrome is the use parasympatholytic drugs (in association
to behavioral treatment); however, they have
failed (20%) or even they have been discontinued
(achieving up to 58% in 6 months) due to side effects,
mainly xerostomia (40 % with the use of
oxybutinin) 4.
As neurostimulators, with an overall success of 56%, are very expensive (U$18mil), it is
necessary an efficient treatment with reasonable costs to
help these patients. Botulinum toxin type-A
initially described in urology for
detrusor-sphincter dyssynergia5, depicted satisfactory results to
control OAB symptoms. We showed our initial
prospective casuistic as well as a literature review of the use
of BTX-A off label in patients with neurogenic and idiopathic OAB that have not improved with
habitual anticholinergic or who had intense side effects
with these drugs.
MATERIALS AND METHODS
The inclusion criteria for this study are: patients that with the use of anticholinergic drugs
in high doses did not improve OAB symptoms within three months or patients in whom the use of
these drugs cause severe side effects (xerostomia,
blurred vision, digestive tract manifestations or
dizziness) leading to treatment discontinuity and
symptomatic recrudescence. Contraindications are: blood
dyscrasia, the use of botulinum toxin A for other
therapeutic purpose in the last three months,
polyneuropathies (such as Guilliam-Barré Syndrome), pregnancy
or suspicion of bladder cancer.
Patients sign an informed consent acknowledging their participation in a study of a
drug approved by the FDA (Food and Drug
Administration), in which the purpose of its use is off label. Before
BTX-A injections the patients fill out a 3-day urinary diary,
a questionnaire of quality of life and perform an urodynamic study. Hospitalization is on the same or
the day before the procedure, where quinolone
prophylaxis has been initiated at home during three days.
Lithotomy position is used and medullar block (raquianesthesia) or propofol sedation and a
laryngeal mask airway are performed. Local anesthesia
is performed in one case using 2% xylocaine gel in
the urethra and instillation of 40ml 2% lidocaine,
where 20 minutes later the device is inserted.
Toxin (Botox®) is diluted in 20 ml normal saline solution, and 100 U was used for
idiopathic overactive bladder and 200 U for
neurogenic overactive bladder. Dilution should be
carefully managed because if the bottle is heavily shaken
to homogenize the content the disulfide bridge that
links the light and heavy toxin chain might be
broken, inactivating the toxin as a consequence. A 24
Fr cystoscope sterilized needle used in the past to
inject Teflon was used to treat stress urinary
incontinence (Figure 1). Injections were performed without
sparing the trigone in 20 different sites with careful
attention not to deepen it too close to the cupula
avoiding inadvertently intraabdominal viscera injection
and observing the development of an increased
local consistency (bulking) (Figure 3), which lead us
to believe that there were no lost and that the
injection was performed in the right place(detrusor). When
there are trabeculations (Figure 2), they should not be
spared from the injections as they derived from a
focal detrusor hypertrophy. A catheter is left in case of
spinal anesthesia and patients are discharged home on
the same day of the treatment or the day after due
to social issues.
 |
Figure 1 - Instruments for injection: 24 Fr rigid
cystoscope, mandrel and needle. |
 |
Figure 2 - Intradetrusor endoscopic needle. Trabeculations
should be prioritized. |
 |
Figure 3 - Bulking depicting the toxin being correctly injected
into the detrusor. |
Ambulatory follow-up is performed at 2, 4, 6, 12 and 24 weeks after BTX-A injection,
symptoms subjective improvement were verified by means of
a questionnaire of quality of life, and objective improvement were confirmed through
urodynamics (on the sixth week and if symptoms got worse on
the following week). Every 6 months reinjection is available to alleviate patients' complaints due
to symptomatic recrudescence.
The topics evaluated through micturition diary were total micturition frequency and nocturia as
well as incontinence episodes. However, the
International Consultation on Incontinence
Questionnaire-Short Form (ICIQ-SF) was evaluated through the
numerical sum of three easily understandable
questions. Urodynamics emphasized the maximum
cystometric capacity and the permanence or not of
uninhibited contraction, and if contraction was present its
intensity and quantity of normal saline solution infusion
was measured.
RESULTS
A total of 11 patients (2 patients were retreated), 7 women and 2 men, were treated
with injections of BTX-A. The mean age was 55.8
years, the cause of overactive bladder syndrome in 6
patients were idiopathic and in 3 patients neurogenic.
Indications to treatment were 8 patients with overactive
bladder refractory to anticholinergic therapy and one
patient with intolerable side effects to the oral drugs.
Regarding the chronic conditions associated with overactive
bladder, systemic arterial hypertension was observed in 5
patients and diabetes in none of them. The mean disease
duration was 5.4 years. Of the patients with
neurogenic overactive bladder two have suffered a medullar
lesion for raquimedular trauma (one with C5 ASIA B
lesion and the other with lesion between T9 and T12
ASIA A) and one patient depicted sequela of tropical
spastic paraparesis by HTLV-1.
The mean operative time was 19.5 minutes, in the majority of the patients the surgery was
under propofol sedation and a laryngeal mask
airway, raquianesthesia was performed in two patients
and local anesthesia in one patient. Patients
received 200 U of BTX-A in 10 injections and 100 U in
one injection. The mean hospitalization time was 24
hours and 2 small complications were reported, one
patient with a light hematuria without hemodynamic repercussion which improved after 3 days
of conservative treatment and a non-neurogenic
patient with urinary retention of 29ml detected by echography ultrasound in whom an
intermittent catheterization was necessary, so patient's
condition improved within 2 weeks.
Nocturia and micturition frequency which were evaluated through the micturition diary
decreased in 64.2% and 50.8%, respectively (Graphic 1).
Among neurogenic patients there was substantial
improvement of incontinence episodes between the
catheterizations, thus a patient continued to have incontinence
episodes at night; however, at re-treatment these
episodes improved considerably. Bladder capacity
improved significantly from 317 ml to 430 ml and
uninhibited contraction pressure decreased 76% (Graphic 2).
In average the quality of life questionnaire
decreased from 14.5 to 2.2 (Graphic 3). A paraplegic patient
with neurogenic overactive bladder and sensibility
partially preserved was retreated after 6 1/2months with
local anesthesia, on a 10 points pain scale the
patient reported pain intensity of 4 points, revealing
similar parameters of the first re-treatment.
 |
Graphic 1 - Improvement of micturition frequency as well as nocturia after BTX-A injection. |
 |
Graphic 2 - Maximum cystometric capacity by urodynamic one month after BTX-A injection, as well as reduction of the voiding pressure of uninhibited contraction. |
 |
Graphic 3 - Important improvement in the quality of life measured by the ICIQ-SF. |
Of the 6 patients that received BTX-A more than 6 months ago, 2 patients have already been
re-treated; one patient is waiting to be called for
re-treatment, another patient lost contact. Although
one patient admits a significant symptomatic
improvement, she is apprehensive and afraid of a new
urinary retention even after it was explained about
its eventuality. One patient is under the suspicion of
a vesical blastoma, in spite of being asymptomatic
at the time of the injection.
DISCUSSION
Several studies have been analyzing the use of botulinum toxin type A (BTX-A) in urology in
which the first approach was for sphincter
dyssynergia5; however, other diseases have been treated
with reasonable success with this medication such as
benign prostatic hyperplasia (BPH) 6 and interstitial
cystitis (IC). Nevertheless, overactive bladder syndrome
of either idiopathic or neurogenic origin is the
pathological condition mostly treated with BTX-A. The effect
of BTX-A in the bladder are inhibition of
acetylcholine release blocking the motor activity, inhibition of
ATP, the calcitonin gene-related peptide (CGRP)
and substance P release7,8,9. BTX-A reduces the
fibrosis on the vesical wall10 and leads to decrease the
nerve growth factor (NGF) 11 content.
Urodynamic (detrusor lost of pressure, maximum cystometric capacity) and quality of life
as well as urinary frequency and leakage have been
the most analyzed factors in studies. In one of the
first manuscripts about BTX-A in patients with spinal
cord injury and neurogenic bladder, Shurch e cols
12 depicted an increased volume reflex and
vesicle capacity from 215.8 +/- 90.4 ml. to 415.7 +/-
211.1 (p <0.016) and 296.3 +/- 145.2 to 480.5 +/-
134.1 (p <0.016), respectively. Detrusor compliance
also decreased significantly from 65.6 +/- 29.2 cm.
de H2O to 35 +/- 32. 1 (p <0.016). Post-void
residual volume reduced from 261.8 +/- 241.3 ml.
to 490.5 +/- 204.8 (p <0.016). Currently, there
have been studies13 with 200 cases of
neurogenic bladder with encouraging outcome. Regarding
the idiopathic overactive bladder the greatest
study performed in only one
institution14 was published and it demonstrated that there was a
significant subjective and objective improvement of
88% among the several parameters analyzed after 4 and 12 weeks. Urgency disappeared in 82%
of the patients and incontinence was successfully treated in 86% of the cases within 1 to 2
weeks, frequency improved in 50% and nocturia
episodes decreased from 4 to 1.5 with maximal
bladder capacity improving in 56%.
In our casuistic, we obtained parameters of decreased micturition frequency and
nocturia similar to the literature and what most
surprised us was the reduction of 76% of the
detrusor pressure of the uninhibited contraction,
depicting the anticholinergic feature of the botulinum
toxin. The quality of life was another parameter
that depicted significant improvement from 14.7 to
2.2, patients with idiopathic detrusor
overactivity(IDO) reported a great satisfaction regarding
urgency. Though among patients with neurogenic
detrusor overactivity (NDO) incontinence episodes between the catheterizations was the factor
that most pleased them, as there is a reduction of
the use of diapers and absorbent pads which
directly affects the patients' daily routine.
One of our questions was if the patient with IDO despite the lower dose of toxin used
would have the same outcome of the patient with neurogenic bladder. This was studied by
POPAT and cols 15, where 31 patients with NDO and
44 patients with IDO received 200 U and 300 U of BTX-A, it was also observed that
urodynamic improvement of micturition diary and quality of
life parameters were similar between both groups
of patients. This question could not be confirmed
in our casuistic, first because of a small number
of patients with NDO (3 patients) when compared to the 6 patients with IDO, and second
because we reduced the number of BTX-A units
injected in the IDO group (from 200 to 100 U) and in
the NDO group (from 300 to 200 U).
According to the majority of the studies the mean BTX-A re-injection is performed
every 6 months; however, would the re-injected
patients have the same results? Grosse and cols. demonstrated that 66 patients retreated up to
6 times with either Botox® or Dysport® had
similar outcomes after repeated injections.
Nevertheless, another author18 depicted that 27 patients
had undergone additional injections, though he concluded repeated injections lasted longer
and delayed the symptomatic recrudescence maintaining its efficacy for one year. In a
cohort study of 20 children with myelomeningcocele,
it was not observed any case of hypersensitivity
to reinjection19. There were only two cases
of repeated injections in patients with NDO who depicted the same improvement outcome of
the first injection.
In our study the trigone was spared and we did not observe any case of symptom of
reflux, in spite of some author have already proved
that there is no difference in injecting BTX-A in
the trigone or not. In a study20 with 10 patients
with IDO, 200 U of intradetrusor BTX-A was
injected and after 6 weeks a voiding uretrocystography
did not show reflux in any of the cases and in
another case series21 of BTX-A injection there were
two groups: the trigone group and trigone-sparing
group and in 6 months of follow-up no difference
was observed between both groups.
The cost of treatment with BTX-A(only the toxin is a great part of the costs) as well as the
necessity to perform it at the ambulatory lead us to use
local anesthesia with 2% lidocaine initially for patients
with spinal cord injury and later for patients with
IDO. Rackley 22 have already described an approach
with local anesthesia with 100ml 2% lidocaine for
15-20 minutes; however, the patient still experienced
some pain as the anesthetic does not fully penetrate
the bladder wall. Drug administration by iontophoresis
has demonstrated satisfactory results with reduction of
pain from 4 to 1.6 on a 10-point pain scale. This
demonstrate that iontophoresis may be associated with
local anesthesia leading to a deeper penetration of
the anesthetic drug 24, which makes the procedure
more feasible and less costly.
CONCLUSION
BTX-A is becoming a viable alternative with good objective and subjective results, when
the parasympatholytics drugs are not effective or
when their side effects lead the patient to abandon
the treatment. However, high costs and necessity of
re-treatment are factors that prevent the widespread
use of botulinum toxin type A.
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Correspondence address:
Lessandro Cursio
Barra da Tijuca, Rio de Janeiro, RJ
CEP: 22790-700
lessandrocg@ig.com.br
Phones: (21) 7896-3739 / 9991-9485 / 2430-3257