Botulinum toxin in Urology

Review Article
Botulinum toxin in Urology
Sanjay Sinha*
Senior Consultant Urologist and Transplant Surgeon, Department of Urology, Apollo Hospitals, Hyderabad, India
a r t i c l e i n f o
Article history:
Received 8 August 2014
Accepted 15 November 2014
Available online xxx
Keywords:
Botulinum toxin
Detrusor overactivity
Overactive bladder
Bladder pain syndrome
Dys-synergic striated urethral
sphincter
a b s t r a c t
Introduction: Botulinum toxin is a neurotoxin produced by Clostridium botulinum species of
bacteria. This powerful toxin, which is the most poisonous substance known to mankind,
has been used in highly dilute concentrations in urology. This review examines the various
applications of botulinum toxin sub-type A (BTA) in the field of Urology.
Material and methods: Recent literature with respect to the use of BTA in Urology was
examined with specific reference to clinical applications.
Results: Intradetrusor injection of BTA has a wide and expanding role in Urology. Intra-
detrusor BTA injections lead to a significant increase in cystometric capacity and reduction
in detrusor pressure in patients with neurogenic detrusor overactivity. In patients with
idiopathic detrusor overactivity, there is significant reduction in urgency and frequency.
There is also evidence to support the use of BTA in overactive bladder without detrusor
overactivity, bladder pain syndrome, detrusor sphincter dyssynergia and dysfunctional
voiding. Initial studies support the continued investigational use of intravesical catheter
instillation of liposomal BTA. Evidence with regard to benign prostatic hyperplasia is
conflicting and this treatment is not recommended for regular clinical use.
Conclusions: There is good quality evidence to support the use of intradetrusor BTA in pa-
tients with detrusor overactivity both neurogenic and idiopathic as well as in overactive
bladder and bladder pain syndrome. The evidence with regards to detrusor sphincter
dyssynergia, dysfunctional voiding and benign prostatic hyperplasia is less robust. Lipo-
somal BTA delivery may present an attractive future option in Urological disorders.
Copyright © 2014, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
Botulinum toxin is the most powerful poison known to
mankind. Just a teaspoon of concentrated toxin could wipe
out all of humanity. However, just like several other poisons
such as digitalis or snake venom, when used in the right
concentration, poisons often transform into powerful medi-
cines. Botulinum poisoning and its link with poorly preserved
meat was possibly noted for the first time in 1793 in Germany
after an outbreak of poisoning with symptoms of paralysis.
Perhaps the earliest account of Botulinum on Pubmed is from
the year 1916 when Lancaster reported strabismus following
suspected Botulinum poisoning.1
Van Ermengen, a microbi-
ologist in Belgium was the first to isolate the Clostridium
botulinum bacteria which produces the toxin and reported it
in 1897 following an outbreak of the poisoning after a meal at a
funeral.2
* Tel.: þ91 9849008150.
E-mail address: drsanjaysinha@hotmail.com.
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e5
Please cite this article in press as: Sinha S, Botulinum toxin in Urology, Apollo Medicine (2014), http://dx.doi.org/10.1016/
j.apme.2014.11.006
http://dx.doi.org/10.1016/j.apme.2014.11.006
0976-0016/Copyright © 2014, Indraprastha Medical Corporation Ltd. All rights reserved.

The first medical use of Botulinum was reported by Alan
Scott for strabismus in 1981 who used Botulinum toxin A, the
serotype of toxin that is currently in common use.3
The first
urological experience was reported in 1988 by Dykstra who
injected it into the striated urethral sphincter for the treat-
ment of detrusor sphincter dyssynergia.4
2. Material and methods
A Pubmed search was conducted with terms botulinum toxin,
detrusor overactivity, overactive bladder, bladder pain syn-
drome, dysfunctional voiding, detrusor sphincter dyssynergia
and benign prostatic hyperplasia. Recent literature was
reviewed and conclusions were made with regards to clinical
application.
3. Pharmacology of botulinum toxin A (BTA)
Botulinum toxin is a neurotoxic protein produced by Clos-
tridium botulinum. There are seven types of toxins (Type AeG)
of which Type A has the longest duration of action and has
been in common clinical use. Botulinum toxin A (BTA) has two
chains, a light chain of about 50 KDa size and a heavy chain of
about 100 KDa size held together by a disulfide bond.5
There are four different sub-types of BTA known with a
15% variation in the amino acid sequence.6
The light chain is a
zinc-dependent endopeptidase responsible for the toxicity
while the heavy chain has three distinct parts, HN, HCN and
HCC. These assist in the internalization and translocation of
the toxin.5
BTA can be complexed to different proteins with
consequential differences in its pharmacokinetic profile.
Hence, one must differentiate between these various com-
mercial types of BTA. Onabotulinum toxin A is most
commonly in use (Botox, Allergan Inc; Neuronox, Medytox
Inc). Abobotulinum toxin A (Dysport, Ispen Biopharm Limited)
and Incobotulinum toxin A (Xeomin, Merz Pharmaceuticals)
are some other preparations that are commercially available.
3.1. Mechanism of action
The heavy chain of BTA binds to receptors on the pre-synaptic
cholinergic neuronal endings with consequent internalization
of the toxin. In the cytoplasm, the toxin is cleaved into its light
and heavy chains. The light chain then interferes with SNARE
proteins that are responsible for the binding of acetylcholine
vesicles to the neuronal membrane. This prevents the binding
of vesicles and subsequent release of acetylcholine. There are
various types of SNARE proteins which are targeted by
different sub-types of botulinum toxin. SNAP 25 protein is
targeted by types A, C and E. VAMP (or synaptobrevin) is tar-
geted by types B, D, F and G while Syntaxin is targeted by type
C. This binding is permanent and cleaved SNAP 25 can be
noted in human nerve terminals upto 11 months following an
injection. The effect wears off as new nerve endings sprout.5,7
SNAP 25 is expressed almost universally by para-
sympathetic fibers and by about half of the sensory and
sympathetic fibers in the bladder wall. It is also expressed by
preganglionic parasympathetic nerve endings in ganglia
located at the bladder wall.5
On injection of the toxin into
bladder wall, there is rapid spread across the detrusor. This is
dependent on the volume of injected fluid as well as the
number of injected sites. Cystoscopic injection into the
bladder wall leads to reduced acetylcholine expression by
parasympathetic efferents at the detrusor neuromuscular
junction. This is accompanied by reduced release of other
neurotransmitters associated with acetylcholine release such
as ATP and Vasoactive intestinal peptide (VIP). There is also
reduction in expression of muscarinic and purinergic re-
ceptors in the detrusor, urothelium and sub-urothelium
which are important for both Ad as well as C fibers.8
In the afferents, there is a reduced expression of neuro-
trophic factor with impairment of nociceptive impulses from
the bladder wall. Hence there is an analgesic effect. Sympa-
thetic fibers show a decrease in norepinephrine release by the
trigone by a poorly understood mechanism.9
In the urothe-
lium, BTA reduces ATP and NO release. ATP is important in
bladder activity. There is also increased cleaving of SNAP 23,
which might be important in ATP release.5
Repeated in-
jections have not been shown to increase fibrosis. On the
contrary, there is some evidence to show that fibrosis might
be reduced in patients who are injected.
Intraprostatic injection can induce apoptosis with involu-
tion in size of the prostate although this finding has not been
consistently seen. There is also decrease in smooth muscle
contraction in the prostate.10,11
4. Clinical applications in Urology
4.1. Neurogenic detrusor overactivity
The first line management of patients with neurogenic
detrusor overactivity is antimuscarinic medication. However,
in patients with unsafe storage pressures despite medication,
or in those with intolerance to antimuscarinic agents, the
options are limited. The time-tested solution is an augmen-
tation cystoplasty. However, augmentation is a major surgical
reconstruction and carries a metabolic consequence. It cannot
be offered in patients with significant reduction in glomerular
filtration rate due to the side effects related to solute reab-
sorption and acidosis. Botulinum toxin injection offers an
attractive solution in these patients.12
BTA has been found to be highly effective with significant
reduction in storage pressures and increase in capacity.13
This
can potentially minimize risk to the upper tracts in patients at
risk. The effect lasts for 6e12 months. The injections need to
be repeated indefinitely and while the effects seem to be
steady at more than five injections, the truly long term or life
long consequences of bladder injections remains uncertain.
Some studies suggest that patients who undergo injections
might in fact, have less long term bladder wall fibrosis
compared to those that are not injected. The effect does seem
to be sustained, however, the numbers of patients studied
with long term injections remains small. In a recent review,
intradetrusor BTA injections were noted to lead to a signifi-
cant improvement in incontinence, maximum cystometric
capacity and maximum detrusor pressures of À63%, þ68%
and À42%, respectively (all p < 0.01).14
j.apme.2014.11.006

At the author's center, patients with neurogenic bladder
have been offered BTA injections for the last 12years. A
limited number of patients have had more than five injections
without any apparent loss of efficacy or increase in adverse
events. None of the patients have needed a repeat injection
before 6 months and most have managed with an annual in-
jection. The author chooses 300 units for all patients who are
adults or children above 40 kg weight. For smaller children, a
dose of 200 units has been used. In the author's experience,
effect of 300 units in general, has lasted longer than 200 units.
All patients in the author's unit have been on clean intermit-
tent self-catheterization (CISC) thus negating any impact of
increased residuals (unpublished data).
For patients who are on a partial CISC combined with
spontaneous “voiding” regimen or who are not on CISC, re-
siduals need to be measured carefully and many of these pa-
tients may need to institute CISC following injection. Even if
the voiding pressures are safe, patients may fail to achieve
continence without CISC. Hence, for such patients, a preop-
erative counseling with discussion regarding the probable
need to migrate to a full CISC regimen must be carried out.
4.2. Idiopathic detrusor overactivity and overactive
bladder
Patients with idiopathic detrusor overactivity differ from those
with neurogenic bladder. They are unlikely to be on CISC,
hence increase in residual urine following BTA becomes criti-
cally important. They are also more likely to be elderly, since
there is a clear link betweenthe incidenceof overactive bladder
and aging. In these patients typically, the upper tracts are un-
likely to be at risk hence the concerns are primarily symp-
tomatic control rather than safety of the clinical condition.
All patients with idiopathic detrusor overactivity should
undergo a medical trial of antimuscarinics before BTA. The
residual urine must be checked and urine should be sterile
before injection. In contrast, in patients with neurogenic
bladder the urine might not be sterile since bacterial coloni-
zation (as contrasted to clinical infection) is exceedingly
common in patients on CISC.
BTA is effective in the control of idiopathic detrusor over-
activity.13
There is increase in bladder capacity and storage
symptoms show a clear and statistically significant decline as
compared to placebo. Most often, a 200 unit dose is used to
minimize the chance of clinical retention. While clinical
retention is not very common, a sub-clinical increase in re-
sidual urine is common and occurs in about 30e40% of pa-
tients. This needs to be carefully monitored since most
patients with eventual retention will show a preliminary in-
crease in residuals indicating a potential for retention. This
can guide suitable action before an emergent clinical crisis.
A recent review noted an improvement of 29%, 38% and
59%, respectively in frequency, urgency and incontinence
episodes following BTA intradetrusor injections.14
However,
there was a significant increase in urinary infection episodes
(21% versus 7%, p < 0.001). There was a 12% risk of needing
clean intermittent self catheterization (p < 0.001).14
Recently, a special formulation of BTA, the liposomal
formulation has been studied in refractory overactive bladder
patients.15
Liposomal BTA is a particularly attractive option in
these patients since it can be delivered by catheter instillation
in the outpatient setting. Cystoscopic injection is not neces-
sary. A recent randomized controlled trial showed that lipo-
somal BTA instillation was associated with reduction in
urinary events and urgency at 4 weeks as compared with pla-
cebo. However, somewhat disappointingly, urgency inconti-
nence episodes were not improved as compared to placebo.
In general, BTA is indicated in patients with refractory
overactive bladder with documented detrusor overactivity
(see the previous section). However, some authors have
studied BTA injections in patients with overactive bladder
without detrusor overactivity. There is evidence to suggest
that the drug is effective in this setting. However, it would be
critically important to ascertain the reasons for possible re-
fractory overactive bladder without detrusor overactivity first.
Specifically, issues related to fluid intake and use of agents
that are potentially diuretic such as excessive caffeine or
alcohol must be excluded prior to injection. The author has
not injected any such patients but recognizes that this might
be a salvage option in some patients. The limited experience
of BTA in this setting must be discussed with the patient.
4.3. Bladder pain syndrome
BTA is a level five treatment in patients with bladder pain
syndrome (BPS) according to the American Urological Asso-
ciation Guidelines.16
In contrast to patients with detrusor
overactivity, the clinical efficacy is not quite as certain. These
patients can be quite desperate for relief by the time one
reaches this level of management and a realistic expectation
of outcome for this invasive and potentially expensive therapy
is important.
In patients with BPS, BTA injections are invariably carried
out after a failure of more conservative treatments such as
oral medication, hydrodistension and intravesical therapy. In
contrast to detrusor overactivity, where the trigone is usually
avoided, in patients with BPS, the trigone is deliberately
targeted with the injections. The usual starting dose is
100e200 units with injections in a wide area of the bladder
usually including the trigone.14
A significant number of patients seem to obtain relief.17
However, the quality of data is poor and most experience
limited to small, uncontrolled series. The author has used BTA
in five patients and found significant benefit in three. In one of
the three patients, however, the patient failed to respond
following the second injection after 11 months. There are no
reliable predictors of efficacy, although some data suggest that
patients with ulcerative BPS respond as well as those without
ulcers.18
4.4. Dyssynergic striated sphincter
Dyssynergic striated sphincter can be a consequence of clas-
sical neurogenic bladder or may be noted in the absence of
neurological basis (termed “Dysfunctional voiding”). Intra-
urethal injection is carried out by a cystoscopic route in
males or by periurethral injection along the side of the urethra
in females. In either case, one must perform cystoscopy.
Typically injection is carried out in four quadrants and most
authors use a starting dose of 100 units of BTA.19
a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e5 3
j.apme.2014.11.006

The effect of BTA on the sphincter is not as reliable as that
of injection into the bladder. Literature suggests that dyssy-
nergia can resolve in some of patients. A recent systematic
analysis showed that four weeks following 100 units of BTA
into the striated sphincter in patients with spinal injury,
multiple sclerosis or congenital disorders, there was a signif-
icant reduction in residual urine. However, voiding Pdet.max
was similar to controls. Since voiding (and storage) pressures
are critical for the long term health of the upper tracts, these
results are not reassuring.20
In the author's experience, most patients who have clas-
sical severe dyssynergia with markedly elevated voiding
pressures and poor flow fail to get off their CISC post injection.
However, the author only has limited experience of the use of
BTA in this setting.
There is data to support the long term use of intrasphincter
BTA in children with dysfunctional voiding. In a recent study,
eight of 12 girls with dysfunctional voiding showed improve-
ment in voiding parameters with reduction in residual urine
from 115 ml to 57 ml and improvement in flow rate from
11 ml/s to 20 ml/s. Half of these girls needed a repeat injection
at a mean of 15 months following the first injection.21
4.5. Benign prostatic hyperplasia
BTA injection has been used in small series of patients with
intractable urinary retention due to BPH when surgery has
been contraindicated. In these small series, the prostate has
often shown significant shrinkage following intra-prostatic
injection with relief of urinary retention.22
This shrinkage
has been documented vividly in the canine model. Injections
are performed under transrectal ultrasonography imaging
guidance. However, the effects have not been universally
observed with some studies showing no impact on prostate
size or lower urinary tract symptoms.23
The conflicting data
with studies showing no benefit led to a recent review
concluding that the modality should not be offered in clinical
practice at this point in time.14
5. Conclusion
In conclusion, botulinum toxin A injection is finding
increasing use in Urology. The position of this modality in the
clinical armamentarium is currently getting established for
the classical indication of both neurogenic and refractory
idiopathic detrusor overactivity. Limited evidence suggests
that BTA injections could be used in patients with intractable
idiopathic overactive bladder, detrusor sphincter dyssynergia,
dysfunctional voiding and bladder pain syndrome. For other
indications, more clinical evidence is needed to confirm the
clinical efficacy before it can be recommended in a general
urological practice setting. Liposomal BTA presents the
intriguing possibility of a simple delivery system.
Conflicts of interest
The author has none to declare.
r e f e r e n c e s
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a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e5 5
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