Botulinum toxin in urology2

Botulinum toxin in urology
Dr V Giriraja
Uroresident

Introduction
1817-1822 – Justinus Kerner – first accurate
description of clinical features of food-borne
botulism
coined the term “botulism”
• from Latin botulus meaning “sausage”

1897 – Emile van Ermengem
– botulin toxin produced by a bacterium
Clostridium botulinum.
1928 – toxin first purified
1949 – Arnold Burgen
– discovered BoNT blocks neuromuscular
function by ↓ACh release

Lower Urinary Tract Applications
1988 – Dykstra D
– first report of urologic application (DSD)
1998 – Schmidt R
– first reported use in prostate
2000 – Schurch B
– first reported high quality studies in urethra and
bladder

Botulinum neurotoxin (BoNT) is a microbial protein
that exists in seven serotypes, designated A through
G. Type A and B used in medicine
1949 recognised that Botulinum toxin blocked
nerve synapses
first medical use in strabismus and
blepharospasm

BoNT-A is marketed as:
Botox® (Allergan, Inc.)
Dysport® (Ipsen Limited)
A Chinese formulation, Hengli (Lanzhou Institute
of Biological Products)
Xeomin® (Merz Pharmaceuticals)
BoNT-B is marketed as:
Myobloc® (Solstice Neurosciences,Inc.), which is
also called Neurobloc® in some countries

Medical Uses of Botulinum Toxin
blepharospasm pelvic pain
strabismus
achalasia focal dystonias
muscle spasms
spasticity wrinkles
hyperhidrosis bladder overactivity
painful bladder migraine

Taking the Wrinkles out of the
Bladder

Clostridium botulinum spore prior
to germination

 The lethal dose of botulinum toxin for humans is not known
but can be estimated from primate studies. By extrapolation,
the lethal amounts of crystalline type A toxin for a 70-kg
human would be approximately 0.09-0.15 μg intravenously or
intramuscularly, 0.70-0.90 μg inhalationally, and 70 μg orally.
 A vial of the type A preparation currently licensed in the
United States contains only about 0.3% of the estimated human
lethal inhalational dose and 0.005% of the estimated lethal oral
dose.
 All forms of botulism result from absorption of botulinum
toxin into the circulation from either a mucosal surface (gut,
lung) or a wound. Botulinum toxin does not penetrate intact
skin

Mechanism of Action of Botulinum
Toxin

 A, Release of acetylcholine at the neuromuscular
junction is mediated by the assembly of a
synaptic fusion complex that allows the
membrane of the synaptic vesicle containing
acetylcholine to fuse with the neuronal cell
membrane. The synaptic fusion complex is a set
of SNARE proteins, which include synaptobrevin,
SNAP-25, and syntaxin. After membrane fusion,
acetylcholine is released into the synaptic cleft
and then bound by receptors on the muscle cell.


 B, Botulinum toxin binds to the neuronal cell
membrane at the nerve terminus and enters the
neuron by endocytosis. The light chain of
botulinum toxin cleaves specific sites on the
SNARE proteins, preventing complete assembly of
the synaptic fusion complex and thereby blocking
acetylcholine release.
 Botulinum toxins types B, D, F, and G cleave
synaptobrevin; types A, C, and E cleave SNAP-
25; and type C cleaves syntaxin. Without
acetylcholine release, the muscle is unable to
contract.
 SNARE indicates soluble NSF-attachment protein
receptor; NSF, N-ethylmaleimide-sensitive fusion
protein; and SNAP-25, synaptosomal-associated
protein of 25.

Insertion Technique-bladder
-Rigid vs flexible scope – GA vs LA
 Volume/dilution
– Botox® - 10 U/ml
ie 100 units diluted with 10mls of normal saline
 given as 1 ml injections
 Injection site
 – non-trigonal vs trigonal
 ??risk of VUR with trigonal-doubtful
 – intra-detrusor vs submucosal

Indications in adults
 1990 detrusor-sphincter-dyssynergia
 1999 neurogenic detrusor hyperactivity ( MS, Parkinson)
 2001 non-neurogenic detrusor hyperactivity
 2004 bladder outlet obstruction due to BPH
 Chronic pelvic pain/intersticial cystitis

Indications in children
 2002 neurogenic detrusor hyperactivity
 2006 non-neurogenic detrusor hyperactivity
 2007 non-neurogenic detrusor-sphincter-dyscoordination
 2010 detrusor-sphincter-dyssynergia

Side Effects
Very rare
no severe effects reported
minor effects
Local effects –– injection site pain, pelvic pain
 UTIs 6.4-35%.
 haematuria 3.2-5%
 constipation (10% with BoNT-B)
 stress urinary incontinence .
Systemic effects:
 dysphagia, diplopia, blurred vision
 peripheral muscle weakness.

Contraindications
-Myasthaenia gravis
Eaton Lambert Syndrome
Motor neurone disease
Pregnancy

Choosing the Botox Patient -DO
Symptoms of urgency, urge incontinence
No UTIs
Failed/intolerant oxybutynin
No voiding dysfunction
Urodynamics

Treating Bladder Overactivity
with Botulinum Toxin
Effects take 1-3 weeks
Check residual if symptoms worsen
Retention improves after 6-8 weeks
Effects last 6-16 months
Can repeat treatment

100 units
Urge incontinence resolved 86%
Nocturia 4-1.5
Frequency 14-7
Retention 4%
200 units
Urge incontinence resolved 50%
Nocturia 5-2
Frequency 15-8
Retention 37%

Repeat Treatments
Effect on smooth muscle
fades after 6-12 months
axonal regeneration
Repeat treatments results in
same response
antibodies to Type A very uncommon

Neurogenic Detrusor Overactivity
Use a higher dose:
300 units

Botulinum toxin in detrusor
sphincter dyssynergia
 Injection into the external urethral sphincter
 In Male-Transurethral/transperineal inj under EMG
/Sonographic guidance.
In Female-Transvaginal,periurethral under Sonographic
guidance.
Dose:100 U BOTOX / 2-4 cc saline
Effective for 2-4 month than
reinjection.

Botulinumtoxin in Parkinson’s disease
 200 U Botox
 500 U Dysport
Results
 Bladder capacity ↑
 QOL ↑
 Incontinence episodes ↓
 PVR ↑ in 2 MSA, CIC required

% of patients becoming completely
continent

Botulinum toxin in bladder outlet
obstruction and BPH
Doggweiler et al. Prostate 1998
 intraprostativ injection in 30 patients with BPH
 200 U Botox® in 4 cc saline vs. 4 ml saline
 Mean Follow-up 19.8 +/- 3.8 Month
 Reduction symptome score by 65%
 Reduction of prostatic volume by 68%
 Reduction PVR by 83%
 Reduction PSA level by 51%
 No changes in placebo group
 Effect may last up to 18 month Silva et al 2009

Botulinum toxin in interstitial
cystitis and chronic pelvic pain
 Study:
 RCT with 67 Patients
 100 or 200 U BOTOX® subendothelial plus hydrodistension
vs. hydrodistension alone
 Results:
 symptome reduction in all three groups
 improvement of bladder capacity only in BOTOX® groups
 effect may last up to 12 month
 Conclusion:
 botulinum toxin may be effective in IC

In Children
 10 publications: main indication myelomeningocele
 Most treated children older than 2 years
 10-12 U BOTOX® per kg body weight up to a maximum
dose of 300 U
 20-30 injections done under general anesthesia
 Continence rates 65-87%
 Reduction of maximum detrusor pressure < 40 cm H2O
 Compliance > 20 ml/cm H2O
 No side effects reported
 Combinded detrusor and sphincter injection may be of
advantage
 Repeated injections are effective

Botulinum toxin in urology2

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