2. Introduction
1817-1822 – Justinus Kerner – first accurate
description of clinical features of food-borne
botulism
coined the term “botulism”
• from Latin botulus meaning “sausage”
3. 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
4. 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
5. 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
6. 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
10. 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
11. 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.
12. 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.
16. 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
25. 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
27. 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.
28. Botulinumtoxin in Parkinson’s disease
200 U Botox
500 U Dysport
Results
Bladder capacity ↑
QOL ↑
Incontinence episodes ↓
PVR ↑ in 2 MSA, CIC required
30. 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
31. 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
32. 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