Botulinum toxin in urology

Dr V GirirajaUroresident

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.

Regrowth of Axons

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 reportedminor effectsLocal 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 incontinenceNo UTIsFailed/intolerant oxybutyninNo voiding dysfunctionUrodynamics

Treating Bladder Overactivitywith Botulinum Toxin

Effects take 1-3 weeksCheck residual if symptoms worsenRetention improves after 6-8 weeksEffects last 6-16 monthsCan 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 musclefades after 6-12 monthsaxonal regeneration

Repeat treatments results insame responseantibodies 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

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