botox in urology

1. Botox in urology
Done by
AMIR S. fazaa
3rd grade urological resident
2021

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”
 1897 – Emile van Ermengem
– botulin toxin produced by a bacterium Clostridium botulinum.
 1928 – toxin first purified

3.  1988 – Dykstra D
– first report of urologic application (DSD)
 approved for clinical use by the Food and Drug Administration in 1989
 1998 – Schmidt R
– first reported use in prostate

4.  Botulinum neurotoxin (BoNT) is a microbial protein that exists in seven serotypes, designated A
through G.
 Type A and B used in medicine
 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 50KDa size and aheavy chain of about
100KDa size held together by a disulfide bond.

5. Mechanism of action
 SNARE proteins are responsible for the binding of acetylcholine vesicles to the neuronal membrane
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.
synaptobrevin is targeted by types B, D, F and G
Syntaxin is targeted by type C.

6. Four Required Steps to Induce Paralysis
1. Binding of the toxin heavy chain to a specific nerve terminal receptor
2. Internalization of the toxin within the nerve terminal
3. Translocation of the light-chain into the cytosol
4. Inhibition of neurotransmitter release

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
 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
 recent basic and clinical evidence suggests that BoNT may have sensory inhibitory effects unrelated
to its actions on acetylcholine release.

9. Clinical applications in Urology
Neurogenic detrusor overactivity
Idiopathic detrusor overactivity and
overactive b
Bladder pain syndrome
Dyssynergic striated sphincter
Benign prostatic hyperplasia

10. 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
Injection site
– non-trigonal vs trigonal
risk of VUR with trigonal-doubtful
intra-detrusor vs submucosal

11. Questions arise regarding how deep to inject the toxin: intramuscular, submucosal, or epithelial.
(a) bladders were injected intramuscularly with 300 U of onabotulinumtoxinA mixed with gadolinium Immediately
following injection, patients underwent an MRI study to document the distribution of the gadolinium. The
investigators found that almost 18% of injected onabotulinumtoxinA was localized outside the bladder wall in the
extraperitoneal fat. .
(b) The middle panel shows
what we would consider “poor” injection technique. The needle placement is too shallow creating
a blistering effect of the urothelium with loss of vascular markings and minimal toxin spread.
As the needle is inserted further (i.e., right panel) the injection is then directed submucosally with
significant elevation of the mucosal wall in both vertical and horizontal planes and persistence of
mucosal vascular markings. We consider the right panel as “good” injection technique. In addition,
because we have avoided intramuscular injection, our risk of extravesical extravasation is
mitigated

12. Side Effects
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.

13. Contraindications
1.Myasthaenia gravis
2.Eaton Lambert Syndrome
3.Motor neurone disease
4.Pregnancy

14. Clinical applications in Urology
Neurogenic detrusor overactivity
BTA has been found to be highly effective with significant reduction in storage pressures and increase in
capacity.
This can potentially minimize risk to the upper tracts in patients at risk.
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 lifelong consequences of bladder injections remains uncertain

15. Neurological conditions frequently associated with neurogenic detrusor
overactivity
Spinal cord conditions (with or without detrusor sphincter dyssynergia)
• Spinal cord injury
• Multiple sclerosis
• Transverse myelitis
• Tropical spastic paraparesis
• Myelomeningocele
• Tethered cord syndrome and short filum terminale
• Ankylosing spondylosis and disc disease
• Acquired immune deficiency syndrome
Supraspinal conditions (without detrusor sphincter dyssynergia)
• Cerebrovascular accident
• Cerebral palsy
• Parkinson’s disease
• Dementia
• Neoplasm
• Cerebellar ataxia

16. What Is the Work-Up?
 History and Physical Examination
One should do a complete history including symptoms related to the neurologic
injury or disease. Past medical history including medical and surgical history is
required and response to any medications, especially if they have had BoNT in the past.
 Urodynamic Evaluation
Urodynamic testing plays a pivotal role in evaluating patients with neurogenic bladder.
This is a valuable tool to establish baseline bladder pressures and behavior that can be
used for the diagnosis, prognosis, and management of their disease
Urodynamic parameters recorded include: bladder sensation, filling pressure, capacity, compliance,
uninhibited detrusor contractions, and residual volume

17. Patient Preparation
• Urine analysis should be negative at the time of the procedure (if the patient has
a history of chronic bacteruria, appropriate preoperative antibiotic coverage is indicated).
• Anticoagulation medicine stopped for at least 5 days.
• Informed consent with drug warning.
• Sterile cystoscopic preparation with standard antibiotic coverage for a minor cystoscopic
procedure.
• Latex allergy survey in this at risk population.
• In spinal cord injured patients with a history of autonomic dysreflexia or lesions
above the T6 spinal cord level, precautions to deal with and procedures to minimize
autonomic dysreflexia should be in place.

18. Bladder Injection
 Bladder injections with BoNT can be done using either a rigid or flexible cystoscope,under local anesthesia.
A total of 100–200 U of onabotulinumtoxinA diluted in 10–20 ml of preservative free saline (i.e., 10 U/ml) are
injected submucosally throughout the bladder using an endoscopic injection needle.
Sphincter Injection
 One Hundred units of onabotulinumtoxinA are generally utilized in women and 200 U in men.
 Each 100 unit vial of onabotulinumtoxinA is diluted in 2 ml of preservative-free saline. For women, a 22
gauge short spinal needle is inserted periurethrally for 1.5–2.0 cm at the 3 o’clock and 9 o’clock positions
and 1 ml of onabotulinumtoxinA is injected at each site.
 Male urethral sphincters are injected with a total of 200 U of onabotulinumtoxinA diluted in 2 ml of
preservative-free saline under local or general anesthesia with a rigid cystoscope using an endoscopic
injection needle .
BoNT is injected in equal aliquots of 0.5 ml at the 12, 3, 6, and 9 o’clock positions.

19.  Intra vesical BoNT injection reduces nerve growth factor(NGF is a signaling protein that interacts with
specific receptors along autocrine, paracrine and endocrine Pathways) content in the bladder tissue of
patients with neurogenic detrusor overactivity
 Effects take 1-3 weeks
 Check residual if symptoms worsen
 Retention improves after 6-8 weeks
 Effects last 6-12 months
the following conclusions can be reached:
1. 73–95% of patients achieve complete continence
2. The frequency of patient leakage episodes is reduced by 32–90%
3. Mean cystometric capacity is increased by 40–178%
4. Maximal detrusor pressure is reduced by 22–51%

20. Idiopathic detrusor overactivity and overactive
bladder
 Overactive bladder is a common medical condition that can have a deleterious impact on a
person’s mental, physical, social, and financial well-being.
Of those that are diagnosed and treated with front-line anticholinergic medications, a
significant proportion of patients cease treatment due to lack of efficacy, cost of medications,
or adverse side effects especially dry mouth and constipation.
 In these patients typically, the upper tracts are un- likely to be at risk hence the concerns
are primarily symptomatic control rather than safety of the clinical condition.
 The residual urine must be checked and urine should be sterile before injection.

21.  BTA is effective in the control of idiopathic detrusor over- activity.
 There is increase in bladder capacity and storage symptoms show a clear and statistically
significant decline as compared to placebo.
 Most often,a200 unit dose is used to minimize the chance of clinical retention

22.  Recently, a special formulation of BTA, the liposomal formulation has been studied in
refractory overactive bladder patients
 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 necessary

23. Bladder pain syndrome
 BTA is a level five treatment in patients with bladder pain syndrome (BPS)
according to the American Urological Association Guidelines
 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 doseis 100-200 units with injections in a wide area of the
bladder usually including the trigone

24. Dyssynergic striated sphincter
 Dyssynergic striated sphincter can be a consequence of classical 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.

25. 1 month after injection
(i.e., note lack of coaptation of urethral mucosa
demonstrating relaxation of sphincter)

26. Botulinum Toxin Injection for Prostate Disorders
 Benign prostatic hyperplasia
 While surgery remains the gold standard for relieving obstruction and symptoms,
more recent attention has been focused on pharmacotherapy as an alternative
approach.
The American Urological Association recommends alpha-adrenergic receptor blockers as first-
line pharmacologic therapy for male patients suffering from BPH.
 alpha-adrenergic receptor blockers directly target sympathetic pathways and ignore the
contributory effect of parasympathetic innervation on prostate growth and lower urinary
tract symptoms.

27.  Intraprostatic injection can induce apoptosis with involution in size of the prostate.
 There is also decrease in smooth muscle contraction in the prostate
 Injections are performed under transrectal ultrasonography imaging guidance.

28.  BoNT has been shown to produce:
 (1) a generalized atrophy of the prostatic gland with no evidence of inflammatory
infiltrate,
 (2) an increase in apoptosis with DNA fragmentation and formation of apoptotic bodies on
Tunnel stain and decrease in proliferation,
 (3) a reduction in the proliferation of epithelial cells, and
 (4) a reduction in alpha-1A adrenergic receptor

29.  Reduction symptome score by 65%
 Reduction of prostatic volume by 68%
Reduction PVR by 83%
 Reduction PSA level by 51%

30. BoNT BPH usually fit the following criteria
• Men aged 45 years or older.
• Lower urinary tract symptoms due to BPH for at least 6 months.
• symptoms refractory to oral BPH drug (>4 week duration for alpha antagonists;
>6 months duration for 5-alpha reductase inhibitors).
• Residual urine volume <200 mL. If residual volume is elevated we would perform
urodynamic testing to evaluate detrusor contractility prior to BoNT injection
consideration.
• Maximum flow rate <12 mL/s with voided volume >125 mL.
• Rule out acute prostatitis or urinary tract infection.
• Recent prostate biopsy.
• Total prostate volume less than 80 mL.
• PSA level <4 mg/L.

32. Prostatitis/Prostatodynia
 BoNT injections can be effective for reducing pain and incomplete emptying symptoms
associated with non-bacterial prostatitis and prostatodynia.
 A positive response, defined as a 50% or greater temporary reduction in pain symptoms,
qualifies the patient to receive a subsequent injection with 100–200 U of onabotulinumtoxinA.

33. Thank you