Urology JC069: The Man Cannot Hold His Water: Physiology Of Micturition, Urinary Incontinence In Man

Question 1

Neurology of Micturition

Answer 1

Somatic control: **External urethral sphincter
1. **Pudendal nerve
- ***S2-S4 Onuf’s nucleus (anterior horn)
- Striated sphincter, Anterior levators, Superficial perineal muscles

2. ***Pontine micturition centre
   - receives cortical input from frontal lobes —> inhibitory
   - afferent stretch input from detrusor
   - cerebellar input for coordinated voiding
3. ***Sacral micturition centre
   - communicates with pons for micturition reflex

Sympathetic: **Hypogastric nerve (忍尿)
- T10-L2
- Forms pelvic plexus with parasympathetic
- Beta vs Alpha
- **Detrusor relaxation + ***Contract internal urethral sphincter

Parasympathetic: **Pelvic nerve (痾尿)
- S2-S4
- **Detrusor contraction, Bladder neck, Levator ani

Question 2

Normal baseline of Micturition

Answer 2

Normal void volume: ***200-400 ml (汽水罐) per void

Normal residual urine (RU): ***<150 ml

Frequency:
- >8 voids during daytime
- IPSS score: ***> 1 void every 2 hour

Nocturia:
- ***>=2 voids during sleeping time
- each void preceded + followed by sleep

Question 3

Enuresis

Answer 3

• Involuntary loss of urine
• Nocturnal enuresis: involuntary loss of urine during sleep

Paediatric population:
- up to 10-12% at 5 yo
- most improve when grow older

Question 4

Function of bladder

Answer 4

1. Storage (Filling) (99% of time)
   - efficient + **low-pressure filling
   - **lower pressure storage
   - ***perfect continence
2. Voiding
   - periodic voluntary urine expulsion at ***low pressure

Bladder filling + Urine storage:
- accommodation of urine at low pressure
- bladder outlet **closed at rest + in increased intraabdominal pressure (e.g. coughing)
- **absence of involuntary bladder contractions

Bladder emptying (Voiding):
- coordinated **contraction of bladder smooth muscle of **adequate magnitude
- concomitant lowering of resistance (i.e. ***relaxation) at level of sphincter muscle
- absence of anatomic obstruction (e.g. prostate)

Question 5

***Pathophysiology of micturition

Answer 5

Any type of voiding dysfunction / continence problem:
- must result from abnormality of >=1 of factors mentioned including ***structural abnormalities of various causes

Micturition: Interaction between bladder + sphincter

Bladder abnormalities:
1. **Detrusor overactivity (idiopathic, neurogenic)
2. **Low bladder compliance (SCI, interstitial cystitis, radiation cystitis, hysterectomy)

Sphincter abnormalities:
1. Extrinsic: **Urethral hypermobility
- weakness of pelvic floor muscle (urethral support)
2. Intrinsic: **Intrinsic sphincter deficiency (ISD)
- defect in urethral musculature, blood flow, innervation

Question 6

Voiding with Normal contraction

Answer 6

1. Actual organisational centre for micturition reflex in an ***intact neural axis in brainstem
2. Initiation of micturition in adult by intravesical pressure for ***involuntary induced emptying
3. Voluntary emptying involves **inhibition of **somatic neural efferent activities

Question 7

Micturition reflex

Answer 7

Reflex at level of spinal cord
- stimulation by **full bladder
—> sudden complete relaxation of sphincter muscles
—> immediately **followed by detrusor contraction

• Organised in Pontine micturition centre
• Voluntary control at cortical level

Question 8

Continence of urine

Answer 8

Depends on:
1. **Normal CNS
2. **Spinal cord control
3. ***Anatomically normal lower UI

Mechanism:
1. Anatomical support by intact pelvic floor
- hold bladder neck + urethra in place (esp important in females)

2. Intrinsic urethral mechanism
   - Coaptation of mucosa
   - Compression by submucosal + sphincters (internal / external)
3. Less important issue in man (∵ with prostate as part of continent device)

Question 9

Urinary incontinence

Answer 9

Definition: Involuntary loss of urine
- social / hygienic problem
- objectively demonstrable (dribbling of small amounts of urine —> continuous UI)

Prevalence:
- F»M
- ↑ with age: 50-70
- **Stress UI (50%), Urge UI (11%), Mix UI (36%)
- 50-75% of patients never complain to physician
- **80% UI can be cured / improved

Question 10

***Types of UI

Answer 10

1. Stress UI
   - involuntary loss of urine on **increased intraabdominal pressure (e.g. effort, exertion, sneezing, coughing)
   - occur when bladder pressure > urethral pressure under increased abdominal pressure
   - caused by **Sphincter weakness
   - female: **Urethral hypermobility / **Intrinsic sphincter deficiency
   - male: ***Post-prostatectomy
2. Urge UI
   - leakage accompanied by / immediately preceded by **urgency (sudden strong desire to void)
   - function of **uncontrolled detrusor contraction that overcome urethral resistance
   - **Overactive bladder (OAB), **Detrusor overactivity, (Food, Atrophic vaginitis)
   - strong sense to void —> involuntary loss of urine
   - symptoms severity could be affected by **stress + **anxiety
   - mixed with stress UI in many cases
3. Mixed UI
   - Stress + Urge
   - treatment focus on predominant symptom
4. Overflow UI
   - leakage of urine when bladder abnormally distended with large **residual volume
   - esp. in men with chronic **retention due to BPH
   - caused by **Overdistension of bladder
   - **overflow with frequent / constant “dribbling”
   - could be **obstructive (e.g. BPH) / **hypotonic detrusor (e.g. medications, SCI, diabetic cystopathy etc.)
   - significant post-void residual urine
   - palpable bladder
   - chronic retention with overflow may be complicated by **UTI, bladder stone
   - outlet obstruction —> **obstructive uropathy, hydronephrosis, deterioration of renal function
5. Functional UI
   - leakage of urine due to inability of getting into toilet
   - esp. in elderly
   - cognitive / physical / environmental limitations
   - ***diagnosis of exclusion as other types might be present in functionally limited individual
   - causes:
   —> impaired mobility
   —> dementia
   —> lack of carer etc.

Question 11

Risk factors for UI

Answer 11

Unmodifiable:
1. White
2. Age (**menopause: 50)
3. **Female

Modifiable:
1. General: **smoking, **caffeine, **obesity, poor mobility
2. **Large fluid intake

Diseases / Conditions:
1. Childbirth esp. Vaginal
2. Infection (UTI)
3. **DM
4. **Neurological disease: CVA, Parkinsonism, MS, Spinal cord injury (SCI)
5. Anatomical disorder: VVF (Vesicovaginal fistula), Ectopic ureter, Urethral diverticulum
6. Previous pelvic, perineal, prostate surgery
7. Renal therapy
8. Medication

Question 12

***Etiology of UI

Answer 12

Anatomical:
1. Congenital (Duplex ureter with insertion below external sphincter —> continuous UI)
2. **Infection
3. **Iatrogenic (Post-prostatectomy sphincteric injury)
4. ***Birth injury (Vesicovaginal fistula, Stress UI etc.)
5. Neoplastic

Question 13

Concept of Compliance

Answer 13

Change in volume / Change in pressure
- depends on thickness, volume, elasticity

Normal compliance: Large volume ↑ —> Little pressure ↑
Decreased compliance: Small volume ↑ —> Large ↑ in pressure

Causes of change in bladder compliance:
1. **Process that alters viscoelasticity / elasticity of wall
2. **Filling rate > Rate of stress relaxation
3. Filling beyond its **limits of distensibility
—> largely altered by **Neurologic + ***Structural status

Question 14

Ketamine cystitis

Answer 14

• Chronic ketamine abuse —> Small + Low compliance bladder (***fibrotic) (TB have similar effects)
• Present with ***Urge incontinence + Frequency of urine
• ***Ureter obstruction —> Obstructive uropathy (e.g. hydronephrosis)

Question 15

***Etiology of OAB / Detrusor overactivity

Answer 15

1. ***Idiopathic
2. Non-neurogenic (secondary to **Bladder pathology)
   - **Bladder outlet obstruction (e.g. BPH, urethral strictures)
   - **Bladder stone, foreign body
   - **Bladder tumour (e.g. CIS bladder)
   - ***Infection (Cystitis) + Inflammation
3. Neurogenic
   - **CVA, PD, Brain tumour, Traumatic head injury, MS
   - **Spinal cord lesions: Injury, Tumour, Transverse myelitis, Myelodysplasia

Question 16

Potentially reversible + transient causes of UI

Answer 16

DIAPPERS
1. Delirium
2. **Infection
3. **Atrophic vaginitis / urethritis
4. **Drugs / Food
5. **Psychological disorders
6. Endocrine disorders
7. Restricted mobility
8. Stool impaction

Question 17

Drugs / Food causing UI

Answer 17

Urge:
1. **Diuretic
2. **Caffeine
3. Alcohol

Overflow:
1. **Anticholinergic (smooth muscle relaxation)
2. **Alpha agonists (↓ presynaptic NE release)
3. ***Beta agonists (smooth muscle relaxation)
4. Sedatives / Antidepressant

Stress:
1. ***ACE-I (cough)

Question 18

Approach to patient with UI

Answer 18

1. History
   - age
   - onset
   - severity
   - nature
   - duration
   - **type —> differentiate Stress vs Urge UI
   - **triggers
   - ***obstructive symptoms
   - pads number / size / wetness
   - lifestyle e.g. caffeine, smoking, alcohol
   - menstrual / obstetric
   - bowel (e.g. constipation)
2. General
3. Mental state
4. Neurological
5. Relevant past medical history + surgical history
   - **surgery on neurological / gynae / urological system
   - **DM
   - drugs

Question 19

***Physical examination of UI

Answer 19

1. Above waist
   - Abdominal exam: ***Palpable bladder, Mass
   - Neurological exam
2. Genital exam
   - **Atrophy (atrophic vaginitis)
   - **Cystocele
   - ***Rectocele
   - Pelvic masses
   - Skin excoriations (due to leakage of urine —> itch)
3. PR exam
   - Anal tone
   - **Prostate (size + consistency)
   - Fecal soiling / impaction
   - **Rectal mass
   - Anal reflex, Cough reflex —> leakage?
   - ***Bulbocavernosus reflex (BCR: internal/external anal sphincter contraction in response to squeezing the glans penis or clitoris) —> S2-4
4. ***Neurological exam
   - Neurological disease (e.g. PD, MS, CVA)
   - Neurological sign of sensory, motor, reflex abnormalities

Question 20

***Investigations of UI

Answer 20

1. Frequency + Volume chart (Voiding diary)
   - semi-objective method of quantifying symptoms (e.g. frequency, UI episodes)
   - tells **Typical urinary habits, **24 hour urine volume, **Frequency, **Nocturia, **Functional bladder capacity
   - record (24-72 hours)
   —> **fluid intake, physical activity
   —> frequency
   —> ***void volume
   —> incontinence episode + associated triggers
2. ***Flow rate + Residual urine (normal <50ml)
3. Lab test
   - **Urinalysis (with culture if infection suspected)
   - **Renal function
   - FG
4. Urodynamic test (**gold standard, but only for complex cases)
   - Uroflowmetry: **Speed, **Max void volume, **Residual urine

Question 21

Urodynamic test

Answer 21

Goal:
- **Duplicate patient symptoms
- Determine etiology of UI
- **Evaluate detrusor function
- ***Determine degree of pelvic floor prolapse
- Identify urodynamic risk factors for development of UT deterioration

Indications:
- Clinical suspicion of **Detrusor overactivity
- **Voiding dysfunction
- Unclear clinical diagnosis before surgery
- Previous surgery for stress UI but recurrent / persistent UI
- Presence of neurological clinical features

Evaluation:
1. **Flowmetry (flow rate + residual urine)
2. **Filling phase (detrusor overactivity / hypotonia)
3. **Voiding phase (obstruction / hypercontractility)
4. Video (look at **shape of bladder + bladder neck + reflux)
- better evaluation of bladder neck descent + urethra
- quantify anterior wall prolapse (Cystocele) more accurately
5. **Electromyography (look at striated sphincter)
6. **Leak point pressure (LPP)
7. ***Urethral pressure profile (UPP)

Detrusor pressure = Vesical pressure - Abdominal pressure
- evaluate compliance + detrusor overactivity

Question 22

***Treatment of UI

Answer 22

Treat according to cause

Urge UI / OAB:
1. Conservative
- **Lifestyle modification
—> fluid management
—> reduce caffeine intake (improve frequency + urge but not actual UI)
—> stop smoking (weak evidence)
—> weight loss
- **Bladder training (6 months)
- **Pelvic floor exercise (3 months)
2. **Pharmacological (70% efficacy)
- Antimuscarinic, β3 agonists (relax bladder)
3. Intravesical instillation therapy
4. **Botox injection
5. Posterior tibial nerve stimulation
6. Sacral neurmodulation (Interstim)
7. **Augmentation cystoplasty
8. Urinary diversion (in refractory case)

Stress UI:
Non-surgical
1. **Lifestyle medication: fluid management, reduce weight, stop smoking
2. Usage of incontinence pad
3. **Pelvic floor exercise
4. **Bladder training
5. Medication: **Duloxetine, ***Estrogen therapy

Surgical
1. ***Occlusive
- Bulking agents
- Artificial urinary sphincter (AUS)

2. Supportive **Sling / **TVT (Tension-Free Vaginal Tape) / **Artificial urinary sphincter
   - **Suburethral sling
   - **Pubovaginal sling
   - **Retropubic suspension: Colposuspension, MMK
   - ***TVT (Tension-Free Vaginal Tape)

Question 23

Urge UI: Pelvic floor muscle training

Answer 23

Repeated voluntary pelvic floor muscle contractions (Kegel)
- Long slow contractions + Short sharp pull-up

Example:
- 15 near-maximal contractions
- 10 second for each contraction with equivalent rest period
- 3 cycles per day
- 30-50 daily contractions
- 3 months
- 60% success rate

Rationale:
1. **Strengthen pelvic floor musculature —> strengthen urethral support
2. Regain normal **unconscious activation of pelvic floor muscle during ***increased abdominal pressure

Question 24

Urge UI: Bladder training

Answer 24

Relearn Central control of voiding (like in infancy)

Components:
1. ***Time voiding
- urinate according to schedule rather than response to urge

2. ***Diverse attention during urge
   - deep breath, mental calculation, squeezing of pelvic floor muscle

—> Aim to ↓ urgency + frequency (2-3 hours)

If fail —> Anticholinergic + β3 agonists

Question 25

Urge UI: Drug treatment

Answer 25

1. Estrogen local therapy
   - Vaginal estrogen therapy in post-menopausal women (may improve Urge UI)
   - esp. ***Atrophic vaginitis
   - NOT Oral —> ↑ risk of stress + urge UI
2. ***Anticholinergic
3. ***β3 agonist
4. Combination

Question 26

Urge UI: Anticholinergic

Answer 26

M1-5 muscarinic receptor:
- M1-5: Brain
- M2-3: Heart, GI
- M3: Eye, Salivary gland

M1: Cognitive function
M2: Tachycardia, Constipation
M3: Dry mouth, Constipation, Blurred vision, Dizziness
M4-5: No known SE

• Bladder: 80% M2, 20% M3
• Bladder contractions involve ***M3 (M2 unknown role)
• Inhibit post-synaptic M3 receptor —> ↓ Smooth muscle contraction
• Takes ***3-4 weeks to work
• Try >=2 types of Anticholinergic before considered failure

Differ in:
1. Selectivity (most non-selective)
2. Duration of action (IR, ER, Transdermal)
3. Structure (tertiary, quaternary)

Drugs:
1. **Oxybutynin
- extended release (ER), transdermal, intravesical gel, rectal suppository
- avoid 1st pass by liver into **desethyloxybutynin —> major cause of SE
- SE: dry mouth, dry eyes
—> if cannot tolerate dry mouth: ER / Tolterodine / Mirabegron / Transdermal / Intravesical

2. ***Tolterodine (functional selectivity for bladder over salivary gland)
3. ***Solifenacin (selective M2 + M3)
4. ***Darifenacin (selective M3)
5. Quaternary (less lipophilic, not cross BBB, less CNS SE e.g. cognitive)
   - Trospium chloride
   - Propantheline

SE:
1. Dry mouth
2. Constipation
3. Blurred vision
4. Dizziness
5. Cognitive impairment (Solifenacin, Darifenacin, Fesoterodine: No cognitive dysfunction in elderly)

CI:
1. Uncontrolled **acute close angle glaucoma
2. **Ulcerative colitis / Toxic megacolon
3. **MG
4. **IO

Efficacy:
- ↓ Daytime frequency, incontinence episodes, improve symptom score
- 70%
- ***No consistent evidence to show superiority of drug over behavioural therapy / other antimuscarinic

Question 27

Urge UI: β3 agonist

Answer 27

***Mirabegron:
- Smooth muscle relaxation
- 25 / 50mg daily
- ↓ incontinence + micturition

SE:
- less SE (considered safe)
- ***HT —> watch out severe HT, CVA, CVS disease
- headache
- UTI
- nasopharyngitis

Combination of Antimuscarinic + β3 agonist:
- act via different mechanisms
- ↑ mean voided volume
- ↓ frequency / urgency (when compared to single agent)
- ***slightly higher constipation rate

Question 28

Urge UI: Botox / Botulinum toxin A

Answer 28

• Neurotoxins from Clostridium botulinum
• 7 subtypes —> target different SNARE protein

MOA:
- cleaves SNAP-25 protein on SNARE protein complex (required for **exocytosis of ACh containing vesicles into NMJ) —> **paralysis of detrusor muscle
- also act on **sensory pathway by reducing expression of vanilloid receptor (TPRV1) + purinoreceptor (P2X3) —> **↓ urgency

Administration:
- **Onset: 1-2 weeks
- **Repeat injection every 6-9 months (∵ neural regeneration)
- Avoid trigone to prevent pain / reflux
- Avoid gentamicin (↑ toxicity of Botox)

Regimen:
- 100IU IDO in 10ml NS —> inject at 20 sites
or
- 200IU NDO in 20ml NS —> inject at 20 sites

Efficacy:
- ↑ symptom score
- ↓ incontinence episode
- ***better than oral medication
- less SE of Anticholinergic
- 70% efficacy

SE:
- ***More UTI
- Transient retention of urine

Complications:
- ***Urinary retention requiring CISC (clean intermittent self-catheterization)
- UTI
- Haematuria
- Systemic absorption (flu-like, muscle weakness)

CI:
- Active UTI
- Bleeding tendency
- **MG
- **Pregnancy / Breast feeding
- Allergy

Question 29

Urge UI: Posterior tibial nerve stimulation

Answer 29

• Indirect stimulation to **S2-4 sacral nerve plexus via **Tibial nerve
• Weekly for 30 mins x 12 weeks
• Effective for Urge UI women who had no benefit from Anticholinergics

Efficacy:
- comparable results to oral medication (no more effective than tolterodine)
- durable response at 1 year

Question 30

Urge UI: Sacral neurmodulation (Interstim)

Answer 30

Influence of activity in 1 neural pathway —> modulate pre-existing activity in another pathway through synaptic interaction

2 stage procedure:
Stage 1: Temporary **electrode placed percutaneously under fluoroscopic control into S3 sacral foramen alongside sacral nerve
- unknown MOA
- **modulate local neural reflex
- ***inhibit bladder contraction (also affect signals from higher brain centre in control)
- stimulation would cause:
—> Dorsiflexion of big toe
—> Bellows reflex = Anal wink
—> Sensation of pulling in rectum / scrotum / vagina

Stage 2:
- Strict voiding diary for 2-4 weeks
- if positive response —> **pulse generator implanted under skin (near PSIS) for **permanent use with continuous pulse
- percutaneous nerve evaluation
- battery lifespan 7 years

Indications:
1. **Intractable OAB
2. **Intractable NDO (neurogenic DO)
3. **Fowler’s syndrome (more effective) (urethral sphincter relaxation disorder)
4. Interstitial cystitis
5. **Underactive bladder
6. ***Fecal incontinence

Complications:
1. Procedure-related
- ***bleeding
- infection
- pain

2. Implant-related
   - ***mechanical failure including migration / displacement 5-10%
   - battery life 7 years
   - lower limb pain / numbness
   - explantation rate 10%

Question 31

Urge UI: Augmentation cystoplasty

Answer 31

Clam cystoplasty
- piece of bowel sutured to bladder to ***increase bowel capacity

Rationale:
- **impair bladder contraction
- ↓ detrusor pressure
- **↑ bladder capacity
- ↓ amplitude of contraction

Complications:
1. Early
- bleeding
- infection
- collection
- ***anastomotic leakage
- ileus

2. Long-term
   - Mechanical (cannot void by themselves)
   —> ***need of CISC
   —> mucus perforation (mucus production —> flooding)
   —> spontaneous rupture

• Metabolic
  —> ***Hypokalaemic hyperchloraemic metabolic acidosis (K-rich alkaline secretion —> NH4Cl absorbed in exchange to carbonic acid)
  —> Acidosis (—> osteoporosis)
• Malabsorption
• Infection
• Malignancy

Question 32

Stress UI: Transvaginal tape

Answer 32

Reinforce “functional” pubourethral ligament —> secure proper fixation of:
1. Mid-urethra to pubic bone
2. Reinforce suburethral vaginal hammock + its connection to the pubococcygeus

2 types:
1. **Retropubic (TVT)
2. **Transobturator (TOT)

Efficacy:
- 80-90% success rate
- FDA warning: foreign body —> erosion, chronic pain

Complications:
Intra-op:
1. ***Perforation (bladder / urethra)
2. Haematoma
3. Haemorrhage
4. Nerve injury

Post-op:
1. **Urinary retention
2. **De novo urgency (new onset of OAB symptoms)
3. ***UTI
4. Tape erosions

Question 33

Stress UI: Artificial urinary sphincter

Answer 33

• AMS800
  —> treatment of choice for persistent moderate / severe **post-prostatectomy incontinence
  —> **Gold standard for Male Stress UI
• Rarely done in female unless everything failed

3 components:
1. Inflatable occluding cuff
2. Pressure regulating balloon
3. Control pump

Need to urinary —> press button —> void —> water fill ballon again —> continent again

Efficacy:
- Highly durable
- Effective
- Safe surgical option
- High satisfaction rate