OAB: Beyond Antimuscarinics. Stephen Kraus MD, FACS Head, Section of Female Urology, Neuro-Urology and Voiding Dysfunction Department of Urology

Transcription

1 OAB: Beyond Antimuscarinics Stephen Kraus MD, FACS Head, Section of Female Urology, Neuro-Urology and Voiding Dysfunction Department of Urology Case Study 63 yo female presents with: Severe frequency & urgency Voids q Unable to sit thru typical TV show Unable to go to movies without BR Nocturia x 6 Urge incontinence >3 accidents per day Needs 3-5 adult depends diapers (adds extra pads) Tried several meds Mild improvement but when goes to higher dose, she is not able to tolerate side effects Miserable Options?? 1

2 Micturition and Storage Reflexs Leng & Chancellor UNA 2005 The Bladder Urothelium Glycosaminoglycan Layer Uroplakin Plaques and Discoidal Vesicles Zonula Occludens Umbrella Cell Stratum Intermediate Cell Stratum Basal Cell Stratum Basal Lamina (courtesy Tim Boone) 2

3 Neuro Urothelial Cells Urothelial Cells Express nicotinic, muscarinic, tachykinins and adrenergic receptors Express vanilloid (VRI) receptors Respond to transmitters released from afferent nerves (ATP, SP) Have a close proximity to afferent nerves Release chemical mediators (ATP,NO) At the Bladder Level Igawa Urology

4 P2X Alternate Mechanisms of Contraction ATP triggers P2X Depolarization Activate membrane bound Ca channels Influx of Ca Alternate to muscarinic activated SR Elevated P2X in DO P2X 3 Knockout mice hyporeflexic Fry Urology 2003 Cockayne Nature 2000 Bladder Receptors NE Ach ATP B 3 (+) M2 M3 AC (-) I P 3 camp SR P2X (+) Ca ++ Ca Channel Compliance Tone (courtesy Tim Boone, modified) Uninhibited Contraction 4

5 Vanilloid Receptors Capsaicin-gated ion channels VR1 or TRPV1 Found on afferent nerve endings & urothelial cells Function of vanilloid receptors Detect noxious stimuli (temp, ph, infection) Initiate pain or reactive responses Via sensory awareness Via reflex pathways (can trigger micturition reflex) Activation of alternative or C fiber pathways (substance P) Trigger DO (either reactive or pathological) Initiate local inflammatory response Release and respond to purinergic (ATP) signaling by the urothelium Ion transfer & Depolarization Osmotic swelling Chancellor JU 1999 Cruz Urology 2002 Urothelial VR1 Expression Birder et al, PNAS (2001) Red VR1 receptors Green urothelial cells (cytokeratin stain) B: Apical cells C: Basal cells depicting VR1 D: Elimination of VR1 stain with Ab Birder PNAS

6 Urothelial Interstitium & Alternative Contraction Mechanism ATP enos VRI VRI P 2 X Interstitial Cells VRI (courtesy Tim Boone) NO nnos Urothelium Suburothelial Plexus Smooth Muscle Normal Neuro-Pathways De Ridder BJU

7 Neuro Pathways with C-Fiber Activation De Ridder BJU 2000 Pharmacologic (nontraditional) Alpha Adrenoceptor antagonist B -adrenoceptor agonist Vanilloids Serotonin mechanisms GABA Dopamine Enkephalins Estrogens Potassium Channel Openers 7

8 Vanilloid Agonists Capsaicin and Resiniferatoxin Potent agonists of VR Rapid activation of VR induced pathways Initiate cascade Densitization Process Neuroplastic changes to sensory afferents Reduction in sensory nerves (V receptors) activity Down regulation of neurotransmitters Cruz, Urology 2003 Vanilloid Agonists RFX such a potent VR1 agonist Scarce dose required to initiate desensitization Low enough not induce painful stimuli Chancellor, JU

9 Vanilloid Agonists: Capsaicin 1-2 mm/l capsaicin in 30% ethanol--administration related discomfort Scarce placebo RCT Mostly in NGB Efficacy at usable dose Good for infra-pontine etiologies Less favorable for non-neurogenic DO, discomfort Ridder BJU 2000 Vanilloid Agonists: Resiniferatoxin Riddler BJU

10 Vanilloid Agonists:RTX Cruz: 12 patients with refractory DO Single intravesical dose 50 nmol/l RTX 3/10 pain with instillation 11/12 marked 3 mos Mean incontinece episode/day 5 to 0.5 Capacity increased 293 to 436ml Phase 2 Clinical trials ongoing in US Cruz Neurourology and UDS 2000 Chancellor JU 1999, pc Botox 10

11 Botulinum Toxin Most potent bio toxin known to man 1897 van Ermengen, outbreak of sausage poisoning Clostridium botulinum (Gram + Anaerobe) 7 distinct toxins (A-G) Blocks presynaptic release of acetyl-choline from cholinergic nerve terminals Two chains (light and heavy) 150 kda (100 kda connects to 50 kda via disulfide bond) Heavy chain binds molecule to target cell membrane (nerve terminal) Light chain internalized and inhibits neurotransmitter release Smith, JU, 2005 Rackley CUR 2004 Presynaptic Release of AcetylCholine Vesicle with ACH SNAP Complex Inside presynap Binds vesicle Exocytosis of vesicle and release of ACH Smith, JU

12 Botox Inhibits Presynaptic Release of ACH Heavy chain gets light chain toxin inside presyn cell Light chain binds up SNARE complex Vesicle unable to exocytose Smith, JU 2005 Preparations BTX-A units Intramuscular detrusor inject cc injections Care in prep Rackley, CU

13 BTX Technique My prep 200 units (DO/OAB) 300 for NGB 15 ml volume 30 injections Collagen inject scope feel for the inject Too deep: inject in serosa or outside bladder Too shallow: waste into lumen Smith, Nature/Urology

14 BTX Results N=7 300 units Radziszewski ICS 2001 BTX Results N=7, refractory to meds and SNM units injected ONLY in Trigone Improvement in 4, lasted 8-20 weeks Frequency Capacity Pre (65-190) Post Zermann ICS

15 BTX Results N=35 (29 female, 6 male) refractory OAB 30 injections, total=300 units IIQ, 3 weeks and 6 months Reduction in pads 3.9 to wks All 35 patients N= 14 patients Rapp, Urology 2004 BTX Results: Refactory OAB Dykstra women with OAB (wet and dry) Botox B 2500 to units Baseline mean frequency 15.7 voids/24hr Results All patients experienced a response Mean reduction 5.3 in 24hr frequency Longest duration 3 mos Dykstra, International Urogyn J

16 BTX Results 18 women with refractory OAB 200 units Retrospective Rackley CUR 2004 BTX Results: UDS Kessler 2005 (n=22) Duration 5 mos 300 units in 30 ml, 1 ml injections Assessments Diary, UDS, Satisfaction Kessler Neurourology

17 Botox Side Effects: Rare Lethal dose 2800 unit (40 unit/kg in 70 kg) Detrusor doses well below Allergic reactions Flu like symptoms Avoid other agents that impair neuromuscular transmission Curare like compounds Aminoglycosides Myasthenia Gravis (relative) Smith, JU 2005 Cost an Issue 17

18 T8 SCI 11/2003 with Severe DO T8 SCI 4/2004 (s/p botox) 18

19 Future Options: Gene Therapy Future Options: Gene Therapy (6880 bp) SpeI(50) EcoRI(4644) XbaI(4673) SpeI(4667) SpeI(736) EcoRI(753) EcoRV(768) NotI(781) XhoI(786) SpeI(3729) EcoRV(1403) EcoRI(1857) Gene therapy (Maxi-K Membrane Ion Channel Plasmid insertion of gene Increase in K channel Increased K efflux Decreased Ca Smooth muscle relax Detrusor relaxation Other roles ED Christ Am J Physiology

20 When Targeting the Bladder Fails Where Should We Aim For? De Ridder BJU 2000 Sacral Nerve Modulation: Theory Relies on existing neural pathways of micturition reflexes 3 functions of micturition reflex pathways Amplification Coordination Timing Leng & Chancellor UNA

21 Sacral Nerve Modulation: Theory Amplification-Basis for effective voiding: CNS must be able to perceive, process and act upon smooth muscle activity Provides sustained/maintained detrusor activity to allow sufficient bladder emptying Coordination: Bladder-sphincter synergy Sphincter remains open with micturition (bladder contraction) Sphincter remains closed when storing Timing-Reflects volitional control over autonomic process Toilet training allows governing over automatic process Allows volitional voiding over wide range of bladder volumes Leng & Chancellor UNA 2005 Guarding Reflex Contraction of EUS Maintains continence Despite increase volume Despite increase intravescial pressure Activation via stimulatory spinal interneurons Relaxes during void Brain inhibits GR Relaxes via activation of negative spinal interneuron Leng & Chancellor UNA 2005 De Groat et al, Brain Res

22 Afferent Modulation of Efferents: How you know to keep voiding Bladder-bladder reflex Leng & Chancellor UNA 2005 De Groat et al, Brain Res 1996 Storage: Brain Control Overrides Afferent Induced Efferent Activity Cortical inhibition of afferent induced bladder activity Leng & Chancellor UNA 2005 De Groat et al, Brain Res

23 Storage: Brain Control Overrides Afferent Induced Efferent Activity Cortical inhibition of afferent induced bladder activity Cortical stimulation of pudenal negative reflex Leng & Chancellor UNA 2005 De Groat et al, Brain Res 1996 Afferent Induced Detrusor Overactivity Leng & Chancellor UNA 2005 De Groat et al, Brain Res

24 C-Fiber Afferent Induced Detrusor Overactivity Leng & Chancellor UNA 2005 De Groat et al, Brain Res 1996 Pudenal Effect on Micturition Reflex & Afferent Induced DO Leng & Chancellor UNA

25 SNM Suppression of Afferent Induced Detrusor Overactivity Leng & Chancellor UNA 2005 SNM Technique 25

26 SNM: The Appropriate Candidate Lower Urinary Tract Symptoms Frequency/urgency Urge incontinence Severe or refractory Retention Non-obstructive Dysfunctional voider (sphincter spasms that shut the bladder down results in retention) Has usually tried multiple drug therapies SNM Technique 2 step process Testing Assess response, determine candidacy 50% improvement in symptoms Temporary (percutaneous) Staged implant Implantation Full implantation Second stage 26

27 SNM Technique: Perc. Test Perc Test 27

28 SNM Technique: Perc. Test Usually 2 leads placed into S3 External generator 7 day trial/testing period Bladder diary Frequency/urge incont Looking for 50% reduction SNM Technique Old Way Current Way 28

29 SNM Technique Sacral Nerve Modulation Randomized clinical trial Placebo vs SNM cross over for placebo Refractory to medical therapy Exclusion criteria Neurologic conditions Pelvic pain Predominant SUI Schmidt JU

30 Sacral Nerve Modulation Significant reduction >50% decrease in leaks Schmidt JU 1999 Sacral Nerve Modulation Stimulation (n=34) Delay (n=42) Mean Baseline Mean 6 mos Mean Baseline Mean 6 mos Incontinent/ day < Severity (1-3) < Pads/day < Schmidt JU

31 Dependent on SNM Temporary 6 mos, n=52 Return to baseline symptoms in ALL patients SNM ON SNM Off Leaks/day <.001 Severity.8 2 <.001 Pads/day <.001 Schmidt JU 1999 SNM AEs generator site 15.9% Infection (requiring explant) 5.7% Lead migration 7% Nerve damage or injury 0% Schmidt JU

32 SNM on OAB Dry Hassouna et al JU 2000 All refractory standard therapies N=52, 6mos Baseline 6 mos Void <.0001 day Volume <.0001 /void Urge (1-3) <.0001 SNM 18 mos Schmidt JU

33 SNM: Really Longterm Bosch and Groen JU 2000 N=45 Refractory UUI, DO on UDS Mean 47 mos 60% successful 40% cured 20% improved >50% 40% failure (<50% or no improvement) ALL Failures identified by 18 mos. Bosch & Groen JU 2000 Neuromodulation: Future Smaller Sacral nerve generator Bilateral SNM Pudenal stimulation Cutaneous stimulation BION implant 33

34 When All Else Fails Ingelman Sundberg Dennervation Urinary diversions Bladder augmentation Conduit/iIeal chimney Ingelman-Sundberg Denervation Trigone & floor most densely innervated Disrupts innervation Terminal plexus of hypogastric nerves Perivesical fascia Westney et al, JU

35 Ingelman-Sundberg Denervation Optimize candidate selection Transvaginal subtrigonal local infiltration Monitor clinical sx Anterior vaginal wall dissection that plane you usually try to avoid because it bleeds.. Westney et al, JU 2002 Ingelman-Sundberg Denervation Westney 2002 N=28, 44 months 15: Cured (denies urge/urge incontinence, no pads), 4: Improved (>50%), 9: No response Garcia-Penit % cured, 50% improved Kindt et al % success Ingelman-Sundberg % cure, 18% improved (n=32) Limitations Retrospective Subjective parameters Nonstandardized No QOL Westney et al, JU 2002 Garcia-Penit, Arch. Esp. Urol,1996 Kindt et al

36 The End 36