The Use of Botox Injection in the Treatment of the Neurogenic Bladder Dr C K Chan Division of Urology Department of Surgery Prince of Wales Hospital EAU guidelines 2003 / 2006 Neurologic disease Dementia ( 30-100% ) Parkinson s disease ( 38 70% ) Stroke ( 20 50% ) Cerebral tumour ( 24 % ) Cerebral palsy ( 36% ) Shy-Drager syndrome ( 100% ) Multiple sclerosis ( 50 90% ) Traumatic injury ( majority ) Haematoma syringomyelia Compression (e.g. tumour, Cervical spondylosis) ( 28 87% ) Disc prolapse ( 6 18% ) ( 28 87% ) Myelitis Spina bifida ( 90 97 % ) Sacral agenesis Cauda equina disease Pelvic disease Pelvic surgery ( 10 60% ) Childbirth injury Diabetes mellitus ( 35 50%, type 2 : 87% ) Alcohol Abuse ( 5 60% ) 2000 1000 B.C. Balkan War (1912 1913) 95% Mortality of spinal cord injury due to renal problems in the past 90 years ( Donnelly J et al 1972; Borges PM et al 1982) World War I ( 1914 1918 ) 80% World War II (1939-1945 ) 40% Foley, June 1935.one having a dislocation in a vertebra of his neck, while he is unconscious of his two legs and two arms and his urine dribbles. An ailment not to be treated. Korean War ( 1950 1953 ) 25% Vietnam War (1964-1975) 5-10% Life expectancy for persons who survive the 1 st year post spinal cord injury ( years) ( National spinal cord injury database USA) 1995 Bladder ( Sphincter ) Dysfunction Age at injury NO spinal Functional at any level l Paraplegia Tetraplegia ( C 5-8 ) Tetraplegia ( C 1-4 ) Ventilator Dependent cord at any level injury 20 57.2 52.5 46.2 41.2 37.1 26.8 40 38.4 34.3 28.7 24.5 21.2 13.7 60 21.2 18.1 13.7 10.6 8.4 4.0 ƒ( t, l, c ) t = time from diease / injury, l = level of disease / injury, c = completeness of disease / injury 1
Neurologic disease Dementia Parkinson s disease Stroke Cerebral tumour Cerebral palsy Shy-Drager syndrome ( Multiple System Atrophy ) Bladder dysfunction Inappropriate toilet behaviour Detrusor hyper-reflexia + co-ordinated external urethral sphincter and bladder neck activity Incontinence Multiple sclerosis Hyper-reflexic with UNcoordinated Traumatic injury external urethral sphincter and Compression Uncoordinated bladder neck (e.g. tumour, ( Autonomic dys-reflexia if lesion Cervical spondylosis) above T6 ) Myelitis Sensory impairment Spina bifida Incontinence / incomplete bladder emptying Level of Spinal Cord Dysfunction in Relation to Vesico-Urethral Dsfnction Dysfunction Sacral agenesis Cauda equina disease Pelvic disease Childbirth injury Diabetes mellitus Areflexic / underactive bladder with denervated / underactive sphincter BUT coordinated bladder neck Sensory impairment Incontinence / incomplete bladder emptying Spinal Cord Injury Incidence of spine injury by highest level ( Northwestern University Acute Spine Injury Centre 1972-1990) Meyer 1994 Complete tetraplegia 25% Incomplete tetraplegia 25% Complete paraplegia 25% Incomplete paraplegia 25% Urinary problem in spinal cord dysfunction Urodynamic findings by level(s) of spinal cord injury. Spinal level No. of pts D H + DESD + D H + DESD - D A Normal cervical N=104 55% 30% 15% 0% Blavivas 1996 N=114 Weld 2000 68% 42% 0% 0% Thoracic N=87 Blavivas 1996 90% 10% 0% 0% Lumbar sacral mixed N=54 Weld 2000 50% 50% 0% 0% N=61 Blavivas 1996 30% 30% 40% 0% N=28 Weld 2000 39% 32% 21% 4% N=32 Blavivas 1996 12% 12% 64% 12% N=14 Weld 2000 14% 14% 86% 0% N=33 Weld 2000 45% 33% 27% 3% DH= detrusor hyper-reflexia ; DESD=detrusor external sphincter dys-synergia DA=detrusor areflexia Normal Voiding Detrusor external sphincter dys-synergia Level of lesion Initial Management of Neuropathic Bladder Peripheral n lesion Pelvic operation Lumbar disc prolapse Suprasacral infrapontine Lesion Trauma / multiple sclerosis Suprapontine Lesion Parkinson s disease CVA Clinical Assessment General Assessment Voiding diary / questionnaire ; QoL ; Physical Examiation Urinalysis / urine culture -> treat UTI if present Urinary tract imaging, renal function PVR by u/s Presumed diagnosis Treatment Sphincter deficiency Poor voiding Intermittent catheterization Neurogenic detrusor overactivity Cooperative pt Mobile pt Behavioural Modification Anti-muscarinics Uncooperative pt Immobile pt External appliance Indwelling catheter SP catheter Specialized Management 2
Level of lesion Clinical Assessment Diagnosis Treatment Specialized Management of Neuropathic Bladder Peripheral n lesion Pelvic operation Lumbar disc prolapse Urodynamics ( VCMG / EMG ) Urinary tract imaging Sphincter deficiency Timed voiding Ext. appliance Bulking agents AUS Sling Poor voiding IC Alpha blocker Intravesical electrostimulation SDAF : sacral deafferenation SARS : sacral anterior root stimulation IC : intermittent catheterization DESD : detrusor external sphincter dys-synergia Suprasacral infrapontine Lesion Trauma / multiple sclerosis Neurogenic detrusor overactivity No DESD DESD + Triggered voiding Anti-muscarinics IC Neurostimulation Anti-muscarinics IC SDAF + IC SDAF + SARS Sphincterotomy Bladder Augmentation + IC Urinary diversion Suprapontine Lesion Parkinson s disease CVA Suprapontine NDO Behavioural Modification Anti-muscarinics Neurostimulation Bladder augmentation Ext appliances IC Anti-muscarincs Adverse Effects of Oral Anti-muscarinics dry mouth, tachycardia, blurred vision, gastrointestinal effects (narrow angled ) glaucoma + CNS effect e.g. poor concentration, confusion The most common adverse effect is dry mouth But blurred vision and CNS effects will render patients to discontinue medication Intravesical Oxybutynin Intravesical Therapies for Neuropathic Bladder Apart From Oral Pharmacotherapay Buyse et al 1985 Brendler et al 1989 Greenfield et al 1991 Madersbacher et al 1995 Haferkamp et al 2000 0.2 0.4 mg / kg per day 5 mg oxybutynin / 15 ml Normal Saline Keep in bladder till next catheterization 61-87% continence rate Buyse et al Eur J Ped Surg 1985 ; 5 ( Suppl. 1 ) 31-34 Brendler et al J Urol; 141: 1350 1351 Greenfield et al J Urol 1991 ; 146 : 532-534 Madersbacher et al Eur Urol 1995 ; 28 : 340 344 Kaplinsky et al J Urol 1996 ; 156 : 753 756 Haferkamp et al Spinal Cord ( 2000 ) 38, 250-254 Intravesical Oxybutynin Intravesical Oxybutynin Haferkamp et al Spinal Cord ( 2000 ) 38, 250-254 Guerra: J. urol., Volume 180(3).September 2008.1091 1097 3
Capsaicin ( 1989 ) / 16 x 10 6 Units Scoville Heat Scale 30000-50000U Capsaicin 1mM; 100ml ; 30min; LA / GA ( ICS committee 2002 ) Pretreatment Post-treatment capacity capacity 144ml 267ml (72-195) (185-321) Subjective clinical improvement 72% ( 40 100%) Vanilloid receptor 1 Non-selective ion channel Intravesical instillation Initial stimulation-> pain +++ then desensitizes C-fibre Long-lasting suppression Micturition reflex in neurologic disease: Predominant afferent input from bladder is through C-fibre Capsaicin Petersen et al : NO benefit Petersen et al Scand J Urol Nephrol. 1999; 33: 104 10 Lazzeri M et al Spinal Cord 1999; 37 : 440 3 Lazzeri M et al Urol Int 2004; 72: 145 9 de Seze et al J Urol 2004 ; 171 : 251-5 Lazzeri et al: NO benefit Autonomic dys-reflexia 12.96% Urgency incontinence 35.18% Pain 96% de Seze et al: When diluted in glucidic acid, few adverse events Capsaicin / Resiniferatoxin 1mM; 100ml ; 30min; LA / GA 1000x more potent sensory antagonist VR-1 NO prior excitatory effect-> NO PAIN Direct desensitization 100ml 50-100nM in 10% alcohol solution Instillation for 30 min Pretreatment post-treatment capacity capacity 175(±36) ml 281(±93) ml (Lazzeri et al 1998) Incontinence decreased by 1 2 episodes (Rivas et al 1999) Capsaicin / Resiniferatoxin -Reduction of nerve density of suburothelial innervations -Reduction in the expression of TRPV1 and P2X receptors Brady C.M. et al Eur Urol 2004 ; 46 : 247 53 Brady C.M. et al BJU Int 2004; 93 : 770-6 efficacy of improvement 92% Silva et al 2000 Eur Urol 38: 444-52 Degree of neurological deficit 4
Time line of the discovery of Clostridium Botulinum toxin and its medicinal use 1817: German physician and poet Justinus Kerner described botulinium toxin, using the terms "sausage poison" and "fatty poison", as this bacterium often causes poisoning by growing in badly handled or prepared meat products. 1870: Müller (another German physician) coined the name botulism from Latin botulus = "sausage". 1895: Prof. Pierre Emile van Ermengem of Ellezelles first isolated the bacterium Clostridium botulinum. ( Gram +ve, rod-shaped anaerobic Clostridium botulinum ) 1923 Dickson et al ; Effect of botulinum toxin upon the autonomic nervous system 1944: cultured Clostridium botulinum and isolated the toxin 1949: Burgen's group discovered that botulinum toxin blocks neuromuscular transmission 1973: Alan B Scott used botulinium toxin type A (BTX-A) in monkey experiment 1980: Alan B Scott used BTX-A for the first time in humans to treat strabismus Time line of the discovery of Clostridium Botulinum toxin and its medicinal use in Urology 1967 Carpenter ; motor responses of bladder following botulinum toxin intoxication in cats 1999: Stohrer et al ; detrusor hyper-reflexia 2000: Schurch et al ; detrusor hyper-reflexia in spinal cord injured patients 2002: Reitz et al ; 184 patients with detrusor hyper-reflexia treated with botulinum toxin injection 1989: BTX-A (BOTOX) was approved by the US FDA for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old 2002: FDA announced the approval of botulinum toxin type A (BOTOX Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines). Immunological subtypes of Botulinum Toxin International Standards for Clostridium botulinum Antitoxin A B Clostridium botulinum Clostridium botulinum C1 Clostridium botulinum D Clostridium botulinum E Clostridium butyricum F Clostridium baratii G Clostridium argentinense Immunological subtypes of Botulinum Toxin A, B, C1, D, E, F, and G Botulinum type A toxin ( BTX-A): Botox USA Dysport United Kingdom Botulinum type B toxin ( BTX-B): Myobloc USA NeuroBloc Europe 1 gm aerosolized botulinum toxin can kill 1.5 million population 1 ng = 20 units 1 unit = 0.05 ng Lethal dose for 70 kg human : 0.09 0.15 ug ( IV / IM ) 0.70 0.90 ug ( inhalation ) 70 ug ( po ) 5
Botulinum Toxin ( Botox ; Dysport; Myobloc ) BTX Protein Commercial Molecular Preparation Formulation Subtypes Target preparation Weight Units (kda) BTX-A SNAP-25 BOTOX 900 100 Vacuum dried Dysport 900 500 Lyophilized BTX-B VAMP/ Myobloc 700 2500 Solution Synaptobrevin 5000 10000 Blockade of the motor and autonomic cholinergic junctions BTX-C Syntaxin N.A. BTX-D VAMP/ N.A. Synaptobrevin Cellubrevin BTX-E SNAP-25 N.A. BTX-F VAMP/ N.A. Synaptobrevin Cellubrevin BTX-G VAMP N.A. Illustration depicting nerve pathways targeted by botulinum toxin to treat lower urinary tract dysfunction Inhibition of acetylcholine exocytosis by BTX-A Smith CP and Chancellor MB (2004) J Urol 171: 2128 2137. The circle with shading represents the prostate gland and the rectangle with shading represents the external urethral sphincter. Positive (+) signs represent sites of nerve activity and the negative (-) sign with associated arrows depicts locations where botulinum toxin may have inhibitory effects. Botulinum toxin in urology: evaluation using an evidence-based medicine approach Christopher P Smith, George T Somogyi and Timothy B Boone Nature Clinical Practice Urology (2004) 1, 31-37 Afferent Denervation Afferent Denervation A schematic diagram of ultrastructural components of the human bladder wall Apostolidis A et al Eur Urol 2006 ; 49: 644-650 BTX-A may inhibit neurotransmitter release and reduce sensory nerve excitability decrease urgency, frequency and pain 6
Botulinum Toxin Detrusor Injection for Detrusor Hyperreflexia Botulinum toxin ( Botox ; Dysport ) flexible cystoscope superfine 27-gauge disposable needle BOTOX (Allergan, Irvine, CA) Bladder wall, avoiding the trigone. 30 different injections, Each containing 10 units of BOTOX (1 ml), equally spaced points 200 units vs 300 units Botulinum toxin ( Botox ; Dysport ) Botulinum toxin ( Botox ; Dysport ) 0.5 1.0 ml per injection Larger dilution volume -> greater suburothelial diffusion-> BTX act on larger surface of detrusor?? Extravasation?? Avoid Trigone? Avoid Dome ( intraperitoneal puncture -> bowel injury) Outpatient vs Inpatient LA vs Anaesthesia Cleveland Clinic Protocol ( Rackley et al 2005 ) Antibiotics 100 ml 2% lignocaine -> bladder x 15 20 min 10 units in 1 ml saline Avoid shaking ( to minimize disulphide bond disruption) Priming of needle sheath ( ~ 0.5 ml ) Injection in even distribution Submucosal injection vs direct detrusor injection Continence rate according to the diluent volume Botulinum toxin ( Botox ; Dysport ) Botulinum toxin ( Botox ; Dysport ) Schulte-Baukloh et al BJU Int 2005; 454 Flexible injection needle ( 27G ) in use for giving intradetrusor botulinum toxin 10 units / ml / site x 20 30 sites sparing trigone Schurch et al 2001 Max. bladder capacity 296 -> 480 ml (p p<0.016) Max. detrusor voiding pressure 65 -> 35 cmh2o ( p<0.016) At 6 wks: 89.5% continent At 36wks: 64.7% continent? effect 7
Botulinum toxin ( Botox ; Dysport ) Botulinum toxin ( Botox ; Dysport ) flexible cystoscope superfine 27-gauge disposable needle BOTOX (Allergan, Irvine, CA) Bladder wall, avoiding the trigone. 30 different injections, Each containing 10 units of BOTOX (1 ml), equally spaced points Bagi et al 2004 Before BTX-A Injection After BTX-A Injection Incontinence ( n ) 15 ( 100% ) 2 ( 13% )** Leaked volume ( ml/d ) 700 ( 200 1800 ) 0 ( 0 250 )*** PdetMax ( cmh2o ) 86 ( 65 192 ) 35 ( 5 73 )*** Volume-Pdet < 40cmH2O ( ml ) Max bladder capacity ( ml ) 185 ( 65 487 ) 434 ( 188 722 ) 350 ( 79 719 ) 457 ( 345 722 )** ** p< 0.01, McNemar ; *** p< 0.005, Wilcoxon Optimal dose? Best method of injection? Suburethral / intramural injection? Durability? Outcome measure? Cost Benefit? Suburothelial injection 100U 150U 200U Difficult voiding ----- 50% 70% AROU ----- 10% 20% Kuo et al AUA 2006 May 20-25 Abstract 347 ; Urology 2005 ; 66: 94-8 effect? 3 months Post injection of Dysport to Detrusor # T11; NDO ; incontinence # T11 The Urodynamic Parameters at Baseline and after Botulinum Toxin Injection Baseline Post-Botox Statistics * Capacity (n=5) 331.4±148.8 333.2±155. 0.922 Qmax (n=5) 6.7± 6.7 9.4± 5.7 0.303 Voiding pressure (n=5) 62.0± 43.1 45.9±37.8 0.051 MUCP (n=5) 97.1±31.7 51.1±23.2 0.027 PVR (n=5) 225.4±174.4 110.1±137 0.07 MUCP=maximal urethral closure pressure, FPL=functional profile length, PVR= postvoid residual volume *Comparison between baseline and 4 weeks after treatment Schurch et al J Urol 2000; 164 ( 3Pt 1 ) : 692-7 8
% patients who are completely continent following injection of BTX to bladder Urodynamic changes following injection of BTX to bladder 600 80 70 500 %complete conti nence 60 50 40 30 20 10 volume in cc 400 300 200 100 mean reflex vol. mean cystometric capacity 0 pre-injection 6wk postbtx 26wk postbtx 39wk postbtx 0 pre-injection 6wk postbtx 26wk postbtx Tow et al Ann Acad Med Singapore 2007 ; 36; 11-7 Tow et al Ann Acad Med Singapore 2007 ; 36; 11-7 Urodynamic changes following injection of BTX to bladder maximal detrusor pre essure cmh2o 70 60 50 40 max pdet cmh2o 30 20 10 0 pre-injection 6wk postbtx 26wk postbtx Authors No. pts Dose ( U ) Outcome Duration ( months ) Bagi et al 2004 15 300 trigone sparing 87% dry; 13% minor 7 ( 4 12 ) leak; pdetmax; cystometric capacity Schurch et al 2000 21 2-300 trigone sparing 89% dry at 6 wk; 9 cystometric capacity; mean reflex vol; pdetqmax Schurch et al 2005 59 2-300 trigone sparing Improved continence; 6 cystometric capacity; mean reflex vol; pdetmax Reitz et al 2004 200 300 trigone sparing Improved continence; 9 cystometric capacity; mean reflex vol. ; pdetqmax Schulte-Baukloh et al 20 300 trigone sparing Improved continence; 6 2003 cystometric capacity; mean reflex volume; pdetmax Hajebrahimi et al 2005 10 3-400 trigone sparing Improved continence; 3+ mean reflex volume; cystometric capacity; pdetmax Tow et al Ann Acad Med Singapore 2007 ; 36; 11-7 Detrusor External Sphincter Dys-synergia 9
Botox Detrusor External Sphincter Dys-synergia Botulinum toxin ( Botox ; Dysport ) Detrusor External Sphincter Dys-synergia First Report : Dysktra et al J Urol 1988 ; 139 : 919 22 Antibiotics 10 units in 1 ml saline Avoid shaking ( to minimize disulphide bond disruption) Standard cystoscope Collagen injection needle Priming of needle sheath ( ~ 0.5 ml ) Localization of external urethral sphincter : contraction of sphincter by patient / Valsalva manoeuvre 3, 6, 9, 12 o clock vs 2, 10 o clock Injection of 3,6, 9, and 12 o clock Position of Urethral Sphincter NDO + DESD NDO + DESD 10
Pre-treatment Reduced voiding pressure after botulinum A toxin injection C5#, ASIA Class A, DH + DESD Poor bladder emptying, RU 426 ml Reduced MUCP after Botulinum A toxin injection Therapeutic Results after Botox Urethral Injection for Voiding Dysfunction Good Improved Failed Detrusor underactivity (n=27) DESD (n=18) Dysfunctional voiding (n=18) 13 (48.2%) 8 (29.6%) 6 (22.2%) 3 10 5 (16.7%) (55.6%) (27.8%) 6 (33.3%) 10 (55.6%) 2 (11%) Poor relaxation of urethral sphincter (n=12) 3 (25%) 7 (58.3%) 2 (16.6%) TOTAL (n=75) 25 (33.3%) 35 (43.7%) 15 (20%) DESD=Detrusor external sphincter dyssynergia Kuo et al 2002 9 months post injection of Dysport to external urethral sphincter 9 months post-injection of Botox: resting UPP study CMG : 9 months post-injection of Botox/ Dysport ( Dysport: 500 IU in 8 ml NS -> 62.5 ml in 1 ml NS ; 3ml injected ) 11
9 months following injection of Dysport to external urethral sphincter Botox Detrusor External Sphincter Dys-synergia CMG 2: 9 months post-injection of Dysport ( voiding phase ) ( Dysport: 500 IU in 8 ml NS -> 62.5 ml in 1 ml NS ; 3ml injected ) Leippold et al Eur Urol 2003; 44: 165-174 Detrusor External Sphincter Dys-synergia Authors No. pts Dose ( U ) Outcome Duration ( months ) Dykstra et al 1988 11 20 240 autonomic dysreflexia; 2 PVR; UPP Dykstra et al 1990 5 140 240 autonomic dysreflexia; 3 PVR; UPP Pre-injection 3 months following treatment ( injection to external urethral sphincter ) Schurch et al 1996 24 100 / 250 UPP; NO autonomic dysreflexia Gallien et al 1998 5 100 autonomic dysreflexia; 40% able to do CISC Rackley et al 2005 16 100 Improved UDI Score; improved bladder perception scores; PVR 2-3 / 9-12 3 ( 3-5) 3 6 Smith et al 2005 68 100 200 need dto do CISC; 6 pdetmax; PVR Kuo et al 2003 20 50 voiding pressure; PVR; UPP; improved QoL Kuo et al 2003 103 50 100 87% discontinued CISC; voiding pressure; PVR; UPP Phelan et al 2001 21 80 100 PVR; voiding pressure; 85% discontinued CISC Petit et al 1998 17 150 CISC frequency; PVR unchanged; voiding pressure; 3 4 ( 2 6 ) NA 2-5 CMG: 3 months post-injection of Dysport ( Dysport: 500 IU in 8 ml NS -> 62.5 ml in 1 ml NS ; 3ml injected ) UDI : Urinary Distress Inventory Botulinum toxin vs DESD Botulinum toxin vs DESD 12
Botox Side Effects Flu-like Symptoms Urinary Tract Infection Generalized Muscle Weakness ( 8 pts ) De Laet K et al Spinal Cord 43: 397-399 Neurostimulation Brindley Sacral posterior root rhizotomy ( sacral deafferentation ) Sacral anterior root stimulation ( SARS ) Supra-sacral lesion with intact efferent neurons and a bladder that is able to contract Abolish reflex voiding Neuromodulation Bemelmans et al 1999 it is not really known how it works, however, there is strong evidence that neuromodulation works at a spinal and at a supraspinal level Leakage due to detrusor hyperreflexia 83% improved ( but still leakage ++ ) Voiding failure 80% improved ( but still need intermittent catheterization) Pain? intradurally $ Extradurally Urodynamics- Videourodynamics CYK M/24 # T6, complete paraplegia, recurrent UTI incontinence Team Work 13
Thank You 14