J7ournal ofNeurology, Neurosurgery, and Psychiatry 1994;57:169-173

Intravesical capsaicin for treatment of detrusorhyperreflexia

Clare J Fowler, R 0 Beck, Sue Gerrard, C D Betts, C G Fowler

AbstractAn intravesical instillation of 100 ml 1 or2 mmolIl capsaicin has been used to treatdetrusor hyperreflexia giving rise tointractable urinary incontinence in 12patients with spinal cord disease and twoother patients with detrusor overactivityof non-spinal origin. Nine patients, all ofwhom had spinal cord disease, showedsome improvement in bladder function.The benefit was only shortlived andpartial in four, but the remaining fiveachieved complete continence while per-forming intermittent self catheterisation.Urodynamic studies in these ninepatients showed an increase in mean(SD) bladder capacity from 106 (57) to302 (212) ml and a fall in the maximumdetrusor pressure from 54 (20) to 36 (10)cm ofwater. There were no short term illeffects from the instillation and theimprovement in bladder function lastedfor between three weeks to six months,when in some patients it was repeated.The improvement in bladder behaviourshown in this study can be interpreted asshowing that capsaicin sensitive afferentsplay an important part in the patho-genesis of detrusor hyperreflexia inspinal humans. Intravesical capsaicinseems a promising means of treatingintractable detrusor hyperreflexia andstudies with this substance may shed newlight on other disorders of detrusoractivity that cause incontinence.

Department of Uro-Neurology, NationalHospital forNeurology andNeurosurgery, QueenSquare, LondonWClN 3BG, UKDepartment ofUrology, RoyalLondon HospitalTrust, Whitechapel,London El 1BB, UKC J FowlerR 0 BeckS GerrardC D BettsC G FowlerCorrespondence to:Dr C J Fowler, Departmentof Uro-Neurology, NationalHospital for Neurology andNeurosurgery, QueenSquare, London WC1N3BG, UK.Received 11 March 1993and in revised form17 May 1993.Accepted 21 May 1993

Neurol Neurosurg Psychiatry 1994;57: 169-173)

Incontinence of neurological origin is mostoften due to detrusor hyperreflexia. Currenttreatment relies on partially blocking theefferent parasympathetic innervation to thedetrusor with anticholinergic drugs. Theseoften have troublesome side effects, however,and may be insufficiently effective to restorecontinence in patients with severe hyper-reflexia. Although there are other treatments,which him to block the afferent arc of thereflex that causes detrusor contractions,sacral root rhizotomy is best limited topatients with a complete suprasacral spinalcord lesion and the various attendant compli-cations of injection of phenol in the subtrigo-nal region of the bladder make thatprocedure, which has only transient benefit,unsuitable for repeated use. A non-surgicaltherapy which could selectively destroy those

afferent nerves that give rise to abnormalreflex detrusor contractions would havesignificant advantages over other means nowavailable to treat neurogenic incontinence,especially if it were easy to administer andrepeat and had a prolonged action.

Detrusor hyperreflexia can result eitherfrom loss of the normal inhibitory input fromhigher centres on to the pontine micturitioncentre or after a spinal lesion from interrup-tion of the spinobulbospinal pathways thatnormally control physiological bladder behav-iour. Animal models of chronic spinal corddisease have shown that after disruption ofthe connections between the pons and thesacral spinal cord a new segmental sacralreflex arc becomes functional.' The afferentneurones of this emergent reflex in the cat aremostly unmyelinated C fibres whereas in theneurologically intact animal afferent neuronesfrom the bladder are small myelinated A5fibres.2 Little is known of the neurologicalmechanism of bladder reflexes in spinallyinjured humans.' Disconnection of the sacralcord from the pons results in detrusor are-flexia that lasts for about six weeks beforevolume determined bladder reflex emptyingbecomes established. A speculative hypo-thesis is that this change in detrusor behav-iour results from synaptic reorganisation andpossibly new nerve growth forming theneurological basis of an emerging reflex arc.

Pharmacological experiments show that inmany species there is a large group of fibresinnervating the bladder that are capsaicinsensitive.3-6 These are mostly unmyelinatedfibres in the cat' and rat.7 They are silentunder physiological conditions but may beactivated by bacterial or chemical irritants inthe bladdere giving rise to symptoms of cysti-tis. It is probably these same fibres thatemerge active and serve as the afferent arc fordetrusor hyperreflexia in spinally injuredanimals.'

Capsaicin activates a vanilloid receptor onthe cell membrane of sensitive primary sen-sory neurones9 causing an increase in cationpermeability and leading to membrane depo-larisation. Activation of the vanilloid receptorproduces a biphasic response. The immediateeffect is stimulatory with transmission ofsensory impulses from the periphery to thecentral nervous system sensed as a painfulirritation and a peripheral release from thereceptor terminals of neuropeptides includingsubstance P and CGRP. After exposure tohigh concentrations of capsaicin, afferent Cfibres may show long lasting functional

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changes, with many unmyelinated fibreshaving morphological evidence of structuraldamage. The degree of neurotoxicity thatfollows exposure to systemic treatment withcapsaicin depends on the age of the animal:high doses given subcutaneously to newbornrats result in a 50% or greater reduction inunmyelinated fibres'0 whereas when given toadult animals there is not so much fibre loss."Applied topically to peripheral nerve, cap-

saicin has an extensive selective neurotoxiceffect on unmyelinated fibres irrespective ofthe animal's age and causes axonal loss ofunmyelinated fibres'2 13 and depletion of neu-ropeptides.'4 Little is known about the longterm neurotoxic effects of capsaicin when it isapplied directly to nerve terminals.

Capsaicin has been enjoyed as a con-stituent of the human diet for thousands ofyears and no long term side effects have beenrecognised from ingestion of large quantitiesof it. Capsaicin applied directly to the eyes,nose, mouth, and throat is intensely painful-a property of the substance now beingexploited by riot control police.'5 Low dosesof capsaicin have been injected intravenouslyinto human volunteers to study its effect onrespiratory and cardiovascular reflexes'6 and itis now being used to examine the coughreflex in patients with various types of lungdisease.'7 Skin ointments containing capsaicinare being used to treat postherpeticneuralgia'8 and painful diabetic neuropathy.Its potential application in the treatment ofother painful disorders has recently beenreviewed.'9 The use of capsaicin in the humanbladder has so far been limited to treatmentof painful bladder disorders, with concentra-tions of 0 1-1O0 jm.20

Systemic administration of capsaicin toneonatal rats results in urinary retention andloss of those bladder afferents immuno-reactive for substance P.21 When capsaicin-sensitive afferents were shown to be presentin the human bladder20 the use of intravesical

capsaicin to lessen detrusor hyperreflexia inhumans was suggested (CA Maggi, personalcommunication). The lessening of detrusorhyperreflexia in spinal cats after a subcuta-neous injection of capsaicin' made bladderinstillation with this substance the logical stepwhen faced by patients with neurogenicincontinence resistant to currently availablemedical treatments and unsuitable forsurgery.The early results of this study were the

subject of a preliminary report."

PatientsAll patients gave informed consent after a

clear explanation that capsaicin was beingobtained as a chemical, not a medicine andhad no certification for use in humans. Amedicine exemption certification wasobtained for the use of capsaicin for intravesi-cal administration from the MedicinesAdvisory Committee and the project was

approved by the Joint Ethics Committee ofthe National Hospital for Neurology andNeurosurgery and Institute of Neurology.The table gives details of patients. Twelve

patients had spinal cord disease: eight hadmultiple sclerosis with varying degrees of dis-ability, one had tropical spastic paraparesiswith moderate lower limb paraparesis butcould walk with sticks, one had had an arteri-ovenous fistula of the spinal cord and wasconfined to a wheel chair, one had had an

episode of transverse myelitis three years ear-lier, and one patient had congenital spinabifida. All patients with multiple sclerosis andthe one with tropical spastic paraparesis hadurodynamically verified hyperreflexia withphasic detrusor contractions and inconti-nence induced at a mean volume of 106 (57)ml. The remaining three patients (2, 4 and 5)had a steady rise in detrusor pressure on fill-ing with poor compliance calculated at 3 7,2-6, and 1-3 ml/cm water, respectively.

Table Clinical details of 14 patients treated with intravesical capsaicin showing the clinical extent of their incontinence and cystometnicfindings beforeand after treatment

Extent of clinical incontinence Detrusor pressure atCapacity (ml) capacity (cm H20)

Patient Age Before Afterno (y) Diagnosis Disability treatment treatment Before After Before After

1 68 Neurologically Walking Pads No improvement 20 20 65 60normal normally

2 27 Vegetative state Bed bound Bypassing and extruding No extrusion for 3 N/P N/Pcatheter weeks

3 22 Spina bifida Chair bound Pads No improvement 130 100 35 604 57 Cord AV Chair bound Indwelling catheter No improvement 220 220 85 80

malformation5 14 Transverse Walking Pads Mostly dry 80 70 60 50

myelitis abnormally6 37 Multiple sclerosis Chair bound Indwelling catheter No improvement 100 300 40 307 38 Multiple sclerosis Bed bound Bypassing and extruding Less bypassing for 8 30 30 30 30

catheter weeks8 57 Multiple sclerosis Bed bound Bypassing and extruding No bypassing for 8 140 N/P 70

catheter weeks9 67 Multiple sclerosis Bed bound Bypassing catheter No improvement 150 N/P 9510 54 Tropical spastic Walking with Pads Continent with ISC 195 400 50 32

paraparesis sticks11 40 Multiple sclerosis Walking with Pads Continent with ISC 130 250 95 45

sticks12 45 Multiple sclerosis Walking with Urosheath and bag Continent with ISC 110 560 60 30

sticks13 57 Multiple sclerosis Walking with Urosheath and bag Continent with ISC -150 260 45 20

sticks14 56 Multiple sclerosis Walking with Indwelling catheter Continent with ISC 50 550 40 28

frame

ISC = intermittent self catheterisation; N/P = not performed.

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Intravesical capsaicin for treatment ofdetrusor hyperreflexia

Intravesical capsaicin was also used in twoother patients, one of whom was in a persis-tent vegetative state with an indwellingcatheter after severe cerebral anoxia. Theother was the only patient in this series whowas neurologically normal and the cause ofher disabling incontinence due to involuntarydetrusor contractions is unknown.The table shows the clinical extent of

incontinence in all patients before capsaicininstillation and the results of urodynamicstudies.

MethodsPreliminary studies in one of the patients (14)carried out in 1990 showed that low concen-trations of capsaicin (0 1-10,um/l) had noeffect on improving bladder capacity or less-ening hyperreflexia. From May 1991onwards, 100 ml of either 1 mmol/l (0 3 g/l)or 2 mmol/l solution of capsaicin dissolved in30% alcohol in saline were used. This wasintroduced into the bladder with a ballooncatheter to minimise the risk of leakage intothe urethra. The instillation was left in thebladder for 30 minutes.

For the first five patients the instillationprocedure was carried out in the operatingtheatre with full cardiovascular monitoringand in the presence of an anaesthetist to giveanalgesia or sedation if required. All patients,except one who had lost bladder sensation,reported immediate suprapubic burning thatpersisted with severe intensity for between5-10 minutes, but no patient requested anal-gesia. When it became clear that the instilla-tion was adequately tolerated in alertsubjects, subsequent patients were treated inthe uro-neurology laboratory with an anaes-thetist available. No medical intervention wasever required either for management of painor cardiovascular support.Two bed-bound patients with multiple

sclerosis and catheter-induced urethralincompetence had a bladder neck suspensionprocedure carried out under general anaes-thetic at the same time as the instillation toprevent leakage of the capsaicin into the urethra.

Blood was taken for measurement of alco-hol concentrations over the period of theinstillation and up to four hours later.

All except one patient had standardmedium fill (50 ml/minute) subtraction cys-tometry studies before and after the instilla-tion. Whenever possible cystometry wascarried out immediately before the capsaicininstillation and intravesical pressure measure-ments were continued during the instillation.Urodynamic studies were repeated four toeight weeks after the capsaicin instillation in11 patients but not in those who were bed-bound (patients 2, 8 and 9).

ResultsIMMEDIATE EFFECTS AND SHORT TERMRESULTS (FIRST 14 DAYS)When the procedure was carried out in theoperating theatre the patients were connected

to a Po, oximeter and ECG monitor. No sig-nificant alteration in cardiovascular stateoccurred during or after the procedure.Although most patients reported immediatesuprapubic pain, lasting with intensity for5-10 minutes and then diminishing, nonereported symptoms that could have beenrelated to systemic effects of capsaicin. Therise in blood alcohol after the instillationnever exceeded 3 mmol/l, indicating thatthere was little diffusion of the alcoholthrough the bladder wall. Patients who hadhad the procedure once and were returningfor repeated treatments denied undue appre-hension of discomfort and it seemed that sub-sequent treatments were less uncomfortablethan the first. Patients were well enough to gohome immediately afterwards.When urodynamic studies were performed

during the instillation a sharp rise in detrusorpressure was immediately seen, often fol-lowed by a series of phasic contractions. Afull report of aspects of this phenomenon willbe the subject of a separate paper.

All patients reported an initial deteriorationof their symptoms with either worseningincontinence or catheter bypassing for aperiod that varied between 24 hours to 14days followed then by clinical improvementor a return to their previous state. Patientswho had the instillation carried out more thanonce seemed to have the same pattern ofresponse on each occasion.

LONG TERM RESULTS (TWO WEEKS TO SIXMONTHS)The table summarises the urodynamicchanges and clinical response after intra-vesical capsaicin. An improvement in someaspect of bladder behaviour was seen in nineof the 14 patients. In five the improvementwas highly satisfactory so that these patientswho had formerly required the long term useof a continence appliance or pads, becamecontinent between intermittent self catheter-isations. The bladder capacity in these fivepatients increased from 127 to 404 ml (fig 1).Hyperreflexic contractions were reduced witha fall in detrusor pressure from 58 to 31 mmH,O and lessening of the degree of urgency.In another four patients the improvement wasless impressive both in terms of degree andduration. Two of these patients had proce-dures for bladder neck suspension carried outat the time of capsaicin instillation becausethey had such severe dilatation of the urethraafter catheter extrusions that leakage of cap-saicin into the urethra during the instillationprocedure would otherwise have beeninevitable. It is possible that the surgical pro-cedure alone improved continence althoughone patient continued to be incontinent fortwo weeks after the procedure and only thenstopped leaking around the catheter for thenext eight weeks before the problemreturned. An improvement in clinical conti-nence was achieved in one other patient (5)in whom medium fill (50 ml/min) cystometryshowed no change although filling at a slowrate (10 ml/min) after the treatment showed a

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Figure 1 Changes inbladder capacity in the 11patients in whom datawere available, before andafter capsaicin instiUlation.

600 r

500 H

400 H

E

a-C._

m 300

C)

m0CU

200 [

100 [-

Before After

greatly improved capacity.The remaining four patients showed

neither clinical nor urodynamic evidence ofimprovement after capsaicin instillation. Thisgroup included the patient who was neuro-logically normal and one with severe multiplesclerosis who was incontinent with severeflexor leg spasms. Also in the non-respondinggroup were two patients (3 and 4) whose uro-dynamic studies had shown poor compliancerather than phasic detrusor hyperreflexia.

DURATION OF ACTION AND REPEATEDINSTILLATIONSFigure 2 shows the timing of the intravesicalinstillations in each patient. Three patientshave had the instillation repeated at intervalsof between four and nine months when theyhave felt a return of their urinary urgency andreduction in their postmicturition residuals asassessed by intermittent self catheterisation.Urodynamic studies carried out at this stageshow that there had been a reduction in blad-

Figure 2 Time in monthssince capsaicin instiMlation.Patient numbers as used inthe table are given on theordinate. Each squareindicates an episode ofintravesical capsaicin. Aline indicates the durationof improved bladderfunction.

1l4 * . _13*12 *11109-8-_7 - .

*'6 -4 -!5 -* -*4_3 .2 -41_0 2 4 6 8 10 12 14 16 18 20

Months since capsaicin instillation

der capacity and return of hyperreflexia, butnever so severe as before the first capsaicininstillation. The instillation has not beenrepeated in those who showed neither clinicalnor urodynamic change.

DiscussionThis is the first human study to show thatcapsaicin-sensitive afferents are important inthe pathophysiological mechanisms whichcause the detrusor hyperreflexia that follows aspinal lesion. Although clinical continencewas achieved in only five out of the 14patients treated with intravesical capsaicin,there was evidence of either short-lived clini-cal improvement in four others and urody-namic evidence of an increased capacity inone further patient. Those who did notrespond included two patients with low blad-der compliance rather than phasic detrusorcontractions, a patient with severe flexor legspasms, and the patient who was neurologi-cally normal. The pathogenesis of low blad-der compliance is unknown but these findingssuggest that it is different from that whichcauses phasic detrusor hyperreflexia. It is notsurprising that the neurologically normalpatient did not respond and the failure ofresponse of the patient with extreme disabilityand multiple sclerosis may lie in the severityof the abnormality in that case.A complete block of the emergent reflex

that drives volume-determined detrusor con-tractions would result in an areflexic bladder,as occurs in neonatal rats treated with cap-saicin.21 The bladder would then require tobe emptied by intermittent self catheterisa-tion; a technique already practised by manypatients with spinal cord disease. This statewas not reached in any of the patients in theseries described here although conditionsapproaching it were achieved in the fivepatients with the best responses. The severityof urinary incontinence of a spinally compro-mised patient depends on a combination offactors that include a reduction in bladdercapacity and the magnitude of hyperreflexicdetrusor contractions. In patient 6 there wasan increase in bladder capacity but persistingclinical continence was not achieved as shewas still incontinent with low pressure rises.The duration of benefit after intravesical

capsaicin is variable and ranged from monthsto weeks (fig 2). There is a clear suggestionthat the effectiveness of intravesical capsaicinin improving continence is related to thepatient's overall neurological state, best illus-trated by the fact that clinical continence wasachieved only in those whose neurologicaldisability was less severe and who were stillable to walk (patients 1-5, table). The benefitin those with the most severe neurologicaldeficit was short lived and difficulties withmobility and transport in such patients maderepeated treatments, with the expectation ofonly temporary relief of symptoms, impracti-cal in a pilot study. This aspect of the relationbetween responsiveness and neurologicaldeficit deserves further study because if it

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were possible to measure the neural depletionresponsible for symptomatic improvement,and in the severely disabled this was only par-tial, a treatment regimen with either higherconcentrations or more frequent instillationswould be rational.

Topical capsaicin applied to the skinresults in a reduction of the flare response

and raising of heat pain thresholds lastingseveral weeks.23 The prolonged effect seen insome of these patients implies that there hasbeen a degree of axonal loss. The rich plexusof suburothelial nerves in the bladder ofhumans are thought to be sensory24 and sub-stance P and other neuropeptides known tooccur in association with sensory nerves havebeen identified in the human bladder.25 It isproposed that in the circumstances of theinstillation procedure described here, highconcentrations of capsaicin reached the nerve

terminals themselves. Future studies willinclude an immunocytochemical examinationof the suburothelial sensory nerves before andafter topical application of capsaicin to assess

the extent of substance P depletion and to

test whether clinical response can be corre-

lated to measurable neuronal loss.Little is known about the effect of alcohol

in the human bladder. Two patients havebeen reported in whom undiluted Bonney'sblue (a 1:1 mixture of brilliant green andcrystal violet dissolved in 90% ethanol) was

mistakenly instilled intravesically, resulting inchemical cystitis and in the long term, a

reduced bladder capacity.26 The possibilitythat the changes in bladder behaviourreported here might be due to the 30% alco-hol in saline solution has not been eliminated.A study is in progress to examine this withpatients who have been shown to respond to

capsaicin, waiting until the benefit of the lastcapsaicin instillation has worn off and theninstilling the solution of alcohol in salinealone. A blinded study will not be possiblebecause the pungent effects of capsaicin are

so obvious to both the administrator andrecipient.The promising results of intravesical cap-

saicin treatment reported here were predictedfrom the extensive animal studies that haveshown the presence of capsaicin-sensitiveafferents in the bladder of many species4 5 andthe work of de Groat and colleagues' whohave shown the change in nature of the affer-ent limb of the reflex arc for detrusor hyper-reflexia in chronic spinal animals. Its use inother conditions where unwanted detrusorcontractions cause incontinence, such as

detrusor instability in the elderly, might shedlight on the neurobiology of such disorders.This study suggests a new method oftreatment for patients with intractable neuro-

genic incontinence and -confirms that cap-

saicin sensory afferents exist in the humanbladder and are functionally significant indetrusor hyperreflexia secondary to spinaldisease.

We thank consultants of the National Hospital for Neurologyand Neurosurgery, Queen Square for referring patients andthe Joint Ethics Committee of the Hospital and Institute ofNeurology for their advice. The assistance given by theDepartment of Anaesthesia and the Pharmacy of the NationalHospital is gratefully acknowledged. Discussions with DrChet de Groat, Dr Bruce Lynn, and Dr Carlo Maggi havebeen invaluable. Equipment used for urodynamic studies waspurchased by a grant from the Multiple Sclerosis Society ofGreat Britain and Northern Ireland.

1 de Groat WC, Kawatani T, Hisamitsu T, et al.Mechanisms underlying the recovery of urinary bladderfunction following spinal cord injury. J Auton Nerv Syst1990;30:S71-8.

2 de Groat WC. Central neural control of the lower urinarytract. In: Bock G, Whelan J, eds. Neurobiology of inconti-nence (Ciba Foundation Symposium 151). Chester:Wiley 1990:27-56.

3 Szolcsanyi J. Capsaicin-sensitive chemoceptive neural sys-tem with dual sensory-efferent function. In: Chahl LA,Szolcsanyi J, Lembeck F, eds. Antidromic vasodilationand neurogenic inflammation. Budapest: AkademiaiKiado 1984:26-52.

4 Jancso G, Maggi CA. Distribution of capsaicin-sensitiveurinary bladder afferents in the rat spinal cord. BrainRes 1987;418:371-6.

5 Maggi CA, Santicioli P, Borsini F, et al. The role of cap-saicin-sensitive innervation of the rat urinary bladder inthe activation of the micturition reflex. NaunynSchmiedebergs Arch Pharmacol 1986;322:276-83.

6 Maggi CA. The role of peptides in the regulation of themicturition reflex: an update. Gen Pharmnacol 1991;22:1-24.

7 Maggi CA, Lippe ITH, Giuliani S, et al. Topical versussystemic capsaicin desensitization: specific and un-specific effects as indicated by modification of reflexmicturition in rats. Neuroscience 1989;31:745-56.

8 McMahon SB, Koltzenburg M. Novel classes of nocicep-tors: beyond Sherrington. Trends Neurosci 1990;13:199-201.

9 Szallasi A., Blumberg PM. Resiniferatoxin and its analogsprovide novel insight into the pharmacology of thevanilloid (capsaicin) receptor. Life Sci 199 1;47:1399-408.

10 Scadding JW. The permanent anatomical effects ofneonatal capsaicin on somatosensory nerves. J Anat1980;131:473-84.

11 Jancso G, Kiraly E, Joo F, Such G, Nagy A. Selectivedegeneration by capsaicin of a subpopulation of primarysensory neurons in the adult rat. Neurosci Lett 1985;59:209-14.

12 Lynn B. The immediate and long-term effects of applyingcapsaicin to cutaneous nerves. Acta Physiol Hung 1986;69:287-94.

13 Pini A, Baranowski R, Lynn B. Long-term reduction inthe number of C-fibre nociceptors following capsaicintreatment of a cutaneous nerve in adult rats. Eur jNeurosci 1990;2:89-97.

14 Jessel TM, Iversen LL, Cuello AC. Capsaicin-induceddepletion of substance P from primary neurones. BrainRes 1978;152:183-8.

15 Park P. Police cool it with cayenne pepper. New Sci 1992;1813:23.

16 Winning AJ, Hamilton RD, Shea SA, Guz A. Respiratoryand cardiovascular effects of central and peripheralintravenous injections of capsaicin in man: evidence forpulmonary chemosensitivity. Clin Sci 1986;71:519-26.

17 Fuller RW. The human pharmacology of capsaicin. ArchIntPharmacodyn Ther 1990;303:147-56.

18 Bemstein JE, Bickers DR, Dahl MV, Roshal JY.Treatment of chronic postherpetic neuralgia with topi-cal capsaicin. JAm Acad Dermatol 1987;17:93-6.

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20 Maggi CA, Barbanti G, Santicioli P, et al. Cysometric evi-dence that capsaicin-sensitive nerves modulate the affer-ent branch of micturition reflex in humans. JT Urol1989b;142: 150-4.

21 Sharkey KA, Williams RG, Schultzberg M, Dockray GJ.Sensory substance P-innervation of the urinary bladder:possible site of action of capsaicin in causing urineretention in rats. Neuroscience 1983;10:861-8.

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24 Dixon JS, Gilpin CJ. Presumptive sensory axons of thehuman urinary bladder. A fine ultrastructural study.

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unnary tract. Neurourol Urodynamics, 1990;9:346-7.26 Christmas TJ, Chapple CR, Payne SDW, et al. Bonney's

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