Focal changes in nerve, muscle and connective tissue in normal and unstable human bladder

BJU International (1999), 84, 953–960

Focal changes in nerve, muscle and connective tissue innormal and unstable human bladderR.G. CHARLTON, A.R. MORLEY, P. CHAMBERS* and J. I . GILLESPIE**School of Surgical and Reproductive Sciences, Newcastle University, and Department of Histopathology, The Freeman Hospital,Newcastle upon Tyne, UK

Objective To compare and quantify, in a morphological (91), 81 (20) and 74 (38) nerves/mm2 in the threedefined areas, respectively. In the neuropathic tissuesstudy, the changes that occur in the connective tissue

elements (elastin and collagen), muscle fibre diameters the nerve profile densities were 672 (249), 57 (23)and 37 (28) nerves/mm2 , respectively. Fibre diameter,and nerve densities between normal, idiopathic and

neuropathic bladders. elastin and collagen content and nerve density weremeasured in normal and unstable bladder tissue usingMaterials and methods Bladder tissue was obtained

from 27 patients undergoing cystectomy for carci- these three defined areas. The mean (sem) fibre diam-eter was 6.81 (0.52) in normal bladder; in idiopathicnoma, from 12 with idiopathic instability and from

seven neuropathic patients who were undergoing ileo- bladder tissue the fibre diameters in the three areaswere 6.72 (0.62), 7.06 (0.62) and 7.34 (1.15) mm,cystoplasty. A combination of histochemical and

immunohistochemical techniques were used to detect respectively, and in neuropathic bladders were 6.75(0.62), 8.24 (0.62) and 9.35 (0.62) mm, respectively.detrusor muscle, connective tissue and nerve profiles

in the bladder tissue. The relative areas of elastin were 0.79 (0.70), 0.56(0.45) and 18.3 (4.1)% for the control, normal andResults In both idiopathic and neuropathic bladder tissue

the structural changes were highly punctate. From aCected areas of the neuropathic bladders, respectively,and the relative areas of collagen were 3.5 (1.3), 6.15the density of nerve profiles, three areas were defined:

(i) apparently unaCected normal fascicles with a high (3.6) and 15.7 (5.0)%, respectively. The pattern wassimilar in idiopathic bladders.density of nerves, no hypertrophy of the muscle and

no infiltration of elastin and collagen. The nerve Conclusion These observations suggest that the primarydefect in the idiopathic and neuropathic bladders isdensity in these areas was similar to that in normal

bladder tissue. (ii) Fascicles with a low density of nerve a loss of nerves accompanied by a hypertrophy ofthe cells. These changes may continue with furtherprofiles, muscle hypertrophy but no connective tissue

infiltration. (iii) Areas with few nerve profiles, muscle hypertrophy of the cells and an increased productionof elastin and collagen within the muscle fascicles.hypertrophy and extensive elastin and collagen infil-

tration within the fascicles. The mean (sem) density Keywords Human bladder, muscle size, nerve density,connective tissueof nerve profiles in control tissue was 752 (53)

nerves/mm2 and in the idiopathic bladders was 905

subject is attempting to inhibit micturition. Patients withIntroduction

DI may be divided into three groups; those with BOO,those with neuropathic lesions or those with neitherUrinary urgency and incontinence are major health

problems. The condition is common in 5–10% of young (idiopathic instability). Little is known about the aeti-ology of the condition or the mechanisms underlyingfemales but in both sexes the numbers who develop the

disorder increase markedly after the age of 65 years [1]. any form of instability.To understand the nature of instability it is essentialThis condition is therefore a major factor aCecting the

quality of life for a significant number of individuals. to identify any structural changes that occur in thebladder; such information can then be interpreted toIncontinence is associated with detrusor instability (DI),

a urodynamic phenomenon in which the bladder con- give some insight into the origins of the problem. Muchwork has focused on the structural changes that occurtracts spontaneously during the filling phase while thein detrusor muscle and its innervation as a consequenceof outlet obstruction [2–6]. In the early stages of thisAccepted for publication 10 August 1999

953© 1999 BJU International

954 R.G. CHARLTON et al.

condition there is hypertrophy of the muscle which mayMaterials and methods

facilitate a compensatory increase in detrusor pressureto overcome the increased resistance caused by the Informed consent was obtained from all patients before

obtaining detrusor biopsies. The control group comprisedobstruction [2]. In some patients, macroscopic muscletrabeculae also appear which may or may not be linked 27 patients undergoing cystectomy for carcinoma whilst

the two groups of 12 patients with idiopathic and sevenwith instability [2]. In conjunction with these alterationsto the macroscopic smooth muscle morphology there is with neuropathic instability had undergone clam ileo-

cystoplasty. Patients with idiopathic bladder instabilityalso a reduction in the expression of proteins associatedwith excitation-contraction coupling [7] and changes in were diagnosed as unstable by routine urodynamic

investigation and a detailed medical history. The meanthe enzymes associated with metabolism [8]. In additionto the changes in muscle it has been reported that there (sd) ages of each group (normal, idiopathic and neuro-

pathic) were 62 (9), 50 (11) and 31 (15) years, respect-is a reduction in the density of motor nerves [9–12],which is associated with a decrease in the neuropeptide ively. None of the control group had received chemo- or

radiotherapy. A combination of histochemical andlevels [13]. These changes may counteract the hyper-trophy and ultimately weaken the bladder [5,6,14]. immunohistochemical techniques were used to detect

detrusor muscle, connective tissue and nerves.In long-term obstruction there are alterations to theconnective tissue matrix which may influence com- Quantitative data were obtained using a Leica Q500

image analyser (Leica Microsystems, Milton Keynes, UK)pliance [14]. This involves an increase in the amountsof collagen and elastin between the muscle fascicles and linked to a colour video camera and light microscope.

Full-thickness specimens of bladder were obtainedmuscle bundles [2]. Once the obstruction is removed thebladder appears to return to normal, with a partial from the bladder dome and fixed in 10% formal saline

for 12–18 h before processing to paraBn wax; 4 mmreduction in the hypertrophy and a re-innervation ofthe muscle [4]. sections were mounted onto aminopropyltriethoxysilane-

coated slides and dried at 65°C for 30 min before stain-There is less information available on the structuralchanges in muscle and its innervation in idiopathic and ing. To measure detrusor fibre diameter, sections were

stained using Carazzi’s haematoxylin, which providedneuropathic instability. In neuropathic patients with DIthe density of presumptive cholinergic nerves is signifi- exceptional delineation of muscle cells, particularly when

the image was made refractile using the substage con-cantly lower than in normal control bladders [3]. Thishas been linked to the development of a supersensitivity denser. The diameter of 200 cross-cut muscle cells was

calculated from the diameter of the fibre at a point thatto applied agonist [3]. These changes may contribute tothe bladder dysfunction seen in these patients. Patients included the nucleus. Only cells where the diameter at

the nucleus was the same in measurements made atwith idiopathic instability are a more varied group whoseinstability is more diBcult to define. Consequently there right angles to each other (±5%) were included in the

analysis of cell diameter. This constraint ensured thatare fewer detailed studies describing the morphologicalchanges in the nerves and muscles in this group of only transversely sectioned cells were measured and

avoided the diBculty of measurements from obliquelypatients. However, it has been reported that the densityof putative sensory nerves is higher in the subepithelial cut cells. All diameters were measured using a ×40

objective after calibrating the image analyser with alayer of the bladders from patients with idiopathic insta-bility than from controls [15]. stage micrometer.

To quantify connective tissue, the Elastic van GiesonIt has been suggested that the denervation in tissuesfrom dysfunctional bladders is not uniform [16]. In a stain was used to selectively detect collagen, muscle and

elastin, stained red, yellow and black, respectively. Totalpreliminary study using full-thickness specimens tocompare and contrast the morphological changes that tissue content was quantified by measuring 10 fields

using a ×4 objective, whilst the content of the muscleoccur between normal, idiopathic and neuropathic blad-ders, it was reported that the changes in nerve, muscle bundles was assessed by measuring 10 fields using a

×10 objective. To enable detection by the image ana-and connective tissue in unstable bladders were notuniform throughout the bladder section [17,18]. Discrete lyser, each of the three elements was assigned a primary

colour (collagen, red; muscle, green; and elastin, blue).areas of extensive connective tissue infiltration, musclehypertrophy and altered innervation were adjacent to Amounts were expressed as a percentage of the three

elements, measured to take into account field variability,apparently normal areas in both idiopathic and neuro-pathic bladders [17,18]. In the present report, we present as not all fields were solid tissue.

Nerve profiles were identified using a polyclonal anti-new data illustrating the complexity of these punctatechanges. The possible implications for the aetiology of body to S100 protein (Dako Ltd., Ely, UK) with a

streptavidin–biotin complex detection system, followedinstability are considered.

© 1999 BJU International 84, 953–960

CHANGES IN NE RVE, MUSCLE AND CONNECTIVE TISSUE 955

by visualization with diaminobenzidine (both Biogenex, In the sections from idiopathic and neuropathic bladdertissue, elastin and collagen also occur between theSanta Barbara, CA). The use of the van Gieson coun-

terstain enabled nerve profiles to be quantified in relation muscle bundles but, in contrast to normal tissue, elastinand collagen are also present within the fascicles. Fromto the deposition of connective tissue. In the idiopathic

and neuropathic groups, well innervated areas lay adjac- Fig. 1B,C, muscle fascicles and bundles infiltrated withelastin and collagen are apparently close to fascicles andent to sparsely innervated bundles, some of which were

infiltrated by collagen. These areas were quantified separ- bundles, which are almost indistinguishable from thecontrol tissue. Thus, at this level, the changes in theately and in each case the number of nerve profiles in

each of 50 fields of 0.1 mm2 was counted, the results unstable bladders appear to be ‘punctate’. Comparingidiopathic and neuropathic bladder, there appeared tobeing expressed as the mean (sem) number of nerve

profiles/mm2. For all data, the significance of diCerences be few diCerences other than the extent of the infiltration.There were generally more fascicles and muscle bundleswas tested using Student’s t-test, with P<0.05 con-

sidered to indicate significant diCerences. infiltrated with elastin and collagen in the tissue fromneuropathic bladders.

The relative areas staining for elastin, collagen andResults

muscle were determined within the whole section usinglow-power image analysis. This generalized analysis does

Regional variation in detrusor structurenot diCerentiate the location of the connective tissue butsimply reflects the extent of the changes with respect toFig. 1A–C shows sections of bladder smooth muscle

isolated from normal, idiopathic and neuropathic the whole muscle. These data are shown in Table 1;areas of collagen and elastin were greater in bothpatients, respectively. At this magnification individual

smooth muscle cells cannot be visualized but muscle idiopathic and neuropathic bladders at the expense ofmuscle and the relative amounts of the connective tissuefascicles (containing smooth muscle cells) and muscle

bundles (consisting of groups of fascicles) are apparent. elements were greater in the neuropathic than in theidiopathic samples.In the normal tissues the elastin and collagen fibres

occur primarily between the fascicles and muscle To quantify regional variations in the connectivetissues in the three groups, the elastin and collagenbundles, with little or no staining within the fascicles.

Fig. 1. Photomicrographs illustrating sections from: A, control; B, idiopathic; and C, neuropathic bladders. The Elastic van Gieson stainwas used to selectively detect collagen, muscle and elastin, stained red, yellow and black, respectively. In B and C apparently normal areasand severely aCected areas are identified by the symbols * and †, respectively. Total tissue content was quantified on images such as theseusing image analysis and by measuring 10 randomly chosen fields using a ×4 objective. Bar=200 mm.



Table 1 An analysis of relative areas ofcollagen and elastin in normal, idiopathicand neuropathic sections of humanbladder, based on large areas of the wholesection or after separating normal anddamaged idiopathic and neuropathic areas

Mean (SEM) % area of

Group Collagen Elastin Muscle

Whole sectionControl 6.7 (4.1) 0.7 (0.7) 92.6 (4.3)Idiopathic 17.5 (8.7) 2.1 (1.2) 80.4 (9.4)Neuropathic 17.2 (6.8) 11.4 (2.6) 71.4 (8.9)

Detailed analysis of fasciclesControl (n=27) 3.48 (1.3) 0.79 (0.7) 95.7 (1.5)Idiopathic normal (n=12) 2.10 (1.1) 0.64 (0.5) 97.2 (1.1)Neuropathic normal (n=7) 6.15 (3.6) 0.56 (0.4) 93.3 (3.7)Idiopathic damaged 8.74 (5.1) 3.71 (3.0) 87.5 (6.2)Neuropathic damaged 15.70 (4.9) 18.26 (4.1) 66.0 (7.0)

content was determined within individual muscle fas- infiltration with few or no nerve profiles (marked †). Thenerve profile density in each area was analysed; thecicles. In control tissue, all fascicles were deemed normal,

but in idiopathic and neuropathic bladders, the fascicles results from five each of normal, idiopathic and neuro-pathic bladder samples are shown in Table 2. In thewere broadly categorized as normal or damaged (heavily

infiltrated) and each analysed (Table 1). There was a idiopathic tissue, there were significantly fewer nerveprofiles/mm2 in areas with sparse innervation and in thesmall but significant increase in the amounts of collagen

in the control compared with the idiopathic normal infiltrated areas than in the normal areas (P<0.05).There were significantly more nerve profiles in thefascicles (Table 1; P<0.05). The functional significance

of this is unknown and may simply reflect the diCerence normal areas of the idiopathic bladders than in normalbladders (P<0.05). It is well known that there are age-in mean age of the control and idiopathic groups. In the

‘normal’ areas in the neuropathic bladders there was dependent changes in the density of innervation andconnective tissue content in the bladder wall. In themore collagen but no significant change in elastin. Thus

the mechanisms regulating the synthesis of these diCer- present study, using the samples available, it was notpossible to make exact age-matched comparisons, butent connective tissue elements may diCer. In contrast,

both collagen and elastin were significantly more abun- the principle finding of punctate changes within any onetissue and the statistical comparison within the tissuedant in the damaged areas of idiopathic and neuropathic

bladders, with the amount in the latter being significantly from the same subject removes the absolute need forage-matching. The comparison between subject groupshigher than in the former. The important observation is

that in diagnosed unstable bladders there were areas may be prone to such age diCerences.which appeared, with respect to their connective tissueprofile, normal.

Muscle hypertrophy

In outlet obstruction there is hypertrophy of the smoothNerve profile analysis

muscle cells and thus in the present study, smoothmuscle fibre diameter was measured in tissue taken fromFig. 2A–C shows sections from normal, idiopathic and

neuropathic bladders; as in Fig. 1, the Elastic van Gieson control, idiopathic and neuropathic patients. In controltissue the smooth muscle cells in each fascicle and instain was used to delineate elastin, collagen and smooth

muscle. Immunocytochemistry using an antibody to each muscle bundle were of uniform diameter andappearance (Fig. 3A). However, in both idiopathic andS-100 was combined with the van Gieson counterstain

to detect nerves in relation to collagen deposition. There neuropathic bladders it was clear that there were regionsof smooth muscle with a control appearance (Fig. 3B*,C*)was a uniform distribution of nerve profiles in all fascicles

and muscle bundles in tissue from normal bladders and regions where the cells were larger and hyper-trophied (Fig. 3B†C†).(Fig. 2A). However, in the idiopathic (Fig. 2B) and neuro-

pathic (Fig. 2C) bladders, three regions could be ident- Fibre diameters were measured systematically on sec-tions similar to those in Fig. 3 from samples in eachified: (i) regions which appeared normal, with numerous

nerve profiles (marked *); (ii) regions with little connec- group (Table 2). In the idiopathic and neuropathicmuscle the areas for fibre diameter measurement weretive tissue infiltration but with few nerve profiles (marked

#); and (iii) regions with marked elastin and collagen divided into normal areas with normal nerve densities



Fig. 2. Photomicrographs illustrating sections from: A, normal; B, idiopathic; and C, neuropathic bladders stained with Elastic van Giesonto selectively detect collagen, muscle and elastin. In addition, sections were exposed to an antibody which recognises nerve profiles (S-100)and subsequently stained with a chromogen giving a characteristic dark-brown stain. Regions which appeared normal (*) with numerousnerve profiles, with little connective tissue infiltration but with few nerve profiles (#) and with marked elastin and collagen infiltrationwith few or no nerve profiles (†) are shown. Bar=200 mm.

Table 2 The number of nerve profiles andmuscle fibre diameters in normal tissue,idiopathic muscle and neuropathic muscle.In the idiopathic and neuropathic sections,three areas were defined: those whichappeared normal with significant numbersof nerve profiles, those with few nerveprofiles but no connective tissueinfiltration, and those with connectivetissue infiltration

Mean (SEM)

Group Number of nerve profiles/mm2 Muscle fibre diameter (mm)

Normal tissue 752 (53) 6.81 (0.52)Idiopathic:

Normal areas 905 (91) 6.72 (0.49)Sparse innervation 81 (20) 7.01 (0.15)Infiltrated areas 74 (38) 7.34 (0.27)

NeuropathicNormal areas 627 (249) 6.75 (0.62)Sparse innervation 57 (23) 8.25 (0.50)Infiltrated areas 37 (28) 9.35 (1.15)

(Fig. 2), areas with no infiltration but sparse nerves, and were diagnosed with interstitial cystitis. Sections fromtheir bladders showed that the morphology of the muscleareas with excess collagen and elastin. Muscle cell

diameters in the control bladders and unaCected areas and connective tissue was similar to the control tissue.The mean fibre diameter was 6.62 mm and the pro-of the idiopathic and neuropathic tissues were not sig-

nificantly diCerent (P=0.04). The areas with low nerve portions of collagen, elastin and muscle were 3.67%,1.02% and 95.3%, respectively; these values were notdensity in the idiopathic bladders were no diCerent from

the unaCected areas (P>0.05) but the cells in the significantly diCerent from the control values (Table 1).However, the density of nerve profiles in the detrusor ininfiltrated areas were significantly larger (P<0.05). In

the low-density and in the infiltrated areas of the neuro- the patients with interstitial cystitis was 2208 (333)nerves profiles/mm2 , greater than in the control tissues,pathic bladders the cells were significantly larger

(P<0.05). at 752 (53) nerve profiles/mm2; the reasons for thisdiCerence are unclear.In the present study, two patients were examined who



Fig. 3. Representative sections showing normal bladder (A), normal areas of idiopathic bladder (B*), hypertrophied areas of idiopathicbladder (B†), normal areas of neuropathic bladder (C*) and hypertrophied areas of neuropathic bladder (C†). Sections were stained usingCarazzi haematoxylin, which provided exceptional delineation of muscle cells particularly when the image was made slightly refractileusing the substage condenser. The diameter of 200 cross-cut muscle cells was determined as the mean of the largest and smallest diameterof the fibre at a point that included the nucleus, all estimated using a ×40 objective after calibration with a stage micrometer. Bar=20 mm.

ently normal areas. While the obstructed bladder appearsDiscussion

to be uniformly modified, the idiopathic and neuropathicbladders have a punctate distribution of defects. ThesePublished reports describing morphological changes in

the unstable bladder have focused mainly on bladders punctate changes must have a diCerent aetiology andsequelae, resulting in an unstable bladder. Therefore,with outlet obstruction [2–6]. In this particular form of

instability there are changes to both the muscle and there are similarities but some key diCerences betweenobstructive and other forms of instability.nerves; in the early stages there is an increase in the

size of muscle cells and loss of nerves, while after In the present analysis the areas of morphologicalchange are taken to represent regions of damage whichprolonged obstruction there are changes in the intra-

cellular proteins associated with contraction and metab- contribute to the instability. In the most general sense,the idiopathic and neuropathic bladders are similar,olism, as well as the formation of muscle trabeculae on

the bladder surface [2,9]. There are few results indicating although the neuropaths are more severely aCected. Inboth idiopathic and neuropathic bladders, some areasan uneven distribution of the defects in the obstructed

bladder. A key feature of the morphological and neuro- were almost indistinguishable from control tissue in theamounts of connective tissue, in muscle cell diameterlogical changes that occur in obstructive instability is

that they can be reversed on removing the obstruction. and the density of nerve profiles. From such a morpho-logical analysis it is not possible to determine whetherThis does not appear to be the case for neuropathic or

idiopathic instability. these are functionally normal areas or if they havechanges at the molecular and functional level. TheThe major finding of the present study is that in both

idiopathic and neuropathic bladders there appears to be second identifiable area showed a dramatic loss in nerveprofiles and a slight muscle hypertrophy. In these regionsa more complex series of morphological changes. Among

the connective tissue elements, smooth muscle and the hypertrophy was more pronounced in the neuro-pathic tissues. In many respects these regions are similarnerves, several major changes were identified which

appear to occur discretely within small areas of the to the changes described in obstructed bladders withmuscle hypertrophy and loss of nerve fibres [5,9]. Thedetrusor, with highly modified areas adjacent to appar-



final area of change consisted of muscle fascicles heavily than in the controls may have a component related toage. However, the increase was slightly greater thaninfiltrated with connective tissue, severe muscle

hypertrophy and pronounced loss of nerve profiles. might be predicted from published data on nerve lossover a 10-year period [19]. In contrast, the apparent lossIt is not possible to be certain of the progression of

events that transform normal bladder into severely dam- of nerves in the ‘normal’ areas of the idiopathic bladderscannot be complicated by diCerences in the mean ages ofaged bladder. One sequence may be that the early stages

involve an initial loss of nerves and hypertrophy of the the diCerent groups, as the mean age of the neuropathicgroup was much lower.muscle, although which occurs first is unknown. In

neuropathic patients it is possible that the initial lesion The analysis of the tissues from patients with inter-stitial cystitis is potentially interesting as there appearedis a neuropathy which aCects the muscle, but it could

equally be the reverse. These regions would then develop to be a significant change in the innervation of thetissue, with no major alteration in muscle morphology.additional changes involving further hypertrophy and

infiltration of connective tissues. Thus, all the stages of In this respect, these tissues showed changes opposite tothose in the unstable bladders. It has been reported thatthe generation of an idiopathic or neuropathic bladder

might be manifest in the same tissue, with normal tissue nerve growth factor (NGF) levels are elevated in womenwith idiopathic sensory urgency and interstitial cystitisbeing present alongside severely aCected tissues.

The punctate distribution of defects implies that the [20], and that purinergic neurotransmission is aCected[21]. Such an increase in NGF may promote nervemechanisms which cause the changes must be highly

localized and restricted; at present these mechanisms are sprouting and an increase in the density of nerve profiles.This possible involvement in the interactions betweenunknown but there are several possibilities. For example,

there may be initial focal damage as a consequence of nerve and muscle in the human bladder deserves furtherconsideration.regional over-stretching of muscle bundles and fascicles

orientated in particular directions. This could damage It is well established that the extent of autonomicinnervation of the bladder is regulated by the levels NGFthe muscle, nerves or both. Also, there may be fascicles

and bundles which have poor vascularization and [22]. In neonatal animals, treatment with antiserumraised to NGF produced a severe loss of nerves in thewhich, during contraction, are predisposed to episodes

of hypoxia. Repeated hypoxic challenges may trigger bladder [22]; similarly, injections with NGF enhancedthe innervation of rat bladder [23]. In the obstructedchanges in both nerve and muscle. Supporting this idea

is that the isoforms of lactate dehydrogenase are altered bladder the well documented changes in the density ofinnervation [4,9,10,12] suggest that there may thereforein unstable bladders, indicative of changes to cope with

low oxygen tensions [8]. However, it is not known be an involvement of NGF. Increased levels of NGF havebeen reported in the bladder tissues of obstructed animalwhether these changes are focal. As the defects in

idiopathic and neuropathic bladders are punctate, and and human bladders [23]. Thus there appears to be aclose link between obstructive instability and NGF. Usingnormal and aCected tissue can be present in the same

tissue, this may have important implications for experi- detrusor smooth muscle cells in vitro it has been shownthat stretch, operating through a mechanism thatments on the nature of instability that use isolated

muscle strips or dissociated cells. involves protein kinase C and intracellular Ca2+ , aCectsthe synthesis of NGF in the detrusor smooth muscle cellsThe density of nerve profiles in the present control

muscle agrees well with previous published estimates [9]. [24–26]. Based on this information the initial defectmay be damage to nerves and a subsequent reductionChanges in nerve density have been reported in the

obstructed bladder and associated with ageing in the in numbers. As a result of either a loss of a neurotrophicstimulus or neurotransmitter-induced activity in thenormal bladder [19]. However, the density found in the

present study in the idiopathic and neuropathic dener- muscles, there would be an increase in NGF productionin an attempt by the muscle cells to redress the dener-vated areas of muscle are lower, at #80 nerve

profiles/mm2, compared with #300 nerve profiles/mm2 vation. As part of the same process, muscle hypertrophymight be triggered. It is possible that there is a trophicin obstructed bladders [9]. Thus changes in nerve density

may be generally associated with the generation of DI. loop whereby signals pass between the nerves andmuscles to maintain structural and functional integrity.The results presented here show that the density of

innervation in the ‘normal’ areas of idiopathic bladders Interrupting this loop either at the level of nerve ormuscle would initiate a compensatory cascade of changeswas greater than in the controls (Table 2). The density of

innervation in the normal bladder is known to decrease with a similar pathology but arising from diCerent initiallesions. Thus it is possible that a similar scheme involvingwith increasing age [19]. In the present study, the control

patients were older than the idiopathic patients and thus NGF may be involved in the punctate morphologicalchanges seen in idiopathic and neuropathic instability.the higher values in the ‘normal’ areas in the idiopathic



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Focal changes in nerve, muscle and connective tissue in normal and unstable human bladder

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