French Guide Lines MS Bladder!!!!Ful Article

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http://msj.sagepub.comMultiple Sclerosis

DOI: 10.1177/13524585060756512007; 13; 915 originally published online Mar 15, 2007;Mult Scler

Francophone Neuro-Urological expert study group (GENULF)

Marianne de Sze, Alain Ruffion, Pierre Denys, Pierre-Alain Joseph, Brigitte Perrouin-Verbe and Internationalguidelines

The neurogenic bladder in multiple sclerosis: review of the literature and proposal of management

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The neurogenic bladder in multiple sclerosis: review ofthe literature and proposal of management guidelines

Marianne de Seze*1, Alain Ruffion2, Pierre Denys3, Pierre-Alain Joseph1 and BrigittePerrouin-Verbe4 and the International Francophone Neuro-Urological expert study group(GENULF)

Vesicourethral dysfunction is very frequent in multiple sclerosis (MS) and has functionalconsequences for patients quality of life and also an organic impact following complications ofthe neurogenic bladder on the upper urinary tract. While the functional impact and its managementare well documented in the literature, the organic impact remains underestimated and there are noconsensual practical guidelines for the screening and prevention of MS neurogenic bladdercomplications. The aim of this review of the literature, focused on identifying the risk factors of

urinary tract complications in MS, is to put forward well informed considerations to help in thedefinition of practical guidelines for the follow-up of the neurogenic bladder in MS in order toimprove its prevention and patient management. Four main risk factors have been identified forupper urinary tract damage: the duration of MS, the presence of an indwelling catheter, high-amplitude neurogenic detrusor contractions and permanent high detrusor pressure. Detrusor-sphincter dyssynergia, age over 50 and male sex may form three additional risk factors.Recommendations for long-term urological follow-up, taking into account these specific risks areconstructed according to the procedures recommended by the French Health Authorities. MultipleSclerosis 2007; 13: 915 928. http://msj.sagepub.com

Key words: multiple sclerosis; neurogenic bladder; overactive bladder; upper urinary tractabnormalities; ureterohydronephrosis; urinary tract infection

Introduction

Urinary tract dysfunction is quite common duringthe course of multiple sclerosis (MS), not onlyrepresenting a considerable psychosocial burden,but also often requiring care, hospitalization andposing a great challenge for the treatment team.While the frequency of micturitional disorders inMS is widely recognized, urinary tract morbidity istraditionally considered to be scarce and functionalconsequences are considered to outweigh organic

impact. However, several studies suggest that upperurinary tract involvement and kidney disease arenot exceptional in patients with MS, leading re-searchers to consider the need for improving theirprevention and management.

The aim of the first part of this work was toidentify, through an exhaustive analysis of theliterature, the factors that influence the prognosisof upper urinary tract complications in MS. Thesecond part, prepared jointly with the InternationalFrancophone Neuro-Urological expert study group(GENULF) aimed at putting forward well informed

1 Unite dEvaluation et de Traitement du handicap Urinaire, Service de Me decine Physique et de readaptation, CHUPellegrin, Equipe de recherche Handicap et Systeme nerveux, Universite Victor Segalen Bordeaux 2, 33076 BordeauxCedex, France2 Service dUrologie, Hopital Henry Gabrielle, CHU Lyon, 69565 Saint Genis Laval Cedex, France3 Service de Reeducation neurologique, Hopital Raymond Poincare, APHP, 92380 Garches Cedex, France4 Service de Medecine Physique et de Readaptation, Hopital Saint Jacques, CHU de Nantes, 44093 Nantes Cedex,FranceAuthor for correspondence: Marianne de Seze, Unite dEvaluation et de Traitement du Handicap Urinaire, Service deMedecine Physique et de Readaptation, CHU Pellegrin, 33076 Bordeaux Cedex, FranceE-mail: [email protected] 19 July 2006; accepted 4 December 2006

ARTICLE Multiple Sclerosis 2007; 13: 915 928

2007 SAGE Publications 10.1177/1352458506075651

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specific recommendations for the medium- andlong-term supervision of MS neurogenic bladdersaccording to the methodology recommended bythe French Health Autorities [1] (HAS).

Material and methods

Our literature review was based on an exhaustivesearch of the Medline, Embase and Pascal databases with one or several of the keywords neuro-genic bladder, multiple sclerosis, upper urinary tractabnormalities and bladder dysfunction. An analysisof the grey literature, ie, proceedings from con-ferences or symposia, specifically dedicated to theneurogenic bladder, MS and the consensus con-ferences of the HAS on MS and nosocomial urinaryinfections was added to the database search re-sults.

In accordance with the HAS guide to literatureanalysis and scoring of recommendations [1], thepublications were classified according to their levelof scientific proof (LSP):

Level 1, called established scientific proof(LSP1), included high-powered randomizedcomparative trials, meta-analyses and decisionanalyses based on properly performed studies.This enabled the presentation of Grade Arecommendations.

Level 2, called scientific assumption (LSP2),

grouped low-powered randomized comparativetrials, properly performed non-randomizedcomparative studies and cohort studies. Thisenabled the presentation of Grade B recom-mendations.

Levels 3 and 4, called low-level scientific proof,included, respectively, control case studies(LSP3) and comparative studies with substantiallevels of bias, retrospective studies, series ofcases and descriptive epidemiological studies(LSP4). They enabled the presentation of GradeC recommendations [1].

Literature analysis

Out of the 202 references indexed over the last30 years in the data bases and in the grey literatureaddressing the MS neurogenic bladder, 52 gavedescriptive or analytical information that wasuseable for the drafting of this document. Twenty-two of these references were at the HAS Level 1of scientific proof and 15 at Level 2 [1] (seeTables 1 3).

Detrusor and sphincter disorders inmultiple sclerosis

Epidemiology

Detrusor and sphincter disorders are all but inevi-table in the evolution of MS. The fluctuations intheir prevalence (reports range from 32% to 96.8%)reflect difference in time of examination from onsetof MS and diagnosis (namely including urody-namics or not) rather than a real heterogeneity ofincidence [2 20] (Table 1). Appearing on average 6years after the onset of the disease (ranges from 5 to9.5 years) [2,9,13,14,16,21,23], detrusor and sphinc-ter disorders may affect one patient out of 10 at thetime of initial clinical manifestation of MS [24 28].This inaugural character has been correlated withthe severity of the further vesicourethral clinicaland urodynamic status and may increase urinarymorbidity [29] (LSP1).

Clinical presentation and influencing factors(Table 1)

The predominance of overactive bladder syndrome[30], characterized by urgency, urinary frequencyand/or urge incontinence (irritative symptoms), isconstantly reported with a prevalence of 37 99% ofpatients [2 22]. Obstructive symptoms [30] arealso frequently reported, affecting between 34%and 79% of patients and in 25% of cases resul-ting in chronic urinary retention [2 22]. Irritativeand obstructive symptoms often coexist, andmay jointly affect up to 59% of men and 51% ofwomen [15].

The clinical presentation of vesicourethral dys-function (VUD) is variable over time [30]. Theappearance of new symptoms, mainly of the irrita-tive type, may affect up to one third of patients overa period of 42 months [31]. Overall, the clinicalpresentation of VUD offers little information on thetype and severity of the detrusor-sphincter disor-ders [2,9,20]. There is little correlation between theclinical and urodynamic symptomatology andwhile a combination of irritative symptoms and

detrusor overactivity is sometimes reported [8,9],the majority of studies offering a satisfactory meth-odology do not objectively confirm this systematiccoexistence [2,13,21,25,31,32].

Two factors likely to influence the clinical pre-sentation of VUD in MS have an established LSP:the MS duration and the severity of the neurologi-cal deficiencies and disabilities. Their independencehas not been asserted. There appears to be asignificant correlation between the MS durationand the presence and the severity of clinical VUD

916 M de Seze et al.

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but not with their clinical presentation [5,6,20,22,29,33]. The prevalence of clinical VUD ap-pears to be correlated with the severity of theoverall deficiencies (EDSS score, Kurtzke scale)[5,6,9,20,33,34]. The prevalence of irritative symp-

toms is also correlated with the severity of pyrami-dal damage (Babinskis sign, EDSS pyramidal score)[5,9,20]. The correlation between urinary retentionand neurological status is still controversial [35,36].

There is no scientific proof of the influence of theprogressive form of MS on theVUD clinical presenta-tion, except for an assumption of proof between theattack of MS and the obstructive syndrome [20].

To date, a link between MRI data and clini-cal symptoms of VUD has not been established[25,37,38]. Demographically, age has no directinfluence. However, as observed in the generalpopulation, women may be predisposed to urinaryincontinence and to the irritative symptoms and

men to the obstructive symptoms [3,6,10,15,20,23,27,28].

Urodynamic presentation and influencing factors[2,3,5,8

17,19

21,23,27,31

34,39

45]

The poor specificity of the clinical symptoms in MSVUD and the identification of specific cystometricrisk factors for uronephrologic prognosis argues forthe use of urodynamic explorations. This wouldallow a precise evaluation of functional physio-pathology of VUD and of risk factors for urinarytract damage in MS patients, thus helping to plantheir optimal management [4,26,33]. The mostfrequent cystomanometric picture is detrusor over-activity (mean occurrence of 65%, ranges from 34%to 99%) followed by detrusor underactivity (meanoccurrence of 25%, ranges from 0% to 40%) andpoor bladder compliance (2 10%) (Table 2). De-trusor-sphincter dyssynergia (DSD) is irregularlyand diversely estimated with a prevalence of5 83% and a mean of 35%, but diagnosis criteriavary between studies. Cystometrogram can beconsidered normal in 1 34% of symptomatic pa-tients [25,26]. The combination of the urodynamicpatterns is frequent and detrusor overactivity can

be combined with DSD in 4380% of patients[2,25,45,46] and with detrusor acontractility in5 9% [29,31]. Cystometrogram may change overtime independently of any micturitional and neu-rological clinical stability [16,31,47]. In Ciancosseries, 55% of 22 patients assessed by repeatedcystomanometric tests presented changes in theirbladder capacity, contractility, pressure or detrusorcompliance over 42 months [31]. Only the DSDappeared stable over time, staying present in 60% ofthe patients [16,31,47]. There is not sufficientargument to claim any direct influence of age onT

able

1

ClinicalpresentationofVUD

inMS

Author,level

ofproof(LP)

Numb

er

ofpatients

Meanduration

ofMS(years)

Timesinceonset

ofVD

(years)

Prevalenceof

urgency(%)

Prevalenceof

pollakiuria(%)

Prevalenceof

incontinence/

urgency(%)

Prevalenceof

dysuria(%)

Prevalenceof

urinary

retention(%)

Amarenco,

1995,

LSP1

225

13.3

7.8

72

42

63

46

24

Andersen,

1976,

LSP2

62

12.2

4.9

71

38.5

50

12

32.7

Awad,

1984,

LSP2

47

16

U

85

65

72

36

Bemelmans,1991,

LSP2

40

5.4

U

25

17.5

Betts,1993,

LSP1

170

12

6

85

82

63

49

34

Bradley,

1978,

LSP4

90

U

U

86

60

28

20

deRidder,1998,

LSP2

30

U

U

36.6

36.6

80

Eardley,

1991,

LSP2

24

11

U

41.6

41.6

25

8.3

Gallien,

1998,

LSP1

149

13

6

69.1

67.7

69.1

Giannantoni,1998,

LSP1

116

14.5

7.1

99

79.5

52

Goldstein,

1983,

LSP4

86

U

U

32

32

49

Gonor,1985,

LSP2

64

13

4.6

70

48

56

30

Hennessey,

1999,

LSP1

221

U

U

71

76

19

48

73.8

Kasabian,

1995,

LSP2

32

18

U

44

66

66

6

Koldewijn,

1995,

LSP1

211

6.5

U

38

26

27

Philp,

1981,

LSP2

52

10

5

61

59

47

Porru,

1997,

LSP1

120

0.19

U

36

49

49

VUD,vesicourethraldisorder;LSP,

ANAESlevelofscientificproof[1];U,

Unknown;DSD,

detrusorandsphincterdiso

rders;VD,voidingdysfunction.

Neurogenic bladder in multiple sclerosis 917

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Table 2 Urodynamic presentation of VUD in MS

Author, levelof proof (LSP) Number of patients

Mean duration of MS(and VD) in years

Detrusoroveractivity (%)

Detrusorhypoactivity (%)

Normal vesicalactivity (%)

Absence ofcompliance (%)

Detrusor-sphincterdyssynergia (%)

Amarenco, 1995 96, LSP1 225 13.3 (7.8) 70 9 21 2 82Anderson, 1976, LSP2 52 12.2 (4.9) 63.5 32.7 3.8 U 30.8Araki, 2003, LSP2 32 11.8 (U) 43.7 37.5 3.1 3.1 40.6Awad, 1984, LSP2 57 16 (U) 66 21 12 U 52Barbalias, 1998, LSP2 90 5 (U) 57.7 16.6 U 5.5 30Bemelmans, 1991, LSP2 40 5.4 years (U) 22.5 12.5 32 U UBetts, 1993, LSP1 170 12 (6) 91 0 9 U UBlaivas, 1979, LSP2 41 12 (7) 56 40 4 U 30Bradley, 1978, LSP4 302 U 62 34 24 U UCianco, 2001, LSP2 22 U (U) 68 14 14 U 23de Ridder, 1998, LSP2 30 U (U) 43 U 36.6Eardley, 1991, LSP2 24 11 (U) 63 13 25 U 27Gallien, 1998, LSP1 149 13 (6) 41 25 34 U 59.7Giannantoni, 1998, LSP1 1 16 14.5 (7.1) 81 24.1 10.3 10.3 42.2Goldstein, 1982, LSP4 86 U 76 19 6 U 66Gonor, 1985, LSP2 64 13 (4.6) 78 20 2 U 12Hinson, 1993, LSP2 70 U (U) 63 28 9 U 21Kasabian, 1995, LSP2 32 18 (U) 56 31 13 U 5Koldewijn, 1995, LSP1 212 6.5 (U) 34 8 34 U 13Mayo, 1992, LSP2 89 12 (4) 78 6 12 U 6Petersen, 1984, LSP2 88 15 (U) 83 16 1 U 41Philp, 1981, LSP2 52 10 (5) 99 0 1 U 37Piazza, 1979, LSP4 31 U (U) 74 6 9 U 47Schoenberg, 1979, LSP2 39 U (U) 69 5 15 U 50Sirls, 1994, LSP4 113 9.9 (U) 70 15 6 U 28Summers, 1978, LSP4 50 1 6 (U) 52 12 18 U 12

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Table 3 Urinary tract complications in MS

Author (levelof proof LSP) N

Duration ofMS (years)median(range)

Duration ofVD (years)

Overallprevalence(%)

Lower urinarytract infections(%)

Damage tolower urinarytract (%)

Upper urinaryinfections (%)

Vesicoureteralreflux (%)

Dilatation ofupper tract(%)

Renal failure(%)

Urinarylithiasis (%)

Amarenco,1995 96(LSP1)

225 13.4 7.8 56 36.6 49.4 15.5 3.3 3.8 0 3.8

Andersen,

1976 (LSP2)

52 12.2 4.9 0 17.3 U 0 0 0 0 U

Barbalias, 1999(LSP2)

90 5 U 13.3 16.6 2.2 6.6 15.5 U 10

Bemelmans,1991 (LSP2)

40 4.6 U 0 0 U 0 0 0 0 0

Betts, 1992(LSP1)

170 12 (0.5 48) 6 U U U U 0 3.6 0

Blaivas, 1979(LSP2)

41 12 (239) 7 15 U U 0 15 0 U U

Gallien,1994 1998(LSP1)

149 13 6 U 32.8 U 22.8 U U 2 2

Giannantoni,1998 (LSP1)

116 14.5 7.1 U U 30.1 U 5.2 6 0 6

Gonor, 1885(LSP2)

64 13 (0.540) 4.6 74 75 3 5 2.8 0 (n0/64) U

Henessey 1998(LSP1)

221 U U 20 30 4 U U 11 3 3

Kasabian, 1995(LSP2)

32 18 U 3.8 U U U 0 3.8 U 0

Koldewijn,1995 (LSP1)

212 6.5 U 11.8 U 11 3 0.9 U U

Mayo, 1992(LSP2)

89 12 4 19 12 U 3.4 2.2 U 2.2

Petersen, 1984(LSP)

88 15 U U 27 U 9 14 U U U

Porru, 1997(LSP1)

120 0.1 9 U 3.3 U U U U 3.3 U U

Sirls, 1994(LSP4)

113 9.9 U 4 21 U U 1.9 6.6 0 4.7

Sliwa, 1996(LSP1)

48 13.4 U 21 54 29 U 4.2 1.8 0 10.8

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the urodynamic presentation of VUD in MS. On theother hand, gender may be an independent factorof influence, with a significant increase in themaximum amplitude of the uninhibited detrusorcontractions, of the detrusor leak point pressure

(lowest detrusor pressure at which urine leakageoccurs in the absence of either a detrusor contrac-tion or increased abdominal pressure) and of themaximum detrusor pressure in men as compared towomen [15] (LSP1).

Duration of the MS evolution influences theurodynamic presentation of VUD only for DSD, theprevalence of which increases with time, probablydue to its low regression rate after its appearance[16,23,31,47] and to its increasing incidence overtime [22]. Thus, DSD is present in 13% of patientsafter 48 months of MS development,in 15%between48 and 109 months and in 48% after 109 months ofMS duration [22]. There is no specific urodynamic

presentation linked to progression form, remittentor progressive, although a link has been reportedbetween the MS activity (estimated by the basicprotein level in the CSF) and the presence of DSDand/or of detrusor overactivity [20].

Correlations between the neurological and cy-stomanometric states have been reported. Thecorrelation between detrusor overactivity and theseverity of sensory-motor deficiencies (EDSS) or ofpyramidal damage appears probable [9,15,29]. Acorrelation between DSD and pyramidal damage orthe degree of disability has been suggested[11,15,29]. No correlation between detrusor under-contractility and neurological status has beenfound [20]. Finally, the existence of a correlationbetween certain lesional sites and the cystomano-metric data remains controversial [34,37,38], butthe presence of encephalic or suprasacral lesionsand lesions on the brain stem may be a predispos-ing factor for DSD and detrusor undercontractilityrespectively [34,42,46].

Urinary tract complications fromneurogenic bladder in MS

The literature review indicates that the overall

prevalence of urinary tract complications in MS isbetween 0% and 40% in series including patientsuntil 18 years of MS follow-up [3,8,9,1315,17 20,22,23,27 29,32,33,44,45].

Complications of lower urinary tract

Lower urinary tract infections

Lower urinary tract infections are reported in 30%of patients on average (ranges from 13% to 80%)

[3,8,9,13,17,18,27,32,33,44,45]. However, the defi-nition of urinary tract infection (diagnostic criteria,diagnostic threshold, symptomatic character ornot) is neither consensual nor systematically stated,limiting the true analysis of its prevalence rate.

Only one clinical study devoted to the lowerurinary infection risk factor in MS was found. Itstresses the deleterious influence of the post-voidresidual volume (180 mL compared to 119 mL onaverage in patients with or without urinary infec-tions respectively) and of the female gender (42% ofurinary infection in women compared to 17% inmen) [14]. No study addressing the specific poten-tial risk factors of the MS population, such asexposure to immunosuppressants or cystonephro-toxic treatments, was found. By analogy with otherneurogenic populations, and particularly traumaticspinal cord injured patients, an indwelling catheter,high bladder pressures and the existence of a post-

void residual volume of more than 300 mL can beconsidered to favour the occurrence of lowerurinary tract infections [48 51].

Morphological damage to lower urinary tract

Morphological damage to the lower urinary tract isreported in an average of 30% of patients (rangesfrom 4% to 49%), including bladder diverticula,trabeculae and parietal thickening, whose relativeextent is not specified [3,8,9,13 15,17 20,22,23,27 29,32,33,44,45].

Bladder cancer

Three publications, including one retrospectiveLSP1 study, suggest that the risk of bladder canceris greater in MS than in the general population,especially in patients under chronic catheterization(indwelling catheter or suprapubic catheter) andhaving been treated with immunosuppressants[52 54]. In addition to two control cases of con-dylomas in two MS patients treated with immuno-suppressants for 13 years [53,54], de Ridder et al.report the occurrence of seven vesical cancers, six

transitional cell carcinomas and one epidermoidcarcinoma in a population of 2351 patients assessedover a period of 31 years [52]. In that series, the1271 patients with an indwelling or suprapubiccatheter benefited from an annual cystoscopiccheck with a biopsy by forceps in the event of anysuspect macroscopic aspect. Six of the seven bladdercancers occurred in patients with an indwelling orsuprapubic catheter for 3.3 years and the last in apatient having been under intermittent self-cathe-terization (ISC) for 4 years. The first alarm signalwas haematuria. All seven patients had previously





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been treated with cyclophosphamide (mean aggre-gate dose of 60.8 g), which had been halted onaverage 5.8 years previously [52]. The overall in-cidence of bladder cancers in that MS populationwas 0.29% higher than in the general population

(0.018 in men, 0.004 in women)[55] and close tothat of the traumatic medullary population (from0.27 to 9.6%) [56]. The risk of bladder cancersappeared higher in patients with indwelling orsuprapubic catheters (an incidence of 0.7%) andin the ISC patients (an incidence of 0.23%), with amaximum risk in the subpopulation of patientsunder chronic catheterization having been treatedwith immunosuppressants (incidence of 5.7%) [52].

Other complications

Complications of the upper urinary tract are re-

ported in 12% of patients on average (rangesfrom 0% to 25%) [3,8,9,13 15,17 20,22,23,27 29,32,33,44,45,51]. These include, in order of fre-quency, upper urinary tract infections, with amedian incidence of 8% (ranges from 0% to 23%),dilatations of the upper urinary tract, observed in8% of patients (0 25%) and vesicoureteral reflux,found in 5% of patients (ranges from 0 to 15%)[3,8,9,13 15,17 20,22,23,27 29,32,33,44,45,51].Estimates of the prevalence of urinary lithiasisvary from 2% to 11% and its localization on theurinary tree is rarely specified [3,8,9,1315,17 20,22,23,27 29,32,33,44,45,51]. Finally, the major-ity of studies report the exceptional character ofrenal failure in MS [3,8,9,13 15,17 20,22,23,27 29,32,33,44,45,51]. No increased risk of renal fail-ure in the MS population as compared to thegeneral English population has been proven [57].On the other hand, populations of patients with atraumatic or malformative spinal cord lesion pre-sent an increased risk of development of severerenal failure by a factor of 5 and 8 respectively [57].

Mortality due to urinary tract disorders

Mortality due to urinary tract disorders remains

underestimated in MS. Two studies mention therate of death related to a urological cause, onegiving 55% of 20 deaths and the other 5% of 75deaths [58,59]. A Dutch epidemiological studyassessing the factors influencing the life expectancyof 216 MS patients fails to prove any death from aurological cause but reports a survival rate after 40years of MS progression [57]. This rate is signifi-cantly lower in those patients with an onset of VUDduring the first 10 years of MS progression (6.4%survivors) compared to those patients where VUDoccurred after 10 years (29.2% survivors) [57]. The

long duration of VUD in MS may have a negativeimpact on MS mortality but the independence ofthis factor has not been asserted and the influenceof its management has not been documented.Unlike renal failure, a neglected aspect is the

infectious mortality from the urinary system, as ithas been shown to be high in traumatic spinal cordinjury [50,60]. Further studies of this specific aspectare needed.

Risk factors of upper urinary tractcomplications in MS

MS duration

Seventeen clinical studies provide useable data onthe prevalence of upper urinary tract complicationsin MS [3,8,9,13 15,17 20,22,23,27 29,32,33,44,45,57]. The majority are retrospective studies, in-dicating the mean duration of MS and of patientfollow-up. Calculation of the cumulative incidencesof morbid events which occurred over time in thesestudies, as shown in Figures 1 4, illustrates anincreasing prevalence of complications with pas-sing years. As these studies do not specify the timebetween the onset of the disease and the appear-ance of upper urinary tract events, it is difficult toprecisely identify the periods with higher risk ofcomplications in the lower and upper urinary tractsof VUD in MS. The slope of the cumulative

Figure 1 Cumulative incidence of vesicoureteral refluxdepending on the MS duration (data from 1348 patientsin 14 studies 60 cases of reflux identified).





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incidences (Figures 1 4) nonetheless suggests thatthe risk of occurrence of an upper urinary tractcomplication increases as of a period betweenthe sixth and eighth year of survival. Two studiestake into account the overall prevalence of upper

urinary tract complications according to the dura-tion of the disease [15,44]. These indicate that thisis greater within the subpopulations of patientspresenting complications of the upper urinary tractthan among patients without any complications,with respective values of 15.2 years as against 11years [44] and 17.8 years as against 13.4 years [15].A correlation between the duration of MS and therisk of pyelonephritis [13,14] or damage to thelower urinary tract [15] has also been reported.

Gender

No direct correlation between gender and upperurinary tract complications has been found [15,44].However, in men the greater frequency of urody-namic criteria predisposing towards damage to theupper urinary tract (high detrusor pressure andfrequent uninhibited contractions of the detrusor)may constitute an additional risk factor [15] (LSP1).

A greater risk of pyelonephritis has also beenreported in men suffering from low urinary infec-tions [13,14].

Age

Two LSP1 studies find that the average age ishigher in the population of patients with uppercomplications compared to the population withoutcomplications (50.6 as against 46 years [2] and53.1 as against 45.5 years, respectively) [15]. The

Figure 2 Annual cumulative incidence of vesicoureteralreflux depending on the MS duration (linear hypothesis)(1348 patients, 14 studies, 60 cases).

Figure 3 Cumulative annual incidence of infections of theupper tract depending on the MS duration (linear hypoth-esis) (961 patients, 9 studies, 95 cases).

Figure 4 Aggregate annual incidence of upper tractdilatations depending on the MS duration (linear hypoth-esis) (1200 patients, 11 studies, 52 cases).





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deleterious influence of age may, however, reflectthat of a prolonged duration and severity of MS.

Progression of MS

No influence of the type of progression of MS,remittent or progressive, on the urinary tract prog-nosis has been proven [9,15].

Pyramidal symptoms

A correlation between the severity of pyramidalsymptoms and the prevalence of complications ofthe upper urinary tract has been reported[14,15,46], with mean EDSS pyramidal scores of4.1 and 3.1 respectively in patients with andwithout damage to the upper urinary tract [15].However, this finding is not reported systemati-cally and may reflect a risk inherent to theprolonged duration of the disease, as is the casewith age.

Urologic clinical symptom

The influence of the urologic clinical symptomon the urinary tract prognosis is modest [15,44].In patients presenting a postmicturitional residue/30% of the vesical capacity, only an increasedfrequency of pyelonephritis has been reported[14]. Urodynamically, correlations have been re-

ported between the prevalence of complicationsof the upper urinary tract and the high ampli-tude of uninhibited contractions of the detrusor[4,15]. Similarly, morphological damage to thelower urinary tract is positively correlatedwith high maximum detrusor pressures andnegatively correlated with detrusor hypocontracti-lity [15].

DSD

The influence of DSD on the urinary tract prognosisin MS is controversial. Several LSP1 publications fail

to prove any correlation between the prevalence ofDSD and urinary complications [2,15,29,44], butone meta-analysis reports that 7 out of 2076patients with an upper tract complication pre-sented a DSD [20] and a correlation between thepresence of a DSD and the incidence of pyelone-phritis has been stressed [46]. There are also argu-ments in support of an indirect influence of DSD onupper urinary tract complications, insofar as thepresence of a DSD has been correlated with theseverity of the neurological status, which itselfimpacts on the urinary tract prognosis [11,16,20].

The respective dangerousness of the various typesof DSD remains unknown [7].

Mode of urinary drainage

An indwelling catheter is a recognized risk factorfor deterioration of the upper urinary tract, forupper and lower urinary infection [10,13,15,25,42,46,48,49], and for increasing the risk of the occur-rence of bladder cancer in MS patients underimmunosuppressants [52]. No specific study de-voted to the influence of the other voiding modeson the urinary tract prognosis in MS was found. Byanalogy with other neurological pathologies, and inparticular traumatic and congenital impairments ofthe spinal cord, it is considered that the presence ofupper urinary tract complications decreases succes-

sively depending on whether the voiding mode isbased on an indwelling catheter, intermittent ca-theterization, suprapubic catheter, intermittentself-catheterization or voluntary voiding [48 50].

Other risk factors

Finally, there is no documentation on the influenceof the type of therapeutic management (pharma-cological, functional or surgical), of the interest ofan early management or of exposure to urotoxictreatments on the urinary tract prognosis in MS.

Thus, four main risk factors for the deteriorationof the upper and lower urinary tracts have anestablished level of proof (LSP1), resulting fromstudies of good metrological quality and/or that arerecognized by the majority of authors: the durationof MS, especially after the 15th year of duration, thepresence of an indwelling catheter, the high max-imum amplitude of the uninhibited contractions ofthe detrusor and the permanent high detrusorpressures during filling (threshold /40 cm H2O inref. [4], LSP1).

Three other factors benefit from an assumptionof proof (LSP2). They are all recognized by at least

one study of good metrological quality, but remaincontroversial in the literature: the DSD, age over 50years (for which independence with respect to theduration of the disease has not been established)and male sex through the presence of negativeurodynamic factors.

It thus appears possible to consider the existenceof two types of urinary tract situations in MSpatients: risk-free patients not presenting any ofthe LSP1 risk factors and no more than one LSP2factor, and patients at risk with at least one LSP1risk factor or more than two LSP2 factors (Table 4).





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Practical guide to diagnosis andfollow-up of neurogenic bladder inMS (Figure 5)

Recommendations for medium- and long-termneurourological monitoring, constructed accordingto the procedures recommended by the healthauthorities [1,61], and taking into account thespecific risks of these two populations, risk-freepatients and risk patients, have been developed bythe International Francophone Neuro-UrologicalStudy Group (GENULF), which involves urologists,neurologists and physical medicine and rehabilita-tion practicians.

Urinary asymptomatic patient (a patient who does

not spontaneously report any urinary disorders)[Figure 5]

In the absence of urinary symptoms, the MS follow-up is usually performed by a neurologist and atreating physician; patients are not referred to aneurourologic unit. In these patients, a minimalevaluation is advocated, on the initiative of theneurologist, the rehabilitation doctor or the generalphysician (GP). This evaluation is based on twosimple parameters:

1) A specific questionnaire about voiding (fre-quency, number and easiness of voiding, ap-

praising voiding volume, sensation of completeemptying or not), continence (number andappraising volume of leakage, use of pads),symptoms of urinary tract infection and anor-ectal symptoms.

2) A measure of postvoid residual urine by supra-pubic ultrasonography.

If this minimal evaluation does not reveal ur-inary disorders, a simple survey based on the abo-ve minimal evaluation is recommended at eachvisit for MS follow-up. In relapsing form, it is

recommended to perform the evaluation at dis-tance from the relapse.

If micturitional disorders are discovered, it isrecommended to address the patient to a practicianexperienced in neurourology.

Symptomatic patient (Figure 5)

When micturitional symptoms are discovered orspontaneously reported during the minimal evalua-tion, the patient should be referred to an experi-enced neurourology practician, who will conduct abaseline evaluation based on six mean parameters:

1) a three-day voiding chart,2) an ultrasound scan of the urinary tract,3) a urine bacteriology,4) a urodynamic study,

5) a urinary creatinine clearance6) an evaluation of the impact of urinary symp-

toms on a quality-of-life scale (which may bebased on the specific and validated QualiveenQuestionnaire [62].

The necessity to perform a complete urodynamicstudy in all symptomatic MS patients is not fullyestablished in the literature. In MS patients suffer-ing from overactive bladder symptoms, someauthors have recommended to restrict the initialevaluation to the association of uroflowmetry and apostvoid residual measure, claiming that theseexams are sufficient to start the initial treatment

[63]. For the management of non-neurologic pa-tients presenting overactive bladder symptoms, thefirst step is to determine whether there is anincomplete voiding (and urinary tract infection),and if not, to introduce anticholinergic drugs,reserving the full urodynamic evaluation to non-responder patients [64]. This view is not yet con-sensual regarding MS patients, for whom detrusorimpairment and/or uronephrologic risk factorsrelating to high detrusor pressure may be under-estimated due to a limited evaluation excludingcystometry. A randomized trial would be required

Table 4 Risk factors of upper urinary tract complications in MS

Definite risk factors Probable risk factors Risk group

Level of scientific proof 1. Established level of proof 2. Assumption of proof Risk patient: at least one definite riskfactor or more than two probable riskfactors

Nature of risk factor - MS duration beyond 15 years Detrusor-sphincterdyssynergia Risk-free patient: No definite risk factorand no more than two probable riskfactors

- Indwelling urinary catheter Age over 50 years- Ample uninhibited contractions

of the detrusorMale sex

- High detrusor pressure





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to address whether these two different first-lineevaluations have any influence on managementand prognosis of vesicourethral dysfunction in MSpatients. In the absence of such a study, mostauthors agree with the view that a thorough

urodynamic evaluation is mandatory for effectivelydiagnosing urinary tract dysfunction, detecting therisk factors for upper urinary tract and planningurinary tract management in MS patients, althoughthis view is challenged by other authors[4,26,33,64,65].

The rhythm and modality of subsequent evalua-tions are then determined according to the natureand number of urinary tract morbidity risk factorsidentified at the above initial evaluation (Table 4,

Figure 5). Two risk situations can be distinguished:a risk-free situation, in patients who do not presentany of the LSP1 risk factors and no more than oneLSP2 factor, and a risky situation in patients whopresented at least one LSP1 risk factor or more than

two LSP2 factors.

Risk-free patients

For risk-free patients, a systematic annual evalua-tion is advocated, including a three-day voidingchart, uroflowmetry (measurement of urinary flowrate) and a postvoid residual measure. If symptomsand risk factors remain stable, a three-year urody-namic exam is recommended. If symptoms and/or

ASYMPTOMATIC PATIENT SYMPTOMATIC PATIENT

Minimal evaluation Neuro-Urologic physician

Specific questionnaire of VUD

Post void residual

Micturitional symptoms ? Baseline evaluation3-days voiding chart

Urinary Echography

Urine bacteriology

No Yes Urodynamic studyUrinary creatinin clearanceQuality of Life related to VUD

Analysis of risk factors

Minimal evaluation

at each MS follow-up visit

Specific questionnaire of VUDPost void residual

Risk-free patient Risk patient

Annual evaluation Annual evaluation

3-days voiding chart 3-days voiding chartUroflowmetry Post void residual

Post void residual Urinary echographyUrinary creatinin clearance

Quality of Life VUD

Urodynamics(1 to 3 year)

Change in risk factors

No Yes

Urodynamics Urodynamics

every 3 years

Upper Urinary tract Risk of bladder cancerdeterioration

Multidisciplinary consideration Annual cystoscopy

Annual cytolopy

Complementary exam

Figure 5 Recommendations for diagnosis and follow-up of neurogenic bladder in MS.





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risk factors have changed, a new evaluation of theurodynamic status is then required.

Risk patients

For risk patients, the annual evaluation should bemore complete, based on five systematic para-meters:

1) a three-day voiding chart,2) a postvoid residual measure,3) an ultrasound scanning of the urinary tract,4) a urinary creatinine clearance,5) an evaluation of quality of life relative to VUD.

The urodynamic follow-up should be systematic,with a timing adapted to the severity of the riskfactors, including a cystometry every one to threeyears.

A morphologic study should be mandated toexplore and follow an upper urinary tract deteriora-tion.

Patients with upper urinary tract deterioration

In patients presenting upper urinary tract deteriora-tion or severe risk factors, especially permanenthigh detrusor pressure, the management should beconducted with multidisciplinary consideration,taking into account the advice of a neurourologistexpert, a neurologist, a physical rehabilitationpractician, the treating physician and the patient,

in order to define the best therapeutic option,adapted to the urinary tract function as well asthe general deficiency and the patients environ-ment. The nature and rhythm of complementaryexams should be decided by this multidisciplinarystaff and could include imaging techniques (cy-stourethrography, scans, cystoscopy . . .), and func-tional exams (renal scintigraphy . . .).

Patients with risk of bladder cancer

Lastly, in patients presenting specific risk of bladder

cancer, in particular those with chronic permanentcatheterization, annual cytology and annual cysto-scopy are recommended.

Conclusion

This literature review suggests that the urinary tractprognosis, commonly reputed to be satisfactory inMS, needs to be reconsidered. More than onepatient out of ten is likely to develop an upper

urinary tract complication during the first 18 yearsof disease duration. Better knowledge of the riskfactors for neurogenic bladder in MS with a urinarytract impact, and of their progressive profile, shouldlead to a controlled and consensual use of monitor-

ing examinations. This could further the adoptionof preventive and curative therapeutic measuresaimed at improving the quality of care and life ofMS patients with a positive individual and eco-nomic impact on public health as a result.

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