INC ONTINENCE
`
`EDITORS
`
`PAUL ABRAMS - LINDA CARDOZO -
`
`SAAD KHOURY - ALAN WEIN
`
`5”‘ International Consultation on Incontinence, Paris February, 2012
`
`‘%J§'ZL'2'ZT;'.T.,n 5"‘ EDITION 201 3
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0001
`
`

`
`© ICUD-EAU 2013
`
`All rights reserved. No part of this publication may be reproduced. stored in a retrieval system, or transmitted in
`any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior permis-
`sion ofthe publisher.
`
`Accurate indications, adverse reactions, and dosage schedules for drugs are provided in this book, but it is possible
`that they may change. The reader is urged to review the package information data of the manufacturers
`of the medications mentioned.
`
`The Publishers have made every effort to trace the copyright holders for borrowed material. If they have inadver-
`tently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity.
`
`The great tragedy of science :
`
`The slaying of a beautiful hypothesis by an ugly fact
`
`Thomas Huxley (1825-1895)
`
`ISBN : 978-9953-493-21-3
`
`LAYOUT: SMART-DOT marketing 8; web consultants - www.smart-dot.com
`
`2
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0002
`
`

`
`Committee 1
`
`Epidemiology of Urinary
`Incontinence (UI) and other Lower
`Urinary Tract Symptoms (LUTS),
`Pelvic Organ Prolapse (POP) and
`Anal Incontinence (Al)
`
`Chair
`
`IAN MILSOM (SWEDEN)
`
`Members
`
`D. ALTMAN (SWEDEN)
`
`R. CARTWRIGHT (UK)
`
`M. C. LAPITAN (THE PHILIPPINES)
`
`R. NELSON (UK)
`
`U. SILLEN (SWEDEN)
`
`K. TIKKINEN (FINLAND)
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0003
`
`I5
`
`

`
`CONTENTS
`
`A. INTRODUCTION
`
`B. BASIC EPIDEMIOLOGICAL
`CONSIDERATIONS
`
`C. EPIDEMIOLOGY OF ENURESIS AND UI IN
`CHILDREN
`
`I. GENERAL COMMENTS AND DEFINITIONS
`
`n. PREVALENCE o|= NOCTURNAL
`ENURESIS (NE)
`
`III. POTENTIAL RISK FACTORS FOR NE
`
`IV. PREVALENCE OF FUNCTIONAL
`INCONTINENCE IN CHILDREN
`
`V. POTENTIAL RISK FACTORS FOR DAY
`WETTING
`
`VI. SUMMARY POINTS
`
`D. EPIDEMIOLOGY OF UI IN WOMEN
`
`I. GENERAL COMMENTS AND DEFINI11ONS
`
`II. PREVALENCE
`
`III. INCIDENCE AND REMISSION
`
`IV. RISK FACTORS
`
`V. SUMMARY POINTS
`
`VI. FUTURE DIRECTIONS
`
`E. EPIDEMIOLOGY OF UI IN MEN
`
`I. GENERAL COMMENTS
`
`II. PREVALENCE
`
`III. POTENTIAL RISK FACTORS FOR UI
`
`IV. FACTORS OF UNCLEAR ASSOCIATION WITH
`UI IN MEN
`
`V. SUMMARY POINTS
`
`F. EPIDEMIOLOGY OF OVERACTIVE
`BLADDER AND NOCTURIA
`
`I. OVE RACTIVE BLADDER
`
`II. NOCTURIA
`
`G. EPIDEMIOLOGY OF POP
`
`I. GENERAL COMMENTS AND DEFINITIONS
`
`II. PREVALENCE OF POP
`
`III. INCIDENCE
`
`IV. POTENTIAL RISK FACTORS
`
`H. THE GENETIC EPIDEMIOLOGY OF UI AND
`POP IN ADULT WOMEN
`
`I. FAMILY STUDIES
`
`II. TWIN STUDIES
`
`III. SEGREGATION ANALYSES
`
`IV. LINKAGE STUDIES
`
`V. GENE ASSOCIATED STUDIES
`
`VI. SUMMARY POINTS
`
`I. EPIDEMIOLOGY OF ANAL INCONTINENCE
`
`I. GENERAL COMMENTS AND DEFINITIONS
`
`II. PREVALENCE
`
`III. INCIDENCE
`
`IV. RISK FACTORS
`
`V. PREVENTION
`
`VI. SUMMARY POINTS
`
`VII. FUTURE NEEDS
`
`J. WHY DO PREVALENCE ESTIMATES
`DIFFER?
`
`I. GENERAL PROBLEMS IN SURVEY RESEARCH
`
`II. DIFFERENT DEFINITIONS AND MEASUREMENT
`
`III. SUMMARY POINTS
`
`K. HELP SEEKING BEHAVIOUR
`
`I. U RINARY INCONTINENCE
`
`II. FAECAL INCONTINENCE AND
`PELVIC ORGAN PROLAPSE
`
`Ill. SUMMARY POINTS
`
`L. EPIDEMIOLOGYAND CLINICAL WORK: FROM
`RESPONDENT TO PATIENT
`
`I. WORLDWIDE ESTIMATES OF CURRENT AND
`FUTURE INDIVIDUALS (220 YEARS WITH LOW-
`ER URINARY TRACT SYMPTOMS NCLUDING
`URINARY INCONTéI|\I-‘EKINI-I’BEE;ND OVERACTIVE
`II. SUMMARY POINTS
`
`M. RECOMMENDATIONS FOR FURTHER
`RESEARCH
`
`I. URINARY INCONTINENCE
`
`ll. FAECAL INCONTINENCE AND PELVIC ORGAN
`PROLAPSE
`
`V. SUMMARY POINTS
`
`REFERENCES
`
`16
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0004
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`

`
`Epidemiology of Urinary Incontinence
`(UI) and other Lower Urinary Tract
`Symptoms (LUTS), Pelvic Organ Pro-
`lapse (POP) and Anal Incontinence (Al)
`
`D. ALTMAN, R. CARTWRIGHT, M. C. LAPITAN, R. NELSON, U. Sittém, K. TIKKINEN
`
`IAN MILSOM
`
`A. INTRODUCTION
`
`here may have equally useful information, but lack of
`space precluded their inclusion.
`
`In this report we focus on the epidemiology (distri-
`bution and determinants) of urinary incontinence
`(UI) and other lower urinary tract symptoms (LUTS),
`pelvic organ prolapse (POP) and anal incontinence
`(Al). We also discuss important topics such as dif-
`ferences between epidemiological and clinical ap-
`proaches to health problems, help seeking behav-
`iour, and methodological issues for this research.
`
`We have included a section on overactive bladder
`
`and nocturia which are commonly occurring LUTS.
`A worldwide estimation of the current and future
`
`number of individuals with LUTS [121 including UI
`and overactive bladder (OAB) is also included at the
`end of this chapter.
`
`The epidemiological population under study for this
`review will mainly be community dwelling non-insti-
`tutionalised persons. The review will include discus-
`sion of the prevalence, incidence. natural history, and
`presence of racial and ethnic differences. We also
`review correlates and potential risk factors that have
`been revealed in epidemiological studies. Progress
`has clearly been made during the 4 years since our
`previous report when the 4th International Consulta-
`tion on Incontinence (4th ICI) was published. Some
`new important areas have been studied with increas-
`ing regularity and quality. We have searched the
`literature for relevant new articles, thus reviewing a
`large number of high-quality and population based
`studies, as well as clinical trials that might include rel-
`evant epidemiological data. Because of an abundant
`number of studies, only a small fraction can be pre-
`sented in a text like this. Other studies not presented
`
`Summary points:
`
`- This review includes discussion of the prevalence,
`incidence. natural history, and presence of racial
`and ethnic differences in the epidemiology of UI,
`OAB, nocturia, POP and Al.
`
`- Correlates and potential risk factors that have
`been revealed in epidemiological studies are
`also reviewed.
`
`B. BASIC EPIDEMIOLOGICAL
`
`CONSIDERATIONS
`
`Epidemiology is the scientific study of the distribution
`and determinants of disease in people. Descriptive
`epidemiology is the description of disease prevalence.
`incidence, (and mortality) by persons, place and time,
`while the term analytical epidemiology describes the
`search for determinants of disease risk. The discovery
`of risk factors and protective factors may then in turn
`lead to primary or secondary prevention.
`
`In order to collect knowledge about risk factors or
`natural history, observational studies are needed.
`Cohort studies and case—control studies are the
`
`most common. However, caution is always needed
`when interpreting the results from such studies, as
`associations found in epidemiological studies may
`not be the same as causes. Longitudinal study de-
`signs and appropriate control for confounding fac-
`tors are preferred, as these increase the validity of
`epidemiologic studies. For practical and ethical rea-
`sons, experimental designs are seldom used.
`
`17
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0005
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`

`
`Recommendations and conclusions should always
`be based on the best available evidence. Studies of
`
`interventions, and studies of risk factors generally
`cannot be randomised because they relate to inher-
`ent human characteristics or practices, and expos-
`ing subjects to harmful risk factors is unethical. No
`uniform guidelines for assessing the results of ob-
`servational studies exist, and the level of evidence
`for risk factors from observational studies should be
`
`judged on the soundness of the exclusion of alter-
`native explanations by statistical and other controls.
`But some initiatives for how to report meta-analyses
`of observational studies have been taken [3].
`
`Studies of disease frequency should rely on a very
`specific definition of the condition under investi-
`gation. The absence of unifying definitions for the
`conditions reviewed here is a fundamental problem
`which has not been resolved. Definitions used and
`
`problems associated with them are discussed in the
`subsections for the particular populations below.
`
`Prevalence is defined as the probability of experienc-
`ing a symptom or having a condition or a disease
`within a defined population and at a defined time
`point. The concept is important for establishing the
`distribution of the condition in the population and for
`projecting the need for health and medical services.
`
`incidence is defined as the probability ofdeveloping
`the condition under study during a defined time pe-
`riod. Incidence is usually reported for one—,
`two— or
`five-year time intervals.
`
`Even in many of the recent studies reviewed analy-
`ses are very simple. Often only proportions or per-
`centages are used to describe differences in differ-
`ent subgroups. Many analyses do not control for
`confounders (by stratification or multivariate analysis
`techniques). There is an obvious need for more ad-
`vanced epidemiological analyses of risk factors and
`comorbidity, and strength of associations should be
`determined by relative risks and odds ratios.
`
`The relative risk (RR) estimates the magnitude of
`an association between exposure and a condition,
`and indicates the likelihood of having the condition
`in the exposed group relative to those who are not
`exposed (e.g. do not have the risk factor). A RR of
`1.0 indicates that the rates in the exposed and non-
`exposed groups are identical and thus that there is
`no association between the exposure and the con-
`dition in that specific dataset. A value greater than
`1.0 indicates a positive association or an increased
`risk. A RR of 2.5 for Ul indicates that there is a 2.5
`
`times increased risk or that the persons in question
`are 150 percent more likely to have incontinence
`than those without the risk factor.
`
`The odds ratio (OR) is the odds for having a risk fac-
`tor in persons with a condition divided by the odds
`among those without the condition. An OR of 2.5 for
`Ul my be interpreted as meaning that in this sample
`
`the odds in favour of having incontinence are 2.5
`times higher among those with the risk factor than
`among those without.
`
`For a condition with high prevalence, like UI or POP,
`OR and RR will not be identical, but in practice the
`results can be interpreted similarly. Results should
`always be given with a 95% confidence interval (CI).
`
`Words like well established and established may be
`used about risk factors and findings with a high level
`of evidence in the literature. For less documented
`
`findings words like " indications of" or " data are sug-
`gestive" may be used.
`
`Summary points:
`
`-Descriptive epidemiology reports disease inci-
`dence, prevalence (and mortality) by persons,
`place and time.
`
`- Analytical epidemiology searches for determinants
`of disease risk. There is a need for good longitudi-
`nal cohort studies.
`
`- Variations in definitions and measurement issues
`
`are fundamental, and lead to problems with as-
`sessing the findings in epidemiological studies.
`
`- There is a need for more advanced epidemiologi-
`cal analyses of risk factors and comorbidity using
`multivariable techniques, and strength of associa-
`tions should be determined by relative risks and
`odds ratios.
`
`C. EPIDEMIOLOGY OF ENURESIS
`
`AND Ul IN CHILDREN
`
`
`I. GENERAL COMMENTS AND
`DEFlNITIONS
`
`The International Children's Continence Society
`(ICCS) has issued new recommendations regard-
`ing terminology of bedwetting or nocturnai enure-
`sis (NE) [4]. NE is now the term for all urinary
`incontinence during sleep taking place in dis-
`crete episodes. regardless of the presence or ab-
`sence of concomitant daytime symptoms. Mono-
`symptomatic nocturnai enuresis (MNE) denotes
`bedwetting without any other LUTS symptoms,
`and non-rnonosyrnptomatic nocturnal enuresis
`(NMNE) should be used for those with any con-
`comitant LUTS.
`
`NE is caused by relative nocturnal polyuria [5]
`andior nocturnal bladder over-activity [6], com-
`bined with the lack of arousal at the time when the
`
`bladder needs to be emptied. The most important
`cause is, of course, the lack of arousal, otherwise
`the child would have had nocturia.
`
`18
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`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0006
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`

`
`Any other leakage of urine in children during both
`the day and night is referred to as Ul, just as it is
`in the adult population. Ul with no obvious cause,
`i.e. without neurological or congenital anatomic al-
`terations, is often seen together with other urinary
`symptoms such as frequency, urgency and infec-
`tions. Altogether these symptoms are referred to
`as functional LUT dysfunction, which is the term
`used to describe the entire spectrum of functional
`filling-voiding disturbances. Several sub-classifi-
`cations have been used for children who present
`with varying degrees of ‘'functional‘‘ urinary symp-
`toms. Some are based on urodynamic patterns.
`others on clinical presentation.
`
`According to recent definitions by the ICCS [4],
`based on symptoms and flow-residual studies
`rather than invasive urodynamic investigations,
`incontinence as a result of a filling-phase dys-
`function, is in most cases due to an OAB, which
`can also be referred to as “urgency syndrome"
`and “urge
`incontinence". Children with OAB
`usually have detrusor overactivity, but this label
`cannot be applied to them without cystometric
`evaluation. When incontinence is the result of a
`
`voiding-phase dysfunction, the diagnosis is often
`dysfunctional voiding (DV), which is induced by
`increased activity in the sphincter and pelvic floor
`during voiding.
`It is subdivided into staccato and
`fractionated voiding, and the terms cannot be ap-
`plied unless repeat uroflow measurements have
`been performed. Voiding postponement (VB) is
`another common LUT dysfunction causing Ul
`in
`children, but differs from the other since it is in-
`duced by a habitual postponement of voiding and
`not a LUT dysfunction per se.
`
`NE and UI due to functional LUT dysfunction are
`the wetting problems addressed in this chapter.
`Both can be either primary (the child has not been
`dry for more than six months) or secondary (the
`wetting has recurred after a dry period lasting more
`than six months). If the complaints are secondary,
`they may signify psychological, neurological or
`even structural anomalies and therefore require
`careful consideration.
`
`is socially incontinent but
`The healthy infant
`physiologically continent, because micturitions
`(about once every hour) are discrete and there
`is no leakage of urine between micturition [7].
`Bladder control develops during the first four to
`six years of life and is a highly complex pro-
`cess, which is still not fully understood. Most
`children are toilet trained by the age of three
`years, although there is huge social and cultural
`variation. By the age of five years, the child is
`normally able to void at will and to postpone
`voiding in a socially acceptable manner [8]. By
`this age, night—time and daytime involuntary
`wetting becomes a social problem and a cause
`for therapeutic intervention.
`
`ll. PREVALENCE or NOCTURNAL
`snueesrs (NE)
`
`As bladder control is something that develops over
`time, longitudinal studies are the best way of defin-
`ing the dynamics of this process. Studies giving us
`the prevalence for all children between five and 15
`years of age, for example, are not appropriate, as
`all the developmental stages are clustered together.
`It is therefore better to give the prevalence for an
`age cohort, such as seven—year—olds. Furthermore,
`random sampling should preferably be used in or-
`der to be able to say anything about the population.
`These problems associated with understanding
`epidemiology were summarised by Krantz [9], who
`also reviewed the epidemiological studies that had
`been published by 1993.
`
`One explanation for the variation in prevalence in
`different studies is the fact that some studies include
`
`only monosymptomatic enuresis (MNE), whereas
`others also include what is defined as non—mono—
`
`symptomatic enuresis (NMNE). Another explana-
`tory factor is that the frequency of enuretic episodes
`differs or is not taken into account in some studies.
`
`Moreover, most epidemiological studies link primary
`and secondary enuresis together.
`
`1. PREVALENCE OF ALL NIGHT WETTING
`
`(MNE+ NMNE) ACCORDING TO AGE
`
`Longitudinal cohort studies should be the ideal
`when analysing epidemiology in childhood NE, as
`there is a successive reduction in prevalence. Only
`a few of these studies are available [10~15] and
`cross-sectional studies at different ages therefore
`have to be used.
`
`Most studies investigate cohorts of children in an age
`span of six to 12 years of age, for example, and give
`the prevalence for the entire group. Some of them also
`give the age-related prevalence [13, 16-26] which is
`summarised in Table 1. Cross-sectional studies of a
`
`specific age are also included [27-31] in Table 1.
`
`In most studies (Table 1), the prevalence for seven-
`year—o|ds was between 7% and 10%. In two studies,
`the prevalence was higher; 15.1% and 16.4% for
`Turkish [20] and Korean [18] children respectively,
`despite the fact that the inclusion criteria were very
`similar in all the studies dealing with seven-yeah
`olds (NE=night wetting oncefmonth or more), apart
`from the studies by Helistrom [27] (oncef3 months
`or more) and Jairvelin [28] (onceifi months or more).
`The prevalence of more frequent wetting (once!
`week or more) was lower compared to the preva-
`lence for all wetting (oncelmonth or more) by age,
`which have been illustrated in Figure 1.
`
`In nine studies at age seven years [‘l2,16,19,21—
`2427-28], (Table 1)the numbers of both non-enuretic
`and enuretic children were given and the definitions
`
`19
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`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0007
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`
`Table 1. Prevalence of nocturnal enuresis (NE) ( =
`Monosymptomatic nocturnal enuresis (MNE) + Non-
`monosymplomatic nocturnal enuresis (NMNE)
`to-
`gether) grouped according to age.
`
`Author and year
`
`Prevalence of NE (%)
`
`7 years 11-12 years 16-17 years
`
`
`
`Chiozza [16]
`Jarvelin [28]
`Spee-van der Wekke [18]
`Cher [19]
`
`Hellstrbm [27, 29]
`Ferguson [12]
`
`Kanaheswari [25]
`
`Serel [20]
`Lee [21]
`Swithinbank [30, 31]
`
`Soderstrorn [23]
`Kajiwara [22]
`
`Yeung [24]
`But|er[15]
`Su [26]
`
`0.5
`
`1.1
`
`1.7
`
`for enuresis were similar (MNE and NMNE, wetting
`oncel1 -3 months or more). A prevalence of 10% was
`obtained by meta-analyses of these studies (cohort
`of 14372 seven-year-old children, of whom 1422
`were enuretic). Only four studies included groups of
`children that were chosen at random from the popu-
`lation [16,21,24,28].
`
`At age 11-12 years. the prevalence of NE had
`decreased and from the studies shown in Ta-
`
`ble I the prevalence varied between 1.7% and
`4.7%.
`In seven of the studies,
`the number of
`12
`
`10
`
`non-enuretics and enuretics were available and
`
`the definition of NE was similar (oncelmonth
`or more), apart from Swithinbanl-<'s [30] study
`(oncei3 months or more).
`In these studies, the
`total number of children included was 8947, while
`the number of children with NE was 278, giving a
`prevalence of 3.1%. So, of those children with NE
`at age seven years, almost 15% spontaneously
`grow out of the wetting every year.
`In a recent
`Japanese study a higher resolution rate was re-
`ported in children with MNE compared to NMNE
`in children 1’ to 12 years of age (21% and 15%,
`respectively) [22]. Similar results were found in
`a study from Hong Kong in which the proportion
`of children with NMNE was significantly greater
`in adolescent boys than in boys aged 5-10 years
`(32% vs 14.6%), even if the total prevalence of
`NE was decreasing as in other studies [24].
`
`The variation in the prevalence of NE at 11-12
`years between the studies is less than that seen
`at age seven years. The highest prevalence is
`no longer found in Turkey or Korea, as was the
`case at age seven years. but instead comes from
`a non-randomised cross-sectional study of 11- to
`12-year-old schoolchildren (n=1145)
`in the UK
`(4.7%). It can therefore be suggested that the high
`prevalence seen in the studies from Turkey and
`Korea at age seven is not due to differences in ge-
`netic predisposition, but rather to phenotypic dif-
`ferences, such as the age of toilet training and the
`subsequent attainment of bladder control, socio-
`economic status, or cultural differences.
`
`At age 16-17, three cross-sectional studies show
`a further reduction in prevalence to 0.5-1.7%. Two
`of the studies re-investigated children who had
`
`- NE>1i6 months
`
`— NE>1/week
`
`L2
`
`$8
`LlJ
`
`2‘
`
`O-
`06
`
`3 53
`
`4>
`
`9 ‘
`
`7
`
`11-12
`
`16-17
`
`Age - years
`
`Flgure 1. Prevalence of nocturnal enuresis (ME) by frequency of enuretlc episodes and age. The data were
`obtained from metaanalyses of the epidemiological studies included in table lll.1. NE>1 episode/émonths:
`at 73/ears [16, 19, 21-25, 27-23,], 11-12 years [16, 19, 21-24, 30} and 16-17years[2-1, 29, 31]. NE:-1 episode/
`week: at age 7 years [23, 24, 27, 28], 11-12 years [23, 24, 30] and 16-17 years [24, 29}.
`
`20
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`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0008
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`previously been studied; at age seven years [29]
`and 11-12 years [30] respectively. The prevalence
`when the cohorts were added together was 1.3%
`(cohort=3819, NE=51) [24,29,31]. which gives a
`spontaneous cure rate of 11% a year among those
`who wet at age 11-12 years.
`
`In a study of 13,081 adults randomly sampled in
`the Netherlands [32], an overall prevalence of NE
`of 0.5% was found. There was no significant dif-
`ference between age groups. Primary NE was re-
`ported by 50% of the men and 19% of the women,
`indicating that a small group of the enuretic chil-
`dren remain enuretic as adults.
`
`2. PREVALENCE OF MONOSYMPTOMATIC
`
`ENURESIS (MNE)
`
`Very few studies make a distinction between MNE
`and NMNE and it
`is therefore difficult
`to obtain
`
`relevant figures for MNE (Table 2). In two studies
`from Scandinavia dealing exclusively with seven-
`year-olds. there was agreement between the stud-
`ies; 6.4% [28] and 7.4% [27]. Recently, a Japa-
`nese study gave similar figures for MNE; 6.2% at
`age 7 years. In this latter study MNE corresponded
`to approximately 60% of all NE in ages from 7 to
`12 years [19]. When it comes to studies in which all
`ages were mixed (5-12 years), four studies were
`identified in which those without daytime voiding
`problems could be identified.
`
`However, the difference in prevalence of MNE var-
`ied in these studies; 3.5% [17], 6.9% [33], 9.4%
`[21] and 15% [34].
`
`3. PREVALENCE OF NE VERSUS GENDER
`
`Almost all epidemiological studies of NE report a
`higher prevalence in boys than in girls, with a ratio
`of 2:1 in western countries [16-23.26-28.30.33-35].
`It appears that the gender difference diminishes
`
`Table 2. Prevalence of Monosymplamallc nocturnal
`enuresis (MNE) at age seven years and overall (in-
`cluding all ages).
`
`Author and year
`
`Prevalence of MNE (%)
`
`Age 7 years
`
`All ages included
`
`Kajiwara [22]
`
`Jarvelin [28]
`
`Hellstrdm [27]
`
`Kanaheswari [25]
`
`Lee [21]
`
`Yeung [17]
`
`Neveus [33]
`
`Bower [34]
`
`with age and becomes less visible and less proven
`among older children [29.31.36] (Figure 2).
`
`4. PREVALENCE OF NE VERSUS ETHNICITY
`
`In a study from The Netherlands [18]. a higher
`prevalence was reported in the Turi<ishlMoroccan
`group (14%) than in the Dutch children (6%) (OR
`3.76 (95°/oC| 1.98—7.12)). An equally high preva
`lence was found in a Turkish study of children with
`NE [20] at age seven years (15.1%).
`In a study
`from Korea [18], the same high prevalence at age
`7 years was identified (16.4%). However, other
`studies from South-East Asia had comparable
`[19,22,24] or even lower levels of prevalence to
`those in western countries.
`In fact.
`two Chinese
`studies have shown a low prevalence of nocturnal
`enuresis [17,37], 3.6% and 4.3% for children aged
`4-12 and 6-16 respectively, which they attribute to
`earlier nocturnal urinary control
`in Chinese chil-
`dren. due to earlier toilet training.
`
`5. PREVALENCE OF NE VERSUS FREQUEN-
`CY OF WET NIGHTS AND AGE
`
`Yeung et al [24]showed in a large epidemiological
`study that the relative proportion of subjects with
`frequent becl—wetting increased with age. Overall
`82% of the adolescents had >3 wet nightslweek
`versus enuretic children aged 5-10 (42%) (Fig-
`ure 3). Such a relationship is also evident in fig
`1,
`in which the proportion of children with severe
`NE increase with age, even if the total number de-
`crease. Further support for severe NE to remain
`in a higher proportion as compared to children
`with infrequent bedwetting was shown in a recent
`study [15]. Findings in epidemiological studies also
`show a correlation between severity of the NE and
`NMNE [15-16,38], meaning that NE in adolescents
`often are combined with LUT dysfunction.
`
`III. POTENTIAL RISK FACTORS FOR NE
`
`Several risk factors have been established or sug-
`gested by epidemiological studies and the most
`important ones will be discussed here.
`
`1. DAYTIME UI AND LUT DYSFUNCTION
`
`Daytime Ul. a symptom of LUT dysfunction, has
`in epidemiological studies been shown to be the
`strongest predictor
`for NE (OR 4.8 (2.9-7.9))
`and has been identified in a third of the patients
`(NMNE) [38]. However. poor concordance was re-
`vealed (kappa 0.25), which confirmed the two to
`be separate entities that should be evaluated and
`treated separately.
`
`2. FAMILY HISTORY
`
`NE is a hereditary disorder and this has been
`demonstrated in many studies
`(for example,
`[16,17,20,28,33,34,39]. The mode of inheritance
`appears to be autosomal dominant. Jarvelin [28]
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0009
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`2
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`2 ‘
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`9O
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`Age - years
`Figure 2. Prevalence of nocturnal enuresis (NE) >1 episode/émonths, by gender and age. The prevalence
`data were obtained from metaanalyses of the following epidemiological studies: at age 7 [16, 22-24, 27, 28},
`age 11-12 [16, 22-24, 30] and age 16-17[24, 29, 31].
`
`18
`
`16
`
`14
`
`I <3 wet nights per week
`
`I 3-6 wet nights per week
`
`I 7 wet nights per week
`
`.1 1'0
`
`
`
`Prevalence(‘/o) E
`
`
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`Age - years
`Figure 3. Prevalence of nocturnal enuresis by frequency of enuretic episodes and age. Data from [21].
`
`if both parents were enuretics as
`showed that,
`children, the RR (95% CI) for the child to have
`NE was 16 (6.3-20.1). while if only one was en-
`uretic, the RR was ?’.8 (5.1—9.8).
`It has recently
`been shown that the risk for the child to have he-
`
`reditary NE is increased with the severity of the
`enuresis. Children with severe NE (>2 episodesl
`week) were combined with odds ratio for maternal
`NE 3.63 (2.56-5.14), whereas mild and moder-
`ate NE (<2 episodeslweek) had 2.14 (1.74—2-64)
`[40]. The association with paternal NE was less
`pronounced. but a similar increased association
`
`to severe NE was observed. Using molecular
`genetic methods, foci have been found on chro-
`mosomes 13, 12, 8 and 22 [41-42. A picture of
`pronounced heterogeneity for both genotype and
`phenotype emerges [43].
`
`3. PSYCHOPATHOLOGY
`
`There are evident connections between childhood
`
`enuresis and mental well-being 13—‘l4.37,39.44—47].
`Evidence is accumulating to show that psychologi-
`cal consequences are probably caused by the en-
`uresis and not a cause of primary NE, which has
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0010
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`been thought for a long time [45]. The findings pre-
`sented by Feehan [14] support this latter statement,
`as he only found an association between psycho-
`pathology and secondary NE. while children with
`primary NE did not display a connection of this kind.
`
`4. DEVELOPMENTAL DELAY AND ADHD
`
`Children with developmental delay and mental re-
`tardation have been shown to have a higher prev-
`alence of NE [12,18,28,48]. Spee—van der Wekke
`[18] found that children who were given special edu—
`cation in school, including both those with and with-
`out mental retardation, had an OR of 3.74 (95%Cl
`2.32-5.03) for NE.
`
`Perinatal events such as toxaemia and low birth
`
`weight. possibly involving an increased risk of mi-
`nor neurological dysfunction, have also been shown
`to be associated with NE [12,28,39]. A connection
`between NE and minor neurological dysfunction of
`this kind has also been shown by Lunsing [49] in
`12-year-old enuretic children. Furthermore, children
`with attention deficit hyperactivity disorders (ADHD)
`are more likely to have enuresis than the general
`child population [46,50-52].
`
`5. SLEEP AND AROUSAL
`
`The main pathology behind NE in children is the in-
`ability to wake up to the sensation of a full bladder.
`Parents often say that their enuretic child “ sleeps
`very deeply". Some recent studies support this view.
`By using auditory signals [53], computerised EEG
`[54] or questionnaires [33], a defect in arousal has
`been largely validated. In the study by Neveus [33],
`the odds ratios were significantly high for a high
`arousal threshold (2.7), pavour nocturnus (2.4) and
`confusion when awoken from sleep (3.4). Computer-
`ised EEG energy analysis has indicated both greater
`depth of sleep and impaired arousal in enuretics [55].
`Difficult arousal from sleep has also been shown in
`children with NE compared to children with isolated
`day—wetting problems and controls, by using a scor-
`ing system in a questionnaire [56].
`
`6. SOCIO-CULTURAL FACTORS
`
`the prevalence of NE [17,20-
`in
`Differences
`21 ,37,57] at early ages in different parts of the world
`are probably partly due to socio-cultural differences
`and not to differences in genetic predisposition [18].
`It has been suggested that socio-economic status
`correlates with NE in some studies [16,46]. whereas
`in others no correlation was found [12].
`
`7. OTHER RISK FACTORS
`
`Obstructive steep apnoea (OSA) has been asso-
`ciated with enuresis in some patients [58].
`In an
`epidemiological study association between severe
`OSA and NE in girls was shown [26], but when in-
`cluding both sexes and all forms of OSA no differ-
`ence was seen. In another study dealing with OSA
`patients versus controls, a significant correlation
`
`between NE and OSA was found (OR 5.1 (2.4-10.7)
`[59]. Removal of large adenoids or tonsils causing
`upper airway obstruction in children with NE sig-
`nificantly reduced or cured NE [60]. Constipation
`(see co-morbidity below) may cause secondary NE
`or make primary NE persist [58]. Enkopresis was
`shown as a risk factor for NE in an epidemiological
`study (OR 2.7 (1.6-4.4)), while no association with
`constipation could be identified [38]. Sexual abuse
`must also be included among the factors that may
`lead to NE [62]. Organic conditions such as infra-
`vesical obstruction and neuropathic bladder may
`also present as NE.
`In most cases, however, ad-
`ditional symptoms are present to make detection
`possible. Type1 diabetes was reported to be a risk
`factor for secondary MNE due to the polyuria seen
`at presentation [63].
`
`IV. PREVALENCE OF FUNCTIONAL
`INCONTINENCE IN CHILDREN
`
`In children with functional LUT dysfunction, OAB is
`far more common than dysfunctional voiding. In a
`urodynamic study of 1,000 patients with functional
`LUT dysfunction, approximately two—thirds had an
`OAB and one-third had dysfunctional voiding [64].
`Based on clinical
`information, another study com-
`prising 226 children revealed that 76% were con-
`sidered to have an OAB and only 1% dysfunctional
`voiding. The difference illustrates that different in-
`clusion criteria influence the rate of prevalence [65].
`
`(all
`When considering the total prevalence of Ul
`frequencies of Ul included) (Table 3), there was a
`variation between 3.2% and 9% in different studies
`
`In the earliest studies
`at the age of seven years.
`the prevalence was lower (3.2%-5.0%), whereas
`in the studies performed later in the 2000 [21, 23,
`66-68], the prevalence was higher 5.3%-9.0%. One
`explanation for the difference was probably an in-
`creased recognition ofthe problem in the population
`through information via media etc. At 11-13 years
`the reported prevalence varied between 1.1% and
`12.5%. Swithinbank’s study [30] showed a very high
`prevalence (12.5%) and differed most from the rest
`(1.1%—4.2"/o). The difference could probably partly
`be explained by different limits for frequency of Ul
`(occasionally [30] vs oncelmonth or more). The fact
`that the studies were performed in different parts
`of the world was also a possible explanatory factor
`(UK and Korea).
`
`The frequency of Ul decreased with age (Table 3),
`which was clearly demonstrated in the subjects with
`frequent episodes of Ul (>1l'week) (figure 4). The
`prevalence at 7 years, 11-13 years and 15-17 years
`was 2.6%, 1.1% and 0.3% respectively. There were
`only two authors who investigated the same cohort
`of children on two occasions; Hellstrom [27, 29] in
`Sweden and Swithlnbank [27, 28] in the UK.
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0011
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`Table 3. Day urinary incontinence (Ul) (including
`mixed day/night)
`
`Author (ref)
`
`Sample size
`
`Prevalence (%)
`
`Jarvelin [28]
`
`Hellstriim [27]
`
`Lee [21]
`
`Kajiwara [66]
`
`Soderstrom [23]
`
`Joinson [57]
`
`Swithinbank [68]
`
`Total: 2892
`Boys: 1444
`Girls: 14