Epidemiology, genetics and pathophysiology: Diagnostic ......YEUNG, CHUNG K., SREEDHAR, BIJI, SIHOE,...

© 2010 Universitair Ziekenhuis Gent

Epidemiology, genetics and pathophysiology: Diagnostic Approach -

Johan van de Walle (Belgium) ICCS Cape Town 2012

2 2 © 2010 Universitair Ziekenhuis Gent

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Epidemiology

Johan Vande Walle (Belgium) ICCS Cape Town 2012


Epidemiology of MNE /NMNE !   All available epidemiological studies do mix up

!   Monosymptomatic !   And non monosymptomatic enuresis

!   Do not take in account difference between !   Primary care / tertiary care / pediatrics /Urology

!   Difference according terminology !   DMSIV / ICCS old /ICCS new

!   Methodology of reporting !   Selfreporting, Questionnaire, Phone call

!   Severe versus less severe enuresis !   Non-reporting of this “taboe” disease

!   cfr Hong Kong : increase from from 2.5-10% over 10 year


THE TOWER OF BABEL: CONFUSION IN TERMINOLOGY

ICD-10

ICCS “new ICCS-definition


Pediatrician Psychological

Maturation Minimal invasiveapproach

Urologist Bladder

Maximal invasive approach

??


Bedwetting Epidemiology §  Primary Nocturnal Enuresis is common in children and adolescents

§  Estimated prevalence of frequent bedwetting:1-5

§  Up to 25% of children aged 4 years §  10% of children aged 7 years

§  With increasing age: §  Prevalence decreases1-5 §  Frequency and severity increases6,7

1. Fergusson et al. Behav Psychother 1986; 78:884-890 2. Foxman et al. Pediatrics 1986; 77: 482-487 3. Hellstrom et al. Eur J Pediatr 1990; 149: 434-437 4. Watanabe & Kawauchi. Scan J Urol Nephrol Suppl 1994; 163: 29-38 5. de jonge, Kovin et al (eds) Bladder control and enuresis 1973: 39-46 6. Wadsworth. Am J Orthopsychiatry 1944; 14: 313 7.Turner & Taylor. Behav Res Ther 1974; 12: 41-52


Bedwetting is a Worldwide Disease with Comparable Prevalence Rates (5-15 years)

35%

21.3%, 17.6% 23.8% 15% 18.6% 9.1%

8%

8%- 5.5%

3.2% 6% 7% 23%, 4%

13.7%, 12.4%, 17.5%, 11.5% 16% 16%


Higher Frequency of Bedwetting in Boys

YEUNG, CHUNG K., SREEDHAR, BIJI, SIHOE, JENNIFER D.Y., SIT, FRANCES K.Y. & LAU, JOSEPH. Differences in characteristics of nocturnal enuresis between children and adolescents: a critical appraisal from a large epidemiological study.BJU International 97 (5), 1069-1073.

Age (years)

Prevalence (%)

Boys All

Girls


Severe Bedwetting is Persistent

YEUNG, CHUNG K., SREEDHAR, BIJI, SIHOE, JENNIFER D.Y., SIT, FRANCES K.Y. & LAU, JOSEPH. Differences in characteristics of nocturnal enuresis between children and adolescents: a critical appraisal from a large epidemiological study. BJU International 97 (5), 1069-1073.

Age (years)

Prevalence (%)

<3 wet nights per week 3-6 wet nights per week 7 wet nights per week


Severe Bedwetting is Persistent

YEUNG, CHUNG K., SREEDHAR, BIJI, SIHOE, JENNIFER D.Y., SIT, FRANCES K.Y. & LAU, JOSEPH. Differences in characteristics of nocturnal enuresis between children and adolescents: a critical appraisal from a large epidemiological study. BJU International 97 (5), 1069-1073.

Age (years)

Prevalence (%)



50% of Adolescent Bedwetting are Severe Cases

Age 5 Age 19

30%

14%

56% 49%

41%

10%


Yeung et al. BJU Int 2006; 97: 1069-1073


Child Bedwetting – Nocturnal Enuresis

Pathogenesis / pathophysiology


In the beginning… !   Enuresis usually just

meant wetting !   Nocturnal enuresis

just meant bedwetting !   Both were thought to

be psychiatric disorders

19 19 © 2010 Universitair Ziekenhuis Gent 11-6-2001 Vande Walle

enuresis fabels


Zal ik het hem eens vertellen waarom ik in bed plas ?


Pediatrician + psychologists It ‘s the child

Urologist It s the bladder

??


PSYCHOLOGICAL ,


What is true ?


Genetics

Johan Vande Walle (Belgium) ICCS Cape Town 2012


Genetics !   Strong genetic predisposition with significant

modulatory effects by somatic and psychosocial environmental factors

!   Positive family history in 63% ! Autosomal dominant transmission with

high penetrance (90%) and complex genetic heterogeneity

!   About 1/3 cases sporadic, with no significant phenotypic differences between sporadic and familial forms

von Gontard et al. J Urol 2001;166:2438–2443


!   77% risk where both parents had been enuretics as a child

!   43% risk where only one parent had been enuretic as a child

!   15% risk where there is no parental history of enuresis

!   40% siblings also had PNE

Parental history

Bakwin. Am J Dis Child 1971;121;222–225; Jarvelin et al. Acta Paediatr Scand 1988;77:148–153


Family studies in nocturnal enuresis

Why do we believe that nocturnal

enuresis is a genetic disorder?

!   Indicates the presence of genetic effects but do not prove it

Study One

parent Both

parents The father The mother Siblings

First degree relatives

Cousins and

uncles +

Frary 1930 32% 23%

Hallgren 1957 39% 23%

Bakwin 1961 72 % 20% 40% of siblings

Elian 1984 and 1991

73% of families

83% of families

Gontard 1997 23% 24% 17% of siblings

Schaumburg 2001 73%

}  Familial occurrence is well recognized (Janet 1890 and Monro 1896)


Linkage studies of nocturnal enuresis Chromosome LOD-score Marker Study OMIM

4p* 3.66 D4S2960 Eiberg 2001

8q - D8S264 Eiberg 1995

12q 4.2 D12S80 Dahl 1995 Arnell 1996 +1997 ENUR2

13q 3.55 D13S291 Eiberg 1995 ENUR1

2.67 D13S263

22q 4.51 D22S446 - D22S343 Eiberg 1998 ENUR3

What have we learned from

molecular genetic studies?

!   Locus heterogeneity in nocturnal enuresis

!   Linkage to 13q, 12q, and 22q have been confirmed in independent families

!   More loci exists as families have been reported with no linkage in these regions


Molecular genetics !   Linkage studies have identified different genetic

loci associated with PNE on chromosomes 4, 8, 12, 13 and 22

!   ‘Genetic heterogeneity’ !   No relation genotype /phenotype B Loeys

Eiberg et al. J Urol 2001;166:2401–2403


What is true ?


Mono- symptomatic Polyuria Small

bladder Dysfunctional

voiding




voiding


Polyuria

Small bladder capacity

Deep sleep arousal

Bedwetting Occurs as a Result of Two or More Causes

Bedwetting Bedwetting


Abnormal circadian rhythm of ADH secretion

Developmental delay

Psychosomatic manifestation

Sleep-arousal disturbances

Bladder detrusor/sphincter

dysfunction Abnormal bladder reservoir function

Genetic predisposition

Primary Nocturnal Enuresis

Pathophysiology of PNE


NOCTURNAL ENURESIS abnormal circadian rhytm vasopressin

primary

J.Vande Walle Pediatric uro-nefrologic center Ghent 12 Sept 2011


Diurnal variation of antidiuretic hormone (vasopressin) secretion

Plasma vasopressin

Day Night

Urine osmolality

Day Night

Urine volume

Day Night

Normal children Enuretic children


Nocturnal vasopressin levels: ‘dry’ vs ‘wet’ nights

1.8

Hansen et al. J Urol 2001;166:2452–2455

Desmopressin responders Desmopressin non-responders

0 0.2 0.4

0.8

1.4

Dry night

0.6

1.0 1.2

1.6

Wet night *p=0.004

*

*

Plas

ma

vaso

pres

sin

(pg/

mL)


3 subtypes of nocturnal polyuria with low urinary osmolality

!   inversed circadian rhytm of diuresis !   nocturnal diuresis > 50% of 24h diuresis !   short period of high diuresis with low urinary

osmolality overnight = fast filling rate !   Related to high 24 h fluid intake

2.Abnormal circadian rhytm of diuresis 3 subtypes


Nocturnal diuresis is related to

!   24 h diuresis and thus 24h fluid intake

!   But what is primum movens !   High fluid intake !   Higher diuresis overnight !   Suboptimal maximal

concentrating capacity

Abnormal circadian rhytm of diuresis related to fluid intake


NOCTURNAL ENURESIS abnormal circadian rythm vasopressin

secundary

J.Vande Walle Pediatric uro-nefrologic center Ghent 12 Sept 2011


•  Renal diabetes insipidus •  X-linked RDI : partial forms in heterozygotic girls

•  Renal diseases are associated with decreased renal concentrating capacity

•  Although the lack of anti-diuresis does not appear to be caused by a renal defect in the majority of patients,

•  since the kidney is able to concentrate urine normally, although the values do vary between 850 to >1200 mosmol/l (range of normal concentrating capacity).

•  There is a subgroup of patients who fail to concentrate > 850 mmol/l

abnormal concentrating capacity


subnormal concentrating capacity fig 2

collections

0 1 2 3 4 5 6 7

U o

smo

l (m

osm

ol/l

)

600

800

1000

1200

1400

dDAVP nasal spray 2 puff's + water-restrictiondDAVP nasal spay 2 puff's + water-load

7- 10 h2 -7 h2 h1 h0 h- 1h

n  Up to 20% does not reach urinary osmolality values > 850 mosmol/l

p < O.O1 * * * * * dDAVP

2 nasal spray


3.subnormal concentrating capacity fig 2

collections

0 1 2 3 4 5 6 7

U o

smo

l (m

osm

ol/l

)

600

800

1000

1200

1400

dDAVP nasal spray 2 puff's + water-restrictiondDAVP nasal spay 2 puff's + water-load

7- 10 h2 -7 h2 h1 h0 h- 1h

n  Up to 20% does not reach urinary osmolality values > 850 mosmol/l

n  Fluid intake prior to desmopressin results in lower / later / shorter maximal concentrating capacity

p < O.O1 * * * * * dDAVP

2 nasal spray


4.Abnormal circadian rhythm of diuresis related to osmotic load / excretion

Strong correlation between nocturnal diuresis volume

!   Nocturnal osmotic excretion !   24 h osmotic excretion !   And thus nutritional intake

!   Primary ?? !   Secundary??


Abnormal circadian rhythm of osmotic excretion

!   3 subtypes High osmotic excretion

!   (J. Dehoorne J Urol 2006)


Fig1

urine-collections1 2 3 4 5 6 7 8

osm

otic

exc

retio

n (m

osm

ol/k

g/h)

0,0

0,5

1,0

1,5

2,0

2,5

3,0

Fig2

urine-collections

1 2 3 4 5 6 7 8

diur

esis

-rate

(ml/k

g/h)

0,0

0,5

1,0

1,5

2,0

2,5

3,0

Fig3

urine-collections

1 2 3 4 5 6 7 8

U o

smol

(mos

mol

/kg)

0

200

400

600

800

1000

1200

Group 1: high 24 h intake, high 24 h excretion of solute, sodium and water, obese children


Fig1


osm

otic

exc

retio

n (m

osm

ol/k

g/h)

0,0

0,5

1,0

1,5

2,0

2,5

Fig2

urine-collections

1 2 3 4 5 6 7 8

diur

esis

-rate

(ml/k

g/h)

0,0

0,5

1,0

1,5

2,0

2,5

Fig3

urine-collections

1 2 3 4 5 6 7 8

U o

smol

(mos

mol

/kg)

0

200

400

600

800

1000

1200

Group 2: (high) Normal 24 h intake, normal 24 h excretion But high nocturnal excretion of osmol and water high osmotic load in the evening


Fig1


osm

otic

exc

retio

n (m

osm

ol/k

g/h)

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

Fig2

urine-collections

1 2 3 4 5 6 7 8

diur

esis

-rate

(ml/k

g/h)

0,0

0,5

1,0

1,5

2,0

2,5

Fig3

urine-collections

1 2 3 4 5 6 7 8

U o

smol

(mos

mol

/kg)

0

200

400

600

800

1000

1200

group 3:normal 24 h intake, normal 24 h excretion But high nocturnal excretion of osmol and water Small bladder volume Low fluid intake during daytime (defense mechanism) Low osmotic excretion during daytime


Abnormal circadian rhytm of sodium excretion

!   High 24 h urinary sodium excretion !   Kuzenetsova in random population : Yes !   Kamperis (JAmPhys 2006) :No

!   Abnormal circadian rhythm of sodium-handling !   Kamperis (J Am Phys 2006): yes !   A. Raes (J Urol 2006) probably related to

primary tubular sodium-handling disorder in distal tubulus

!   Abnormal circadian rhythm of bloodpressure


controls non-polyurics polyurics dry night

E-Na (mmol/h/kg) FE-Na (%)

8–12 12–16 16–20 20–bed night 0.00

0.05

0.10

0.15

0.20

0.25

P<0.01

NS NS NS NS

8–12 12–16 16–20 20–bed night 0.0

0.2

0.4

0.6

0.8

1.0

P<0.001

NS NS NS NS

Clearance periods Clearance periods

Kamperis. PhD thesis 2004

Polyurics excrete more sodium at night


6.Abnormal circadian rhythm of prostaglandins

Kamperis: Nocturnal polyuria = Higher PG overnight


Absence of circadian rhythm of GFR only in MNE +NP

Control Group MNE-NP−

(20)

Study Group MNE-NP+

(15)

Uvol (ml/min) 1.7 ± 0.4/0.8 ± 0.4*

1.0 ± 0.3†/1.7 ± 0.5†

GFR(ml/min/1.73m²) 126 ± 25/112 ± 23* 121 ± 27/119 ± 29

FE Na (%) 1.1±0.6/0.6±0.4* 0.8±0.2/1.0±0.4†

†: p<0.05 between the two groups * : p<0.05 between day and nighttime

Deguchtenaere A et al. J Uro 2007;178:2626-2629


THE COMORBIDITIES


Constipatie/diarree


encopresis

62 62 © 2010 Universitair Ziekenhuis Gent 11-6-2001 Vande Walle

enuresis fabels

ATTENTION DEFICIT


Cognitive disturbances night-time wetting enuresis in children 1.  The CK Yeung theory 2.  Is there evidence ? 3.  Can we extrapolate to nocturia in adults?


Theory from CK Yeung

!   Nocturnal enuresis !   Causes sleep disturbance

!   Overstimulation of central brain

!  Cognitive dysfunction !   Treatment of nocturnal enuresis

!   Amelioration of sleep !   Less exhaustion of the brain

!  Amelioration of cognitive function


Nocturnal

Polyuria NOCTURIA

Reduced Nocturnal Bladder Capacity

NOCTURIA Impaired Arousal Response

to Bladder Fullness

Pathophysiology of MNE ( A heterogeneous disorder )

Nocturnal Enuresis


MNE

treatment


Why to treat?

!   Emotional impact !   Poor self esteem !   Social impact !   Parenteral impact /intolerance !   Sleepdisturbances !   Relation to attention deficet


1.  Who should treat the patient ?

2.  When to treat the patient

3.  Treatment of choice

4.  Which patient to treat ?


How to treat?

!   Practical guidelines !   J. Vande Walle, S.Bauer, S Tekgull, J Evans, S

Rittig, P Eggert !   Eur J Pediatrics 2012


Step 1

!   Step 1 Urotherapy advice !   Step 2 based on clinical management tool


Child ≥5 years who wets bed

Advice (eg causes, fluid and food intake)

CMT questioning Physical examination and dipstick

Symptoms suggestive of bladder dysfunction/comorbidity?

YES: Treat these first/refer if

necessary NO: MNE

Advice on treatment options: shared decision based on preferences,

motivation and diary if completed

Alarm Desmopressin

Strategy 1 = MINIMAL


screening

!   Evidence for MNE or NMNE !   Identifying comorbidities that might interfere with

response-rates !   Compliance !   Combined disorder !   Constipation/ encopresis !   History of UTI, uropathy, day time symptoms !   ADHD, ADD, autism !   Mentally and motoric disability !   Sleeping disorders (snorring, waking up, restless legs )


Practical consensus guidelines for the management of nocturnal enuresis in children seen in primary care

!   screening minimal !   Clinical history !   Clinical examination

!   Screening optimal !   Daytime diary !   Nighttime diary


PNE treatment: tailor to pathophysiology

!   Normal urine output/normal bladder capacity !   Let the family choose either alarm or desmopressin

!   Nocturnal polyuria !   Initiate desmopressin treatment

!   Low FBC/high arousal threshold !   Initiate alarm treatment

!   If one treatment fails, try: !   Desmopressin plus alarm (nocturnal polyuria/low

FBC/high arousal threshold) !   Desmopressin plus anticholinergics (nocturnal

polyuria/nocturnal detrusor instability)


Voided volumes/NP help guide treatment choice in Strategy 2

EXTENSION

Child ≥5 years who wets bed

Advice (eg causes, fluid and food intake)

CMT questioningPhysical examination and dipstick

Night + daytimeDiary

Symptoms suggestive of bladder dysfunction/comorbidity?

YES: Treat these first/refer if

necessaryNO: MNE

Advice on treatment options:shared decision based on preferences,

motivation and diary if completed

Alarm(reduced MVV)

Desmopressin(NP)

Strategy 2 = OPTIMAL


Alarm

Medical follow-up contact 1–2 times/month

No improvement

Clinical re-evaluation (including diary)

Confirmation of MNEChange treatment

Improvement

Continue alarm with regular re-evaluation

Dry for 14 consecutive nights

Discontinuation

Advise family to resume

contact/treatment if relapse

No improvement at 6–8 weeks

Combination alarm + desmopressin or refer to specialist


Desmopressin

Medical follow-up contact 1–2 times/month

Titrate dose if necessary

No improvement

Clinical re-evaluation (including diary)

Confirmation of MNEChange treatment

Improvement

Continue desmopressin with regular re-evaluation

Dry for 3 months

Cease treatment(May try gradual

withdrawal)

Advise family to resume contact/treatment if relapse

Unsatisfactory improvement at 6–8 weeks

Combination alarm + desmopressin or refer to specialist


PK and PD characteristics (4) !   Clinical impression that spray was better than tablet !   And that melt might be superior to tablet

!   Advice to take tablet two hours after meal and one hour before sleeping time is not realistic in younger children

!   Pharmacodynamic study on antidiuretic effect of desmopressin melt / tablet in children in combination with meal

Desmopressin: clinical response melt / tablet


1. Ghent food study : superiority of melt versus tablet

• -

-‐U1-‐2-‐3-‐..: urinecollec1ons 1-‐2-‐3-‐..hours a5er desmopressin administra1on. Desmopressin MELT (white bars) compared to desmopressin tablet (striped bars). * = p<0.05; +


Duration of Action (Urine Osmolality ≥ 200 mOsm/kg)

Duration of Action (Kaplan-Meier)

Time (h)

Pro

babi

lity

of C

ontin

ouos

Act

ion

0 2 4 6 8

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8

0.0

0.2

0.4

0.6

0.8

1.0

MeltTablet


0

200

400

600

800

1000Melt

0

200

400

600

800

1000

0 1 2 3 4 5 6 7 8

Tablet

Time (h)

Urin

e O

smol

ality

Melt vs Tablet : Urine osmolality


0

200

400

600

800

1000Melt

0

200

400

600

800

1000

0 1 2 3 4 5 6 7 8

Tablet

Time (h)

Urin

e O

smol

ality

Melt vs Tablet :Urine osmolality


Melt vs Tablet Pharmacokinetics

Values < LLOQ set to LLOQ/2 0

5

10

15

0 1 2 3 4 5 6 7 8

MeltTablet

LLOQ/2

Time (h)

Des

mop

ress

in C

once

ntra

tion

(pg/

mL)Median (10th-90th percentiles)


Long term follow up tablet / melt n= 23


Why is melt superior to tablet ? !   Prefered by children Palat study !   Superior PharmacoKinetic –data

!   Higher biodisponibility, Lower standard deviation !   More predictability

!   Superior Pharmacodynamic data !   superior anti-diuretic effect !   Superior concentrating capacity !   Superior duration of action, Faster to reach max effect !   Less interference with nutrition

!   Superior anti-enuretic effect !   Follow up study !   Confirmed in reanalysis

!   No need for fluid to swallow tablet = safety !   Higher compliance?


Treatment Level of evidence Grade of

recommendation Pharmacological treatments Antidiuretics (desmopressin) 1 A

Desmopressin + alarm combination 1 A

Tricyclic antidepressants 1 C (cardiotoxicity)

Anticholinergics

3

C

Conditioning treatments Alarm 1 A Dry bed training No more effective than alarm treatment alone Arousal training 2 B

ICI Recommendations for the Treatment of Bedwetting

ICI, International Consultation on Incontinence. Nijman et al. In: Incontinence. 3rd InternConsultation on Incontinence. Abrams et al. 2005

Epidemiology, genetics and pathophysiology: Diagnostic ......YEUNG, CHUNG K., SREEDHAR, BIJI, SIHOE,...

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