MONOSYMPTOMATIC ENURESIS NOCTURNA

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MONOSYMPTOMATIC ENURESIS NOCTURNA
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• Johan,
• Have you had any thoughts about the workshop?
• We could both play the devils advocate,
• Me for the Evidence Based
• And you for the scientific aproach
• Jonathan

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Some questions

• Johan,
• Have you had any thoughts about the workshop?
• We could both play the devils advocate,
• Me for the Evidence Based
• And you for the scientific aproach
• Jonathan

4
Some questions

• Johan,
• Have you had any thoughts about the workshop?
• We could both play the devils advocate,
• Me for the Evidence Based
• And you for the scientific aproach
• Jonathan

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WHAT IS EVIDENCE

• UK is the wettest country of Europe
• Is A. Watson the devil (??)
• A. Watson wins a golf-tournement in Palermo, the
  day that he is organizing this meeting
• Is the evidence based medecine evident?
• NO because none of the old publications does
  follow the new ICCS-standardisation, thereby have
  extremely heterogeneous study-populations.

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WHAT IS EVIDENCE

• UK is the wettest country of Europe
• Is A. Watson the devil (??)
• A. Watson wins a golf-tournement in Palermo, the
  day that he is organizing this meeting
• Is the evidence based medecine evident?
• NO because none of the old publications does
  follow the new ICCS-standardisation, thereby have
  extremely heterogeneous study-populations.
• All studies are performed in primary care
  patients, and not in the hardcore patients that
  we see

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WHAT TO DO WITH THERAPY REFRACTORY MNE?

• J. Vande Walle
• PUNC Ugent Belgium
• Palermo 2006

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Use it as national monument
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You have to nod it
Je zou er moeten
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What is a refractory MNE?

• After exclusion of NMNE
• No response after at least 1 y
• on conventional therapy
• lege artis,
• as described in the EBM paper of Hjalmas 2004
• including
• Cognitive training
• dDAVP
• Alarm
• Urotherapy
• And combination-therapy
• an ad hoc definition for this talk

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Refractory MNE ?

• The major reason for not responders is
• that the initial intake was not performed
  appropriately,
• that patients according to the new
  ICCS-standardisation should be considered as
  NMNE.

• READ THE NEW ICCS-STANDARDISATION
• Pray for forgiveness to Neveus, Von Gontard,
  Hoebeke that you did not follow their advice
• REDO THE FULL SCREENING

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1.Symptoms suggestive for underlying OAB

• REDO THE FULL SCREENING
• history of incontinence diurna (ID)
• diurnal symptoms after the age of 3,5 years,
• high /low frequency, postponing during normal
  fluid intake
• are very suggestive for OAB dysfunction.
• Low fluid intake is suggestive for a defense
  mechanism

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1.Symptoms suggestive for underlying OAB

• Bladder dysfunction symptoms in OAB are masked by
  
• the low fluid intake as compensatory mechanism
• Are not mentioned by parents
• Repeat questioning,
• Perform a bladder diary during standardized
  fluid intake 1,5ml/1.73m²/day can give
  additional information.
• Take your time for the firstintake

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1. Symptoms suggestive for underlying OAB

• Both measurement of max. voided volume and
  uroflow during forced fluid-intake and diuresis
  may give additional information, because symptoms
  of OAB may become detectable during fast filling
  of the bladder.
• Values of diuresis and enuresis-volume overnight
  may give indices on a possible role of
  OAB-contractions overnight.
• (Incontinentia) enuresis nocturna with only
  drops (new ICCS)
• early night wetting with small enuresis -and low
  overnight diuresis-volume
• therapy resistance correlates with
• Thick bladder wall (Yeung)
• small bladder volume for age. (but only voided
  volume available)

residue for a small BV
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2. Symptoms suggestive for dysfunctional voiding
and/or UAB

• History of UTI, constipation
• Absence of daytime symptoms does not exclude
  dysfunctional voiding perform an uroflow and
  ultrasonography for residue (3x)
• Large BV with high compliance or UAB (lazy
  bladder) is frequent associated with nocturnal
  polyuria and may therefore be a consequence of
  it.
• To make the Urotherapy effective for the UAB
  bladder, nocturnal polyuria should be treated to
  avoid the overnight distention.

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3. DDAVP-therapy partial responder nocturnal
polyuriaA) poor compliance

• Not taking the drug consider to let the patient
  fill in a drug-diary. Register the number of
  prescriptions
• If the child forgets to void before sleeping, you
  start already with a full bladder
• the minimum time to reach maximum concentrating
  capacity is one hour, and therefore the drug
  should be taken at least one hour before the last
  void before sleeping.

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Effet anti-diurétique maximale rapide
effet anti-diuretique maximale rapide
Pharmacodynamic studies of dDAVP melt during
water-load Vande Walle JG et al. BJU Int
200697(3)6039
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Capacité de concentration maximale rapide /- 1h
Pharmacodynamic studies of dDAVP melt during
water-load Vande Walle JG et al. BJU Int
200697(3)6039
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3. DDAVP-therapy partial responder nocturnal
polyuria B) poor pharmacokinetic and dynamic
characteristics

• The 3 formulations (tablet, melt spray) have a
  poor biodisponibility ( 0,2-2- 4)
• but with a rather large SD.
• Only for the melt are dose-response-data and
  proper pharmacodynamic and kinetic data in
  children available.
• Rationale that it might be worse for
• - spray nasal congestion (higher or lower
  resorption)
• - tablet interference of nutrition

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/- 1SD
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/- 2SD
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/- 2SD
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3.DDAVP-therapy partial responder nocturnal
polyuria B) poor pharmacokinetic and dynamic
characteristics

• This high SD might be the explanation of the
  documented prolonged bioactivity (J.Dehoorne J
  Urol 2006)
• resulting not only in side-effects,
• but it can also lead to apparent dDAVP
  resistance.
• Only for the melt are proper dose-response-studies
  and pharmacodynamic and kinetic data in children
  available.
• Rationale that it might be worse for the spray
• nasal hyperaemia increased resorption
• insufficient dosing or overdosing ( PWP ICCS
  2006)

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/- 1SD
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/- 2SD
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4. DDAVP-therapy resistant nocturnal polyuria A)
poor pharmacodynamic characteristics lack of
anti-diuretic and enuretic effect

• Renal diabetes insipidus
• X-linked RDI partial forms in heterozygotic
  girls
• Renal diseases are associated with decreased
  renal concentrating capacity
• Only in minority of patients,
• since the kidney is able to concentrate urine
  normally, although the values do vary between
  800 to gt1200 mosmol/l (range of normal
  concentrating capacity).

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EVIDENCE OF PARTIAL dDAVP RESPONSE RELATED TO
POORPHARMACODYNAMIC EFFECTS OF dDAVP NASAL
SPRAY A. Raes ICCS Antalya 2006 long oral

• Significant number does not reach values gt 850
  mosmol/l
• Is fluid-intake dependent
• Loss of dDAVP-activity after lt 7h
• 30 higher U osmol results in 30 higher
  diuresis-rate

p lt O.O1
dDAVP 2 nasal spray
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DDAVP-therapy resistant nocturnal polyuria 3)
despite appropriate dDAVP-response good
concentrating capacity, no anti-diuretic effect

• 24 h urinary excretion
• high sodium excretion,
• Kuzenetsova in random population Yes
• Kamperis (JAmPhys 2006) No
• Hypercalciuria
• Chiozza,Valenti, Italian studies yes, yes yes
• Neveus No
• A. Raes (J Urol 2006) probably related to tubular
  sodium-handling disorder
• High osmotic excretion (J. Dehoorne J Urol 2006)
  
• Dietary advice is logical, should always be apart
  of urotherapy, but data on the effectiveness are
  insufficient.(Rittig Iccs 2006)

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DDAVP-therapy resistant nocturnal polyuria 3)
despite appropriate dDAVP-response good
concentrating capacity, no anti-diuretic effect

• Abnormal circadian rhythm of
• sodium excretion, prostaglandins
• Kamperis (JAmPhys 2006) yes
• Indication for indomethacin?
• Indication diuretics ?
• GFR (A. Deguchtenaere ICCS 2006)

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DDAVP-therapy resistant nocturnal polyuria 3)
despite appropriate dDAVP-response good
concentrating capacity, no anti-diuretic effect

• High osmotic excretion (J. Dehoorne J Urol 2006)
  
• Group 1
• high 24 h intake, high 24 h excretion of sodium
  and water
• Obese children
• 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
• 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
• Dietary advice is logical, should always be apart
  of urotherapy, but data on the effectiveness are
  insufficient.

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Refractory MNE Psychological and social
disturbance

• Primary cause NO (?) A. Von Gontard ICCS 2006  
• Secondary effect PNE may have a profound
  psychological and social impact on the affected
  child and their families.
• Comorbidity Children with enuresis have
  significantly more behavioural and psychological
  problems, worse self-esteem
• more attention problems, anxiety and depression,
  thought problems, internalizing and externalising
  signs, delinquent and aggressive behaviour.
• Although uncertain if they play a major role in
  the pathogenesis, they do play a major role in
  therapy-resistance.
• Psychological screening and approach is indicated
  in therapy-resistant children

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Refractory MNEconclusion

• Did you follow the ICCS-standardisation ?
• Is there any evidence for underlying
  bladderdysfunction not included in de ICCS.
  Consider cystomanometry.
• dDAVP-partial responders nocturnal polyuria
• Improve compliance
• Titrate dDAVP (by performing simple PD-tests)
• Switch to the best biodisponible form
• Reduce fluid intake in the evening (and not only
  at night)
• dDAVP resistance
• Consider fluid intake, osmotic load,
  hypercalciuria, indomethacin, diuretics
• Consider psychological problems, ADHD, ADD