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PEDIATRICS: FUNCTIONAL DISORDERS OF THE LOWER URINARY TRACT

Clinical Significance

LUT dysfunction (LUTD), bladder and bowel dysfunction, and the antiquated dysfunctional elimination syndrome, are terms that describe the common array of symptoms that include overactive bladder (OAB), voiding postponement, underactive bladder, dysfunctional voiding, primary bladder neck dysfunction, giggle incontinence, vaginal reflux, pollakiuria, and enuresis.

Epidemiology

OAB is the most commonly encountered LUT disorder in children and has a peak incidence between age 5-7 years
Daytime incontinence varies with both age and gender; in school-age children, daytime urinary incontinence is 2-5x more common in girls

Comorbidities in Children with NLUTD

Urinary Tract Infections

Incomplete bladder emptying can lead to urinary stasis with subsequent UTI causing inflammatory changes in the bladder wall that stimulate hypertrophy and overactivity

Vesicoureteral Reflux (VUR)

Detrusor hypertrophy may alter the closure mechanism at the ureterovesical junction, leading to reflux
Targeted treatment for LUTD has been demonstrated to improve spontaneous resolution rates for VUR
Continued LUTD is a risk factor for treatment failure after surgical correction for reflux.

Psychological Associations

LUTD in children is assocaited with self-esteem and quality-of-life issues
Screening of psychosocial comorbidities during the evaluation of pediatric LUTD is recommended

Up to 1/3 of children with enuresis may have clinically significant behavioral problems

Bowel Dysfunction

The relationship between abnormal bowel and bladder activity is termed bowel-bladder dysfunction (BBD), and, if present, needs to be managed for treatment of the LUT condition to be successful

Terminology

When applying terminology to describe pediatric LUT function, the reference point used by the International Children's Continence Soecity for the term "child" is age ≥ 5 years (≥4 years of age for bowel dysfunction) by the ICCS

Daytime Urinary Incontinence and Bladder Dysfunction

Diagnosis and Evaluation
- Objective is to determine whether the patient has a filling or emptying (or both) phase abnormality.
  - If an abnormality is found, the evaluation should then be directed toward determining the underlying cause and distinguishing whether the dysfunction stems from an anatomic or functional issue.
- Recommended:
  - History (including psychological screening) and Physical Exam
  - Labs: urinalysis
  - Imaging: pelvic US
  - Other:
    - Voiding diary
    - Uroflow

History and Physical Exam
- History
- Physical Exam
  1. Abdomen
    - A child with constipation may have tenderness of the left upper and lower quadrants resulting from colonic distention secondary to fecal impaction and/or gaseous distention
  2. Back and Spine
    - Special attention should always be paid to the lower back for cutaneous manifestations of an occult spinal dysraphism or sacral agenesis (See Pediatrics Neuromuscular Dysfunction of the Lower Urinary Tract Chapter Notes)
  3. Genitals
  4. Neurologic
Labs
- Urinalysis +/- culture
  - The single most important and perhaps only laboratory test that should be performed in all children who present with LUTD
  - Evaluate specific gravity and for the presence of white or red blood cells, bacteria, protein, and glucose; a low specific gravity may be secondary to a renal concentrating defect and often will lead to polyuria
Imaging
- Pelvic Ultrasound
  - Postvoid Residual
    - Children 4-6 years: Single PVR > 30 mL or > 21% of bladder capacity (BC); it is recommended that a repeat PVR be performed with dual measurements a repetitive PVR > 20 mL or > 10% BC is considered significantly elevated
    - Children 7-12 years: A single PVR > 20 mL or > 15% BC or repetitive PVR > 10 mL or > 6% BC is considered elevated
  - Bladder Wall Thickness
    - Normally <3 mm when full and <5 mm when relatively empty
  - Rectal Distention

Other
- Voiding diary
  - Objective record of the child's bowel habits and urinary voiding pattern
  - One of the most helpful diagnostic tools for children with LUTD
- Uroflowmetry
  - See CW11 Figure 143-5 or Figure 6.4
  - Child must be toilet-trained to obtain an interpretable uroflow
  - Provides useful information regarding the pattern or shape of urine flow curve that can often be diagnostic of an underlying cause.
    - Qmax is the most relevant quantitative variable when assessing bladder outflow
    - Staccato-shaped curve: often associated with dysfunctional voiding
    - Interrupted-shaped curve: suggests an underactive bladder
      - Will display discrete (albeit low amplitude) peaks similar to a staccato-shaped curve; however, there will be segments where the flow rate is zero with complete cessation of urinary flow between these peaks.
      - Each peak represents abdominal muscle straining (i.e., Valsalva) creating the main force for urine evacuation. In between each strain, the flow ceases as a result of an absent or weak detrusor contraction.
- Bristol Stool Scale

Source: Wikipedia

Questionnaires
- Pediatric Urinary Incontinence Quality of Life Score (PIN-Q) and Dysfunctional Voiding Symptom Score questionnaire have been found to be complementary

Management
- Primarily directed at improving symptoms (e.g., urinary and/or fecal incontinence, recurrent UTIs) and protecting the upper urinary tract from permanent damage
- First-line: conservative management/urotherapy (4):
  1. Bowel Dysfunction/treatment of constipation
    - Daily fiber intake in total number of grams should be age in years + 15-20
    - Increased fluid intake
    - In one large study, relief of constipation alone resulted in the disappearance of daytime urinary incontinence in 89% and enuresis in 63% of patients
  2. Behavioral Modification
    - Timed voiding with frequent voids scheduled every 2 hours during the day
    - Reward system can significantly improve the child’s self-esteem and compliance
  3. Biofeedback
    - Uses electronic or mechanical instruments to relay perceptual evidence to assist a person in gaining control over a physiologic process or function
  4. Clean Intermittent Catheterization
    - A safe, effective, and well-tolerated treatment strategy to attain continence and reduce the rate of recurrent UTI in children with LUTD
- Second-line: pharmacotherapy
  - See Pharmacological Management of LUTS Chapter Notes
  - Initiated once all other conservative measures have been exhausted
  - Has traditionally encompassed anticholinergic agents and α-adrenergic receptor antagonists (i.e., α-blockers) to enhance bladder filling and emptying, respectively.
  - Anticholinergic Agents
    - Current gold standard in the treatment of patients with symptoms referable to OAB
    - Oxybutynin
      - MOA: antimuscarinic, antispasmodic, and analgesic properties
        
        Causes the antispasmodic effect by acting as a calcium channel blocker
      - Effects on bladder (4)
        
        Reduces the frequency of uninhibited detrusor contractions
        
        Reduces the amplitude of uninhibited detrusor contractions
        
        Increases functional bladder capacity
        
        Increases compliance
      - Main side effects include constipation, dry mouth, blurred vision, reduced sweating, flushing, and altered behavior and cognition
      - The intravesical method of delivery avoids the first-pass effect and leads to increased amounts of oxybutynin available compared to immediate-release oral oxybutynin.
      - The transdermal patch is as efficacious as the immediate-release oral form but with nearly half the incidence of dry mouth. Local skin erythema and pruritus are side effects unique to this route of administration that can be seen in over 1/3 of patients
  - α-Adrenergic Receptor Antagonists (α-Blockers)
    - α-Adrenergic blockade results in smooth muscle relaxation and decreased bladder outlet resistance to facilitate bladder emptying
    - The uroflow finding of a prolonged “EMG lag time” is associated with bladder neck and internal urethral sphincter discoordination and may be used to select patients for α-blocker therapy
  - Botulinum Toxin
    - Clinical effects begin within 5-7 days of injection with maximal effects reached within 4-6 weeks
    - BTX-A is directly injected into the detrusor muscle (in patients with OAB) or external urinary sphincter (in patients with dysfunctional voiding)
- Neuromodulation
  - See Neuromodulation Chapter Notes
  - In neuromodulation, electrical stimuli are exerted in a noninvasive manner to alter the existent neural transmission pattern and modulate detrusor activity. The putative mechanism involves acting centrally by rebalancing excitatory and inhibitory information and returning the neural drive toward a more neutral status
  - A number of modalities have been studied in children, including sacral neuromodulation, pudendal nerve stimulation, and tibial nerve stimulation.
  - Although preliminary results have been promising, electrical nerve stimulation’s role in children with non-neurologic LUTD nevertheless remains controversial because of the lack of controlled trials and largely obscure mechanism of action
  - Transcutaneous electrical nerve stimulation (TENS)
    - Superficial electrodes are placed on each side of the S3 and S2 spinal cord segments
    - In general, therapy consists of 20-minute sessions three times per week.
  - Percutaneous tibial nerve stimulation (PTNS)
    - The posterior tibial nerve is a mixed sensory and motor nerve originating from the L4 to S3 spinal roots that also contributes to sensory and motor control of the bladder, urinary sphincter, and pelvic floor musculature.
    - Performed with a needle inserted ≈5 cm cephalad to the medial malleolus and a grounding pad placed just posterior to the medial malleolus. Proper needle placement in children is confirmed by observing ipsilateral plantar and/ or toe flexion or fanning.
      - Based on the traditional Chinese practice using the Sanyinjiao acupuncture point, which overlies the posterior tibial nerve.
  - Sacral nerve modulation (SNM)
    - Has gained widespread recognition in adults
    - Despite off-label use, a number of groups have reported on their experience with SNM in children with non-neurogenic LUTD.
    - Before sacral implantation can be performed, percutaneous transforaminal access to the S3 spinal nerve must be achieved. Once the correct responses are obtained, the quadripolar tined lead of the neurostimulator device can be implanted. This lead can then be connected to an external neurostimulator device via a tunneled subcutaneous extender for programming and trial assessments. If this is successful, the patient undergoes a second procedure to implant the permanent neurostimulator device into a subadipose pocket in the upper gluteal region.
    - Complications commonly cited with implantable SNM devices are device and/or wound infection, electrode migration, loss of effect, and lead fracture.
    - Revision rates range between 7-18%, secondary to lead migration, faulty connection, and infection.

Special Conditions of Lower Urinary Tract Dysfunction and Their Treatment

Giggle Incontinence (Enuresis Risoria)

Enuresis risoria is moderate-to-large amounts of urinary leakage triggered by laughing alone.
Currently, available treatment strategies include biofeedback or methylphenidate

Pollakiuria (Extraordinary Daytime Urinary Frequency)

Disorder characterized by a very high daytime frequency of micturition (sometimes as high as 50x per day)
- Symptoms are limited only to the daytime, a key aspect of this syndrome, which differentiates it from OAB
Seen in early childhood (4-6 years of age) in both genders and associated with a history of recent death or life-threatening event in the family
Usually, runs a benign, self-limited course over a period of ≈6 months; no specific treatment, apart from reassurance, is necessary

Underactive Bladder

Describes a child who is required to raise intra-abdominal pressure to initiate, maintain, and complete voiding.
Once a functional or anatomic cause for BOO has been ruled out, there are two main approaches to this entity:

Timed voiding and double voiding to more efficiently empty the bladder and lower the ultimate PVR volume of urine.
If the above strategy fails, CIC with frequency dependent on symptom severity

Vaginal Reflux (Vaginal Entrapment and Vaginal Voiding)

Characterized by incontinence after normal voiding in the absence of other LUTS.
Commonly seen in prepubertal girls
Typical history is that of wetting of undergarments ≈10-15 minutes after a normal void
Often associated with labial adhesions as a result of chronic irritation and inflammation from skin exposure to relatively caustic urine.
Reassurance and postural modification to ensure complete vaginal emptying is the only treatment required.

Enuresis (also known as nocturnal enuresis)

Definition of enuresis: discrete episodes of urinary incontinence during sleep in children age >5 in the absence of congenital or acquired neurologic disorders

The child who wets during the day and night can be said to have daytime urinary incontinence and enuresis

Classified as monosymptomatic (MSE) vs. non-monosymptomatic (NMSE)

Definition of MSE: enuresis in children without any other LUTS and without a history of bladder dysfunction
- MSE is further subdivided into primary and secondary forms:
  - Primary MSE: children who have never achieved a satisfactory period of nighttime dryness
  - Secondary MSE: children who develop enuresis after a dry period of ≥6 months are said to have secondary enuresis
    - Often ascribed to an unusually stressful event (e.g., parental divorce, birth of a sibling, sexual abuse) or an organic (e.g., UTI, diabetes, obstructive sleep apnea, neurogenic bladder) or psychological cause (e.g., ADHD or conduct disorder) at a time of vulnerability in a child’s life. These children are more likely to have NMSE (see below) and respond less well to treatment.
  - The clinical presentations of children with primary and secondary MSE are otherwise similar
Definition of NMSE: enuresis with any daytime LUTS
- The majority of children who present with enuresis have the NMSE
- Initial approach to NMSE is nearly identical to approach for children with LUTD:
  - Evaluation: history and physical exam, laboratory and imaging studies
  - Identify and treat constipation
  - Treat the underlying LUTD symptoms first, because effective treatment of OAB (or dysfunctional voiding) can lead to cessation of the enuresis entirely
    - If enuresis persists after the previously mentioned interventions, standard treatment for MSE can follow.
MSE
- Epidemiology and Natural History
  - ≈15% of children will have some degree of enuresis at 5 years of age, with a spontaneous resolution rate of ≈15% per year. Consequently, at 15 years of age, only 1-2% of teenagers still have enuresis
  - More common in boys than in girls; 2:1 ratio
    - By adolescence the prevalence in both males and females reaches equipoise
  - Enuresis is also known to be common in children with comorbid behavioral issues such as ADHD, oppositional defiant disorder, conduct disorder, anxiety, and depression
  - Strong genetic underpinning
- Pathophysiology
  - Enuresis stems from a maturational delay in the ultimate development of bladder control
  - Organ systems implicated in the pathogenesis of enuresis (3):
    1. Bladder (i.e., a reduced nocturnal bladder capacity)
    2. Kidney (i.e., nocturnal polyuria)
    3. Brain (i.e., a disorder affecting arousal from sleep)
  - Bladder Overactivity and Reduced Nocturnal Bladder Capacity
    - There is a subset of children with primary MSE who have nocturnal bladder overactivity regardless of amount of urine production.
  - Nocturnal Polyuria
    - In children and adolescents without enuresis, the diurnal pattern of urine production results in a relative reduction in nocturnal diuresis to ≈50% of daytime levels. The prevailing mechanism for how this occurs is thought to result from a nocturnal circadian peak of antidiuretic hormone (ADH) release that regulates free water excretion
    - Mechanisms for increased nocturnal urine production may include:
      - Increased fluid intake before bedtime
      - Blunted response to ADH
      - Increased evening dietary solute load with high nocturnal urine osmolarity
      - Abnormal renal sodium handling abnormal circadian rhythm of glomerular filtration rate
      - Abnormal sodium and calcium excretion
      - Obstructive sleep apnea/hypoventilation
  - Children with enuresis sleep normally (i.e., the distribution and proportion of the various stages of sleep are within normal limits) but are unable to awaken in response to nocturnal detrusor contractions or bladder fullness
- Diagnosis and Evaluation:
  - The principal objective of the evaluation is to rule out BBD or enuresis as a manifestation of an underlying medical disease (e.g., posterior urethral valves, spinal dysraphism, diabetes mellitus) and to identify that the enuresis is truly monosymptomatic
  - Recommended (3):
    - History and physical exam
    - Labs: urinalysis
    - Other: voiding diary

History and Physical Exam
- History
  - Social history: somatic and psychological comorbid conditions are more common in children who were previously dry (secondary MSE) than in those with primary MSE.
  - Family history: often helpful in establishing a genetic pattern
  - Interventions the family has already tried
  - BBD, if present, should be treated as described previously before initiating therapy for MSE
- Physical exam
  - Should be focused and is similar in scope to that described in the prior section on LUTD.
    - Briefly, examination should include palpation of the abdomen to screen for constipation, examination of the lower spine for cutaneous stigmata of spinal dysraphism, examination of the genitalia to screen for meatal stenosis, introital erythema or damp/wet underwear, assessment of the sacral reflex arc, and evaluation of the motor strength, tone, reflexes, and sensation in the legs for evidence of a neurogenic bladder.
Labs
- Urinalysis
Other
- Voiding diary
  - Kept by the parents
  - Should help assess:
    - Times at which a child voids
    - Relationship between voiding and common events such as meals, breaks at school, and play activities
    - Occurrence of urgency or incontinence; and voided volume.
Neither imaging nor urodynamics has a role in the evaluation of MSE
- If based on history and physical examination the patient is suspected to have NMSE, evaluation following the previously described protocol for children with LUTD (i.e., pelvic ultrasound and uroflowmetry) is recommended

Management
- The decision about when to start treatment generally should be guided by the degree of concern and motivation on the part of the child rather than the parents.
  - For the child, nocturnal enuresis usually becomes significant when it interferes with his or her ability to socialize with peers (e.g., sleepovers, summer camps).
- The child must be highly motivated to participate in a treatment program that may take months to achieve successful results
  - It is important to determine whether the child is mature enough to assume responsibility for treatment.
- Although general advice should be given to all bedwetting children, active treatment should usually not be started before 6 years of age
- Treatment options (4):
  1. Observation
  2. Behavioral modification
  3. Enuresis “moisture” alarm
  4. Pharmacologic therapy (e.g., desmopressin, anticholinergics, imipramine)
- Observation
  - Given the self-limiting nature of enuresis, observation and allowing the natural history to follow its predetermined course is an option. However, enuresis that occurs as infrequently as once per month is associated with reduced self-esteem and treatment has been reported to improve self-worth, regardless of the type or the success of therapy
  - The longer the enuresis persists, the lower the probability is that it will resolve spontaneously
- First-line: behavioral modification (5):
  1. Good bladder and bowel habits
  2. Void regularly during the day and just before going to bed.
  3. Daily fluid intake should be concentrated in the morning and early afternoon, and both fluid and solute intake should be minimized during the evening.
  4. High-sugar and caffeine-based drinks should be avoided, particularly in the evening hours.
  5. Children should be reassured that enuresis is not their fault, and children should not be punished for bedwetting, because this practice is often counterproductive
- Second-line: enuresis alarm or desmopressin, in addition to behavioral therapy
  - Enuresis Alarm
    - See CW11 Figure 143-11
    - Most effective long-term treatment of MSE
    - Alarms are activated when a sensor, placed in the undergarments or on a bed pad, detects moisture, with both types demonstrated to be equally effective.
    - The arousal device is usually an auditory alarm and/or a vibrating belt.
    - The family should be instructed that the child is in charge of the alarm. After the alarm goes off, only the child should turn off the alarm, get up, and finish voiding in the toilet
    - Best suited for (3):
      1. Motivated families
      2. No polyuria
      3. Low bladder capacity
    - Alarm treatment should be continued until the child has had ≥14 consecutive dry nights.
    - Children who do not continue to improve after 6 weeks of alarm training are unlikely to become completely dry with this technique
  - Desmopressin
    - Best suited for (4):
      1. Nocturnal polyuria (defined by the ICCS as nocturnal urine production >130% of expected bladder capacity for age)
      2. Normal bladder capacity (maximum voided volume >70% of expected bladder capacity for age)
      3. Infrequent wet episodes
      4. Families in whom alarm treatment has failed or who have refused alarm treatment
    - Clinical effects appear immediately, with a serum half-life of ≈2-3 hours when taken in oral form
    - Main safety concern is the risk of water intoxication with resultant hyponatremic seizures should the drug be taken with excessive fluids.
      - Risk seems to be somewhat higher with the intranasal form, which has a prolonged half-life, and thus use of the spray is discouraged
    - The usual starting dose is 0.2 mg orally 1 hour before bedtime, and the drug can be titrated up incrementally by 0.2 mg to a maximum dose of 0.6 mg at bedtime.
    - The response to desmopressin should be assessed within 2 weeks
    - In contrast to the enuresis alarm, treatment effects are not sustained
      - After discontinuation of therapy, with a relapse rate of 65% vs. 46% with DDAVP versus the alarm, respectively
  - Children in whom one second-line treatment has failed should be offered the other, and for those in whom both have failed, second- and third-line treatments can be tried, either alone or in combination (e.g., desmopressin plus enuresis alarm or desmopressin plus oxybutynin).
    - Desmopressin plus enuresis alarm combination therapy
      - A reduction in the number of wet nights is consistently observed when using combination therapy of desmopressin and the moisture alarm compared to monotherapy.
      - Enuresis relapse is noted in some patients with long-term follow-up.
- Third-line: anticholinergics, tricyclic antidepressants (TCAs)
  - Anti-cholinergics
    - Monotherapy with drugs, such as oxybutynin or tolterodine, is ineffective as a first line of treatment for MSE
    - Anti-cholinergics have a role is combination therapy in the treatment of children who are refractory to DDAVP monotherapy
  - Tricyclic antidepressants (TCAs e.g., imipramine, amitriptyline, and desipramine)
    - Considered a third-line treatment for therapy-resistant MSE given the efficacy and safety of enuresis alarms and DDAVP
    - MOA:
      1. Decrease the amount of time spent in rapid eye movement (REM) sleep
      2. Stimulate ADH secretion
      3. Relax the detrusor muscle via weak anti-cholinergic properties
    - Effective at reducing the number of wet nights and at achieving 14 consecutive dry nights (i.e., cure) but essentially becomes ineffective once treatment is discontinued.
    - Although other TCAs are effective, imipramine is used most often in the treatment of enuresis.
    - If there is no improvement after 3 months, it should be discontinued as a gradual taper (as is done with other TCAs)
    - Adverse effects:
      - ≈5% of children treated with TCAs develop neurologic symptoms, including nervousness, personality change, and disordered sleep.
      - TCAs (as with other antidepressants) are required by the FDA to carry a black box warning regarding the possibility of increased suicidality, particularly in individuals with preexisting depressive symptoms.
      - The most serious adverse effects of TCAs involve the cardiovascular system: cardiac conduction disturbances and myocardial depression, particularly in cases of overdose.
        
        Before initiation of therapy with a TCA, a thorough cardiac history (e.g., palpitations, syncope) and family cardiac history (e.g., arrhythmias, sudden cardiac death) should be obtained with a baseline electrocardiogram to rule out a prolonged QT interval if history or physical examination raises suspicion.

Questions

Describe the management of children with LUTD
What are the mechanisms of action of oxybutynin?
How do the initial investigations for non-monosymptomatic enuresis differ from monosymptomatic enuresis?
Describe the management of enuresis

Answers

Describe the management of children with LUTD
What are the mechanisms of action of oxybutynin?
How do the initial investigations for non-monosymptomatic enuresis differ from monosymptomatic enuresis?
Describe the management of enuresis

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 4, chap 143