Enuresis

- ENT: evaluation for adenotonsillar hypertrophy - Abdomen: enlarged bladder, kidneys, fecal masses, or impaction - Back: Look for dimpling or tufts of hair on sacrum. - Genital urinary exam - Males: meatal stenosis, hypospadias, epispadias, phimosis - Females: vulvitis, vaginitis, labial adhesions, ureterocele at introitus; evidence of abuse

- Primary NE - Delayed physiologic urinary control - UTI (both) - Spina bifida occulta - Obstructive sleep apnea (both) - Idiopathic detrusor instability - Previously unrecognized myelopathy or neuropathy (e.g., multiple sclerosis, tethered cord, epilepsy) - Anatomic urinary tract abnormality (e.g., ectopic ureter)

- Use nonpharmacologic approaches as first line before prescribing medications (1)[A]. - Simple behavioral interventions (e.g., scheduled wakening, positive reinforcement, bladder training, diet changes) are effective though less so than alarms or medications (2)[B]. - Explain the three pathophysiologic factors. - Encourage normal drinking patterns during daytime hours and reduction of intake in the hours prior to sleep. - Emphasize regular bedtime with full night's sleep. - Scheduled voiding before bed - Nightlights to light the way to the bathroom - Reward system for dry nights - Use pull up over regular underwear or cloth underwear with built in waterproof barrier.

- Desmopressin (DDAVP): synthetic analogue of vasopressin that decreases nocturnal urine output (5)[A] - Adults only: 20 mg (2 sprays) intranasally at bedtime - FDA recommends against use in children due to reports of severe hyponatremia resulting in seizures and deaths in children using intranasal formulations of desmopressin. - Oral DDAVP: dose-dependent: begin at 0.2 mg tablet taken at bedtime on empty stomach; may titrate to 0.6 mg - Maximally effective in 1 hour; cleared within 9 hours - Trial nightly for 6 months, then stop for 2 weeks for test of dryness - Suspend dose in children who experience acute condition affecting fluid/electrolyte balances (fever, vomiting, diarrhea, vigorous exercise).

- Anticholinergics - Oxybutynin (Ditropan, Ditropan XL, Oxytrol patch): anticholinergic; smooth muscle relaxant, antispasmodic; may increase functional bladder capacity and aids in timed voiding (6)[B] - Ditropan: adults and children >5 years of age: 5 mg PO TID to QID; children 1 to 5 years of age: 0.02 mg/kg/dose BID to QID (syrup 5 mg/5 mL) - Ditropan XL: adults: 5 mg/day PO; increase to 30 mg/day PO (5-, 10-mg tabs) - Oxytrol patch: 1 patch every 3 to 4 days (3.9 mg/patch) (periodic trials off the medication, that is, weekends or weeks at a time, will help determine efficacy and resolution of primary disturbance) - Ditropan: 5 to 10 mg at night; 30-50% success; 50% relapse after stopped

- Imipramine (Tofranil): tricyclic antidepressant, anticholinergic effects; increases bladder capacity, antispasmodic properties - Primarily in adults; use in children is reserved for resistant cases. - Dose: adults, 25 to 75 mg and children >6 years, 10 to 25 mg PO at bedtime; increase by 10 to 25 mg at 1- to 2-week intervals; treat for 2 to 3 months; then taper - 25-30% success when used <3 months. - Pretreatment ECG recommended identifying underlying rhythm disorders.

- Precautions - Oxybutynin: glaucoma, myasthenia gravis, GI or genitourinary obstruction, ulcerative colitis, megacolon; use a decreased dose in the elderly. - Tolterodine: urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma; significant drug interactions with CYP2D6, CYP3A3/4 substrates - DDAVP: Avoid in patients at risk for electrolyte changes or fluid retention (congestive heart failure [CHF], renal insufficiency). Stop during gastroenteritis or other acute illness with risk of dehydration. - Imipramine: Do not use with monoamine oxidase inhibitors (MAOIs), hypotension, and arrhythmias; low-toxic therapeutic ratio

para>Adult-onset NE with absent daytime incontinence is a serious symptom; complete urologic evaluation and therapy are warranted. пїЅ

System(s) affected: nervous, renal/urologic
Synonym(s): bed wetting; sleep enuresis; nocturnal incontinence; primary NE

EPIDEMIOLOGY

Incidence

Depends on family history
Spontaneous resolution: 15% per year, 99% of children are dry by age 15 years.

Prevalence

Very common. 5 to 7 million children in the U.S.
40% of 3-year-olds; 10% of 6-year-olds; 3% of 12-year-olds; 1% of adults
Male > female (3:1)
Nocturnal > day (3:1)

Geriatric Considerations

Infrequent; often associated with daytime incontinence (formerly referred to as diurnal enuresis)

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ETIOLOGY AND PATHOPHYSIOLOGY

A disorder of sleep arousal, a low nocturnal bladder capacity, and nocturnal polyuria are the three factors that interrelate to cause NE.
Both functional and organic causes (below); many theories, none absolutely confirmed
Detrusor instability
Deficiency of arginine vasopressin (AVP); decreased nocturnal AVP or decreased AVP stimulation secondary to an empty bladder (bladder distension stimulates AVP)
Maturational delay of CNS
Severe NE with some evidence of interaction between bladder overactivity and brain arousability: association with children with severe NE and frequent cortical arousals in sleep
Organic urologic causes in 1-4% of enuresis in children: UTI, occult spina bifida, ectopic ureter, lazy bladder syndrome, irritable bladder with wide bladder neck, posterior urethral valves, neurologic bladder dysfunction
Organic nonurologic causes: epilepsy, diabetes mellitus, food allergies, obstructive sleep apnea, chronic renal failure, hyperthyroidism, pinworm infection, sickle cell disease
NE occurs in all stages of sleep.

Genetics

Most commonly, NE is an autosomal-dominant inheritance pattern with high penetrance (90%). пїЅ

1/3 of all cases are sporadic.
75% of children with enuresis have a first-degree relative with the condition.
Higher rates in monozygotic versus dizygotic twins (68% vs. 36%)
If both parents had NE, risk in child is 77%; 44% if one parent is affected. Parental age of resolution often predicts when child's enuresis should resolve.

RISK FACTORS

Family history
Stressors (emotional, environmental) common in secondary enuresis (e.g., divorce, death)
Constipation
Encopresis
Organic disease: 1% of monosymptomatic NE (e.g., urologic and nonurologic causes)
Psychological disordersComorbid disorders are highest with secondary NE: depression, anxiety, social phobias, conduct disorder, hyperkinetic syndrome, internalizing disordersAssociation with ADHD; more pronounced in ages 9 to 12 years
Altered mental status or impaired mobility

GENERAL PREVENTION

No known measures пїЅ

COMMONLY ASSOCIATED CONDITIONS

Obstructive sleep apnea syndrome: atrial natriuretic factor inhibits renin-angiotensin-aldosterone pathway leading to diuresis
Constipation (в…“; of patients with NE)
Behavioral problems (specifically ADHD)

DIAGNOSIS

HISTORY

Age of onset, duration, severity
LUT tract symptoms
Constipation and encopresis (15% with comorbid encopresis)
Daily intake patterns
Voiding and elimination patterns (voiding diary)
Psychosocial history
Family history of enuresis
Investigation and previous treatment history

PHYSICAL EXAM

ENT: evaluation for adenotonsillar hypertrophy
Abdomen: enlarged bladder, kidneys, fecal masses, or impaction
Back: Look for dimpling or tufts of hair on sacrum.
Genital urinary examMales: meatal stenosis, hypospadias, epispadias, phimosisFemales: vulvitis, vaginitis, labial adhesions, ureterocele at introitus; evidence of abuse
Rectal exam: tone and constipation
Neurologic exam, especially lower extremities

DIFFERENTIAL DIAGNOSIS

Primary NEDelayed physiologic urinary controlUTI (both)Spina bifida occultaObstructive sleep apnea (both)Idiopathic detrusor instabilityPreviously unrecognized myelopathy or neuropathy (e.g., multiple sclerosis, tethered cord, epilepsy)Anatomic urinary tract abnormality (e.g., ectopic ureter)
Secondary NEBladder outlet obstructionNeurologic disease, neurogenic bladder (e.g., spinal cord injury)

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Only obligatory test in children is urinalysis.
Urinalysis and urine culture: UTI, pyuria, hematuria, proteinuria, glycosuria, and poor concentrating ability (low specific gravity) may suggest organic etiology, especially in adults.
Urinary tract imaging is usually not necessary.
If abnormal clinical findings or adult onset: renal and bladder US
IV pyelogram, voiding cystourethrogram (VCUG), or retrograde pyelogram as indicated
Spine radiographs for spina bifida occulta

Follow-Up Tests & Special Considerations

Secondary enuresis: serum glucose, BUN, creatinine, thyroid-stimulating hormone (TSH), urine culture
In children, imaging and urodynamic studies are helpful for significant daytime symptoms, history of UTIs, suspected structural abnormalities, and in refractory cases.

Diagnostic Procedures/Other

Urodynamic studies may be beneficial in adults and nonmonosymptomatic NE. пїЅ

Test Interpretation

Dysfunctional voiding
Detrusor instability and/or reduced bladder capacity most common findings

TREATMENT

GENERAL MEASURES

Use nonpharmacologic approaches as first line before prescribing medications (1)[A].
Simple behavioral interventions (e.g., scheduled wakening, positive reinforcement, bladder training, diet changes) are effective though less so than alarms or medications (2)[B].Explain the three pathophysiologic factors.Encourage normal drinking patterns during daytime hours and reduction of intake in the hours prior to sleep.Emphasize regular bedtime with full night's sleep.Scheduled voiding before bedNightlights to light the way to the bathroomReward system for dry nightsUse pull up over regular underwear or cloth underwear with built in waterproof barrier.
Do not shame or punish bedwetting but have the child participate in removing and laundering soiled bedding and garments.
If behavioral interventions alone have no success, combined therapy (e.g., enuresis alarm, bladder training, motivational therapy, and pelvic floor muscle training) is more effective than each component alone or than pharmacotherapy (1)[A].
Enuresis alarms (bells or buzzers)66-70% success rate; must be used nightly for 3 to 4 months; offers cure; significant parental involvement; disruption of sleep for entire familyIn children, number needed to treat (NNT) = 2 (3)[A].If successful, it should be used until 14 consecutive dry nights achieved (4)[B].
See "Patient Education"пїЅ for options.

MEDICATION

First Line

Desmopressin (DDAVP): synthetic analogue of vasopressin that decreases nocturnal urine output (5)[A]Adults only: 20 mg (2 sprays) intranasally at bedtimeFDA recommends against use in children due to reports of severe hyponatremia resulting in seizures and deaths in children using intranasal formulations of desmopressin.Oral DDAVP: dose-dependent: begin at 0.2 mg tablet taken at bedtime on empty stomach; may titrate to 0.6 mgMaximally effective in 1 hour; cleared within 9 hoursTrial nightly for 6 months, then stop for 2 weeks for test of drynessSuspend dose in children who experience acute condition affecting fluid/electrolyte balances (fever, vomiting, diarrhea, vigorous exercise).10-70% success; safe even when used for >12 months; high relapse rate after discontinuation without a structured withdrawal programIn children, NNT = 6 (6)[A].
AnticholinergicsOxybutynin (Ditropan, Ditropan XL, Oxytrol patch): anticholinergic; smooth muscle relaxant, antispasmodic; may increase functional bladder capacity and aids in timed voiding (6)[B]Ditropan: adults and children >5 years of age: 5 mg PO TID to QID; children 1 to 5 years of age: 0.02 mg/kg/dose BID to QID (syrup 5 mg/5 mL)Ditropan XL: adults: 5 mg/day PO; increase to 30 mg/day PO (5-, 10-mg tabs)Oxytrol patch: 1 patch every 3 to 4 days (3.9 mg/patch) (periodic trials off the medication, that is, weekends or weeks at a time, will help determine efficacy and resolution of primary disturbance)Ditropan: 5 to 10 mg at night; 30-50% success; 50% relapse after stoppedTolterodine (Detrol, Detrol LA): anticholinergic; fewer side effects than Ditropan (7)[B]Detrol: 1 to 2 mg PO BIDDetrol LA: 2 to 4 mg/day

Pediatric Considerations

FDA recommends against using intranasal formulations of desmopressin in children due to reports of severe hyponatremia resulting in seizures and deaths (8)[A].

пїЅ

Second Line

Imipramine (Tofranil): tricyclic antidepressant, anticholinergic effects; increases bladder capacity, antispasmodic propertiesPrimarily in adults; use in children is reserved for resistant cases.Dose: adults, 25 to 75 mg and children >6 years, 10 to 25 mg PO at bedtime; increase by 10 to 25 mg at 1- to 2-week intervals; treat for 2 to 3 months; then taper25-30% success when used <3 months.Pretreatment ECG recommended identifying underlying rhythm disorders.
PrecautionsOxybutynin: glaucoma, myasthenia gravis, GI or genitourinary obstruction, ulcerative colitis, megacolon; use a decreased dose in the elderly.Tolterodine: urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma; significant drug interactions with CYP2D6, CYP3A3/4 substratesDDAVP: Avoid in patients at risk for electrolyte changes or fluid retention (congestive heart failure [CHF], renal insufficiency). Stop during gastroenteritis or other acute illness with risk of dehydration.Imipramine: Do not use with monoamine oxidase inhibitors (MAOIs), hypotension, and arrhythmias; low-toxic therapeutic ratio
Combination therapy with DDAVP and oxybutynin has better results than individual use (7)[B].
Prostaglandin inhibitors (e.g., indomethacin) have been studied; may increase bladder capacity, not as effective as DDAVP, and increase adverse effects (7)[B]

ALERT

Imipramine: cardiotoxicity and death with overdose

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ISSUES FOR REFERRAL

Primary NE: persistent enuresis despite nonpharmacologic and pharmacologic therapies
Diurnal incontinence or nonmonosymptomatic enuresis with voiding dysfunction or underlying medical condition

ADDITIONAL THERAPIES

Individual and family psychotherapy, crisis intervention пїЅ

SURGERY/OTHER PROCEDURES

Only for surgically correctable causes (e.g., tethered cord, ectopic ureter, benign prostatic hypertrophy, obstructive sleep apnea) пїЅ

COMPLEMENTARY & ALTERNATIVE MEDICINE

Acupuncture and hypnosis are other treatments offered; small amounts of supportive data (9,10)[B] пїЅ

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

DIET

Limit fluid and caffeine intake 2 hours before sleep.
Limit dairy products 4 hours before sleep (decrease osmotic diuresis).

PATIENT EDUCATION

Web resources for hypnosis scripts, alarms, and supplies пїЅ

http://www.hypnoticworld.com/hypnosis-scripts/habits-disorders/enuresis
www.bedwettingstore.com/index.htm; www.dri-sleeper.com; www.enurad.com; www.nitetrain-r.com; www.sleepydryalarm.com; www.wetstop.com; www.pottypager.com/

PROGNOSIS

In children, NE is usually self-limiting; 1% will persist as adult; evaluate for organic causes. пїЅ

COMPLICATIONS

UTI, perineal excoriation, psychological disturbance (especially in children) пїЅ

REFERENCES

11 Robson пїЅWL. Clinical practice. Evaluation and management of enuresis. N Engl J Med. 2009;360(14):1429-1436.22 Caldwell пїЅPH, Nankivell пїЅG, Sureshkumar пїЅP. Simple behavioural interventions for nocturnal enuresis in children. Cochrane Database Syst Rev. 2013;(7):CD003637.33 Glazener пїЅCM, Evans пїЅJH, Peto пїЅRE. Alarm interventions for nocturnal enuresis in children. Cochrane Database Syst Rev. 2005;(2):CD002911.44 Bayne пїЅAP, Skoog пїЅSJ. Nocturnal enuresis: an approach to assessment and treatment. Pediatr Rev. 2014;35(8):327-335.55 Vande Walle пїЅJ, Stockner пїЅM, Raes пїЅA, et al. Desmopressin 30 years in clinical use: a safety review. Curr Drug Saf. 2007;2(3):232-238.66 Glazener пїЅCM, Evans пїЅJH. Desmopressin for nocturnal enuresis in children. Cochrane Database Syst Rev. 2002;(3):CD002112.77 Deshpande пїЅAV, Caldwell пїЅPH, Sureshkumar пїЅP. Drugs for nocturnal enuresis in children (other than desmopressin and tricyclics). Cochrane Database Syst Rev. 2012;(12):CD002238.88 Graham пїЅKM, Levy пїЅJB. Enuresis. Pediatr Rev. 2009;30(5):165-172.99 Neveus пїЅT, Eggert пїЅP, Evans пїЅJ, et al. Evaluation of and treatment for monosymptomatic enuresis: a standardization document from the International Children's Continence Society. J Urol. 2010;183(2):441-447.1010 Bower пїЅWF, Diao пїЅM. Acupuncture as a treatment for nocturnal enuresis. Auton Neurosci. 2010;157(1-2):63-67.

ADDITIONAL READING

Vande Walle пїЅJ, Rittig пїЅS, Bauer пїЅS, et al. Practical consensus guidelines for the management of enuresis. Eur J Pediatr. 2012;171(6):971-983. пїЅ

CODES

ICD10

N39.44 Nocturnal enuresis
R32 Unspecified urinary incontinence
F98.0 Enuresis not due to a substance or known physiol condition

ICD9

788.36 Nocturnal enuresis
788.30 Urinary incontinence, unspecified
307.6 Enuresis

SNOMED

8009008 Nocturnal enuresis (disorder)
165232002 urinary incontinence (finding)
450844008 Non-organic nocturnal enuresis (finding)
281862002 Daytime enuresis
450845009 primary nocturnal enuresis (finding)
450846005 secondary nocturnal enuresis (finding)

CLINICAL PEARLS

Initial evaluation is history, exam, and urinalysis.
For PMNE in children, if the condition is not distressing to child and caretakers, treatment is unnecessary.
Behavioral and lifestyle interventions are the first-line treatment for PMNE, alarms and desmopressin are the most effective treatments.
Dryness is possible for most children.