BASICSCody B. Godfrey, DO • Swati Avashia, MD, FAAP, FACP, ABIHM
BASICS
DESCRIPTION
• Classification
– Primary nocturnal enuresis (NE): 80% of all cases; child/adult who has never established urinary continence on consecutive nights for a period of ≥6 months
– Secondary NE: 20% of cases; resumption of enuresis after at least 6 months of urinary continence
• NE: intermittent nocturnal incontinence after the anticipated age of bladder control (age 5 years)
– Primary monosymptomatic NE (PMNE): bed wetting with no history of bladder dysfunction or other lower urinary tract (LUT) symptoms
– Nonmonosymptomatic NE (NMNE): bed wetting with LUT symptoms such as frequency, urgency, daytime wetting, hesitancy, straining, weak or intermittent stream, posturination dribbling, lower abdominal or genital discomfort, or sensation of incomplete emptying
ALERT
Adult-onset NE with absent daytime incontinence is a serious symptom; complete urologic evaluation and therapy are warranted.
• 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)
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%).
• 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 disorders
– Comorbid disorders are highest with secondary NE: depression, anxiety, social phobias, conduct disorder, hyperkinetic syndrome, internalizing disorders
– Association with ADHD; more pronounced in ages 9 to 12 years
• Altered mental status or impaired mobility
GENERAL PREVENTION
No known measures
COMMONLY ASSOCIATED CONDITIONS
• Obstructive sleep apnea syndrome: atrial natriuretic factor inhibits renin-angiotensin-aldosterone pathway leading to diuresis
• Constipation (1/3 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 exam
– Males: meatal stenosis, hypospadias, epispadias, phimosis
– Females: vulvitis, vaginitis, labial adhesions, ureterocele at introitus; evidence of abuse
• Rectal exam: tone and constipation
• Neurologic exam, especially lower extremities
DIFFERENTIAL DIAGNOSIS
• 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)
• Secondary NE
– Bladder outlet obstruction
– Neurologic 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.
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 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.
• 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 family
– In 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” 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 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).
– 10–70% success; safe even when used for >12 months; high relapse rate after discontinuation without a structured withdrawal program
– In children, NNT = 6 (6)[A].
• 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
– Tolterodine (Detrol, Detrol LA): anticholinergic; fewer side effects than Ditropan (7)[B]
Detrol: 1 to 2 mg PO BID
Detrol 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].
Second Line
• 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
• 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
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
SURGERY/OTHER PROCEDURES
Only for surgically correctable causes (e.g., tethered cord, ectopic ureter, benign prostatic hypertrophy, obstructive sleep apnea)
COMPLEMENTARY & ALTERNATIVE MEDICINE
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
• 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.
COMPLICATIONS
UTI, perineal excoriation, psychological disturbance (especially in children)
REFERENCES
1. Robson WL. Clinical practice. Evaluation and management of enuresis. N Engl J Med. 2009;360(14):1429–1436.
2. Caldwell PH, Nankivell G, Sureshkumar P. Simple behavioural interventions for nocturnal enuresis in children. Cochrane Database Syst Rev. 2013;(7):CD003637.
3. Glazener CM, Evans JH, Peto RE. Alarm interventions for nocturnal enuresis in children. Cochrane Database Syst Rev. 2005;(2):CD002911.
4. Bayne AP, Skoog SJ. Nocturnal enuresis: an approach to assessment and treatment. Pediatr Rev. 2014;35(8):327–335.
5. Vande Walle J, Stockner M, Raes A, et al. Desmopressin 30 years in clinical use: a safety review. Curr Drug Saf. 2007;2(3):232–238.
6. Glazener CM, Evans JH. Desmopressin for nocturnal enuresis in children. Cochrane Database Syst Rev. 2002;(3):CD002112.
7. Deshpande AV, Caldwell PH, Sureshkumar P. Drugs for nocturnal enuresis in children (other than desmopressin and tricyclics). Cochrane Database Syst Rev. 2012;(12):CD002238.
8. Graham KM, Levy JB. Enuresis. Pediatr Rev. 2009;30(5):165–172.
9. Neveus T, Eggert P, Evans J, 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.
10. Bower WF, Diao M. Acupuncture as a treatment for nocturnal enuresis. Auton Neurosci. 2010;157(1–2):63–67.
ADDITIONAL READING
Vande Walle J, Rittig S, Bauer S, et al. Practical consensus guidelines for the management of enuresis. Eur J Pediatr. 2012;171(6):971–983.
SEE ALSO
• Incontinence, Urinary Adult Female; Incontinence, Urinary Adult Male
• Algorithm: Enuresis
CODES
ICD10
• N39.44 Nocturnal enuresis
• R32 Unspecified urinary incontinence
• F98.0 Enuresis not due to a substance or known physiol condition
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.