The prevalence of enuresis (NE) is as high as 8% to 20% in the population of children aged 5 years. Although there are many treatment methods for enuresis, some children still have poor treatment results or relapse after stopping medication. In recent years, emphasis has been placed on identifying the possible causes and pathogenesis based on the child’s medical history, physical examination, urinary diary, urinary routine and, if necessary, urodynamic examination, and developing an individualized treatment plan taking into account the child’s age, type of enuresis and willingness to treat.
Nocturnal enuresis (NE), commonly known as “bedwetting”, has a prevalence of 8% to 20% in children aged 5 years and 1.5% to 10% in children aged 10 years [1]. It is defined by the International Children’s Continence Society (ICCS) as involuntary urinary leakage during sleep in children aged 5 years or older [2]. According to the definition and criteria of The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) of the World Health Organization, the following conditions must be met to diagnose enuresis (i) the child is ≥5 years old; (ii) involuntary nocturnal leakage occurs at least once a month; and (iii) the duration of symptoms is ≥3 months [3]. Although there are many treatment methods for enuresis, some children still have poor treatment results or relapse after stopping the medication. A clear diagnosis and individualized treatment according to the child’s condition are the keys to ensure the treatment effect and prevent relapse.
1.Evaluation of enuresis
Enuresis affects the healthy development and quality of life of children, so children with enuresis should be given high priority. If enuresis is clinically suspected, history taking, physical examination, urination diary, laboratory tests and X-ray should be performed according to the condition to clarify whether the diagnosis of enuresis is met and to identify the type of enuresis.
1.1 History taking History taking should ask about daily urinary habits, frequency of enuresis, whether enuresis is constant and accompanied by polyuria; whether there are lower urinary tract symptoms such as urinary urgency, intermittent urination, weakness of urinary line, abdominal pressure to urinate; whether there are any symptoms of urinary tract infection; whether there is a history of daytime urinary incontinence; understanding defecation habits: if chronic constipation is not treated first, it will be more difficult to treat enuresis [4]; asking about daily dietary and drinking habits If secondary enuresis is suspected, the child’s parents should be asked about any major family events; the importance of enuresis to the parents and the child, family conditions and willingness to treat; and whether the child suffers from severe snoring or nocturnal sleep apnea [5]. Based on the medical history, monosymptomatic enuresis and (monosymptomaticnocturnal enuresis, MNE) non-monosymptomatic enuresis (NMNE) can be identified; to understand the severity of symptoms and to judge the prognosis, such as frequent enuresis (≥3 times/week) is an indicator of poor prognosis; to understand the treatment compliance of the child and family to facilitate the development of an individualized treatment plan. History taking is the basis for effective assessment and treatment of enuresis.
1.2 Physical examination Children with MNE usually have a normal physical examination, but if the history reveals the presence of other voiding disorders, such as weakness and severe urinary incontinence, a thorough physical examination is required, in which a low back and genital examination is necessary [4]. Note the presence of neuropathic signs, such as spinal deformity, abnormal gait, abnormal tendon reflexes, asymmetric foot atrophy and high arches; signs of spinal dysplasia, such as dorsal masses, hyperpigmentation, microsomia, hirsutism and gluteal cleft tilt [6]; the presence of circumcision, prepuce and glansitis; and rectal palpation is necessary if the medical history is suspicious of chronic constipation.
1.3 Urinary diary The ICCS in its 2014 guidelines recommends recording the number of episodes of enuresis and the volume of enuresis continuously for 7 nights to assess the severity of enuresis, along with a 48-h frequency volume chart (FVC) if accompanied by daytime symptoms [3]. Parameters of the voiding diary that may reflect the cause of enuresis include functional bladder capacity (FBC) and nocturnal urine output [6]. It is necessary to complete a voiding diary in children with enuresis for the following reasons: (1) to provide objective data related to the child’s voiding to support the medical history; (2) to detect positive symptoms in children with NMNE; (3) to provide information on the prognosis of treatment; (4) to determine the need for further investigations based on the results; (5) to detect the presence or absence of associated thirst; and (6) to understand the compliance of the child and family with treatment based on the completion of the voiding diary [4].
1.4 Laboratory tests Some literature reported that routine urine and urine culture may be the only necessary ancillary tests for MNE to check for diabetes, proteinuria or urinary tract infection [7]. If secondary enuresis is suspected, blood glucose, hemoglobin electrophoresis, and thyroid stimulating hormone levels may be tested to exclude diabetes, sickle cell disease, and hyperthyroidism, respectively, depending on the situation [8].
1.5 Ultrasound examinations are performed to examine the urinary system of children with enuresis and to exclude organic diseases; they can also safely and non-invasively detect FBC, bladder wall thickness, and residual urine volume to help understand their bladder function and guide the development of medication regimens. Studies have shown that ultrasound findings such as increased bladder volume (>150% of expected bladder volume), incomplete emptying (residual urine volume >10% of expected bladder volume) and bladder wall thickening are associated with NMNE [9].Elsayed et al [10] found that the bladder volume andwall thickness index (BVWI) The effectiveness of behavioral therapy was correlated with the efficacy of behavioral therapy: for children with normal BVWI (70-130), the efficiency of behavioral therapy was 97%, while for children with low BVWI and high BVWI, the efficiency of behavioral therapy was only 18% and 25%, respectively. ultrasound examination in children with NMNE is usually normal, so ultrasound examination is mostly indicated in children with NMNE and refractory disease [11].
1.6 X-ray examination Lumbosacral plain radiographs can rule out spinal disorders, confirm the diagnosis of occult spina bifida and define the site and extent of occult spina bifida. Occult spina bifida can significantly affect the prognosis of treatment for enuresis, and those with occult spina bifida have poorer outcomes [12]. In order to screen children with enuresis for the presence of occult spina bifida and to understand the prognosis, X-ray examination is recommended as a routine screening test for enuresis.
1.7 Urodynamic tests (free flow rate combined with residual urine volume and, if necessary, cystometry) are recommended in the presence of suspected NMNE, secondary enuresis, or when treatment is ineffective for more than 1 year to determine the presence of lower urinary tract dysfunction (LUTD). Among them, free flow rate combined with residual urine volume ultrasonography is the most commonly used method to screen children for the presence of LUTD and to determine the need for invasive urodynamic testing [6]. Invasive urodynamic examinations include bladder pressure-volume, pressure-flow rate, urethral pressure, and imaging urodynamic examinations, among which imaging urodynamic examinations can accurately visualize the dysfunction of the forced urinary sphincter, vesicoureteral reflux, and vesicourethral morphology in children with enuresis.
In addition, if the child has a severe behavioral or psychological disorder, a relevant psychological evaluation should be performed [13]. There are controversies regarding the assessment of children with enuresis. The UK National Institute of Clinical Medicine guidelines (2010) recommend, based on the “best available evidence”: (i) routine urinalysis if diabetes mellitus, urinary tract infection, secondary enuresis and/or daytime symptoms are suspected; (ii) a diary of urination and fluid intake should be recorded; and (iii) imaging is not required [14]. The European Association of Urology guidelines (2009) suggest that the diagnosis of MNE is based on history alone and no further investigations are required [15]. The International Society for Pediatric Urinary Control recommends, based on available evidence (which is weak) and expert consensus: (i) checking for diabetes and proteinuria by urinalysis; (ii) no need for urological ultrasound; (iii) recording 2 days of FVC and fluid intake; and (iv) recording 1 week of enuresis, daytime incontinence and defecation [4,16].
2. Treatment of enuresis
The diagnostic criteria for enuresis are not yet unified, the etiology and pathogenesis are not fully understood [17], and the pathogenesis varies among children, which determines the difficulty and complexity of treatment.
MNE treatment is generally divided into two cases: simple cases and refractory cases [4]. For simple cases, in addition to conventional treatment, there are two proven treatments of choice: enuresis alarms and desmopressin, both of which have no difference in treatment efficacy. For those with a strong desire for treatment and a small volume of enuresis, the enuresis alarm treatment is the most effective; for those with nocturnal polyuria and a normal bladder volume, who fail or refuse the alarm treatment, desmopressin is preferred. In refractory cases, i.e., children who have failed both preferred treatments, it is necessary to first confirm that the preferred treatment is correctly applied and that their completion of a voiding diary is essential. In addition, many children fail treatment due to concomitant psychological disorders, which require psychotherapy. With regard to pharmacological treatment, anticholinergics (to exclude constipation and contraindications to their use) and desmopressin can be used in combination. If the treatment is still unsuccessful, the child may be treated with promethazine if there are no contraindications to the use of the drug, or with desmopressin if there is nocturnal polyuria [4].
NMNE recommends following the following treatment steps: (i) treat the chronic constipation problem (or fecal incontinence) first, as effective treatment of fecal problems may lead to self-resolution of daytime incontinence symptoms; (ii) treat the underlying LUTD first, as effective treatment of overactive bladder or other LUTDs may cure enuresis; (iii) if accompanied by psychobehavioral disturbances, additional treatment or psychotherapy is often required, such as the use of CNS stimulant medications and behavioral therapy for ADHD; (iv) if enuresis persists despite effective treatment of the underlying LUTD, standard MNE treatment (enuresis alarms combined with desmopressin) may be used [16].
The treatment of enuresis should be based on the child’s symptoms and type of enuresis to develop the best treatment plan, and the available treatment options include psychotherapy, behavioral therapy, pharmacotherapy, Chinese medicine, and surgery.
2.1 Psychological treatment Since many children with enuresis have a tendency toward shame and low self-esteem, parents should try to reduce the psychological pressure on the child and avoid criticizing and humiliating the child, and some studies have reported that punishing the child can have a negative effect on treatment [18]. After the diagnosis of enuresis, the child and family should be informed first of the possible causes of enuresis, and ideological education and psychological comfort should be provided to build up confidence that enuresis is curable. If the child is found to have a psychological behavior disorder such as ADHD, active treatment should be given at the same time. Psychotherapy can improve treatment compliance and is best applied simultaneously with other treatments [14].
2.2 Behavioral treatment
2.2.1 Urinary training The main aim is to gradually increase the volume and duration of urination intervals in children by extending the interval between urination during the day and recording the duration and volume of urination. Overtraining (treatment with enuresis alarms along with more fluids at bedtime) has been reported in the literature to improve the efficacy [19] and may reduce the recurrence rate [18]. Waking children from sleep to urinate is an effective method to prevent and treat enuresis: children can be awakened to urinate in a timely manner according to the temporal pattern of enuresis occurrence or the child’s pre-enuresis behavior such as rolling over or limb movements. This method can significantly reduce the frequency of enuresis and decrease the recurrence rate compared with the control group [20].
2.2.2 Enuresis alarm Enuresis alarm treatment, as one of the preferred treatments for enuresis, is the best method for treating children with arousal difficulties, but requires high compliance with treatment from the child and family [21]. The therapeutic mechanism may be related to the stimulation of enhanced bladder filling to induce arousal and accelerate the formation of normal voiding reflex in the child. The success rate after 10-20 weeks of treatment with alarms is 66% [7] and the cure rate is 43% [15], and the combination with a reward mechanism can improve the treatment effect [22]. iccs recommends the use of alarms for a maximum of 16 weeks or until 14 consecutive d without bedwetting [3]. Factors that contribute to the good prognosis of alarm bell treatment for enuresis include family harmony, absence of psycho-behavioral disorders, and small bladder capacity, and are particularly suitable for older children with strong treatment intentions and failed behavioral therapy. It has been reported in the literature that winter is associated with alarm treatment failure and that treatment outcomes are more favorable in summer [23]. Evidence-based medical evidence found [18] that: (i) the alarm treatment group versus the untreated group: approximately 2/3 of children in the alarm treatment group no longer micturate and approximately 50% fail or relapse after discontinuation of alarm treatment, whereas almost all children in the control group still micturate; (ii) the alarm treatment group versus the placebo control group: the former reduced the occurrence of micturition more during and after treatment; (iii) the alarm treatment group versus the desmopressin treatment group: there was no difference in the efficacy of the two groups during treatment, and there was no difference in the efficacy of the two groups during treatment. There was no difference in efficacy between the two groups during the treatment period, but desmopressin had a faster onset of action and the relapse rate was lower in the alarm treatment group; ③Alarm treatment group versus tricyclic antidepressant treatment group: there was no significant difference in efficacy between the two groups during the treatment period, but the relapse rate was lower in the alarm treatment. In addition, there was no significant difference in the effect of different types of alarm treatment, including alarm [18].
2.2.3 Dietary treatment Encourage children to consume laxative foods, such as vegetables and bananas, and avoid foods that tend to make stools dry without restricting the amount of diet; reduce fluid intake if there is no physical exercise or social activity after dinner; and avoid caffeinated beverages, especially at night [14]. If a child with enuresis has a history of chronic constipation, treatment of constipation may also reduce the occurrence of enuresis.
2.2.4 Other treatments Drybed training, which combines alarm therapy, reward reinforcement, bladder training, and psychotherapy as a whole, is slightly more effective than alarm therapy alone and can reduce the recurrence rate [18]; biofeedback is effective in treating voiding dysfunction and has a longer duration of effect. The success rate of treatment is 64% [24]; if treatment is refused, diapers can be used at night to improve the sleep quality of the child [25].
2.3 Medication The following drugs are currently used clinically to treat enuresis: (1) desmopressin; (2) anticholinergic drugs; (3) botulinum toxin A; (4) central nervous system stimulant drugs such as promethazine; and (5) other drugs.
2.3.1 Desmopressin Desmopressin has been used for the treatment of enuresis for 40 years and is currently used as the treatment of choice for enuresis together with enuresis alarms and is recommended as level Ia evidence by the International Advisory Committee on Incontinence [4,14]. Its mechanism of action is to reduce nocturnal urine production below FBC and is most effective in children with nocturnal polyuria, normal bladder capacity, and infrequent bedwetting [8]. One study found that for children with nocturnal polyuria, oral desmopressin (200-400 μg) at bedtime was 70% effective, but the relapse rate was high after discontinuation of the drug, ranging from 62% to 82% [1]. Desmopressin consists of three dosage forms: oral tablet (200-400 μg once a night), nasal spray (20-80 μg once a night), and sublingual (60-240 μg once a night), and its effect lasts for 8-12 h. Its adverse effects are rare and mostly mild [15,26]. The sublingual formulations improve the therapeutic efficiency and compliance of children compared with oral tablets [26]. The use of nasal sprays is no longer recommended because of the higher risk of overdose and greater susceptibility to hyponatremia and water toxicity [15]. Evidence of a positive correlation between desmopressin efficacy and dose is insufficient, and the lowest effective dose of desmopressin should be used to reduce the occurrence of adverse effects. If the child continues to urinate after 1 to 2 weeks of treatment at the initial dose, an increase in dose may be considered [14]. The effect of drug therapy is evaluated after 4 weeks of treatment, and if there are signs of improvement, treatment is continued for 3 months; if there are no signs of improvement, discontinuation of the drug is considered. Signs of treatment improvement included: (i) reduction in the amount of urine loss; (ii) reduction in the number of urine loss per night; and (iii) reduction in the frequency of urine loss. There is controversy as to whether tapering at discontinuation reduces the recurrence rate [27-28].
2.3.2 Anticholinergics, including oxybutynin, tolterodine, and probenecid, work by increasing bladder capacity and inhibiting detrusor overactivity (DO), and are most effective in children with DO, small bladder capacity, or failure of bowel function therapy for enuresis [16]. It is most effective in children with DO, small bladder capacity, or failed bowel function therapy [16]. Common side effects of these drugs include dry mouth, blurred vision, headache, nausea, and gastrointestinal discomfort [29]. Anticholinergics alone should not be used to treat MNE; anticholinergics and promethazine should not be combined to treat enuresis [14]; in children with enuresis with DO, anticholinergics may be the treatment of choice, along with a combination of alarms or desmopressin. There are no clear criteria regarding which anticholinergic drug to choose for the treatment of enuresis: tolterodine has a lower incidence of side effects than oxybutynin; while the new generation anticholinergic drug solifenacin has better efficacy and higher safety than tolterodine for DO [30]. Overall, all types of currently applied anticholinergics have a good safety profile, but the efficacy and tolerability of treatment of enuresis need to be verified in more clinical studies.
2.3.3 Botulinum toxin A (botulinum toxin-A) has been widely demonstrated to be safe and effective in the treatment of DO, and botulinum toxin A injections can be used as an alternative treatment option in children with proven DO who are ineffective or intolerant to anticholinergic therapy [31]. The mechanism of botulinum toxin A treatment may include both peripheral and central aspects: peripheral by inhibiting the release of acetylcholine, ATP, and substance P, and reducing the expression of axonal capsaicin and purinergic receptors, thus reducing the occurrence of DO; central by reducing the uptake of substance P and neurotransmitters to exert a central desensitizing effect [16]. In addition, it has been reported in the literature that botulinum toxin A injections are equally effective in the treatment of synergistic disorders of the forced urinary sphincter [32]. Currently, Botulinum toxin A treatment for enuresis is not yet popular in China.
2.3.4 Central nervous system excitatory drugs are more effective in the treatment of children with hypersomnia [4]. One of the most widely used drugs for enuresis is promethazine (a tricyclic antidepressant), whose exact mechanism of treatment is unclear and may be related to its antidepressant effect and improvement of sleep to make the child easily awake. In children ≥6 years of age, promethazine is given at an initial dose of 25 mg one hour before bedtime, and if treatment is not effective after 1 to 2 weeks, the dose may be increased to 50 mg in children 7 to 12 years of age, and to a maximum dose of 75 mg in older children [8]. 20% to 33% of children taking promethazine are free of enuresis for 14 consecutive days, but symptoms recur in about 2/3 of children after 3 months of discontinuation of the drug [33]. Promethazine has potential dose-related adverse effects such as drowsiness, dry mouth, nausea and vomiting, and in severe cases, seizures, cardiac arrhythmias, and death due to overdose [33], so an electrocardiogram is recommended before treatment to determine the presence of potential cardiac arrhythmias in the child. The status of tricyclic antidepressants for the treatment of enuresis has been reduced by their side effects and the use of desmopressin, which is currently used only in children aged 6 years and older with refractory enuresis [1].
The mechanism of meclofenoxate, also known as encephalin, for the treatment of enuresis may be related to the increased synthesis and release of dopamine from nerve endings in the brain, which increases the excitability of the cerebral cortex and makes it easy for the child to awaken. One study reported that meclofenoxate and oxybutynin combined with psychotherapy and bladder training in children with enuresis with occult spina bifida had a cure rate of 93.3% and no recurrence at 3-month follow-up [34]. In addition, the Lundmark study found that reboxetine (an antidepressant) was uniquely effective in the treatment of refractory enuresis with a 52% treatment success rate [35]; sertraline had a higher success rate in children who failed desmopressin treatment without adverse effects, but there is a lack of confirmation in a large sample study [36].
2.3.5 Other drugs Mainly include nonsteroidal anti-inflammatory drugs, such as ibuprofen, indomethacin, and diclofenac, which are based on the principle of inhibiting prostaglandin synthesis or antagonizing its binding to prostaglandin receptors in the bladder, thereby reducing nocturnal urine production and increasing bladder volume [16]. Compared to placebo, these drugs improve the therapeutic effect, but are less effective than the preferred therapeutic measures such as desmopressin, and have more side effects and are prone to relapse after discontinuation, and more studies are needed to prove their place in the treatment of enuresis [29].
2.4 Traditional Chinese medicine treatment Traditional Chinese medicine treatment has its own unique theory for the diagnosis and treatment of enuresis. In recent years, many TCM treatments for enuresis have been reported in the literature, among which the efficacy of using acupuncture for enuresis is more accurate. The principle is to stimulate specific acupuncture points to regulate the excitability of the central nervous system, strengthen its connection with the vegetative and peripheral nerves, harmonize their functions and regulate bladder function, thus achieving therapeutic goals. A systematic review comparing acupuncture treatment with other therapeutic measures found that the efficiency of acupuncture treatment appeared to be the same as desmopressin, but there was a lack of reported cure rates [37]. The current literature on Chinese herbal medicine for enuresis all has a small sample size and no control group, and efficacy needs further confirmation [38].
2.5 Surgical treatment includes bladder enlargement, external urethrotomy, and bladder neck reconstruction surgery, but the effectiveness of surgical treatment is inexact and has more complications, such as urinary incontinence, epididymitis, and azoospermia, which have not been reported in the literature compared with other treatments [38]. Therefore, surgical treatment is not yet considered as an appropriate treatment for enuresis.
Hypnotherapy, induction current therapy, and chiropractic therapy are also available, but all lack cure rates reported [38-39]. The prognosis of enuresis is varied, ranging from cure to complete failure to respond to treatment, with enuresis persisting into adulthood in about 1% of children; epidemiological surveys show that about 15% of children heal spontaneously each year without treatment, and there are no randomized controlled trials to confirm the optimal age for treatment of enuresis [2].
In conclusion, clinicians should identify the etiology and pathogenesis of enuresis in children with enuresis based on their medical history, physical examination, urinary diary, urinary routine and, if necessary, urodynamic examination, and develop an individualized treatment plan considering the child’s age, type of enuresis and willingness to treat [40], which can later be adjusted in a timely manner according to changes in the condition. The main research directions of enuresis currently include the optimal combination of various assessment and treatment protocols, validation of efficacy, and discovery of new treatment methods. Although the pathogenesis of enuresis is still not uniform and the treatment options are diverse, it is believed that more and more research results and clinical practice will further improve the cure rate and reduce the recurrence rate of enuresis.