The pathophysiology of OAB has not been thoroughly studied and is believed to be multifactorial. One representative theory proposes that urinary urgency and related symptoms result from the immaturity of the neural centers controlling urination [14], which is supported by the fact that voiding ability improves with age. In the first few months of life, a child’s voiding pattern is characterized by an intermittent urinary flow [15]. During this period, micturition is controlled by the brainstem, similar to involuntary reflex voiding. At ages 1–3 years, voiding ability improves as the cortical inhibitory pathway, periaqueductal gray matter (PAG), anterior cingulate gyrus (ACG), and autonomic/somatic nervous system develop [6]. As the child matures, the prefrontal cortex (PFC) develops top-down control over more primitive afferent brain pathways, such as the limbic and paralimbic systems. Frontal lobe maturation occurs throughout childhood and adolescence until the mid-20s, which explains the gradual resolution of OAB as children age. Chung et al. [16] reported an age-dependent decrease in OAB prevalence from approximately 23% at 5 years to 12.2% at 13 years of age.

Urgency is defined as the “intense desire” to urinate, suggesting that higher brain centers are involved in this process. Functional magnetic resonance imaging (MRI) and positron emission tomography revealed differences in brain lesions and activity between patients with normal LUT function and those with detrusor overactivity [17,18]. During the storage phase, the PAG, which is located in the midbrain, receives information from the medial PFC, ACG, thalamus/hypothalamus, and insula (Fig. 2) [17].

An MRI-based study revealed that a small bladder volume is associated with decreased ACG activity, and higher bladder volumes correlate with significantly increased ACG activity [14]. Patients with urgency have increased ACG activity and decreased PFC activity, which leads to more frequent bladder repletion and, therefore, the urge to void.

Urotherapy is a nonsurgical, nonpharmacological approach (rehabilitation) that is considered a first-line treatment for OAB. Standard urotherapy begins with educating the child and family to explain and understand the child’s specific dysfunction. Motivation is an integral determinant of treatment success. A child who cannot anticipate the benefits of treating his or her dysfunction may not be ready to initiate treatment [42]. Timed voiding, approximately 6 times a day, can help relieve symptoms. For relatively large amounts of residual urine, double voiding is recommended. Fluid intake should be regular during the day and minimized before bedtime. In the presence of urinary urgency, DV, or abnormal defecation dynamics caused by problems with the pelvic floor or sphincter muscle relaxation during elimination, pelvic floor muscle training may be the next step [43]. For this, proper education should be provided to ensure an adequate voiding or defecation position where the feet are supported on a flat surface, with attention to the pelvic musculature to improve the coordination between bladder contraction and pelvic muscle relaxation [20]. A simple behavioral treatment can improve frequency and urgency rates in 50% of children [44]. For children unresponsive to simple urotherapy and those without cystourethrogram- or uroflowmetry-confirmed DV, pharmacotherapy is the treatment of choice.

There are no standard evaluation and management protocols for constipation. Simple constipation may be treated by increasing hydration, adding high-sorbitol juices (e.g., prune, pear, or apple juice), or increasing the number of vegetables in a child’s normal diet. Avoiding excessive milk consumption is also helpful. Currently, there is no evidence supporting the treatment of constipation with pre/probiotic supplements [14]. If dietary interventions fail, polyethylene glycol (PEG), lactulose, or sorbitol may be administered. PEG may be introduced at an initial dose of 1.5 g/kg/day for 6 days, followed by 0.5–0.7 g/kg/day after 24 days.

Treatment-refractory OAB in children can be addressed using second-line approaches, such as biofeedback, transcutaneous electrical nerve stimulation, and botulinum toxin. In a study involving 24 children with standard urotherapy- and antimuscarinic therapy-resistant OAB, Pekbay et al. [45] reported that biofeedback-assisted pelvic floor muscle therapy provided symptomatic relief and increased functional bladder capacity.

Nonneurogenic voiding dysfunction in children is a dysmotility disorder related to external sphincter dysfunction. A recent systematic review revealed that biofeedback is effective in alleviating UTI symptoms or constipation. Moreover, biofeedback can improve postvoid residual and electromyography during voiding and has a longer-term effect [46].

Although stepwise therapy, such as behavioral treatment, is important, pharmacotherapy remains the mainstay of treatment. A well-balanced micturition cycle consists of coordinated sympathetic and parasympathetic activities; a reduced parasympathetic tone and an increased sympathetic tone may improve urgency. Muscarinic receptor blockers can be administered to regulate the parasympathetic tone; alpha or beta-agonists may be indicated for sympathetic tone regulation because, during the storage phase, the pontine micturition center is continuously activated and sends descending signals to the hypogastric nerve, which subsequently relaxes the detrusor muscle through beta-adrenoceptor (AR) activation and contracts the internal sphincter through alpha AR activation [10]. However, in practice, alpha agonists are not recommended for OAB because of their systemic effects (especially on vascular smooth muscles). In human bladder smooth muscles, 96% of sympathetic receptors are beta-3 receptors, which represent 97% of the total beta AR mRNA expression in the bladder [18]. Several studies have revealed that beta-3 AR stimulation is associated with increased micturition capacity without aggravating residual volume or contraction power. Targeting beta-3 ARs, therefore, increases the bladder storage volume without affecting the contraction amplitude [47–49].

Antimuscarinics (also known as anticholinergics) are generally used as the first-line treatment in children who remain symptomatic after urotherapy. Currently, only 2 antimuscarinic agents have received formal approval for use in children (oxybutynin by the U.S. Food and Drug Administration [FDA] and European Medicines Agency [EMA]; tolterodine by the EMA). While several studies have reported significant results with fesoterodine, propiverine [50,51], solifenacin [52,53], and trospium [54], the administration of these drugs, which depends on age and national discipline, has not received official permission.

Although antimuscarinics are the mainstay of medical treatment, their use is associated with significant side effects, such as dry mouth, constipation, and blurred vision, especially at high doses [55]. Many antimuscarinics, including oxybutynin, cross the blood-brain barrier and bind to M2 receptors, negatively affecting cognitive functions in the central nervous system [56]. Adverse events include sedation, confusion, amnesia, and abnormal dreams, which are more common in children [57].

Beta-3 AR agonists, which were approved for their favorable tolerability profile in pivotal phase 2 and 3 studies, are currently one of the main treatment options for adult patients with OAB. Their use in children with neurogenic detrusor overactivity has only recently been approved by the FDA [50,63,74]. Beta-3 AR agonists increase bladder capacity without changing the bladder pressure or postvoid residual volume by promoting the relaxation of bladder smooth muscles [14]. Compared with antimuscarinics, beta-3 AR agonists show adequate efficacy and have fewer adverse effects (dry mouth 2.0%, constipation 1.6%, headache 2.0%) [74].

The generally accepted mechanism of smooth muscle relaxation comprises downstream adenyl cyclase activation and subsequent cyclic adenosine monophosphate (cAMP) production, followed by Rho-kinase pathway inhibition [75,76]. Additionally, increased cAMP levels lead to protein kinase A activation, which activates large-conductance, calcium-dependent K+ (BK) channels. These activated BK channels hyperpolarize bladder smooth muscles, which increases detrusor stability [77]. Despite the paucity of literature, promising results have recently been reported. In their study, Blais et al. [71] demonstrated that mirabegron is safe and effective in children (median age, 10.1 years) with idiopathic, antimuscarinic-refractory OAB. The results showed that the median bladder capacity (150 → 200 mL), continence rate (89.6%), and quality of life significantly improved without noticeable side effects (P < 0.001).

Having fewer treatment options for pediatric OAB creates significant problems, especially in treating refractory OAB because the next level of therapy is frequently more invasive. In a prospective, off-label study, Morin et al. [78] employed a combination of mirabegron and a standard, maximized antimuscarinic for a mean of 16 months to treat 35 children (median age, 10.3 years) who had an inadequate response or refractory side effects during a 6-month trial of escalating doses of oxybutynin-ER, solifenacin, or fesoterodine. Continence improved in all children, and the median bladder capacity increased from 50% to 74% of that expected for age; 12 remained completely dry, and 2 were withdrawn owing to side effects.

Including the above 2 studies, Kim et al. [79] recently reported the first systematic review (3 prospective and 5 retrospective studies) suggesting the therapeutic role of beta-3 agonists in children: beta-3 agonists significantly improve urodynamic parameters and self-reported outcomes, such as incontinence. After treatment, the pooled effect estimates for maximum cystometric capacity had a mean difference of +99 mL (95% confidence interval, 74.72–122.96).

Clinical trials involving intravesical injections of botulinum toxin A (BoNTA) in children with OAB are currently underway. Despite its off-label use, BoNTA is an alternative for anticholinergic-intolerant patients. BoNTA blocks acetylcholine release at the parasympathetic presynaptic neuromuscular junction, leading to decreased regional muscle contractility and injection site atrophy. Subsequent chemical denervation is a reversible reaction, and inactivation and removal occur over time. The clinical effect appears after approximately 5–7 days, and the maximum effect appears after 4–6 weeks [80]. The paralytic effect varies depending on the muscle type at the injection site; however, it is known that it usually lasts for 3–9 months with no apparent tachyphylaxis [81]. The major disadvantage of BoNTA injections is the need for re-treatment due to temporary chemical denervation, which occurs because synaptic respouting occurs after approximately 6 months. According to a preliminary study, repeated BoNTA injections are safe for children and do not cause additional bladder wall fibrosis [82]. In another histological study, no ultrastructural changes were noted in the bladder muscles after Botox injection [83].

Other studies used varying Botox doses, ranging from 50 to 200 units (up to 200–300 units is commonly used for neurogenic OAB) [84–86]. Botox should be used in children over 3 years old at a dose of 5–10 units/kg of body weight [87]. Furthermore, because the effect of Botox is cumulative when treating a child with spasticity, precautions should be taken to determine a history of BoNTA administration at another site within the same period [9]. The full clinical response, defined by complete continence in pediatric patients, was 44%–95% in 2 level 3 studies [84,88]. Moreover, urodynamic improvements (38%–70%) were also reported in 2 laboratory studies [75,76].

Over the last 2 decades, neuromodulation has been employed to treat children with nonneurogenic LUTD (Table 1), and several studies have reported that it can significantly improve bladder volume, decrease urgency severity, improve continence, and decrease UTI incidence [89–91]. Urodynamic parameters, including bladder compliance, episodes of detrusor overactivity, and volume at first detrusor contraction, also significantly improved [92].

Neuromodulation delivers electrical stimulation that changes existing neural transmission patterns and modulates detrusor activity. It also rebalances excitatory and inhibitory information to put the neural drive into a more neutral state. Although the exact mechanism of action remains unclear, data from many studies reveal that this approach is effective. A meta-analysis has reported that neuromodulation may lead to better partial improvement in children with nonneurogenic OAB; however, a complete response is not guaranteed [93]. The EAU guidelines recommend various neuromodulation modalities only in cases refractory to standard therapy [94]. Despite an initial successful response, a high recurrence rate that warrants long-term follow-up has been reported [95]. Additionally, many children may present with other forms of LUTD as adults [96].