Overactive bladder (OAB) is a common lower urinary tract disorder in children, defined as the presence of "urgency to urinate, usually accompanied by urgency and nocturia, with or without urinary incontinence, without urinary tract infection or other obvious pathology".1Clinically, urinary urgency is often associated with urinary incontinence and frequency per day; However, it can be due to delayed urination and overstretching of the bladder.2,3
OAB is not associated with neurological and anatomical abnormalities of the lower urinary tract. The overall prevalence ranges from 1.5 to 36.4%; The peak incidence is known to occur between the ages of 5 and 7 years, with a higher prevalence in males.4,5The quality of life of these patients may be associated with emotional and behavioral changes such as symptoms of depression and anxiety. Patients may have problems such as Attention Deficit Hyperactivity Disorder (ADHD) and Oppositional Defiant Disorder.6-8
Although OAB can resolve spontaneously, urinary tract symptoms can persist into adulthood.9,10The correlation between urination and bowel symptoms is already well established. Children with OAB have three times as many constipation symptoms as children without urgency.11-13Possible explanations are that bowel and bladder functions are controlled by the supraspinal region,14-17and there appears to be crosstalk between the lower urinary tract and the rectum (illustration 1).18In addition, it has been suggested that contractions of the external urethral sphincter to prevent urine leakage and simultaneous contraction of the anal sphincter may decrease rectal passage through negative feedback.14,18Also, the hard stool mass in the rectum could compress the bladder and alter its function.19-21Obese children have a higher incidence of overactive bladder than eutrophic children. Studies suggest that there may be frontal lobe disinhibition that is responsible for this phenomenon.14,15,22Children with sickle cell and those in care also have a higher prevalence of OAB.22This article reviews the pathophysiology, associated disorders, and aspects related to the diagnosis and treatment of OAB.
The pathophysiology of OAB is not fully understood and is thought to be multifactorial. One theory holds that the urge to urinate and its associated symptoms stem from a cortical immaturity of the centers responsible for controlling urination.14To support this hypothesis, voluntary and coordinated urination develops over time. In the first 2 months of life, the child urinates once an hour with an intermittent stream. In this phase, urination is mainly controlled by the brainstem.19,23From the first to the third year of life, cortical inhibitory pathways develop together with the periaqueductal gray matter, the anterior cingulate gyrus (ACG) and the autonomic, somatic and sensory nervous systems as well as micturition and the pontine micturition center becomes voluntary. .19,23Typically, as the child develops, the prefrontal cortex begins to control the more primitive afferent pathways of the brain, such as the limbic and paralimbic systems, from top to bottom.
The child may also experience urgency when choosing not to urinate as part of a behavioral disorder. Like inattention, delayed voiding can be the result of a behavioral disorder or neurophysiological immaturity. Children with oppositional defiant disorder who have trouble following commands often refuse to go to the bathroom to urinate or defecate and may be affected by functional fecal incontinence.24,25Unfortunately, there is little in the literature on the neurofunctional assessment of these patients, but hypoactivation of the prefrontal cortex appears to be present.26-28In situations of delayed urination, the child resorts to techniques such as penile constriction, which stimulates the dorsal nerve of the penis, causing the external urethral sphincter to contract and the bladder to relax.
OAB patients appear to have increased ACG activity and deactivation of the urinary pontine micturition center process, resulting in a higher frequency of bladder overflow.3Therefore, an overactive ACG can lead to an increased response to bladder filling and consequently urinary urgency.
CLINICAL HISTORY AND DIAGNOSIS
Medical history should include family history, neuropsychomotor development, bowel exercise and defecation, history of urinary tract infections (UTIs), academic performance, and the child's behavior and psychosocial development.23Recently it has been shown that there is an association between mothers and daughters with OAB.10,29Intestinal obstruction should be evaluated and assessed using the Bristol Stool Diary and the Rome III or IV score.11
OAB occurs during the storage phase of the bladder. However, it may be accompanied by changes in the micturition phase, such as B. Dysfunctional micturition. In one study, the authors showed that some urinary symptoms show low correlation with more objective data.30Therefore, additional tests should be ordered, e.g. B. Urinalysis, ultrasound (US) of the urinary tract, uroflowmetry, bladder diary and bowel diary. Ultrasound should measure postvoid residual (PVR) and bladder wall thickness and check for rectal extension (≥3 cm suggests fecal impaction).11PVR varies by age. PVR is considered high in children aged 4 to 6 years when it is ≥ 30 mL or > 21% of bladder capacity and in children aged 7 to 12 years when it is ≥ 20 mL or > 15% of bladder capacity .2
A patient with OAB has a bell- or tower-shaped uroflowmetry curve suggestive of urinary urgency (Figure 2).1The urodynamic study should be reserved for those cases where post-treatment failure occurs or for patients who show signs of non-neurogenic bladder failure or even myogenic failure.23,31
The bladder diary consists of recording the frequency and amount of urine and urinary incontinence per day over a 48-hour period. The expected bladder capacity is calculated as [age (years) + 1] x 30 mL. The International Children's Continence Society (ICCS) defined this as an increase in diurnal frequency ≥ 8 times daily and a decrease in diurnal frequency ≤ 3 times daily.2The intestinal diary is also kept over a period of 7 days using the Bristol stool scales. Tools such as the Dysfunctional Emptying Symptom Score (DVSS), the Vancouver Symptom Score for Dysfunctional Elimination Syndrome (VSSDES), and the ROME III and IV questionnaires should be used. The VSSDES can indicate diagnostic validity. The cut-off is 11 with a diagnostic sensitivity and specificity threshold of 80% and 91%, respectively.32On the DVSS questionnaire, scores greater than six in girls and nine in boys are considered to indicate lower urinary tract dysfunction.33
Urotherapy is a very important measure in the treatment of OAB and is considered the therapy of first choice. It consists of nutritional hygiene changes in terms of fluid intake, appropriate interval between micturitions, appropriate position for urination and defecation, with the feet supported on a flat surface, paying attention to the perineal muscles, so that a coordination between relaxation of the pelvic floor and contraction of the bladder11Caffeine, chocolate, and citrus fruits can be avoided as they can stimulate the symptom of urgency, although there is little scientific evidence supporting these measures.3,5,11,23,34The approach to constipation must be aggressive through hydration and fiber intake. We treated all children with constipation with polyethylene glycol (PEG 3350). Initially, we treated fecal congestion at a dose of 1.0-1.5 g/kg/day (maximum dose of 100 g/day) for at least 2 months. The child should be encouraged to stay in the bathroom for 15 to 20 minutes on a regular basis.11
Anticholinergics are the first line of medical treatment for children who have overactive bladders after urotherapy.3All anticholinergic drugs can cause side effects, including dry mouth, constipation, blurred vision, urinary retention, fullness, dizziness, and delirium, especially at high doses. Oxybutynin is the most common drug and can be administered as immediate release (IR) or extended release (ER) with a recommended dose of 0.3 to 0.6 mg/kg.5van Arendonket al.35retrospectively analyzed 27 patients with daytime urinary incontinence who were using oxybutynin IR and switched to oxybutynin ER slow. Complete or partial improvement in symptoms was seen in 13 of the 27 patients with an increase in micturition volume (33% vs. 53%; p<0.01) and an improvement in bladder capacity (55% vs. 70%; p=0.03 ) observed. .35Intravesical administration is an alternative that allows for higher doses with fewer side effects. However, this method is of little use since children are not catheterized intermittently.34Tolterodine is also available in two formulations, and some studies indicate good efficacy and tolerability in children.36,37Bolduc et al.36showed that 77% of children taking tolterodine for oxybutynin intolerance had no significant side effects. Tolterodine IR is available in doses of 1 mg or 2 mg, while ER is 2 mg or 4 mg. Studies comparing the outcomes of oxybutynin and tolterodine in children with overactive bladder are limited; However, they suggest that tolterodine is at least as effective as oxybutynin.38,39Fesoterodine is the newer long-acting antimuscarinic and is available as 4 mg or 8 mg. It is recommended for children weighing > 25 kg and is well tolerated by children and adolescents.40Solifenacin is a slow-acting antimuscarinic available in 5 mg or 10 mg doses. Hoebek et al.41showed an overall response rate of 85% and the presence of side effects in 6.5% of patients with the use of solifenacin. Darifenacin is a more selective antimuscarinic with fewer central nervous system side effects.5Combination therapy with two antimuscarinics (such as oxybutynin and tolterodine) is also possible; A previous study showed that combination drugs showed an improvement in urinary continence, with 63% of patients experiencing moderate side effects, but not enough to stop the drug.41
Mirabegron is the approved β3 agonist for the treatment of OAB in adults and there are few studies in children.5It increases bladder capacity without altering bladder pressure and PVR and promotes smooth muscle relaxation by increasing cyclic adenosine monophosphate.3Side effects that are common with antimuscarinics have not been demonstrated with mirabegron.5Blaise et al.42conducted a study in 58 children with refractory OAB and treated them with mirabegron for 11.5 months. They showed a statistically significant improvement in bladder capacity and continence in these patients with moderate side effects in 13% of cases. This medication can be used as an add-on medication to another anticholinergic drug if needed.11
Electrical neural stimulation (ENS) is thought to stimulate nerves in the bladder, spinal cord, and central nervous system. The mechanism of action is still uncertain. There may be a local effect with activation of bladder C-fibers or a spinal effect with sympathetic activation and/or parasympathetic inhibition.43Dasgupta et al.44performed positron emission tomography/computed tomography (PET/CT) scans in eight patients with Fowler syndrome and eight healthy controls to map these patients' brain function during bladder fullness and modulation during sacral nerve stimulation. In healthy controls, there was an increase in midbrain function and chromogranin A during a full bladder. Patients with Fowler's syndrome showed no increase in brainstem activity, despite an increase in chromogranin A function in the absence of neuromodulation. The hypothesis is that neuromodulation helps restore patients' urinary urgency and micturition capacity.44
The main types of ENS are a) parasacral transcutaneous electrical nerve stimulation (TENS);3,5,43,45b) Stimulation des N. tibialis posterior (PTNS);3,4,43,46and c) stimulation by sacral implantation.3,43In TENS, two surface electrodes are placed at the S3 level, while in PTNS, a 34-gauge needle is placed two finger widths above the medial malleolus. Quintillian et al.47conducted a review study in which patients undergoing ENS showed complete resolution of symptoms of overactive bladder, urinary urgency, and daytime wetting in 31-78%, 25-84%, and 13-84% of patients, respectively. Randomized trials have shown that TENS is an effective way to treat symptoms of overactive bladder in children and adolescents.47,48The complete resolution rate of symptoms in TENS is about 60%, with a recurrence rate of 10%.43,46
Borchet al.4951 patients were randomly assigned to three treatment groups. Group 1 received TENS plus active oxybutynin administration, Group 2 received TENS plus placebo oxybutynin administration and Group 3 received placebo TENS plus active oxybutynin administration. All three groups showed a positive effect in terms of reduced urinary incontinence, incontinence severity and urinary frequency, as well as improved mean and maximum bladder capacity, but in group 3, one-third of the patients had urinary retention that was absent in group 1. ; this indicated the importance of TENS in voiding. Group 1 had a more significant improvement in daytime urinary incontinence (p<0.01), urinary incontinence severity (p<0.05), and urinary frequency (p<0.001) compared to the other groups.49
Recent studies have compared established treatments for OAB and TENS. Quintillian et al.47analyzed two methods of treating OAB in children: a) oxybutynin plus sham electrotherapy for the scapula and b) TENS plus placebo. They showed that TENS is as effective as oxybutynin in treating OAB. There was a decrease in stool frequency in the oxybutynin group, but the TENS group showed an improvement in constipation. Side effects occurred only in the oxybutynin group and led to treatment discontinuation in 13.3% of patients.47
TENS can also be used to treat constipation. Veiga et al.50showed that TENS resolved 60% of cases of constipation in patients with OAB, although it was not associated with improvement in OAB. Two other randomized studies have already been completed. In one study, participants who received 20-minute TENS sessions showed longer colonic transit time compared to a control group.51The second study was a double-blind, controlled study that evaluated the acute effects of TENS on rectal motility and showed that bowel contractions improved after TENS.52
The PTNS approach is well tolerated by children and studies have shown it to be an effective method of treating overactive bladder.53Initial studies have shown an improvement in complete resolution of OAB symptoms from 56% to 100%.5,54The rate of complete resolution of symptoms was significantly higher in the TENS group than in the PTNS group (70% vs. 9%).55Boudaudet al.56analyzed PTNS versus sham treatment and concluded that despite the improvement in urodynamic parameters in the PTNS group, there was no difference in clinical outcomes between the two groups. Peters et al.57conducted a randomized multicenter trial comparing PTNS and tolterodine ER and found similar reductions in urinary frequency, urinary urgency severity and increased voiding volume.
We recommend ENS when standard urotherapy fails, as there are no direct side effects and greater efficacy against OAB and constipation. The sacral implant is performed through a percutaneous transforaminal approach to stimulate the S3 nerve.3,43Rothet al.58showed complete or >50% improvement in 88% of children. Of these, 63% had nighttime wetting, 89% improved daytime urinary frequency, and 59% had constipation.2However, due to the high rate of reoperations, this method is limited to patients who do not respond to the other methods.
Botulinum toxin A acts at the neuromuscular junction, preventing the action of acetylcholine and adenosine-5-triphosphate on parasympathetic presynaptic terminals and promoting chemically reversible desensitization and flaccid paralysis of the muscle.45The effects start 5-7 days after the injection and can last for about 6 months. Injection of botulinum toxin A is a viable option for patients with refractory HAV, but few studies have been conducted in non-neurogenic patients. Hoebek et al.59reported a study in 21 children with non-neurogenic HAV in which 100 U of botulinum toxin was administered at 15 injection sites on the bladder wall. Few side effects were reported, with a complete success rate of 42% on first use, 61% increase in bladder capacity (p<0.001), and 11% recurrence within one year.59It should be used in children ≥ 3 years at a dose of 5-10 U/kg. It is contraindicated in patients with peripheral motor neuropathy, disorders of neuromuscular synapses, UTI, uncorrected coagulopathy and in pregnant women. Side effects include pain, UTI, hematuria, and autonomic dysreflexia. About 2 to 9% of patients may experience transient acute urinary retention after the procedure, which requires clean intermittent catheterization at this stage.5
OAB is a common clinical entity in children, and knowledge of the neurophysiological factors of micturition provides information to help control it. The diagnosis is clinical and should be supplemented by a bladder diary, ultrasound of the urinary tract with PVR evaluation and uroflowmetry. Treatment should begin with urotherapy and may include TENS, PTNS, and medications in refractory cases. If symptoms persist, botulinum toxin A and sacral neuromodulator implants may be alternatives.