1.INTRODUCTION

1.1.Aim

The European Association of Urology (EAU) Paediatric Urology Guidelines Panel has prepared these Guidelines with the aim of increasing the quality of care for children with urological conditions. This Guideline document is limited to a number of common clinical pathologies in paediatric urological practice, as covering the entire field of paediatric urology in a single guideline document is unattainable.

The majority of urological clinical problems in children are specialised and in many ways differ to those in adults. This publication intends to outline a practical and preliminary approach to paediatric urological conditions. Complex and rare conditions that require special care with experienced doctors should be referred to designated centres where paediatric urology practice has been fully established and a multidisciplinary team is available.

Over time, paediatric urology has developed and matured, establishing its diverse body of knowledge and expertise and may now be ready to distinguish itself from its parent specialties. Thus, paediatric urology has recently emerged in many European countries as a distinct subspecialty of both urology and paediatric surgery and presents a unique challenge in the sense that it covers a large area with many different schools of thought and a huge diversity in management.

Knowledge gained by increasing experience, new technological advances and non-invasive diagnostic screening modalities has had a profound influence on treatment modalities in paediatric urology, a trend that is likely to continue in the years to come.

It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of children and their caregivers into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2.Panel composition

The EAU Paediatric Urology Guidelines Panel consists of an international group of clinicians with particular expertise in this area. All experts involved in the production of this document have submitted potential conflict of interest statements, which can be viewed on the EAU Website: http://uroweb.org/guideline/paediatric-urology/.

1.3.Available publications

A quick reference document (Pocket guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. A number of translated versions, alongside several scientific publications are also available [1-7]. All documents can be viewed through the EAU website: http://uroweb.org/guideline/paediatric-urology/.

1.4.Publication history

The Paediatric Urology Guidelines were first published in 2001 [8]. This 2021 publication includes a number of updated chapters and sections as detailed below.

1.5.Summary of changes

The literature for the complete document has been assessed and updated, wherever relevant. Key changes in the 2021 publication:

• Section 3.2 - Management of undescended testes: Both the literature and the text have been updated;
• Section 3.3 - Testicular Tumours in prepubertal boys: This is a new section in the Guideline;
• Section 3.5 - Acute Scrotum: Both the literature and the text have been updated;
• Section 3.6 - Hypospadias: Both the literature and the text have been updated;
• Section 3.7 - Congenital penile curvature: Both the literature and the text have been updated;
• Section 3.9 - Urinary Tract Infections: Both the literature and the text have been extensively updated;
• Section 3.10 - Day-time lower urinary tract conditions: The literature has been updated resulting in minor amendments to the text;
• Section 3.13 - Dilatation of the upper urinary tract (UPJ and UVJ obstruction): The literature has been updated resulting in minor amendments to the text:
• Section 3.15 - Urinary stone disease: The literature has been updated resulting in minor amendments to the text;
• Section 3.18 - Congenital lower urinary tract obstruction (CLUTO): Both the literature and the text have been updated;
• Section 3.19 – Rare Conditions - This is a new section in the Guideline comprising of urachal remnants, papillary tumours of the bladder and penile rare conditions.

1.5.1.New recommendations

3.3 Recommendations for testicular tumours in prepubertal boys

Recommendations	LE	Strength rating
High-resolution ultrasound (7.5 – 12.5 MHz), preferably a doppler ultrasound, should be performed to confirm the diagnosis.	3	Strong
Alpha-fetoprotein (AFP) should be determined in prepubertal boys with a testicular tumour before surgery.	2b	Strong
Surgical exploration should be done with the option for frozen section, but not as an emergency operation.	3	Strong
Organ-preserving surgery should be performed in all benign tumours.	3	Strong
Staging (MRI abdomen /CT chest) should only be performed in patients with a malignant tumour to exclude metastases.	3	Strong
MRI should only be performed in patients with the potential malignant Leydig or Sertoli-cell-tumours to rule out lymph node enlargement.	4	Weak
Patients with a non-organ confined tumour should be referred to paediatric oncologists post-operatively.	4	Weak

3.19 Recommendations for rare conditions in children

3.19.1 Urachal remnants

Recommendations	Strength rating
Urachal remnants with no epithelial tissue carry little risk of malignant transformation.	Strong
Asymptomatic and non-specific atretic urachal remnants can safely be managed non-operatively.	Strong
Urachal remnants (UR) incidentally identified during diagnostic imaging for non-specific symptoms should also be observed non-operatively since they tend to resolve spontaneously.	Strong
A small urachal remnant, especially at birth, may be viewed as physiological.	Strong
Urachal remnants in patients younger than 6 months are likely to resolve with non-operative management.	Strong
Follow-up is necessary only when symptomatic for 6 to 12 months.	Strong
Surgical excision of urachal remnants solely as a preventive measure against later malignancy appears to have minimal support in the literature.	Strong
Only symptomatic URs should be safely removed by open or laparoscopic approach.	Strong
A voiding cystourethrogram is only recommended when presenting with febrile UTIs.	Strong

3.19.2 Papillary tumours of the bladder

Recommendations	LE	Strength rating
Ultrasound is the first investigation of choice for the diagnosis of paediatric bladder tumours.	3	Strong
Cystoscopy should be reserved if a bladder tumour is suspected on imaging for diagnosis and treatment.	3	Strong
After histological confirmation, inflammatory myofibroblastic bladder tumours should be resected locally.	4	Weak
Follow-up should be every 3-6 months in the first year, and thereafter at least annually with urinanalysis and an ultrasound for at least 5 years.	4	Weak

3.19.3 Penile conditions

Recommendations	LE	Strength rating
Treatment of penile cystic lesions is by total surgical excision, it is mainly indicated for cosmetic or symptomatic (e.g. infection) reasons.	4	Weak
Propranolol is currently first line treatment for infantile haemangiomas.	2b	Strong
Conservative management is the first-line treatment for penile lymphedema.	4	Weak
In symptomatic cases or in patients with functional impairment, surgical intervention may become necessary for penile lymphedema.	4	Weak

2.METHODS

2.1.Introduction

These Guidelines were compiled based on current literature following a structured review. Databases covered by the searches included Pubmed, Ovid, EMBASE and the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Application of a structured analysis of the literature was not possible in many conditions due to a lack of well-designed studies. The limited availability of large randomised controlled trials (RCTs) - influenced also by the fact that a considerable number of treatment options relate to surgical interventions on a large spectrum of different congenital problems - means this document is largely a consensus document. Clearly there is a need for continuous re-evaluation of the information presented in this document.

For each recommendation within the guidelines there is an accompanying online strength rating form, the basis of which is a modified GRADE methodology [9,10]. Each strength rating form addresses a number of key elements namely:

1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [11];
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact of patient values and preferences on the intervention;
6. the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [12]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. The strength rating forms will be available online.

Additional information can be found in the general Methodology section of this print, and online at the EAU websit; http://www.uroweb.org/guideline/.

A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2.Peer review

All chapters of the Paediatric Urology Guidelines were peer-reviewed in 2015.

3.THE GUIDELINE

3.1.Phimosis

This chapter does not deal with neonatal circumcision as practised in the USA, nor mass circumcision as practised in many African countries as part of a national program to prevent HIV. Also “religious and cultural” circumcision is not discussed. At present in some European countries professional organisations do not support circumcision for these reasons and it is no longer covered by insurance in these countries. Special centres have been set up, where well-trained doctors perform circumcisions under sedation and local anaesthetics at a lower cost. In all circumstances facilities have to comply with national regulations regarding hygiene, special equipment, pain protocols and follow-up. Usually these clinics have an agreement with a nearby hospital for the immediate treatment of possible complications. It is estimated that 37-39% of men worldwide are circumcised [13].

3.1.1.Epidemiology, aetiology and pathophysiology

At the end of the first year of life, retraction of the foreskin behind the glandular sulcus is possible in approximately 50% of boys; this increases to approximately 89% by the age of three years. The incidence of phimosis is 8% in six to seven year olds and in just 1% in males aged sixteen to eighteen years [14].

3.1.2.Classification systems

Phimosis is either primary with no sign of scarring, or secondary (pathological) to a scarring such as balanitis xerotica obliterans (BXO) [14]. Balanitis xerotica obliterans, also termed lichen sclerosis, has been recently found in 35% of circumcised prepuce in children and adolescents and in 17% of boys younger than ten years presenting with phimosis. The clinical appearance of BXO in children may be confusing and does not always correlate with the final histopathological results. Lymphocyte-mediated chronic inflammatory disease was the most common finding [15,16] (LE: 2b).

Phimosis has to be distinguished from normal agglutination (adhesion) of the foreskin to the glans, which is a more or less lasting physiological phenomenon with clearly-visible meatus and partial retraction [17]. Separation of the prepuce from the glans is based on accumulated epithelial debris (smegma) and penile erections. Forceful preputial retraction should be discouraged to avoid cicatrix formation [18].

Paraphimosis must be regarded as an emergency situation: retraction of a too narrow prepuce behind the glans penis into the glanular sulcus may constrict the shaft and lead to oedema of the glans and retracted foreskin. It interferes with perfusion distally from the constrictive ring and brings a risk of preputial necrosis.

3.1.3.Diagnostic evaluation

The diagnosis of phimosis and paraphimosis is made by physical examination. If the prepuce is not retractable, or only partly retractable, and shows a constrictive ring on drawing back over the glans penis, a disproportion between the width of the foreskin and the diameter of the glans penis has to be assumed. In addition to the constricted foreskin, there may be adhesions between the inner surface of the prepuce and the glanular epithelium and/or a fraenulum breve. Paraphimosis is characterised by a retracted foreskin with the constrictive ring localised at the level of the sulcus, which prevents replacement of the foreskin over the glans.

3.1.4.Management

Conservative treatment is an option for primary phimosis. The class 4 therapies were more effective over placebo and manual stretching [19]. A corticoid ointment or cream (0.05-0.1%) can be administered twice a day over a period of 4-8 weeks with a success rate of > 80% [20-23] (LE: 1b). A recurrence rate of up to 17% can be expected [24]. This treatment has no side effects and the mean bloodcortisol levels are not significantly different from an untreated group of patients [25] (LE: 1b). The hypothalamic pituitary-adrenal axis was not influenced by local corticoid treatment [26]. Adhesion of the foreskin to the glans does not respond to steroid treatment [20] (LE: 2).

Operative treatment of phimosis in children is dependent on the caregivers’ preferences and can be plastic or radical circumcision after completion of the second year of life. Alternatively, the Shang Ring may be used especially in developing countries [27]. Plastic circumcision has the objective of achieving a wide foreskin circumference with full retractability, while the foreskin is preserved (dorsal incision, partial circumcision, trident preputial plasty, combining 2 Z-plasties and a Y plasty) [28,29]. However, this procedure carries the potential for recurrence of the phimosis [30]. In the same session, adhesions are released and an associated fraenulum breve is corrected by fraenulotomy. Meatoplasty is added if necessary. In all cases meticulous haemostasis is mandatory and absorbable interrupted sutures are most often used.

An absolute indication for circumcision is secondary phimosis. In primary phimosis (including those not responding to medical treatment), recurrent balanoposthitis and recurrent urinary tract infections (UTIs) in patients with urinary tract abnormalities are indications for surgical intervention [31-34] (LE: 2b). Male circumcision significantly reduces the bacterial colonisation of the glans penis with regard to both non-uropathogenic and uropathogenic bacteria [35] (LE: 2b). Simple ballooning of the foreskin during micturition is not a strict indication for circumcision.

Routine neonatal circumcision to prevent penile carcinoma is not indicated. A meta-analysis could not find any risk in uncircumcised patients without a history of phimosis [36]. Contraindications for circumcision are: an acute local infection and congenital anomalies of the penis, particularly hypospadias or buried penis, as the foreskin may be required for a reconstructive procedure [37,38]. Circumcision can be performed in children with coagulopathy with 1-5% suffering complications (bleeding), if haemostatic agents or a diathermic blade are used [39,40]. Childhood circumcision has an appreciable morbidity and should not be recommended without a medical reason and also taking into account epidemiological and social aspects [41-45] (LE: 1b). Balanitis xerotica obliterans is associated with meatal pathology (stenosis) after circumcision in up to 20% of boys and adjuvant local steroid treatment is advised [16,46].

Treatment of paraphimosis consists of manual compression of the oedematous tissue with a subsequent attempt to retract the tightened foreskin over the glans penis. Injection of hyaluronidase beneath the narrow band or 20% mannitol may be helpful to release the foreskin [47,48] (LE: 3-4). If this manoeuvre fails, a dorsal incision of the constrictive ring is required. Depending on the local findings, a circumcision is carried out immediately or can be performed in a second session.

3.1.5.Complications

Complications following circumcision vary and have been reported between 0-30% [45]. In a recent study Hung et al. found during a 5-year follow-up period 2.9% complications in non-neonates of which 2.2% were early (within 30 days after circumcision). Non-healing wounds, haemorrhage, wound infection, meatal stenosis, redundant skin and non-satisfying cosmetic appearance as well as cicatrix formation and trapped penis all may occur [49].

3.1.6.Follow-up

Any surgery done on the prepuce requires an early follow-up of four to six weeks after surgery.

3.1.7.Summary of evidence and recommendations for the management of phimosis

Summary of evidence	LE
Treatment for phimosis usually starts after two years of age or according to caregivers’ preference.	3
In primary phimosis, conservative treatment with a third generation corticoid ointment or cream is a first-line treatment with a success rate of more than 80%.	1b

Recommendations	LE	Strength rating
Offer corticoid ointment or cream to treat primary symptomatic phimosis.	1b	Strong
Circumcision will also solve the problem.	2b	Strong
Treat primary phimosis in patients with recurrent urinary tract infection and/or with urinary tract abnormalities.	2b	Strong
Circumcise in case of lichen sclerosus or scarred phimosis.	2b	Strong
Treat paraphimosis by manual reposition and proceed to surgery if it fails.	3	Strong
Avoid retraction of asymptomatic preputial adhesions.	2b	Weak

3.2.Management of undescended testes

3.2.1.Background

Cryptorchidism or undescended testis is one of the most common congenital malformations of male neonates. Incidence varies and depends on gestational age, affecting 1.0-4.6% of full-term and 1.1-45% of preterm neonates. Following spontaneous descent within the first months of life, nearly 1.0% of all full-term male infants still have undescended testes at one year of age [50]. This congenital malformation may affect both sides in up to 30% of cases [51]. In newborn cases with non-palpable or undescended testes on both sides and any sign of disorders of sex development (DSDs) like concomitant hypospadias, urgent endocrinological and genetic evaluation is required [52].

3.2.2.Classification

The term cryptorchidism is most often used synonymously for undescended testes. The most useful classification of undescended testes is distinguishing into palpable and non-palpable testes, and clinical management is decided by the location and presence of the testes (see Figure 1). Approximately 80% of all undescended testes are palpable [53]. Acquired undescended testes can be caused by entrapment after herniorrhaphy or spontaneously referred to as ascending testis.

Palpable testes include true undescended testes and ectopic testes. Non-palpable testes include intra-abdominal, inguinal, absent, and sometimes also some ectopic testes. Most importantly, the diagnosis of palpable or non-palpable testis needs to be confirmed once the child is under general anaesthesia, as this is the first step of any surgical procedure for undescended testes.

Figure 1: Classification of undescended testes

3.2.2.1.Palpable testes

Undescended testes

A true undescended testis is on its normal path of descent but is halted on its way down to the scrotum. Depending on the location, the testes may be palpable or not, as in the case of testes arrested in the inguinal canal.

Ectopic testes

If the position of a testis is outside its normal path of descent and outside the scrotum, the testis is considered to be ectopic. The most common aberrant position is in the superficial inguinal pouch. Sometimes an ectopic testis can be identified in a femoral, perineal, pubic, penile or even contralateral position. Usually, there is no possibility for an ectopic testis to descend spontaneously to the correct position; therefore, it requires surgical intervention. In addition, an ectopic testis might not be palpable due to its position.

Retractile testes

Retractile testes have completed their descent into a proper scrotal position but can be found again in a suprascrotal position along the path of their normal descent. This is due to an overactive cremasteric reflex [54]. Retractile testes can be easily manipulated down to the scrotum and remain there at least temporarily.

They are typically normal in size and consistency. However, they may not be normal and should be monitored carefully since up to one-third can ascend and become undescended [55].

3.2.2.2.Non-palpable testes

Among the 20% of non-palpable testes, 50-60% are intra-abdominal, canalicular or peeping (right inside the internal inguinal ring). The remaining 20% are absent and 30% are atrophic or rudimentary.

Intra-abdominal testes

Intra-abdominal testes can be located in different positions, with most of them being found close to the internal inguinal ring. However, possible locations include the kidney, anterior abdominal wall, and retrovesical space. In the case of an open internal inguinal ring, the testis may be peeping into the inguinal canal.

Absent testes

Monorchidism can be identified in up to 4% of boys with undescended testes, and anorchidism (bilateral absence) in < 1%. Possible pathogenic mechanisms include testicular agenesis and atrophy after intrauterine torsion with the latter one most probably due to an in utero infarction of a normal testis by gonadal vessel torsion. The term “vanishing testis” is commonly used for this condition [56].

3.2.3.Diagnostic evaluation

History taking and physical examination are key in evaluating boys with undescended testes. Localisation studies using different imaging modalities are usually without any additional benefit.

3.2.3.1.History

Caregivers should be asked for maternal and paternal risk factors, including hormonal exposure and genetic or hormonal disorders. If the child has a history of previously descended testes this might be suggestive of testicular ascent [57]. Prior inguinal surgery is indicative of secondary undescended testes due to entrapment.

3.2.3.2.Physical examination

An undescended testis is pursued by carefully advancing the examining fingers along the inguinal canal towards the pubis region, perhaps with the help of lubricant. A possible inguinal testis can be felt to bounce under the fingers [58]. A non-palpable testis in the supine position may become palpable once the child is in a sitting or squatting position. If no testis can be identified along the normal path of descent, possible ectopic locations must be considered.

In the event of unilateral non-palpable testis, the contralateral testis needs to be examined. Its size and location can have important prognostic implications. Any compensatory hypertrophy suggests testicular absence or atrophy [59]. Nevertheless, this does not preclude surgical exploration since the sign of compensatory hypertrophy is not specific enough [60,61].

In the event of bilateral undescended testes and any evidence or sign of DSDs, such as genital ambiguity, or scrotal hyperpigmentation, further evaluation including endocrinological and genetic assessment becomes mandatory [62].

3.2.3.3.Imaging studies

Imaging studies cannot determine with certainty that a testis is present or not [63]. Ultrasound (US) lacks the diagnostic sensitivity to detect the testis confidently or establish the absence of an intra-abdominal testis [64]. Consequently, the use of different imaging modalities, such as US or Magnetic resonance imaging (MRI) [65], for undescended testes is limited and only recommended in specific and selected clinical scenarios (e.g. identification of Müllerian structures in cases with suspicion of DSDs) [64].

3.2.4.Management

Treatment should be started at the age of six months. After that age, undescended testes rarely descend [66]. Any kind of treatment leading to a scrotally positioned testis should be finished by twelve months, or eighteen months at the latest, because histological examination of undescended testes at that age has already revealed a progressive loss of germ cells and Leydig cells [67]. The early timing of treatment is also driven by the final adult results on spermatogenesis and hormone production, as well as on the risk of tumour development [68].

3.2.4.1.Medical therapy

Unfortunately, most of the studies on hormonal treatment have been of poor quality, with heterogeneous and mixed patient populations, testis location, schedules and dosages of hormonal administration. Additionally, long-term data are almost completely lacking.

Short-term side effects of hormonal treatment include increased scrotal erythema and pigmentation, and induction of pubic hair and penile growth. Some boys experience pain after intramuscular injection of human chorionic gonadotropin (hCG). All of these tend to regress after treatment cessation [69,70].

3.2.4.1.1.Medical therapy for testicular descent

Hormonal therapy using hCG or gonadotropin-releasing hormone (GnRH) is based on the hormonal dependence of testicular descent, but has a limited success rate of only 20% [71]. However, it must be taken into account that almost 20% of these descended testes have the risk of re-ascending later [72]. In general, success rates depend on testicular location. The higher the testis is located prior to therapy, the lower the success rate, suggesting that testicular position is an important determinant of success [69]. Some authors recommend combined hCG-GnRH treatment. Unfortunately, it is poorly documented and the treatment groups were diverse. Some studies reported successful descent in up to 38% of non-responders to monotherapy [73]. The Panel consensus is that endocrine treatment to achieve testicular descent is not recommended (LE: 4).

Human chorionic gonadotropin

Human chorionic gonadotropin (hCG) stimulates endogenous testosterone production and is administered by intramuscular injection. Several dose and administration schedules are reported. There is no proven difference between 1.5 IU and weight-based doses up to 3.0 IU every other day for fourteen days [74]. Similar response rates were achieved with 500 IU once weekly and 1.50 IU three times weekly [75]. However, there is evidence that dosing frequency might affect testicular descent rates. Fewer lower dose injections per week for five weeks seem to be superior to one higher dose every seven to ten days for three weeks with regard to testicular descent [76].

Gonadotropin-releasing hormone

Gonadotropin-releasing hormone (GnRH) analogues (e.g., buserelin and gonadorelin) are available as nasal sprays, thus avoiding painful intramuscular injections. A typical dosage regimen consists of 1.2 mg per day in three divided doses, for four weeks. Success rates are wide ranging, from 9 to 60%, due to multiple treatment strategies and heterogeneous patient populations [77].

3.2.4.1.2.Medical therapy for fertility potential

Hormonal treatment may improve fertility indices [77,78] and therefore serve as an additional tool to orchidopexy. There is no difference in treatment with GnRH before (neo-adjuvant) or after (adjuvant) surgical orchidolysis and orchidopexy in terms of increasing fertility index, which may be a predictor for fertility later in life [79]. It is still unknown whether this effect on testicular histology persists into adulthood but it has been shown that men who were treated in childhood with buserelin had better semen analyses compared with men who had childhood orchidopexy alone or placebo treatment [77].

It is reported that hCG treatment may be harmful to future spermatogenesis through increased apoptosis of germ cells, including acute inflammatory changes in the testes and reduced testicular volume in adulthood [80].

Identification of specific subgroups of boys with undescended testes who would benefit from such an approach using hormones is difficult. Since these important data on specific groups as well as additional support on the long-term effects are still lacking, the Nordic consensus does not recommend hormonal therapy [81]. The consensus of the Panel is to recommend endocrine treatment with GnRH analogues in a dosage described above for boys with bilateral undescended testes to preserve the fertility potential (LE: 4).

3.2.4.2.Surgical therapy

If a testis has not concluded its descent at the age of six months (corrected for gestational age), and since spontaneous testicular descent is unlikely to occur after that age, surgery should be performed within the subsequent year, and by age eighteen months at the latest [68]. In addition, early orchidopexy can be followed by partial catch-up testicular growth, which is not the case in delayed surgery [79]. All these findings recommend performing early orchidopexy between the ages of six and twelve months [66]. But despite early and successful orchiopexy within the first year of life up to 25% of boys with nonsyndromic undescended testes may be at risk for infertility based on hormonal and histological data, as a recently published series on 333 boys showed. This is especially true for bilateral cases, but in addition in about 5% of unilateral cases reduced numbers of germ cells were detected in testicular biopsies as well [82].

3.2.4.2.1.Palpable testes

Surgery for palpable testes includes orchidofunicolysis and orchidopexy, either via an inguinal or scrotal approach. The latter approach is mainly reserved for low-positioned, undescended testes, with the pros and cons of each method being weighed against each other [83].

3.2.4.2.1.1.Inguinal orchidopexy

Inguinal orchidopexy is a widely used technique with a high success rate of up to 92% [84]. Important steps include mobilisation of the testis and spermatic cord to the level of the internal inguinal ring, with dissection and division of all cremasteric fibres, to prevent secondary retraction and detachment of the gubernaculum testis. The patent processus vaginalis needs to be ligated proximally at the level of the internal ring, because an unidentified or inadequately repaired patent processus vaginalis is an important factor leading to failure of orchidopexy [85]. Any additional pathology has to be taken care of, such as removal of an appendix testis (hydatid of Morgagni). At this moment the size of the testis can be measured and the connection of the epididimis to the testis can be judged and described in the protocol. Some boys have a significant dissociation between testis and epididymis which is prognostically bad for fertility. Finally, the mobilised testicle needs to be placed in a sub-dartos pouch within the hemi-scrotum without any tension. If the length achieved using the above-mentioned technique is still inadequate, the Prentiss manoeuvre, which consists of dividing the inferior epigastric vessels and transposing the spermatic cord medially, in order to provide a straight course to the scrotum, might be an option [86]. With regard to fixation sutures, if required, they should be made between the tunica vaginalis and the dartos musculature [87]. Lymph drainage of a testis that has undergone surgery for orchidopexy may have changed from high retroperitoneal drainage to iliac and inguinal drainage, which might become important in the event of later malignancy [88].

3.2.4.2.1.2.Scrotal orchidopexy

Low-positioned, palpable undescended testis can be fixed through a scrotal incision including division of the gubernaculum, and the processus vaginalis needs to be probed to check for patency [89]. Otherwise, fixation in the scrotum is carried out correspondingly to the inguinal approach. In up to 20% of cases, an inguinal incision will be compulsory to correct an associated inguinal hernia [90]. Any testicular or epididymal appendages can be easily identified and removed. A systematic review shows that the overall success rates ranged from 88 to 100%, with rates of recurrence and post-operative testicular atrophy or hypotrophy < 1% [83]. Another recently published systematic review and meta-analysis revealed similar outcome data regarding post-operative complications, including wound infection, testicular atrophy, testicular reascent, and hernia for palpable low positioned undescended testes. The only siginificant difference was the shorter operative time [91].

3.2.4.2.2.Non-palpable testes

For non-palpable testes, surgery must clearly determine whether a testis is present or not [92]. If a testis is found, the decision has to be made to remove it or bring it down to the scrotum. An important step in surgery is a thorough re-examination once the boy is under general anaesthesia, since a previously non-palpable testis might be identifiable and subsequently change the surgical approach to standard inguinal orchidopexy, as described above. Otherwise, the easiest and most accurate way to locate an intra-abdominal testis is diagnostic laparoscopy [93]. Subsequent removal or orchidolysis and orchidopexy can be carried out using the same approach to achieve the therapeutic aims [94]. Some tend to start with inguinal surgical exploration, with possible laparoscopy during the procedure [95]. If an ipsilateral scrotal nubbin is suspected, and contralateral compensatory testicular hypertrophy is present, a scrotal incision with removal of the nubbin, thus confirming the vanishing testis, is an option avoiding the need for laparoscopy [96].

During laparoscopy for non-palpable testes, possible anatomical findings include spermatic vessels entering the inguinal canal (40%), an intra-abdominal (40%) or peeping (10%) testis, or blind-ending spermatic vessels confirming vanishing testis (10%) [97].

If there is a vanishing testis, the procedure is finished once blind-ending spermatic vessels are clearly identified. If the vessels enter the inguinal canal, an atrophic testis may be found upon inguinal exploration or a healthy testis that needs to undergo standard orchidopexy [98]. A peeping testis can be placed down in the scrotum laparoscopically or via an inguinal incision [99]. Placement of an intra-abdominal testis can sometimes be a surgical challenge. Usually, testes lying > 2 cm above the internal inguinal ring may not reach the scrotum without division of the testicular vessels [100]. Under such circumstances, a Fowler-Stephens orchidopexy may be an option [101] (see Figure 2).

Proximal cutting and transection of the testicular vessels, with conservation of the collateral arterial blood supply, via the deferential artery and cremasteric vessels comprise the key features of the Fowler-Stephens procedure. Recently, a modification with low spermatic vessel ligation has gained popularity, allowing blood supply from the testicular artery to the deferential artery. An additional advantage is the position of the peritoneal incision, leading to a longer structure, to ease later scrotal placement [102]. Due to the nature of these approaches the testis is at risk of hypotrophy or atrophy if the collateral blood supply is insufficient [103]. The testicular survival rate in the one-stage Fowler-Stephens technique varies between 50 and 65% based on post-operative Doppler-ultrasound findings [104]. For two-stage procedures success rates increase up to 90% [105]. The advantages of two-stage orchidopexy, with the second part done usually six months after the first, are to allow for development of collateral blood supply and to create greater testicular mobility [106]. In addition, preservation of the gubernaculum may also decrease the chance of testicular atrophy [107]. An alternative might be microsurgical auto-transplantation, which has a success rate of up to 90%. However, this approach requires skilled and experienced surgeons and is performed in a limited number of centres [108].

3.2.4.2.3.Complications of surgical therapy

Surgical complications are usually uncommon, with testicular atrophy being the most serious. A systematic review revealed an overall atrophy rate for primary orchidopexy of 1.83%, 28.1% for one-stage Fowler- Stephens procedure, and 8.2% for the two-stage approach [109]. Other rare complications comprise testicular ascent and vas deferens injury besides local wound infection, dehiscence, and haematoma.

3.2.4.2.4.Surgical therapy for undescended testes after puberty

A study on 51 men diagnosed with inguinal unilateral undescended testis and a normal contralateral one, with no history of any previous therapy, demonstrated a wide range of changes upon histological evaluation. Nearly half of the study population still had significant germ cell activity at different maturation levels. Importantly, the incidence of intratubular germ cell neoplasia was 2% [110].

The Panel consensus recommends orchiectomy in post-pubertal boys with an undescended testis and a normal contralateral one in a scrotal position.

Figure 2: Treatment of unilateral non-palpable undescended testes

3.2.5.Undescended testes and fertility

The association of undescended testes with compromised fertility [111] is extensively discussed in the literature and seems to be a result of multiple factors, including germ cell loss, impaired germ cell maturation [112], Leydig cell diminution and testicular fibrosis [113].

Although boys with one undescended testis have a lower fertility rate, they have the same paternity rate as those with bilateral descended testes. Boys with bilateral undescended testes suffer both lower fertility and paternity rates. Fertility rate is the number of offspring born per mating pair, individual or population, whereas paternity reflects the actual potential of fatherhood [114]. The age at which surgical intervention for an undescended testis occurs seems to be an important predictive factor for fertility later in life. Endocrinological studies revealed higher inhibin-B and lower follicle-stimulating hormone (FSH) levels in men who underwent orchidopexy at two years of age compared to individuals who had surgery later, which is indicative of a benefit of earlier orchidopexy [115]. In addition, others demonstrated a relation between undescended testes and increased loss of germ cells and Leydig cells, which is also suggestive of prompt orchidopexy being a significant factor for fertility preservation [116]. Outcome studies for untreated bilateral undescended testes revealed that 100% are oligospermic and 75% azoospermic. Among those successfully treated for bilateral undescended testes, 75% still remain oligospermic and 42% azoospermic [113].

In summary, early surgical correction of undescended testes is highly recommended before twelve months of age, and by eighteen months at the latest for preservation of fertility potential [67].

3.2.6.Undescended testes and malignancy

Boys who are treated for an undescended testis have an increased risk of developing testicular malignancy. Screening and self-examination both during and after puberty is therefore recommended [117]. A Swedish study, with a cohort of almost 17,000 men (56 developed a testicular tumour) who were treated surgically for undescended testes and followed for 210,000 person-years, showed that management of undescended testes before the onset of puberty decreased the risk of testicular cancer. The relative risk of testicular cancer among those who underwent orchidopexy before thirteen years of age was 2.2 compared to the Swedish general population; this increased to 5.4 for those treated after thirteen years of age [118].

A systematic review and meta-analysis of the literature have also concluded that pre-pubertal orchidopexy may reduce the risk of testicular cancer and that early surgical intervention is indicated in boys with undescended testes [119].

3.2.7.Summary of evidence and recommendations for the management of undescended testes

Summary of evidence	LE
An undescended testis justifies treatment early in life to avoid loss of spermatogenic potential.	2a
A failed or delayed orchidopexy may increase the risk of testicular malignancy later in life.	2a
The earlier the treatment, the lower the risk of impaired fertility and testicular cancer.	2a
In unilateral undescended testis, fertility rate is reduced whereas paternity rate is not.	1b
In bilateral undescended testes, fertility and paternity rates are impaired.	1b
The treatment of choice for undescended testis is surgical replacement in the scrotum.	1b
The palpable testis is usually treated surgically using an inguinal approach.	2b
The non-palpable testis is most commonly approached laparoscopically.	2b
There is no consensus on the use of hormonal treatment.	2b

Recommendations	LE	Strength rating
Do not offer medical or surgical treatment for retractile testes instead undertake close follow-up on a yearly basis until puberty.	2a	Strong
Perform surgical orchidolysis and orchidopexy before the age of twelve months, and by eighteen months at the latest.	2b	Strong
Evaluate male neonates with bilateral non-palpable testes for possible disorders of sex development.	1b	Strong
Perform a diagnostic laparoscopy to locate an intra-abdominal testicle.	1a	Strong
Hormonal therapy in unilateral undescended testes is of no benefit for future paternity.	2a	Strong
Offer endocrine treatment in case of bilateral undescended testes.	4	Weak
Inform the patient/caregivers about the increased risk of a later malignancy with an undescended testis in a post-pubertal boy or older and discuss removal in case of a contralateral normal testis in a scrotal position.	3	Weak

3.3.Testicular Tumours in prepubertal boys

3.3.1.Introduction

Testicular tumours account for approximately 1-2% of all paediatric solid tumours. [120]. Testicular tumours in prepubertal boys differ in several aspects to testicular tumours in adolescent and adult men: they have a lower incidence, they have a different histologic distribution (teratomas and yolk sac tumours are more common and germ cell tumours are less common) and they are more often benign. A recent epidemiological study showed that in children under the age of 15 years the incidence is highest in Asia (4.2 per million) and South America (5 per million) and lowest in Europe (2.1 per million) and North America (2.5 per million). This is in contrast to the incidence in adolescent and young adults where the highest incidence is in Europe (137.4 per million), and North America (94.9 per million), while a lower incidence was observed in South and Central America (66.5 per million) and Asia (27.1 per million) [121]. For age distribution in prepubertal boys, there is a small peak around the age of two years [122]. Some recent studies demonstrated that up to 60-75% of the tumours are benign [120,123-127]. Intratubular neoplasia (TIN) is practically non-existent in children [128-131]. Testicular tumours can generally be classified as germ cell or stromal tumours. One specific tumour type is the gonadoblastoma, which contains germ cell and stromal cell tumour types and will occur almost exclusively in the setting of disorders of sexual differentiation [132].

In the past 30 years, it has clearly been shown, that there is a fundamental difference between testicular tumours in childhood and those in adulthood - not only in terms of the difference and incidence [121] but also in terms of histology [128]. In prepubertal boys, most intratesticular tumours are benign, whereas post puberty the tumours are most likely malignant.

3.3.2.Clinical presentation

Clinical presentation is a painless scrotal mass in more than 90% of the patients, detected by the caregiver, physician or the patient himself. A history of a trauma, pain or hernia is rare. A hydrocele can be found in 15 – 50% [124,133]. In boys with early onset of puberty (e.g. early penile and prepubic hair growth) as well as high testosterone and low gonadotropin levels, a Leydig cell tumour should be excluded [134].

In patients presenting with a scrotal mass, paratesticular tumours should also be taken into account as a differential diagnosis. However, these are even less common compared to intratesticular tumours. The spectrum of paratesticular tumours includes benign tumours such as leiomyoma, fibroma, lipoma, haemangioma, cystic lymphangioma and lipoblastoma as well as malignant tumours such as the paratesticular rhabdomyosarcoma with an excellent prognosis and the rare melanotic neuroectodermal tumour of infancy with a high recurrence rate [135-138]. As most of them are benign, intra-operative frozen section should be available during surgery. An organ sparing surgical approach is preferred in benign tumours, whereas in malignant tumour standard orchiectomy is carried out.

3.3.3.Evaluation

To confirm the diagnosis, a high-resolution ultrasound (US) examination (7.5 – 12.5 MHz), preferably a doppler ultrasound, is required. The detection rate is almost 100% [139-142]. With high-resolution US, microlithiasis - small hyperdense areas without sound shadows - is increasingly seen in prepubertal boys. A recent meta-analysis showed that only 4 out of 296 boys (< 19 years of age diagnosed with microlithiasis) developed a testicular tumour of whom two previously had a testicular tumour on the opposite or ipsilateral site [143]. If microlithiasis shows up in patients with additional risk factors for testicular tumour, then the caregivers/patients should be informed about the increased risk and encouraged to carry out regular self-examinations - similar to patients treated for undescended testis [144]. There is no evidence, that regular sonographic follow-up is useful [143]. The risk for infertility may be higher in patients with microlithiasis and if these patients have any sign of infertility later, the risk of developing a tumour seems to be higher compared to patients without microlithiasis and infertility [145]. Due to the low incidence of a contralateral tumour, even in cases of testicular microlithiasis, there is no indication for contralateral testicular biopsy in prepubertal boys.

Age should be taken into account, when tumour markers are used. Human chorionic gonadotropin (ß-hCG) is derived from chorion carcinoma, embryonal carcinoma or seminoma. However, these tumours are extremely rare in prepubertal boys and therefore ß-hCG is not useful in prepubertal boys. Alpha-fetoprotein (AFP) has a clear limitation of its sensitivity and specificity in the first months of life [133] and sometimes takes up to 12 months before the serum concentration reaches the known standard values (< 10 ng/mL) [127,146]. It is produced by > 90% of yolk sac tumours. Teratomas can also produce AFP, but not to that extent of yolk sac tumours [147]. Alpha-fetoprotein should be measured before any therapeutic intervention (tumour enucleation/orchiectomy) and ideally should be available at the time of the procedure. Alpha-fetoprotein has a serum biological half-life of 5 days and should be measured 5 days after tumour resection/orchiectomy in those with an elevated AFP. There is no urgent need for pre-operative staging, as this has no consequence before the definitive histology is available.

3.3.4.Treatment/Management

If a testicular tumour is suspected, surgery with the option of intra-operative frozen section should be performed. It is not necessary to do this as an emergency procedure. However, in order to confirm the diagnosis and to avoid familial anxiety, the operation should be scheduled as soon as possible, preferably within the next few days. Organ-preserving surgery should be performed, whenever possible. A recent published review article showed that out of 227 patients with organ-sparing surgery only two cases (one in a patient with an epidermoid cyst and one in a patient with a mature teratoma) had a recurrence [148-150].

Orchiectomy could be considered only if normal testicular parenchyma is no longer detectable in the pre-operatively high-resolution ultrasound and/or the AFP is > 100 ng/mL in a > 12-month-old boy: highly suspicious of a yolk sac tumour.

For surgical technique, the Panel is in favour of an inguinal approach. Furthermore, clamping of the vessels has the advantage of a better view, when organ sparing surgery is performed. However, there is no evidence in the literature, that tumour-spread is prevented by clamping the vessels. Whenever possible, testis sparing surgery should be performed along with frozen sections during surgery to confirm the diagnosis (begin vs. malignant tumour) and to confirm if a microscopically margin-negative resection is performed, in which no gross or microscopic tumour remains in the primary tumour bed (R0 resection). In cases of an R0 resection, the tunica is closed and the testis is replaced in the scrotum. In case of R1 resection (removal of all macroscopic disease, but microscopic margins are positive for tumour) confirmed by frozen section in a malignant or potential malignant tumour, an orchiectomy should be performed at the same time of surgery. If the final pathology later demonstrates a R1 resection in a malignant tumour despite intra-operative negative margins on frozen section, an inguinal orchiectomy can safely be performed.

In patients with a malignant tumour (yolk sac tumour, immature teratoma) staging should be performed including an MRI of the abdomen and a CT-scan from the chest. If there is any suspicion of a non-organ confined tumour, the patient should be referred to a paediatric oncologist. In patients with the rare diagnosis of a Granulosa cell tumour, imaging of the abdomen to exclude enlarged lymph nodes is reasonable as this may be a potentially malignant tumour; in those with Sertoli or a Leydig cell tumour, an MRI is recommended, as 10% are malignant and the metastases do not respond very well to chemotherapy or radiation in the adult literature [151,152]. The TNM classification from 2015 for adult testicular tumours can be used in patients with a malignant tumour [153]. In benign tumours (mature teratoma, epidermoid cysts) no further staging is required.

3.3.5.Tumour entities in prepubertal boys

Teratomas are usually benign in prepubertal children and represent the greatest proportion of intratesticular tumours (around 40%) [120,154]. They present at a median age of 13 months (0-18 months). Only in adolescent and adults, they should be considered as malignant tumours. Histologically they can consist of a combination of the three primitive embryological germ-cell layers (ectoderm, mesoderm and endoderm). Most of these elements shows microscopically mature elements [155]; however, some immature teratomas in this age group have also been reported [156]. To exclude any malignant potential, like focal areas of a yolk-sac tumour, the entire specimen should be investigated. On US examination a heterogenous picture with some calcification is seen [157] and AFP should be less than 100 ng/mL in an infant. After organ-sparing surgery only one recurrence was reported in the literature [150].

Epidermoid cysts are of ectodermal origin and seem to be related to well-differentiated teratomas; they are always benign [155]. Keratin-producing epithelium is responsible for the keratinised-squamous-epithelial deposits, which appear hyperechogenic in an US [157]. Organ-sparing surgery should be performed and if confirmed by histology, there is no need for surveillance despite the fact that one “recurrence” has been reported 13 years after diagnosis [149].

Juvenile granulosa cell tumours occur usually in the first year of life, typically within the first 6 months [158]. They are well circumscribed and have a typical yellow-tan appearance; 2/3 have cystic elements, 1/3 solid [158]. The stroma can be fibrous or fibromyxoid. So far, no recurrence has been reported after organ-sparing surgery [158,159].

Leydig cell tumours arising from the testosterone producing Leydig cells should be suspected in boys with early onset of puberty with high testosterone and low gonadotropin levels [134]. Patients are usually between 5 and 10 years of age; the tumours are well circumscribed with yellow-brown nodules. In children there are no reports of malignant Leydig cell tumours and after organ sparing surgery, there are no reported recurrences to date [160,161]. In the adult literature, there is a malignancy rate of 10% reported and primary retroperitoneal lymphadenectomy should be discussed in cases with enlarged lymph nodes, as these metastases do not respond very well to chemotherapy or radiation [162].

Around 1/5 of the Sertoli-cell tumours occur in children; usually within the first year of life [163]. In the paediatric age group, the large-cell calcifying Sertoli cell tumours (LCCSCT) are the most common tumour variant [164,165]. They can occur in patients with complex dysplastic syndromes, such as the Carney or Peutz-Jeghers syndrome [165-167]. Except one case report with the histological diagnosis of a malignant LCCSCT [164], all other reported tumours are benign, therefore organ-sparing surgery should be performed.

Yolk sac tumours are the predominant prepubertal malignant germ cell tumours and may represent around 15% of the prepubertal tumours in boys [120]. They also have a number of other names: endodermal sinus tumours, juvenile embryonal carcinoma, clear cell carcinoma, orchioblastoma, vitellineum, archenteronoma and sometimes extraembryonal mesoblastoma [168]. They are histologically mostly solid, yellow-grey tumours. They occur usually within the first two years of life [169]. Up to 80-85% of the tumours are organ confined (Stage I) [170]. The tumour usually spreads haematogenously (chest). Twenty percent of those with Stage I disease may develop visible metastasis in 20% within the next 2 years. In a German study, 14 out of 91 patients with Stage I had a recurrence after observation – all were cured by chemotherapy alone. Four out of five with metastatic disease initially, were cured by chemotherapy after radical orchiectomy [171]. In a recent published series from China, 21 out of 90 paediatric patients with a Stage I yolk sac tumour received primary chemotherapy. One of the 21 had a recurrence, whereas 29 out of 69 who underwent surveillance after initial orchiectomy had a recurrence. The overall 4-year survival rate was 97.8% [169], almost the same recurrence rate has also been reported by American oncology groups [172,173]. Therefore in patients with Stage I disease (no metastatic disease in the MRI-abdomen and CT scan of the chest as well as normal age-adapted AFP-values) close follow-up together with the paediatric oncologists including AFP every 2-3 months and MRI of the abdomen is recommended, at least for the first 2-3 years [133]. This is especially recommended in those with invasions of the lymphatic vessels, as this has been shown to be a prognostic factor in one of the recent series [169]. In cases of recurrence, chemotherapy should be performed by paediatric oncologists according to national study protocols.

3.3.6.Follow-up

Regular US examination is recommended in the follow-up period to detect any recurrence and/or other abnormalities. As there are only a few studies with recurrence after testicular sparing surgery or orchiectomy, no clear recommendation can be made concerning the interval and the duration of follow-up. However, doing an US examination every 3-6 months within the first year seems reasonable, as few recurrences have been detected at this time and the rate of atrophy is extremely low after organ-sparing surgery [148]. Only in patients with a malignant tumour, regular follow-up examination after the first year of surgery seems reasonable (see above). The follow-up in patients with a Leydig cell tumour should include endocrinological examinations. Using the SEER data base, the 5-year relative survival for testicular malignancies for patients < 14 years of age diagnosed with localised testicular cancer was 97.4%, and for those with distant disease 72.6% [174].

3.3.7.Congenital Adrenal Hyperplasia

Boys with a congenital adrenal hyperplasia (CAH) represent a special group. Up to a third of the patients have so-called testicular adrenal rest tumours (TARTs) This proportion increase with age [175,176]. It is most likely to be ectopic adrenal cells, which are growing under pathological stimulation from Adrenocorticotropic Hormone (ACTH) [177]. They have no malignant potential, but they can have a lasting impact on fertility by displacing the normal testicular parenchyma [177,178]. These patients should be offered US screening and advice on fertility with the option of cryopreservation [178]. As far as is known, no malignant tumour has been described in patients with a typical TART. As a result, the indication for surgical intervention in these patients to rule out a malignant tumour should be offered very cautiously.

Summary of evidence	LE
Testicular tumours in prepubertal boys have a lower incidence and a different histologic distribution compared to the adolescent and adult patients.	2a
In prepupertal boys up to 60-75% of testicular tumours are benign.	3

Recommendations	LE	Strength rating
High-resolution ultrasound (7.5 – 12.5 MHz), preferably a doppler ultrasound, should be performed to confirm the diagnosis.	3	Strong
Alpha-fetoprotein should be determined in prepubertal boys with a testicular tumour before surgery.	2b	Strong
Surgical exploration should be done with the option for frozen section, but not as an emergency operation.	3	Strong
Organ-preserving surgery should be performed in all benign tumours.	3	Strong
Staging (MRI abdomen/CT chest) should only be performed in patients with a malignant tumour to exclude metastases.	3	Strong
Magnetic resonance imaging should only be performed in patients with the potential malignant Leydig or Sertoli-cell-tumours to rule out lymph node enlargement.	4	Weak
Patients with a non-organ confined tumour should be referred to paediatric oncologists post-operatively.	4	Weak

3.4.Hydrocele

3.4.1.Epidemiology, aetiology and pathophysiology

Hydrocele is defined as a collection of fluid between the parietal and visceral layers of the tunica vaginalis [179]. Pathogenesis of primary hydrocele is based on patency of the processus vaginalis in contrast with secondary hydrocele. Incomplete obliteration of the processus vaginalis peritonei results in formation of various types of communicating hydrocele; a large open processus vaginalis allowing passage of abdominal viscera results in clinical hernia [180]. The exact time of spontaneous closure of the processus vaginalis is not known. It persists in approximately 80-94% of newborns and in 20% of adults [181]. If complete obliteration of the processus vaginalis occurs with patency of mid-portion, a hydrocele of the cord occurs. Scrotal hydroceles without associated patency of the processus vaginalis are also encountered in newborns [182]. Non-communicating hydroceles, based on an imbalance between the secretion and re-absorption of this fluid, are found secondary to minor trauma, testicular torsion, epididymitis, varicocele operation (due to ligation of the lymphatics) or may appear as a recurrence after primary repair of a communicating or non-communicating hydrocele.

3.4.2.Diagnostic evaluation

The classic description of a communicating hydrocele is that of a hydrocele that fluctuates in size, and is usually related to ambulation. It may be diagnosed by history-taking and physical investigation. Transillumination of the scrotum provides the diagnosis in the majority of cases, keeping in mind that fluid filled intestine and some pre-pubertal tumours may transilluminate as well [183,184]. If the diagnosis is that of a hydrocele, there will be no history of reducibility and no associated symptoms; the swelling is translucent, smooth and usually not tender. If there are any doubts about the character of an intrascrotal mass, scrotal US should be performed and has nearly 100% sensitivity in detecting intrascrotal lesions. Doppler US studies help to distinguish hydroceles from varicocele and testicular torsion, although these conditions may also be accompanied by a hydrocele.

3.4.3.Management

In the majority of infants, surgical treatment of hydrocele is not indicated within the first twelve months because of the tendency for spontaneous resolution [185] (LE: 2). Little risk is taken by initial observation as progression to hernia is rare and does not result in incarceration [185]. Early surgery is indicated if there is suspicion of a concomitant inguinal hernia or underlying testicular pathology [186,187] (LE: 2). Persistence of a simple scrotal hydrocele beyond twelve months of age may be an indication for surgical correction. There is no evidence that this type of hydrocele risks testicular damage. The natural history of hydrocele is poorly documented beyond the age of two years and according to a systematic review there is no good evidence to support current practice. Delaying surgery may reduce the number of procedures necessary without increasing morbidity [188].

The question of contralateral disease should be addressed by both history-taking and physical examination at the time of initial consultation [189] (LE: 2). In late-onset hydrocele, suggestive of a non-communicating hydrocele, there is a reasonable chance of spontaneous resolution (75%) and expectant management of six to nine months is recommended [190]. In the paediatric age group, the operation consists of ligation of the patent processus vaginalis or scrotal via inguinal incision and the distal stump is left open, whereas in hydrocele of the cord the cystic mass is excised or unroofed [184,186,191,192] (LE: 4). In expert hands, the incidence of testicular damage during hydrocele or inguinal hernia repair is very low (0.3%) (LE: 3). Laparoscopic hernia repair with percutaneous ligation of the patent processes vaginalis is a minimally invasive alternative to open inguinal herniorrhaphy [193,194]. Sclerosing agents should not be used because of the risk of chemical peritonitis in communicating processus vaginalis peritonei [184,186] (LE: 4). The scrotal approach (Lord or Jaboulay technique) is used in the treatment of a secondary non-communicating hydrocele.

3.4.4.Summary of evidence and recommendations for the management of hydrocele

Summary of evidence	LE
In the majority of infants, surgical treatment of hydrocele is not indicated within the first twelve months due to the tendency for spontaneous resolution. Little risk is taken by initial observation as progression to hernia is rare.	2a
In the paediatric age group, an operation would generally involve ligation of the patent processus vaginalis via inguinal incision.	4

Recommendations	LE	Strength rating
In the majority of infants, observe hydrocele for twelve months prior to considering surgical treatment.	2a	Strong
Perform early surgery if there is suspicion of a concomitant inguinal hernia or underlying testicular pathology.	2b	Strong
Perform a scrotal ultrasound in case of doubt about the character of an intrascrotal mass.	4	Strong
Do not use sclerosing agents because of the risk for chemical peritonitis.	4	Strong

3.5.Acute scrotum

3.5.1.Epidemiology, aetiology and pathophysiology

Acute scrotum is a paediatric urological emergency, most commonly caused by torsion of the testis or appendix testis, or epididymitis/epididymo-orchitis [195-200]. Other causes of acute scrotal pain are idiopathic scrotal oedema, mumps orchitis, varicocele, scrotal haematoma, incarcerated hernia, appendicitis or systemic disease (e.g. Henoch-Schönlein purpura) [201-213]. Trauma can also be a cause of acute scrotum due to post-traumatic haematomas, testicular contusion, rupture, dislocation or torsion [214-219]. Scrotal fat necrosis has also been reported to be an uncommon cause of mild-to-moderate scrotal pain in pre-pubertal overweight boys after exposure to cold [220].

In this chapter testicular torsion and epididymitis are discussed, while recurrent epididymitis is discussed in the chapter dealing with infections. Torsion of the testis occurs most often in the neonatal period and around puberty, whereas torsion of the appendix testis occurs over a wider age range [221]. Epididymitis affects two age groups: less than one year and twelve to fifteen years [222,223]. One study predicted the annual incidence of epididymitis around 1.2 per 1,000 children [224].

Perinatal torsion of the testis most often occurs prenatally. Bilateral torsion comprises 11-21% of all perinatal cases [225]. Most cases of perinatal torsion are extravaginal, in contrast to the usual intravaginal torsion which occurs during puberty.

3.5.2.Diagnostic evaluation

Patients usually present with scrotal pain, except in neonatal torsion. The sudden onset of invalidating pain in combination with vomiting is typical for torsion of the testis or appendix testis [226,227].

In general, the duration of symptoms at presentation is shorter in testicular torsion (69% present within twelve hours) and torsion of the appendix testis (62%) compared to epididymitis (31%) [197,198,223]. Prepubertal males are more likely to present with atypical symptoms and delayed presentation and diagnosis, leading to delayed surgical intervention and a higher rate of orchiectomy, compared to postpubertal boys [228].

In the early phase, location of the pain can lead to diagnosis. Patients with acute epididymitis experience a tender epididymis, whereas patients with testicular torsion are more likely to have a tender testicle, in case of torsion of the appendix testis there may be isolated tenderness of the superior pole of the testis [223].

An abnormal (horizontal) position of the testis is more frequent in testicular torsion than epididymitis [197]. Looking for absence of the cremasteric reflex is a simple method with 100% sensitivity and 66% specificity for testicular torsion [222,227] (LE: 3). Elevation of the scrotum may reduce complaints in epididymitis, but not in testicular torsion.

Fever occurs more often in epididymitis (11-19%). The classical sign of a “blue dot” was found only in 10-23% of patients with torsion of the appendix testis [196,197,222,229]. In many cases, it is not easy to determine the cause of acute scrotum based on history and physical examination alone [195-200,222,229]. A positive urine culture is only found in a few patients with epididymitis [199,222,229,230]. It should be remembered that a normal urinalysis does not exclude epididymitis. Similarly, an abnormal urinalysis does not exclude testicular torsion.

Doppler US is useful to evaluate acute scrotum, with 63.6-100% sensitivity and 97-100% specificity, a positive predictive value of 100% and negative predictive value of 97.5% [231-236] (LE: 3). The use of Doppler US may reduce the number of patients with acute scrotum undergoing scrotal exploration, but it is operator-dependent and can be difficult to perform in pre-pubertal patients [233,237]. It may also show a misleading arterial flow in the early phases of torsion and in partial or intermittent torsion. Of key importance, persistent arterial flow does not exclude testicular torsion. In a multicentre study of 208 boys with torsion of the testis, 24% had normal or increased testicular vascularisation [233]. A comparison with the other side should always be done.

Better results were reported using high-resolution US (HRUS) for direct visualisation of the spermatic cord twist with a sensitivity of 97.3% and specificity of 99% [233,238] (LE: 2). A so-called positive whirlpool sign (the presence of a spiral-like pattern), has a pooled sensitivity and specificity of 0.73 (95% CI, 0.65-0.79) and 0.99 (95% CI, 0.92-0.99), respectively, and may be viewed as a definitive sign for testicular torsion. But its role in neonates is limited [239].

Scintigraphy and, more recently, dynamic contrast-enhanced subtraction MRI of the scrotum also provide a comparable sensitivity and specificity to US [240-243]. These investigations may be used when diagnosis is less likely and if torsion of the testis still cannot be excluded from history and physical examination. This should be done without inordinate delays for emergency intervention [229].

The diagnosis of acute epididymitis in boys is mainly based on clinical judgement and adjunctive investigation. However, it should be remembered that findings of secondary inflammatory changes in the absence of evidence of an extra-testicular nodule by Doppler US might suggest an erroneous diagnosis of epididymitis in children with torsion of the appendix testes [244]. Pre-pubertal boys with acute epididymitis have an incidence of underlying urogenital anomalies of 25-27.6%. Complete urological evaluation in all children with acute epididymitis is still debatable [199,222,224].

3.5.3.Management

3.5.3.1.Epididymitis

In pre-pubertal boys, the aetiology is usually unclear, with an underlying pathology in about 25%. A urine culture is usually negative, and unlike in older boys, a sexually transmitted disease is very rare.

Antibiotic treatment, although often started, is not indicated in most cases unless urinalysis and urine culture show a bacterial infection [224,245]. Epididymitis is usually self-limiting and with supportive therapy (i.e. minimal physical activity and analgesics) heals without any sequelae (LE: 3). However, bacterial epididymitis can be complicated by abscess or necrotic testis and surgical exploration is required [246].

3.5.3.2.Testicular torsion

Manual detorsion of the testis is done without anaesthesia, and should be attempted in all patients if possible, because it is associated with improved surgical salvage rates [247]. It should initially be done by outward rotation of the testis - like opening a book -, unless the pain increases or if there is obvious resistance. Success is defined as the immediate relief of all symptoms and normal findings at physical examination [248] (LE: 3;). Doppler US may be used for guidance [249]. Bilateral orchiopexy is still required after successful detorsion. This should not be done as an elective procedure, but rather immediately following detorsion. One study reported residual torsion during exploration in 17 out of 53 patients, including eleven patients who had reported pain relief after manual detorsion [248,250].

External cooling before exploration may be effective in reducing ischaemia reperfusion injury and preserving the viability of the torsed and the contralateral testis [251]. Medical treatments aimed at limiting such injury remain experimental [252-255].

Torsion of the appendix testis can be managed non-operatively with the use of anti-inflammatory analgesics (LE: 4). During the six-week follow-up, clinically and with US, no testicular atrophy was revealed. Surgical exploration is done in equivocal cases and in patients with persistent pain [236]. Although metachronous torsion of the appendix testis may occur in up to 8.5%, it is not necessary to explore the contralateral side, given the benign nature ot the problem. Besides it has been demonstrated that the NNT is 24 [256].

3.5.3.3.Surgical treatment

Testicular torsion is an urgent condition which requires prompt surgical treatment. The two most important determinants of early salvage rate of the testis are the time between onset of symptoms and detorsion, and the degree of cord twisting [257]. Severe testicular atrophy occurred after torsion for as little as four hours when the turn was > 360°. In cases of incomplete torsion (180-360°), with symptom duration up to twelve hours, no atrophy was observed. However, a necrotic or severely atrophied testis was found in all cases of torsion > 360° and symptom duration > 24 hours [258].

Early surgical intervention with detorsion (mean torsion time less than thirteen hours) was found to preserve fertility [259]. Urgent surgical exploration is mandatory in all cases of testicular torsion within 24 hours of symptom onset. In patients with testicular torsion > 24 hours, exploration may be performed as a semi-elective exploration procedure [257,258] (LE: 3), unless there is a clear history of torsion-detorsion in which urgent exploration should still be considered. In case of prolonged torsion (> 24 hours) it is still subject to debate whether the surgically detorsed testis should be preserved. An alternative to detorsion and fixation may be to perform orchiectomy. A study found that sperm quality was preserved after both orchiectomy and orchidopexy in comparison to normal control men, although orchiectomy resulted in better sperm morphology [260]. Incision of the tunica albuginea with tunica vaginalis graft to prevent or treat compartment syndrome has also been suggested [261].

In neonates with signs of testicular torsion at birth the duration of symptoms will not be clear. The decision to perform surgical exploration should be weighed against the general condition of the child. In this age group the operation can safely be done under spinal anesthesia. New onset of symptoms of testicular torsion in neonates should be considered a surgical emergency similar to older boys.

During exploration, fixation of the contralateral testis is also performed. It is good clinical practice to also perform fixation of the contralateral testis in prenatal and neonatal torsion, although there is no literature to support this, and to remove an atrophied testicle [262]. Recurrence after orchidopexy is rare (4.5%) and may occur several years later. There is no consensus recommendation about the preferred type of fixation and suture material [260,261,264].

3.5.4.Follow-up

Patients require follow-up mainly for fertility issues and hormonal consequences. Despite timely and adequate detorsion and fixation of the testicle, up to half of the patients may develop testicular atrophy, even when intraoperatively assessed as viable, and should be counselled accordingly [264,265].

3.5.4.1.Fertility

The results vary and are conflicting. In one study, unilateral torsion of the testis seriously intervened with subsequent spermatogenesis in about 50% of the patients and produced borderline impairment in another 20% [242]. Although, 30% of affected testicles with mumps orchitis show a degree of atrophy, long-term outcome in terms of fertility is not conclusive [266].

A recent study showed a normal pregnancy rate after unilateral testicular torsion, with no difference between the patients undergoing orchidopexy and those after orchidectomy [267].

3.5.4.2.Subfertility

Subfertility is found in 36-39% of patients after torsion. Semen analysis may be normal in only 5-50% in long-term follow-up [257]. Early surgical intervention (mean torsion time less than thirteen hours) with detorsion was found to preserve fertility, but a prolonged torsion period (mean 70 hours) followed by orchiectomy jeopardised fertility [259].

Subfertility and infertility are consequences of direct injury to the testis after the torsion. This is caused by the cut-off of blood supply, but also by post-ischaemia-reperfusion injury that is caused after the detorsion when oxygen-derived free radicals are rapidly circulated within the testicular parenchyma [257].

3.5.4.3.Androgen levels

Even though the levels of FSH, luteinising hormone (LH) and testosterone are higher in patients after testicular torsion compared to normal controls, endocrine testicular function remains in the normal range after testicular torsion [260].

3.5.4.4.Unanswered questions

Although testicular torsion is a common problem, the mechanism of neonatal and prenatal torsion is still not exactly known, as well as whether fixation of the contralateral testicle in these cases is really necessary. The influence of an atrophied testicle on fertility is also unclear.

Summary of evidence	LE
Diagnosis of testicular torsion is based on presentation and physical examination.
Doppler US is an effective imaging tool to evaluate acute scrotum and comparable to scintigraphy and dynamic contrast-enhanced subtraction MRI.	2a
Neonates with acute scrotum should be treated as surgical emergencies.	3

Recommendations	Strength rating
Testicular torsion is a paediatric urological emergency and requires immediate treatment.	Strong
In neonates with testicular torsion perform orchidopexy of the contralateral testicle. In prenatal torsion the timing of surgery is usually dictated by clinical findings.	Weak
Base the clinical decision on physical examination. The use of Doppler ultrasound to evaluate acute scrotum is useful, but this should not delay the intervention.	Strong
Manage torsion of the appendix testis conservatively. Perform surgical exploration in equivocal cases and in patients with persistent pain.	Strong
Perform urgent surgical exploration in all cases of testicular torsion within 24 hours of symptom onset. In prenatal torsion the timing of surgery is usually dictated by clinical findings.	Strong

3.6.Hypospadias

3.6.1.Epidemiology, aetiology and pathophysiology

3.6.1.1.Epidemiology

The total prevalence of hypospadias in Europe is 18.6 new cases per 10,000 births (5.1-36.8) according to the recent EUROCAT registry-based study. This incidence was stable over the period of 2001 to 2010 [268,269]. The mean worldwide prevalence of hypospadias according to an extended systematic literature review varies: Europe 19.9 (range: 1-464), North America 34.2 (6-129.8), South America 5.2 (2.8-110), Asia 0.6-69, Africa 5.9 (1.9-110), and Australia 17.1-34.8. There are conflicting data on the recent trends of prevalence – different trends in Europe and an increasing trend in the USA [270,271].

3.6.2.Risk factors

Risk factors associated with hypospadias are likely to be genetic, placental and/or environmental [268,269] (LE: 2b). Interactions between genetic and environmental factors may help explain non-replication in genetic studies of hypospadias. Single nucleotide polymorphisms seemed to influence hypospadias risk only in exposed cases [269,272] (LE: 2b).

• An additional family member with hypospadias is found in 7% of families, but this is more predominant in anterior and middle forms [272-275].
• Endocrine disorders can be detected in rare cases.
• Babies with a low birth weight have a higher risk of hypospadias [272-275].
• Over the last 25 years, a significant increase in the incidence of hypospadias has been found.
• Endocrines disruptors are one component of a multi-factorial model for hypospadias.
• The use of oral contraceptives prior to pregnancy has not been associated with an increased risk of hypospadias in offspring, but their use after conception increased the risk of middle and posterior hypospadias [273-276] (LE: 2a).

3.6.3.Classification systems

Hypospadias are usually classified based on the anatomical location of the proximally displaced urethral orifice:

• distal-anterior hypospadias (located on the glans or distal shaft of the penis and the most common type of hypospadias);
• intermediate-middle (penile);
• proximal-posterior (penoscrotal, scrotal, perineal).

The pathology may be different after skin release and should be reclassified accordingly. Anatomical location of the meatus may not always be enough to explain the severity and the complex nature of this pathology. Therefore, a simple classification related to severity of the problem, which considers penile length, glans size, shape, urethral plate quality and penile curvature is commonly used. In that classification there are two types: mild hypospadias (glanular or penile isolated hypospadias without associated chordee, micropenis or scrotal anomaly); severe hypospadias (penoscrotal, perineal hypospadias with associated chordee and scrotal anomalies).

3.6.4.Diagnostic evaluation

Most hypospadias patients are easily diagnosed at birth (except for the megameatus intact prepuce variant which can only be seen after retraction of foreskin). Diagnosis includes a description of the local findings:

• position, shape and width of the orifice;
• presence of atretic urethra and division of corpus spongiosum;
• appearance of the preputial hood and scrotum;
• size of the penis;
• curvature of the penis on erection.

The diagnostic evaluation also includes an assessment of associated anomalies, which are:

• cryptorchidism (in up to 10% of cases of hypospadias);
• open processus vaginalis or inguinal hernia (in 9-15%).

Severe hypospadias with unilaterally or bilaterally impalpable testis, or with ambiguous genitalia, requires a complete genetic and endocrine work-up immediately after birth to exclude DSD, especially congenital adrenal hyperplasia. Urine trickling and ballooning of the urethra requires exclusion of meatal stenosis. The relationship between the severity of the hypospadias and associated anomalies of the upper or lower urinary tract were not confirmed [277] (LE: 3).

3.6.5.Management

3.6.5.1.Indication for reconstruction and therapeutic objectives

Differentiation between functionally necessary and aesthetically feasible operative procedures is important for therapeutic decision making.

The indications for surgery are:

• proximally located (ectopic) meatus causing ventrally deflected or spraying urinary stream;
• meatal stenosis;
• anterior curvature of the penis;
• cleft glans;
• rotated penis with abnormal cutaneous raphe;
• preputial hood;
• penoscrotal transposition;
• split scrotum.

Physical examination should check all anatomic components of the penis and evaluate the degree and nature of abnormality in each component. The examination should evaluate location of the meatus, the degree of proximal spongiosal hypoplasia, presence and degree of penile curvature, width and depth of the urethral plate, size of the glans, degree of ventral skin deficiency, availability of the foreskin and scrotal abnormalities like penoscrotal transposition and bifid scrotum.

As all surgical procedures carry the risk of complications, thorough pre-operative counselling of the caregiver is crucial.

To achieve an overall acceptable functional and cosmetic outcome, the penile curvature must be corrected and a neo-urethra of an adequate size with opening on the glans formed with proper skin coverage of the penile shaft [278] (LE: 4) (Figure 3). The use of magnifying spectacles and fine synthetic absorbable suture materials (6.0-7.0) are required. As in any penile surgery, exceptional prudence should be adopted with the use of cautery. Bipolar cautery is recommended. Knowledge of a variety of surgical reconstructive techniques, wound care and post-operative treatment are essential for a satisfactory outcome.

3.6.5.2.Pre-operative hormonal treatment

There is a lack of high-quality evidence to support that pre-operative hormonal treatment with androgen stimulation improves surgical outcomes. Yet, this treatment in the form of systemic testosterone, topical testosterone, and derivatives like dihydrotestosterone (DHT) and hCG are commonly being used to increase glans size pre-operatively to allow better tubularisation of the urethral plate and decrease the incidence of glans dehiscence. This treatment is usually limited to patients with proximal hypospadias, a small appearing penis, reduced glans circumference or reduced urethral plate [276,279,280]. Studies have shown that it leads to significant enlargement of the glans and shaft of the penis (LE: 1b) [281,282].

Moderate quality evidence from three randomised studies demonstrate significantly lower rates of urethracutaneous fistulae and re-operation rates in patients who received pre-operative hormonal treatment [283].

Pre-operative testosterone administration is most often well tolerated. Transient side effects on child´s behaviour, increased genital pigmentation, appearance of pubic hair, penile skin irritation and redness, increased erections and peri-operative bleeding have been reported, but no persistent side effects related to hormonal stimulation have been reported in the literature. There is also no evidence about possible effects on bone maturation [280,283,284].

There are concerns regarding the negative impacts of testosterone on wound-healing and increased bleeding during surgery. Cessation of therapy is recommended one or two months prior to surgery to avoid adverse effects during or after surgery [285].

3.6.5.3.Age at surgery

The age at surgery for primary hypospadias repair is usually 6-18 (24) months [278,286,287] (LE: 3). Age at surgery is not a risk factor for urethroplasty complication in pre-pubertal tubularised incised plate urethroplasty (TIP) repair [286] (LE: 2b). Complication rate after primary TIP repair was 2.5 times higher in adults than in the paediatric group according to a recent prospective controlled study [288] (LE: 2a).

3.6.5.4.Penile curvature

If present, penile curvature is often released by degloving the penis (skin chordee) and by excision of the connective tissue of the genuine chordee on the ventral aspect of the penis in up to 70% [289]. The urethral plate has well vascularised connective tissue and does not cause curvature in most cases [290,291]. The residual curvature is caused by corporeal disproportion and requires straightening of the penis, mostly using dorsal midline plication or orthoplasty (modification of the Nesbit plication with or without elevation of the neurovascular bundle). In more severe curvature (> 45°), which is often combined with a short urethral plate requiring transection, ventral penile lengthening is recommended to prevent shortening of the penis. This consists of a ventral transverse incision of the tunica albuginea extending from the 3 to 9 o´clock position patched with tunica vaginalis flap or graft, or in several short ventral corporotomies without grafting (LE: 2b) [292]. After the ventral lengthening, a shorter dorsal midline plication is usually added.

According to a retrospective study, dorsal plication remained significantly associated with recurrent ventral curvature independently of the other factors. Ventral corporeal grafting for severe penile curvature gives good long-term results and safety profiles for erectile function [293] (LE: 2b).

3.6.5.5.Urethral reconstruction

The mainstay of hypospadias repair is preservation of the well-vascularised urethral plate and its use for urethral reconstruction has become standard practice in hypospadias repair [291]. Mobilisation of the corpus spongiosum/urethral plate and the bulbar urethra decreases the need for urethral plate transection [292] (LE: 2b).

If the urethral plate is wide, it can be tubularised following the Thiersch-Duplay technique. If the plate is too narrow to be simply tubularised, it is recommended relaxing the plate by a midline incision and its subsequent tubularisation according to the Snodgrass-Orkiszewski TIP technique. This technique has become the treatment of choice in distal- and mid-penile hypospadias [294-297]. If the incision of the plate is deep, it is recommended to cover the raw surface with inner preputial (or buccal) inlay graft in primary and secondary repairs [298]. This also enables extension of the incision beyond the end of the plate to prevent meatal stenosis [299,300] (LE: 2a).

For distal forms of hypospadias, a range of other techniques is available (e.g. Mathieu, urethral advancement) [301] (LE: 2b). The TIP technique has become an option for proximal hypospadias as well [294-297,302]. However, urethral plate elevation and urethral mobilisation should not be combined with TIP repair because it results in focal devascularisation of the neo-urethra with symptomatic stricture development [303] (LE: 2b). The onlay technique using a preputial island flap is a standard repair, preferred in proximal hypospadias, if a plate is unhealthy or too narrow [289]. An onlay preputial graft is an option for single-stage repair [304] (LE: 2b).

If the continuity of the urethral plate cannot be preserved, single or two-stage repairs are used. For the former, a modification of the tubularised flap (Duckett tube), such as a tube-onlay or an inlay-onlay flap, or onlay flap on albuginea are used to prevent urethral stricture [305-307] (LE: 3); alternatively the Koyanagi-Hayashi technique is used [308-311]. The two-stage procedure has become preferable over the past few years because of lower recurrence of ventral curvature and more favourable results with variable long-term complication rates [300,305,312-316].

3.6.5.6.Re-do hypospadias repairs

For re-do hypospadias repairs, no definitive guidelines can be given. All the above-mentioned procedures are used in different ways and are often modified according to the individual findings and needs of the patient.

Figure 3: Algorithm for the management of hypospadias

DSD = disorders of sex development; TIP = tubularised incised plate urethroplasty; MAGPI = meatal advancement and glanuloplasty incorporated.

3.6.5.7.Penile reconstruction following formation of the neo-urethra

Following formation of the neo-urethra, the procedure is completed by glansplasty and by reconstruction of the penile skin. If there is a shortage of skin covering, the preputial double-face technique or placement of the suture line into the scrotum according to Cecil-Michalowski is used. In countries where circumcision is not routinely performed, preputial reconstruction can be considered. Preputial reconstruction carries a risk of specific complications but does not seem to increase the risk of urethroplasty complications [317]. In TIP repair, the use of a preputial dartos flap reduces the fistula rate [294,295] (LE: 2b).

3.6.5.8.Urine drainage and wound dressing

Urine is drained transurethrally (e.g. dripping stent) or with a suprapubic tube. No drainage after distal hypospadias repair is another option [318,319]. Circular dressing with slight compression, as well as prophylactic antibiotics during surgery, are established procedures [319] (LE: 4). Post-operative prophylaxis after hypospadias repair has limited benefit and it only reduces the risk of asymptomatic bacteriuria [320-322] (LE: 2b). There is no consensus on duration of stenting and dressing.

3.6.5.9.Outcome

Some studies have tried to determine risk factors for complications after hypospadias repair. An analysis of prospectively collected data found glans size (width < 14 mm), proximal meatal location and re-operation as independent risk factors for urethral complication [319,323]. Low surgeon volume independently increases the risk of fistula, stricture or diverticulum repair [319,324] (LE: 3).

A meta-analysis of complication rates of TIP repair found lower complication rates and incidence of re-operations in primary distal repairs (in 4.5%) than in primary proximal repairs (in 12.2%) and in secondary repair (in 23.3%) [294-297,301,319]. One should expect a predictable outcome with complication rates below 10% in distal hypospadias (fistula, meatal stenosis, dehiscence, recurrent ventral curvature, and haematoma) [324,325]. A similar incidence of fistula (3.4-3.6%) can be expected after the Mathieu and TIP repairs of distal hypospadias [302,326-328].

The complication rates of TIP and onlay repairs of primary severe hypospadias are similar, 24% and 27%, respectively. It is higher in free graft and in preputial island tube urethroplasty [289]. There is no strong evidence to suggest that the use of inlay grafts in TIP repair improves the outcome [329].

The complication rates of single-stage Koyanagi and Hayashi modification repairs go up 61%, according to a comparative study [308,319]. Staged buccal mucosa graft requires a redo grafting in 13% of patients, after the second stage more than one third of patients have complications, mostly with some degree of graft fibrosis [327,330]. A recent long-term study on two-stage flap repair showed a complication rate of 68% [319]; another study showed a re-operation rate of 28% [300,319].

3.6.6.Follow-up

Long-term follow-up is necessary up to adolescence to detect urethral stricture, voiding dysfunctions and recurrent penile curvature, diverticula, glanular dehiscence [331]. Up to half of complications requiring re-operation present after the first year post-operatively [332] (LE: 2b).

Obstructive flow curve is common after hypospadias repair and while most are not clinically significant, long-term follow-up is required [333-336] (LE: 2a). Urine flow is significantly lower in patients after hypospadias surgery, especially in those who had corrected chordee, but without significant association with lower urinary symptoms [337] (LE: 2a).

Objective scoring systems have been developed in order to evaluate the results of hypospadias surgery (HOSE) [338] (LE: 2b) and cosmetic appearance (HOPE-Hypospadias Objective Penile Evaluation) [339] (LE: 2a). The Pediatric Penile Perception Score (PPPS) is a reliable instrument to assess penile self-perception in children after hypospadias repair and for appraisal of the surgical result by caregivers and uninvolved urologists [340] (LE: 2a). Cosmetic results were judged more optimistically by surgeons as compared to caregivers using validated tools [341]. Current scoring systems have deficiencies in terms of patient reported outcomes, the long term outcomes and sexual function [342].

Adolescents and adults, who have undergone hypospadias repair in childhood, have a slightly higher rate of dissatisfaction with penile size, especially proximal hypospadias patients, but their sexual behaviour is not different from that of control groups [343,344] (LE: 2a-b). Another long-term follow-up of men born with hypospadias revealed, in a controlled study, that these patients are less satisfied with penile cosmetic outcome according to all parameters of the PPPS; there was a difference in penile length (9.7 vs. 11.6 cm) and more patients had lower maximum urinary flow. More prominent results were found in proximal hypospadias vs. controls [319,345].

According to a systematic review of long-term patient satisfaction with cosmetic outcomes [346]:

• patient perception of penile size does not differ greatly from the norm;
• patients approaching puberty have a more negative perception and are more critical about the cosmetic outcomes of surgery;
• patients report high levels of perception of deformity and social embarrassment.

There is a wide range of parameters that are measured to assess outcome after hypospadias surgery in the literature. There is a need for age-specific core outcome set [347].

The majority of identified instruments focused on post-operative cosmetic satisfaction, with only one instrument considering urinary function, and no instruments evaluating sexual function and psychosocial sequelae [348].

3.6.7.Summary of evidence and recommendations for the management of hypospadias

Summary of evidence	LE
The suggested age at surgery for primary hypospadias repair is 6 - 18 (24) months.	3
The therapeutic objectives are to correct the penile curvature, to form a neo-urethra of an adequate size, to bring the new meatus to the tip of the glans, if possible, and to achieve an overall acceptable cosmetic appearance.	4
Androgen stimulation therapy results in increased penile length and glans circumference.	1b
The complication rate is about 10% in distal and 25% in proximal hypospadias one-stage repairs. Higher and variable rates (between 28 and 68%) can occur in two-stage repairs.	3
Sexual functions are usually well preserved but patients report high levels of perception of deformity and social embarrassment.	2b

Recommendations	Strength rating
At birth, differentiate isolated hypospadias from disorders of sex development which are mostly associated with cryptorchidism or micropenis.	Strong
Counsel caregivers on functional indications for surgery, aesthetically feasible operative procedures (psychological, cosmetic indications) and possible complications.	Strong
In children diagnosed with proximal hypospadias and a small appearing penis, reduced glans circumference or reduced urethral plate, pre-operative hormonal androgen stimulation treatment is an option and the body of evidence to accentuate its harms and benefits is inadequate.	Weak
For distal hypospadias, offer Duplay-Thiersch urethroplasty, original and modified tubularised incised plate urethroplasty; use the onlay urethroplasty or two-stage procedures in more severe hypospadias. A treatment algorithm is presented (Figure 3). Correct significant (> 30°) curvature of the penis.	Weak
Ensure long-term follow-up to detect urethral stricture, voiding dysfunctions and recurrent penile curvature, ejaculation disorder, and to evaluate patient´s satisfaction.	Strong
Use validated objective scoring systems to assist in evaluating the functional and cosmetic outcome.	Strong

3.7.Congenital penile curvature

3.7.1.Epidemiology, aetiology and pathophysiology

Congenital penile curvature presents penile bending of a normally formed penis due to corporal disproportion. The incidence at birth is 0.6% and congenital penile curvature is caused by asymmetry of the cavernous bodies and an orthotopic meatus [349] because of developmental arrest during embryogenesis [350]. On the other hand, the incidence of clinically significant congenital penile curvature is much lower, because the extent of the curvature and its associated sexual dysfunction varies widely [351]. Most of the cases are ventral deviations (48%), followed by lateral (24%), dorsal (5%), and a combination of ventral and lateral (23%) [352]. Most ventral curvatures are associated with hypospadias due to chordee or ventral dysplasia of cavernous bodies [353]. Similarly, dorsal curvature is mostly associated with exstrophy/epispadias complex. Congenital penile curvature can decrease sexual quality of life in adults and successful repair can restore patients’ psychosocial and sexual wellbeing [354]

Curvature > 30° is considered clinically significant; curvature > 60° may interfere with satisfactory sexual intercourse in adulthood (LE: 4). Minor penile curvature may be the result of ventral penile skin deficiency only and should be distinguished from corporal anomalies. For penile curvature associated with hypospadias or epispadias refer to the relevant chapters.

3.7.2.Diagnostic evaluation

Penile curvature is frequently not documented until later in childhood since the penis only appears abnormal when erect. Patients are usually concerned with the aesthetic and/or functional aspects of their penis [355]. Besides exact history taking to exclude any possibility of acquired penile curvature (e.g. post-traumatic), a thorough clinical examination is mandatory. In addition, photo documentation of the erect penis clearly showing the curvature from different angles serves as a pre-requisite in pre-operative evaluation [356]. The exact degree of curvature is generally determined at the time of surgery using an artificial erection test.

3.7.3.Management

The treatment is surgical, starting with an artificial erection to determine the degree of curvature and to check symmetry after the repair [357]. The ultimate goal of any surgical method used to correct the curvature is to achieve corpora of similar size. Various procedures are in use ranging from simple de-gloving and plication procedures, to corporal rotation, use of free dermal or tunica vaginalis grafts, to complete penile disassembly techniques [358,359]. Reviews comparing the outcome of Nesbit/modified Nesbit procedures [360] to plication procedures [361] were able to demonstrate that while there is a decreased risk of complications and loss of sensation, it remains unclear whether plication techniques can lead to increased risk of recurrence [362,363]. Altogether these methods include the risk of post-operative shortening of the penis with an average loss of 2.5 cm in stretched penile length depending on the pre-operative degree of curvature and the type of repair used [364-366].

Recently the non-corporotomy technique has been introduced with promising results enabling correction of any degree of ventral curvature with neither shortening of the penis nor the risk of post-operative erectile dysfunction [367].

3.7.4.Summary of evidence and recommendations for the management of congenital penile curvature

Summary of evidence	LE
Isolated congenital penile curvature is relatively uncommon.	2a
Congenital penile curvature is often associated with hypospadias.	2a
Diagnosis is usually made late in childhood.	2a
The penis only appears abnormal when erect.	1b
Congenital penile curvature can cause aesthetic as well as functional sexual problems.	1b
Congenital penile curvature is treated with surgery.	1b
The goal of surgery is to achieve corpora of similar size.	1b

Recommendations	LE	Strength rating
Ensure that a thorough medical history is taken and a full clinical examination done to rule out associated anomalies in boys presenting with congenital curvature.	1a	Strong
Provide photo documentation of the erect penis from different angles as a prerequisite in the pre-operative evaluation.	1b	Strong
Perform surgery after weighing aesthetic as well as functional implications of the curvature.	2b	Weak
At the beginning as well as at the end of surgery, perform artificial erection tests.	2a	Strong

3.8.Varicocele in children and adolescents

3.8.1.Epidemiology, aetiology and pathophysiology

Varicocele is defined as an abnormal dilatation of testicular veins in the pampiniformis plexus caused by venous reflux. It is unusual in boys under ten years of age and becomes more frequent at the beginning of puberty. It is found in 14-20% of adolescents, with a similar incidence during adulthood. It appears mostly on the left side (78-93% of cases). Right-sided varicoceles are less common; they are usually noted only when bilateral varicoceles are present and seldom occur as an isolated finding [368-370].

Varicocele develops during accelerated body growth and increased blood flow to the testes, by a mechanism that is not clearly understood. Genetic factors may be present. An anatomic abnormality leading to impaired venous drainage is expressed by the considerable prevalence of the left side condition where the internal spermatic vein drains into the renal vein. Varicocele can induce apoptotic pathways because of heat stress, androgen deprivation and accumulation of toxic materials. Severe damage is found in 20% of adolescents affected, with abnormal findings in 46% of affected adolescents. Histological findings are similar in children or adolescents and in infertile men. In 70% of patients with grade II and III varicocele, left testicular volume loss was found.

Several authors reported on reversal of testicular growth after varicocelectomy in adolescents [371,372]. An average proportion of catch-up growth of 76.4% (range: 52.6-93.8%) has been found according to a meta-analysis [373] (LE: 2a). However, this may partly be attributable to testicular oedema associated with the division of lymphatic vessels [374] (LE: 2).

In about 20% of adolescents with varicocele, fertility problems will arise [375]. The adverse influence of varicocele increases with time. Improvement in sperm parameters has been demonstrated after adolescent varicocelectomy [376-379] (LE: 1).

3.8.2.Classification systems

Varicocele is classified into 3 grades [380]:

• Grade I - Valsalva positive (palpable at Valsalva manoeuvre only);
• Grade II - palpable (palpable without the Valsalva manoeuvre);
• Grade III - visible (visible at distance).

3.8.3.Diagnostic evaluation

Varicocele is mostly asymptomatic, rarely causing pain. It may be noticed by the patient or caregivers, or discovered by the paediatrician at a routine visit. The diagnosis depends upon the clinical finding of a collection of dilated and tortuous veins in the upright posture; the veins are more pronounced when the patient performs the Valsalva manoeuvre. The size of both testicles should be evaluated during palpation to detect a smaller testis.

Venous reflux into the plexus pampiniformis is diagnosed using Doppler US colour flow mapping in the supine and upright position [381]. Venous reflux detected on US only is classified as subclinical varicocele. To discriminate testicular hypoplasia, the testicular volume is measured by US examination or by orchidometer. In adolescents, a testis that is smaller by > 2 mL or 20% compared to the other testis is considered to be hypoplastic [382] (LE: 2).

Extension of Wilms tumour into the renal vein and inferior vena cava can cause a secondary varicocele. A renal US should be routinely added in pre-pubertal boys and in isolated right varicocele (LE: 4). In order to assess testicular injury in adolescents with varicocele, supranormal FSH and LH responses to the luteinising hormone-releasing hormone (LHRH) stimulation test are considered reliable, because histopathological testicular changes have been found in these patients [378,383].

3.8.4.Management

There is no evidence that treatment of varicocele at paediatric age will offer a better andrological outcome than an operation performed later. Beneficial effect of pubertal screening and treatment for varicocele regarding chance of paternity has been questioned according to a corresponding questionnaire in adult patients [384] (LE: 4). The recommended indication criteria for varicocelectomy in children and adolescents are [369]:

• varicocele associated with a small testis;
• additional testicular condition affecting fertility;
• bilateral palpable varicocele;
• pathological sperm quality (in older adolescents);
• symptomatic varicocele [384].

Testicular (left + right) volume loss in comparison with normal testes is a promising indication criterion, once the normal values are available [385]. Repair of a large varicocele, causing physical or psychological discomfort, may also be considered. Other varicoceles should be followed-up until a reliable sperm analysis can be performed (LE: 4).

Surgical intervention is based on ligation or occlusion of the internal spermatic veins. Ligation is performed at different levels:

• inguinal (or subinguinal) microsurgical ligation;
• suprainguinal ligation, using open or laparoscopic techniques [386-389].

The advantage of the former is the lower invasiveness of the procedure, while the advantage of the latter is a considerably lower number of veins to be ligated and safety of the incidental division of the internal spermatic at the suprainguinal level.

For surgical ligation, some form of optical magnification (microscopic or laparoscopic) should be used because the internal spermatic artery is 0.5 mm in diameter at the level of the internal ring [386,388]. The recurrence rate is usually < 10%.

Lymphatic-sparing varicocelectomy is preferred to prevent hydrocele formation and testicular hypertrophy development and to achieve a better testicular function according to the LHRH stimulation test [374,386,387,390] (LE: 2). The methods of choice are subinguinal or inguinal microsurgical (microscopic) repairs, or suprainguinal open or laparoscopic lymphatic-sparing repairs [386,388,391,392]. Intrascrotal application of isosulphan blue was recommended to visualise the lymphatic vessels [393,394]. In suprainguinal approach, an artery sparing varicocelectomy may not offer any advantage in regards to catch-up growth and is associated with a higher incidence of recurrent varicocele [395,396].

Angiographic occlusion of the internal spermatic veins also meets the requirements of lymphatic sparing repair. It is based on retrograde or antegrade sclerotisation of the internal spermatic veins [397,398]. However, although this method is less invasive and may not require general anaesthesia, it is associated with radiation burden, which is less controllable in the antegrade technique [369,397,398] (LE: 2).

There is low to moderate level of evidence that radiological or surgical treatment of adolescent varicocele is associated with improved testicular size/growth and sperm concentration - based on current available RCTs. The ultimate effects on fertility and paternity rates are not known [399].

Microsurgical varicocele repair in adolescents with varicocele significantly increases paternity rates and decreases time to conception post-operatively. Patients with varicocele who underwent microsurgical varicocele repair had increased sperm parameters and 3.63 times greater odds of paternity than controls who did not undergo varicocele surgery [400].

The Panel recently conducted a systematic review and meta-analysis regarding the treatment of varicocele in children and adolescents [401]. Of 1,550 articles identified, 98 articles including 16,130 patients were eligible for inclusion (12 RCTs, 47 NRSs and 39 case series). The key findings are summarised in the following paragraphs:

The meta-analysis of the twelve RCTs revealed that varicocele treatment improved testicular volume (mean difference 1.52 ml, 95% CI 0.73-2.31) and increased total sperm concentration (mean difference 25.54, 95% CI 12.84-38.25) when compared with observation. Lymphatic sparing surgery significantly decreased hydrocele rates (p=0.02) and the OR was 0.08 (95% CI 0.01, 0.67). Due to the lack of RCTs, it was not possible to identify a surgical technique as being superior to the others. It remains unclear whether open surgery or laparoscopy is more successful for varicocele treatment (OR ranged from 0,13 to 2,84).

The success rates of the treatment (disappearance of varicocele) were between 85.1% and 100% whereas the complication rates were between 0% and 29% in the included studies. The most common complication reported was hydrocele. Resolution of pain after treatment was more than 90% in the reported series.

In conclusion, moderate evidence exists on the benefits of varicocele treatment in children and adolescents in terms of testicular volume and sperm concentration. Current evidence does not demonstrate superiority of any of the surgical/interventional techniques regarding treatment success. Lymphatic sparing surgery significantly decreases hydrocele formation. Long-term outcomes, including paternity and fertility, still remain unknown.

3.8.5.Summary of evidence and recommendations for the management of varicocele

Summary of evidence	LE
Varicocele becomes more frequent at the onset of puberty and is found in 14-20% of adolescents. Fertility problems are expected in up to 20% of adolescents with a varicocele.
Pubertal patients with a left grade II and III varicocele have the left testis smaller in up to 70% of cases; in late adolescence the contralateral right testis also becomes smaller.	1b
After adolescent varicocelectomy, left testis catch-up growth and improvement in sperm parameters has been demonstrated.	1a
There is no evidence that treatment of varicocele at paediatric age will offer a better andrological outcome than an operation performed later.	1b
Division of testicular lymphatics leads to hydrocele in up to 40% and to testicular hypertrophy.	1b
Lymphatic sparing surgery significantly decrease hydrocele rates.	1a

Recommendations	LE	Strength rating
Examine varicocele in the standing position and classify into three grades.	4	Strong
Use scrotal ultrasound to detect venous reflux without Valsalva manoeuvre in the supine and upright position and to discriminate testicular hypoplasia.		Strong
In all pre-pubertal boys with a varicocele and in all isolated right varicoceles perform standard renal ultrasound to exclude a retroperitonal mass.		Strong
Inform caregivers and patients and offer surgery for: varicocele associated with a persistent small testis (size difference of > 2 mL or 20%); varicocele associated with additional testicular condition affecting fertility (cryptorchidism, history of torsion, trauma); varicocele associated with pathological sperm quality (in older adolescents); symptomatic varicocele.	2	Weak
Use some form of optical magnification (microscopic or laparoscopic magnification) for surgical ligation.	2	Strong
Use lymphatic-sparing varicocelectomy to prevent hydrocele formation and testicular hypertrophy.	1	Strong

3.9.Urinary tract infections in children

3.9.1.Epidemiology, aetiology and pathophysiology

Urinary tract infections (UTIs) represent the most common bacterial infections in children [402-404]. There are several classification systems used to define a UTI. In neonates, the symptoms differ in many aspects from those in infants and children. The prevalence is higher; there is a male predominance; infections caused by other organisms than Escherichia coli are more frequent; and there is a higher risk of urosepsis [405,406].

In children presenting with urinary symptoms a pooled prevalence of UTI was 7.8% (CI: 6.6-8.9) [405]. The incidence varies depending on age and sex. One meta-analysis showed that in children presenting with fever in the first three months of life UTIs were present in 7.5% of girls, 2.4% (CI: 1.4-3.5) of circumcised boys, and 20.1% (CI: 16.8-23.4) of uncircumcised boys [405]. The incidence for boys is highest during the first 6 months of life (5.3%) and decreases with age to around 2% for the ages 0-6 years. In girls, UTIs are less common during the first 6 months of life (2%) and incidence increases with age to around 11% for the ages 0-6 years [407].

Associated risk factors for recurrent UTIs include bladder and bowel dysfunction (BBD), vesicoureteral reflux (VUR) and obesity [408-410]. In older children a delay in treatment is more often seen than in younger infants [411]. These risk factors in combination with delay in treatment have been associated with renal scarring [412]. Recurrent febrile UTIs, especially in combination with high-grade VUR, lead to renal scarring [413,414]. Each new febrile UTI increases the risk of renal scarring with an incidence of renal scarring after the first UTI, of 2.8% (CI:1.2-5.8), 25.7% (CI:12.5-43.3) after the second infection and up to 28.6% (CI:8.4-58.1) after 3 or more febrile UTIs [414].

The leading causative organism for UTIs has been E. coli, but other bacteriae have been rising in prevalence. In a large European study E. Coli was found in less than 50% of urine cultures. Klebsiella pneumoniae, Enterobacter spp., Enterococcus spp., Pseudomonas spp., Proteus spp. and Candida spp. are more frequent in nosocomial infections than in community-acquired UTIs, even though, their prevalence has increased outside of the hospital setting [415]. Neonatal UTI is frequently complicated by bacteraemia. In a retrospective study, 12.4% of blood cultures from neonates admitted for UTI were positive for bacteraemia [416], however, it is less frequent in community-acquired than in nosocomial UTI [416,417].

3.9.2.Classification systems

There are five widely used classification systems according to; site, severity, episode, symptoms and complicating factors. For acute treatment, site and severity are most important.

3.9.2.1.Classification according to site

Lower urinary tract infection (cystitis) is an inflammatory condition of the urinary bladder mucosa with general signs and symptoms including infection, dysuria, frequency, urgency, malodorous urine, enuresis, haematuria, and suprapubic pain.

Upper urinary tract infection (pyelonephritis) is a diffuse pyogenic infection of the renal pelvis and parenchyma. The onset of pyelonephritis is generally abrupt. Clinical signs and symptoms include fever (> 38°C), chills, costovertebral angle or flank pain, and tenderness.

3.9.2.2.Classification according to severity

In a lower urinary tract infection, children may have only mild pyrexia; are able to take fluids and oral medication; are only slightly or not dehydrated; and have a good expected level of compliance. When a low level of compliance is expected, such children should be managed as those with severe UTI. In severe UTI, infection is related to the presence of fever of > 39°C, the feeling of being ill, persistent vomiting, and moderate or severe dehydration. Most severe UTIs are upper urinary tract infections.

3.9.2.3.Classification according to episode first/persistent/recurrent/breakthrough

The first UTI may be a sign of anatomical anomalies. Anatomical evaluation is recommended (see below). Recurrent infection can be divided into unresolved and persistent infection.

In unresolved infection, initial therapy is inadequate for elimination of bacterial growth in the urinary tract (inadequate therapy, inadequate antimicrobial urinary concentration [poor renal concentration/gastrointestinal malabsorption], and infection involving multiple organisms with differing antimicrobial susceptibilities).

Persistent infection is caused by re-emergence of bacteria from a site within the urinary tract coming from a nidus for persistent infection that cannot be eradicated (e.g. infected stones, non-functioning or poorly functioning kidneys/renal segments, ureteral stumps after nephrectomy, necrotic papillae, urachal cyst, urethral diverticulum, peri-urethral gland, vesicointestinal, rectourethral or vesicovaginal fistulas). The same pathogen is identified in recurrent infections, but episodes of sterile urine may occur during and shortly following antimicrobial treatment.

A breakthough infection in patients under antibacterial prophylaxis is usually caused by resistent bacteria, parental non-compliance and/or severe urogenital anomalies [418,419].

In re-infection, each episode can be caused by a variety of new infecting organisms, in contrast to bacterial persistence in which the same infecting organism is always isolated. However, the most common general pathogenic species is E. coli, which occurs in many different serotypes. Therefore, recurrent E. coli UTI does not equate to infection with the same organism.

3.9.2.4.Classification according to symptoms

Children may have typical or atypical symptoms regarding a UTI.

In neonates and infants the most commen symptoms are fever, vomiting, lethargy and/or irritability. Infants and children may have non-specific signs such as poor appetite, failure to thrive, lethargy, irritability, vomiting or diarrhoea. Toilet trained children may report cystitis symptoms along with fever/flank pain.

Asymptomatic bacteriuria indicates attenuation of uropathogenic bacteria by the host, or colonisation of the bladder by non-virulent bacteria that are incapable of activating a symptomatic response (no leukocyturia, no symptoms). Asymptomatic UTI includes leukocyturia but no other symptoms.

Symptomatic UTI, includes irritative voiding symptoms, suprapubic pain (cystitis), fever and malaise (pyelonephritis). Cystitis may represent early recognition of an infection destined to become pyelonephritis, or bacterial growth controlled by a balance of virulence and host response.

3.9.2.5.Classification according to complicating factors

In uncomplicated UTI, infection occurs in a patient with a morphologically and functionally normal upper and lower urinary tract, normal renal function and competent immune system. This category includes mostly isolated or recurrent bacterial cystitis and is usually associated with a narrow spectrum of infecting pathogens that are easily eradicated by a short course of oral antimicrobial agents. Patients can be managed on an outpatient basis, with an emphasis on documenting resolution of bacteriuria, followed by elective evaluation for potential anatomical or functional abnormalities of the urinary tract [420].

A complicated UTI occurs in children with known mechanical or functional pathology of the urinary tract. Mechanical obstruction is commonly due to the presence of posterior urethral valves, strictures or stones, independent of their location. Functional obstruction often results from lower urinary tract dysfunction (LUTD) of either neurogenic or non-neurogenic origin and dilating VUR. Patients with complicated UTI require hospitalisation and parenteral antibiotics. Prompt anatomical evaluation of the urinary tract is critical to exclude the presence of significant abnormalities [421]. If mechanical or functional abnormalities are present, adequate drainage of the infected urinary tract is necessary.

3.9.3.Diagnostic evaluation

3.9.3.1.Medical history

Medical history includes the question of a primary (first) or secondary (recurring) infection; possible malformations of the urinary tract (e.g. pre- or post-natal US screening); prior operation; family history; and, whether there is constipation or presence of lower urinary tract symptoms (LUTS).

3.9.3.2.Clinical signs and symptoms

Neonates with severe UTI can present with non-specific symptoms (failure to thrive, jaundice, hyperexcitability) and without fever. In neonates it is important to rule out a co-existing meningitis [422]. Urinary tract infection is the cause of fever in 4.1-7.5% of children who present to a paediatric clinic [423,424]. Septic shock is unusual, even with very high fever. Signs of a UTI may be vague and unspecific in small children, but later on, when they are more than two years old, frequent voiding, dysuria and suprapubic, abdominal or lumbar pain can be detected.

3.9.3.3.Physical examination

Physical examination includes a general examination of the throat, lymph nodes, abdomen (constipation, palpable and painful kidney, or palpable bladder), flank, the back (stigmata of spina bifida or sacral agenesis), genitalia (phimosis, labial adhesion, vulvitis, epididymo-orchitis), measurement of body weight and temperature.

3.9.3.4.Urine sampling, analysis and culture

Urine sampling has to be performed before any antimicrobial agent is administered. The technique for obtaining urine for urinalysis as well as culture affects the rate of contamination, which influences interpretation of the results. Especially in early infancy, it can be challenging and depends on the mode of urine sampling [425].

3.9.3.4.1.Urine sampling

Urine must be collected under defined conditions and investigated as soon as possible to confirm or exclude UTI, especially in children with fever. In neonates, infants and non-toilet-trained children, there are four main methods with varying contamination rates and invasiveness to obtain urine:

(1) Plastic bag attached to the cleaned genitalia: Although this technique is most often used in daily practice, contamination rates are high with around 50-60% [426]. It is helpful when the culture results are negative. Also, if the dipstick is negative for both leukocyte esterase and nitrite, or microscopic analysis is negative for both pyuria and bacteriuria, UTI can be excluded without the need for confirmatory culture [427].

(2) Clean-catch urine (CCU) collection: The infant is placed in the lap of a caregiver or member of the nursing staff, who holds a sterile foil bowl underneath the infant’s genitalia. The infant is offered oral fluids and urine collection is awaited [428]. Suprapubic tapping alternated with paravertebral lumbar massage can stimulate sponateous voiding [426,429]. There seems to be a good correlation between the results of urine culture obtained by this method and suprapubic aspiration (SPA), with a false-positive rate of 5% and false-negative rate of 12% [428,430]; however, the contamination rate is higher for CCU with up to 26% compared to catheterisation 10% and SPA 1% [426,431]. In one prospective cohort study in infanty below the age of 6 months, the success rate was 49% and the contamination rate 16% with some differences in the culture results between those obtained by CCU and those by more inavsive methods [432].

(3) Transurethral bladder catheterisation: is the fastest and safest method to obtain a reliable urine sample for microscopic and bacteriological evaluation to rule out or to document a UTI in non-toilet trained infants and children.

(4) Suprapubic bladder aspiration: This is the most invasive but also the most sensitive method to obtain an uncontaminated urine sample in this age group [433,434]. For suprapubic puncture ultrasound imaging should be performed to asses bladder filling.

A two-step procedure where the CCU is screened and a catheter or SPA confirmation of the positive screens is used can lead to a reduction in invasive procedures [426,431].

In older, toilet-trained children who can void on command, after carefully retracting the foreskin and cleaning the glans penis in boys and spreading the labia and cleaning the peri-urethral area in girls, the use of clean catch, especially midstream urine, could be an acceptable technique for obtaining urine. After cleaning the urethral meatus and perineum with gauze and liquid soap twice, the risk of contamination was reduced from 23.9% (41/171) to 7.8% (14/171) in a randomised trial [435].

3.9.3.4.2.Urinalysis

There are three methods that are commonly used for urinalysis:

(1) Dipsticks: These are appealing because they provide rapid results, do not require microscopy, and are ready to use. Leukocyte esterase (as a surrogate marker for pyuria) and nitrite (which is converted from dietary nitrates by most Gram-negative enteric bacteria in the urine) are the most frequent markers, and are usually combined in a dipstick test. The conversion of dietary nitrates to nitrites by bacteria takes approximately four hours in the bladder [430,436]. Using only nitrate sticks to screen febrile children < 2 years of age has a too low sensitivity and relevant UTIs can be missed. However, the specificity is high for children at any age [437,438]. In febrile infants < 90 days old urine dipstick tests using CCU samples can be used for screening for a UTI when nitrites and leukocyte esterase combined are used with a sensitivity of 86% and a specificity of 80% [439].

(2) Microscopy: This is the standard method of assessing pyuria after centrifugation of the urine with a threshold of five white blood cells (WBCs) per high-power field (25 WBC/μL) [440]. In uncentrifuged urine, > 10 WBC/μL has been demonstrated to be sensitive for UTI [441] and this could perform well in clinical situations [442]. However, this is rarely done in an outpatient setting. No significant differences was found between dipsticks and microscopy testing for UTI [438]. A meta-analysis showed, that only microscopy with Gram staining has a higer sensitivity compared to dipsticks [443].

(3) Flow imaging analysis technology: This is being used increasingly to classify particles in uncentrifuged urine specimens [444]. The numbers of WBCs, squamous epithelial cells and red cells correlate well with those found by manual methods [430]. Flow cytometry-based bacterial and leukocyte count analysis when using a cut-off value of 250 bacteria/uL in the presence of leukocyturia has a sensitivity of 0.97 and specificity of 0.91 for diagnosing UTI [445].

3.9.3.4.3.Urine culture

After negative results for dipstick, microscopic or automated urinalysis, urine culture is generally not necessary, especially if there is an alternative source of fever. If the dipstick result is positive, confirmation by urine culture is strongly recommended.

It is unclear what represents a significant UTI. In patients with a severe UTI, ≥ 105 cfu/mL can be expected. However, the count can vary and be related to the method of specimen collection, diuresis, and time and temperature of storage until cultivation occurs [406]. Clean-catch urine, midstream and catheterisation urine cultures can be considered positive as 103 - 104 cfu/mL in a monoculture, and any counts obtained after SPA should be considered as significant. Mixed cultures are indicative of contamination. In febrile children < 4 months of age a cut-off value of 103 cfu/mL can be used when clinical and laboratory findings match and a correct sampling method has been used [446].

A negative culture with the presence of pyuria may be due to incomplete antibiotic treatment, urolithiasis, or foreign bodies in the urinary tract, and infections caused by Mycobacterium tuberculosis or Chlamydia trachomatis.

A flowchart was developed as guidance during the basic diagnostic evaluation and subsequent management of febrile children with clinical symptoms of UTI, Figure 4.

Figure 4: Diagnostic evaluation and subsequent management of a febrile child with clinical symptoms of UTI

CRP = C-reactive protein; AB = antibiotic.

3.9.3.5.Imaging

3.9.3.5.1.Ultrasound

Renal and bladder US within 24 hours is advised in infants with febrile UTI to exclude obstruction of the upper and lower urinary tract. Abnormal results are found in 15% of cases, and 1-2% have abnormalities that require prompt action (e.g., additional evaluation, referral or surgery) [427]. When a renal US is performed in all children presenting with a UTI, 7% will have an abnormal US warranting further investigations [447]. The sensitivity to detect high-grade VUR with US was found to be 0.59 (CI: 0.45-0.72) with a specificity of 0.79 (CI: 0.65-0.87) [448]. Renal ultrasound should be performed before and after voiding. Post-void residual (PVR) urine should be measured in toilet-trained children to exclude voiding abnormalities as a cause of UTI. Elevated PVR urine volume predicts recurrence of UTIs in toilet-trained children [449]. When peri-renal or psoas abcesses or renal masses are seen on US, it is important to consider xanthogranulomatous pyelonephritis, and subsequent CT imaging is proposed [450].

3.9.3.5.2.Radionuclide scanning/MRI

Changes in dimercaptosuccinic acid (DMSA) clearance during acute UTI indicate pyelonephritis or parenchymal damage, correlated with the presence of dilating reflux and the risk of further pyelonephritis episodes, breakthrough infections [451] and future renal scarring. In the acute phase of a febrile UTI (up to four to six weeks), DMSA-scan can demonstrate pyelonephritis by perfusion defects. Renal scars can be detected after three to six months [452]. Diffusion-weighted MRI has shown to accurately diagnose acute pyelonephritis and reveal late renal scars and could be an alternative to DMSA; therefore, avoiding radion burden [453]. The average effective radiation dose of a single DMSA scan was 2.84 (1-12) mSv in one study [454]. These findings are different in neonates. After the first symptomatic, community-acquired UTI, the majority of renal units with VUR grade III or higher had normal early DMSA scanning [455]. The sensitivity of the DMSA scan to detect VUR is 0.75 (CI:0.67-0.81) with a specificity of 0.48 (CI: 0.38-0.57), and a negative DMSA scan resulting in a very low probability of high-grade VUR [456].

3.9.3.5.3.Voiding cystourethrography/urosonography

The optimum method to exclude or confirm VUR is VCUG. The timing of VCUG does not influence the presence or severity of VUR [457]. Performance of early VCUG in patients with proven sterile urine does not cause any significant morbidity [458]. Using harmonic voiding urosonography may be an alternative to the standard VCUG avoiding radiation [459]. Visulatisation of the urethra may be difficult with this technique.

It is important to diagnose high-grade VUR after the first UTI since this is an important risk for renal scarring. On the other hand, physicians want to avoid unnecessary VCUG investigations at the same time, given its invasive character and radiation burden [447,460]. Various studies have investigated the risk factors for high-grade VUR and a top down approach is feasible. The most important risk factors for high-grade VUR and subsequent renal scarring are: abnormal renal US, high fever UTI and non-E. Coli infections. Different top down strategies with selective VCUG investigations have been proposed [461-465]. Based on these studies we recommend the following updated diagnostic strategy (see Figure 5).

Figure 5: Diagnosis strategy for first febrile UTI

UTI = urinary tract infection; VUR = vesicoureteral reflux; i.v. = intravenous.

3.9.4.Management

3.9.4.1.Administration route of antibacterial therapy

The choice between oral and parenteral therapy should be based on patient age; clinical suspicion of urosepsis; illness severity; refusal of fluids, food and/or oral medication; vomiting; diarrhoea; non-compliance; and complicated pyelonephritis (e.g. urinary obstruction). As a result of the increased incidence of urosepsis and severe pyelonephritis in newborns and infants aged less than two months, parenteral antibiotic therapy is recommended. Electrolyte disorders with life-threatening hyponatraemia and hyperkalaemia based on pseudohypoaldosteronism can occur in these cases [466,467].

The choice of agent is also based on local antimicrobial sensitivity patterns, and should later be adjusted according to sensitivity-testing of the isolated uropathogen [430]. Not all available antibiotics are approved by national health authorities, especially in infancy. When recent urinary cultures are available use these sensitivity patterns in the choice for treatment. In children who require intravenuous treatment tobramycin or gentamicin is recommended if there is normal kidney function. When abnormal kidney function is suspected, ceftriaxon or cefotaxime are alternative treatment options. In children who can receive oral treatment without any known resistant urinary cultures, cefixime or amoxicillin-clavulanate are the empirical treatment options [468]. Some studies have demonstrated that once daily parenteral administration of gentamicin or ceftriaxone in a day treatment centre is safe, effective and cost-effective in children with UTI [469-471]. Delaying treatment in children with a febrile UTI for more than 48-72 hours increases the risk of renal scars [412,472].

3.9.4.2.Duration of therapy

Prompt adequate treatment of UTI can prevent the spread of infection and renal scarring. In newborns and young infants with a febrile UTI, up to 20% may have a positive blood culture [416,421]. Children with bacteremia did not show significant clinical differences with non-bacteremic infants, but did receive longer parental treatment [473]. In late infancy, there are no differences between strategies regarding the incidence of parenchymal scars, as diagnosed with DMSA scan [474]. Outcomes of short courses (one to three days) are inferior to seven to fourteen-day courses [430]. However, a simple cystitis can be treated with 3-5 days of antibiotics [468]. No significant difference in recurrent UTIs and rehospitalisation was found between seven day parental treatment and longer regimens for bacteremic UTI in younger infants [475]. In young infants a short course of parental treatment with early conversion to oral antibiotics may be considered. The use of exclusively oral therapy with a third-generation cephalosporin (e.g. cefixime or ceftibuten) has been demonstrated to be equivalent to the usual two to four days intravenous therapy followed by oral treatment [476-479]. Similar data have been shown for amoxicillin-clavulanate [480]. If ambulatory therapy is chosen, adequate surveillance, medical supervision and, if necessary, adjustment of therapy must be guaranteed. In the initial phase of therapy, a close ambulant contact to the family is advised [481].

In complicated UTI, uropathogens other than E. coli, such as Proteus mirabilis, Klebsiella spp., Pseudomonas aeruginosa, enterococci and staphylococci are more often the causative pathogens [421]. A temporary urinary diversion (transurethral catheter, suprapubic cystostomy, percutaneous nephrostomy or ureteral stenting) might be required in case of failure of conservative treatment in obstructive uropathy. Children with acute focal bacterial nephritis often present without pyyuria and significant bacteriuria. For the majority of children, the pathogenesis is related to ascending infection due to pre-existing uropathy, especially VUR or urinary obstruction. Initial management consists of broad-spectrum antibiotics with good tissue penetration. A treatment regimen of a total of 3 weeks with initial intravenous and subsequently oral therapy tailored to the pathogen identified in culture is recommended [482].

3.9.4.3.Antimicrobial agents

There is a great difference in the prevalence of antibiotic resistance of uropathogenic E. coli in different countries, with increased high resistance patterns in countries outside of the Organisation for Economic Co-operation and Development (OECD) [483]. There are upcoming reports of UTIs caused by extended spectrum ß-lactamase-producing enterobacteriaceae (ESBL) in children, with pooled numbers of UTI caused by ESBL producing bacteria of around 14% [484]. Within OECD countries the prevalence of resistance was 53% for ampicillin, 24% for trimethoprim, 8% for co-amoxiclav, 2% for ciproxin and 1% for nitrofurantoin [483]. Several risk factors and determinants for UTIs caused by ESBL and non-E. Coli bacteriae have been identified: history of infection, recent hospitalisation, short-term exposure to antiobiotics, and prophylaxis [483,485,486]. Overall, oral nitrofurantoin seems to be a good empirical choice in the treatment of cystitis [487].

The choice of antibiotics should be guided by good antibiotic stewardship. It is important to be aware of the local resistance patterns. These are variable between countries and moreover between hospitals. Local antibiotic protocols and web-based recommendations can guide the choice for type of antibiotic therapy. The individual patient’s previous urine cultures should also be taken into account in this decision. The daily dosage of antibiotics is depended on the age, weight of the child as well as on renal and liver function.

3.9.4.4.Preventative measures

Recurrent UTIs are problematic because the symptoms are bothersome to children and recurrent febrile UTIs will also result in renal scarring [414]. Therefore, it is important to prevent the incidence of recurrent UTIs.

3.9.4.4.1.Chemoprophylaxis

Chemoprophylaxis is commonly used to prevent UTIs in children. However, with the increasing bacterial resistance numbers, it should be carefully considered which patients should receive antibacterial prophylaxis. The evidence for the use of antibacterial prophylaxis has been conflicting. Its use causes a reduction of the number of recurrent symptomatic UTIs, but long-term use of antibacterial prophylaxis has also been associated with increased microbial resistance [418,488]. Its use did not reduce newly acquired renal damage in children with first or second UTI [488]. However, when used in patients with anatomic abnormalities of the urinary system a reduction in UTIs and subsequent renal scarring was shown [418,488]. In children with BBD and VUR, a benefit was seen in the reduction of recurrent UTI with the use of antomicrobial prophylaxis [489,490] (see also Chapter 3.14 on VUR).

For the specific group of patients with incomplete bladder emptying with properly performed clean intermittent catheterisation but still suffering from recurrent UTIs the intravesical application of gentamycin has proven to be effective [491].

Table 1: Drugs for antibacterial prophylaxis*

Substance	Prophylactic dosage (mg/kg bw/d)	Limitations in neonates and infants
Trimethoprim**	1	Not recommended under six weeks of age
Trimethoprim Sulfamethoxazole	1-2 10-15	Not recommended under two months of age
Sulfamethoxazole	1-2	Until three months of age
Nitrofurantoin**	1-2	Not recommended under two months of age
Cefaclor	10	No age limitations
Cefixim	2	Preterms and newborns

* Reproduced with permission from the International Consultation on Urological Diseases (ICUD), International

Consultation on Urogenital Infections, 2009. Copyright© by the European Association of Urology [492].

** Substances of first choice are nitrofurantoin and trimethoprim. In exceptional cases, oral cephalosporin can be used.

3.9.4.4.2.Dietary supplements

Cranberry, mostly as juice, has been shown to prevent UTIs in healthy children, while in children with urogenital abnormalities, cranberries appear to be just as effective as antibiotic prophylaxis [493]. The results for probiotics are somewhat more conflicting, with one systematic review not ruling out any effect [298] and a RCT showing promising results in children with normal urogenital anatomy [494]. A meta-analysis could not demonstrate a beneficial effect, only as an adjuvant to antibiotic prophylaxis [495].

Other supplements of interest were Vitamin A, which showed promising results in preventing renal scarring in children with acute pyelonephritis [496,497]. The use of Vitamin E could possibly improve the symptoms of UTI [498]. More studies into these supplements are warranted.

3.9.4.4.3.Preputium

A risk reduction of recurrent UTI regarding the preputium has been shown in two studies. When a physiologic phimosis is present in boys with a UTI the use of steroid cream significantly reduced recurrent UTIs [499]. In boys with recurrent UTIs and hydronephrosis present, 10 boys would need to be circumcised to prevent one UTI [34].

3.9.4.4.4.Bladder and bowel dysfunction

Bladder and bowel dysfunction is a risk factor for which each child with UTI should be screened upon presentation [409]. Normalisation of micturition disorders or bladder overactivity is important to lower the rate of UTI recurrence. If there are signs of BBD at infection-free intervals, further diagnosis and effective treatment are strongly recommended [490]. Treatment of constipation leads to a decrease in UTI recurrence and a multidisciplinary approach is recommended [409,489,490]. Therefore, exclusion of BBD is strongly recommended in any toilet-trained child with febrile and/or recurrent UTI, and it should be treated (For treatment see chapter for LUTS).

3.9.4.5.Monitoring of UTI

With successful treatment, urine usually becomes sterile after 24 hours, and leukocyturia normally disappears within three to four days. Normalisation of body temperature can be expected within 24-48 hours after the start of therapy in 90% of cases. In patients with prolonged fever and failing recovery, treatment-resistant uropathogens or the presence of congenital uropathy or acute urinary obstruction should be considered. Repeated US examination is recommended in these cases.

Procalcitonin (among other laboratory inflammatory parameters such as C-reactive protein and leukocyte count) can be used as reliable serum marker for early prediction of renal parenchymal inflammation [500]. A cut-off value of serum procalcitonin of 1.0 ng/mL has been shown to be predictive of acute pyelonephritis in young children [501]. In patients with febrile UTI, serum electrolytes and blood cell counts should be followed up.

3.9.5.Summary of evidence and recommendations for the management of UTI in children

Summary of evidence	LE
Urinary tract infection represents the most common bacterial infection in children less than 2 years of age. The incidence varies depending on age and sex.	1b
Classifications are made according to the site, episode, severity, symptoms and complicating factors. For acute treatment, site and severity are most important.	2b
The number of colony forming units in the urine culture can vary, however, any colony count of one specimen indicates a high suspicion for UTI.	2b
Due to increasing resistance numbers good antibiotic stewardship should guide the choice of antibiotics, taking into account local resistance patterns, old urine cultures (when available) and clinical parameters.	2a
Preventive measures against recurrent UTIs include: chemoprophylaxis (oral and intravesical), cranberries, probiotics and Vitamin A and E.	2a
Urinalysis by dipstick yields rapid results, but it should be used with caution. Microscopic investigation is the standard method of assessing pyuria after centrifugation.	2a
During acute UTI both DMSA and diffusion-weighted MRI can confirm pyelonephritis or parenchymal damage.	2a

Recommendations	LE	Strength rating
Take a medical history, assess clinical signs and symptoms and perform a physical examination to diagnose children suspected of having a urinary tract infection (UTI).	3	Strong
Exclude bladder- and bowel dysfunction in any toilet-trained child with febrile and/or recurrent UTI.	3	Strong
Clean catch urine can be used for screening for UTI. Bladder catheterisation and suprapubic bladder aspiration to collect urine can be used for urine cultures.	2a	Strong
Do not use plastic bags for urine sampling in non-toilet-trained children since it has a high risk of false-positive results.	2a	Strong
Midstream urine is an acceptable technique for toilet-trained children.	2a	Strong
The choice between oral and parenteral therapy should be based on patient age; clinical suspicion of urosepsis; illness severity; refusal of fluids, food and/or oral medication; vomiting; diarrhoea; non-compliance; complicated pyelonephritis.	2a	Strong
Treat febrile UTIs with four to seven day courses of oral or parenteral therapy.	1b	Strong
Treat complicated febrile UTI with broad-spectrum antibiotics.	1b	Strong
Offer long-term antibacterial prophylaxis in case of high susceptibility to UTI and risk of acquired renal damage and lower urinary tract symptoms.	1b	Strong
In selected cases consider dietery supplements as an alternative or add-on preventive measure.	2a	Strong
In infants with febrile UTI use renal and bladder ultrasound to exclude obstruction of the upper and lower urinary tract within 24 hours.	2a	Strong
In infants, exclude vesicoureteral reflux after first epidose of febrile UTI with a non-E. Coli infection. In children more than one year of age with an E. Coli infection, exclude VUR after the second febrile UTI.	2a	Strong

3.10.Day-time lower urinary tract conditions

3.10.1.Terminology, classification, epidemiology and pathophysiology

Urinary incontinence in children may be caused by congenital anatomical or neurologic abnormalities such as ectopic ureter, bladder exstrophy or myelomeningocele (MMC). In many children, however, there is no such obvious cause for the incontinence, and they are referred as having functional bladder problems. The most recent International Children’s Continence Society (ICCS) document suggests using the term day-time lower urinary tract (LUT) conditions to group together all functional bladder problems in children.

Normal storage and emptying of the bladder at a socially accepted place and time is mostly achieved by age three to four. Children with LUT conditions would present with failure to achieve continence (being still wet after the age of four), urgency, weak stream, hesitancy, frequency and accompanied UTIs. Isolated night-time wetting without any day-time symptoms is known as ‘enuresis’ and considered as a different entity (see chapter 3.11) [502].

As different studies have used varying definitions and criteria, it is difficult to give reliable percentages regarding the incidence of this problem. Reported prevalence ranges widely from 1% to 20% [503-511]. Due to increasing awareness and better access to specialised health care, the prevalence seems to be increasing [512,513].

Lower urinary tract conditions in children may be due to disturbances of the filling phase, the voiding phase or a combination of both in varying severity. Mainly the conditions are divided into either overactive bladder (OAB) or dysfunctional voiding. They can, of course, coincide and one may even be causative of the other. Dysfunctional bowel emptying may also be part of the clinical problems and BBD is the term used to cover concomitant bladder and bowel disturbances.

Lower urinary tract conditions are considered to be the result of incomplete or delayed maturation of the bladder sphincter complex. The pons is considered to be responsible for detrusor sphincter co-ordination while the cortical area is responsible for inhibition of the micturition reflex and voluntary initiation of micturition. Therefore overactivity would be the result of delayed maturation of cortical control, while dysfunctional voiding would be the result of non-maturation of the co-ordination. Detrusor overactivity should not be considered as a sole bladder based problem but more a symptom of a centrally located dysfunction affecting bladder, bowel and even mood and behaviour [514].

A link between LUT and behavioural disorders such as ADHD (attention deficit/ hyperactivity disorder) has also been shown [515-517].

3.10.1.1.Filling-phase (storage) dysfunctions

In filling-phase dysfunctions, the detrusor can be overactive, as in OAB, or underactive, as in underactive bladder (UAB). Overactivity of the bladder is the most common problem, seen mostly around five to seven years of age. This may lead to disturbances characterised by urgency, frequency and at times urgency incontinence. Some children habitually postpone micturition leading to voiding postponement. Therefore, holding manoeuvres such as leg crossing and squatting can often be seen in this group. Recurrent UTIs are common and high-pressure state of the bladder can be a cause of VUR. Constipation can be an additional aetiological factor, which needs to be assessed. In children with an underactive detrusor, voiding occurs with reduced or minimal detrusor contractions with post-void residuals. Urinary tract infections, straining to void, constipation and incontinence is common. Incontinence often occurs when the bladder is over-distended in the form of overflow incontinence.

3.10.1.2.Voiding-phase (emptying) dysfunctions

In voiding-phase (emptying), incomplete relaxation or tightening of the sphincteric mechanism and pelvic floor muscles results in staccato voiding pattern (continuous urine flow with periodic reductions in flow rate precipitated by bursts of pelvic floor activity) or an interrupted voiding pattern (unsustained detrusor contractions resulting in infrequent and incomplete voiding, with micturition in fractions). The general term for this condition is dysfunctional voiding and is associated with elevated bladder pressures and PVRs. Symptoms will vary depending on the severity of inco-ordination between bladder and the sphincter. Staccato voiding is in less severe forms and interrupted voiding and straining is in more severe forms. The co-existence of constipation and LUTD and recurrent UTI is well described [518]. There is no evidence to conclude if bladder problems or bowel problems are the leading cause. The prevalence of constipation in older children varies from 5 to 27%. Approximately 90% of them being functional constipation without an organic cause In children with functinal constipation the prevelance of bladder symptoms have been shown to be as high as 64% [519,520].

In incomplete emptying, high voiding pressures generated by bladder working against a functional obstruction caused by non-relaxing sphincter may induce not only UTIs but also VUR. It is been shown that LUTD is more significant for the occurrence of UTI than VUR itself [521]. In the majority of children with dysfunctional voiding the recurrent infections disappear following successful treatment, which confirms the hypothesis that dysfunctional voiding is the main factor responsible for the infections. Spontaneous resolution of VUR may also be seen after successful treatment of dysfunctional voiding.

3.10.2.Diagnostic evaluation

The evaluation of LUT conditions includes medical and voiding history (bladder diaries and structured questionnaires), a physical examination, a urinalysis, and uroflowmetry with PVR. The upper urinary tract (UUT) needs to be evaluated in children with recurrent infections and dysfunctional voiding. Uroflowmetry can be combined with pelvic floor electromyography to demonstrate overactivity of the pelvic floor muscles during voiding. Urodynamic studies are usually reserved for patients with therapy resistant dysfunctional voiding and those not responding to treatment who are being considered for invasive treatment [517,522-525].

In addition to a comprehensive medical history a detailed voiding diary provides documentation of voiding and defecation habits, frequency of micturition, voided volumes, night-time urine output, number and timing of incontinence episodes, and fluid intake. A voiding diary should at least be done for two days, although longer observation periods are preferred. A voiding diary provides information about storage function and incontinence frequency, while a pad test can help to quantify the urine loss. In the paediatric age group, where the history is taken from both the caregivers and child together, a structured approach is recommended using a questionnaire. Many signs and symptoms related to voiding and wetting will be unknown to the caregivers and should be specifically requested, using the questionnaire as a checklist. Some symptom scorings have been developed and validated [526,527]. Although the reliability of questionnaires are limited they are practical in a clinical setting to check the presence of symptoms and have also been shown to be reliable to monitor the response to treatment. History taking should also include assessment of bowel function. For evaluation of bowel function in children, the Bristol Stool Scale is an easy-to-use tool [528,529].

Urinalysis and urinary culture are essential to evaluate for UTI. Since transient voiding symptoms are common in the presence of UTI, exclusion of UTI is essential before further management of symptoms. During clinical examination, genital inspection and observation of the lumbosacral spine and the lower extremities are necessary to exclude obvious uropathy and neuropathy.

Uroflowmetry with PVR evaluates the emptying ability, while an UUT US screens for (secondary) anatomical changes. A flow rate which reaches its maximum quickly and levels off (‘tower shape’) may be indicative of over-active bladder whereas interrupted or staccato voiding patterns may be seen in dysfunctional voiding. Plateau uroflowmetry patterns are usually seen in anatomic obstruction of flow. A single uroflowmetry test may not always be representative of the clinical situation and multiple uroflowmetry tests, which all give a similar result, are more reliable. Uroflowmetry examination should be done when there is desire to empty the bladder and the voided volume should at least be 50% of the age-expected capacity [(age in years) + 1] x 30 mL for the children. While testing the child in a clinical environment, the impact of stress and mood changes on bladder function should also be taken into account [530,531].

In the case of treatment failure re-evaluation is warranted and (video)-urodynamic (VUD) studies and neurological evaluation may be considered. Sometimes, there are minor, underlying, urological or neurological problems, which can only be suspected using VUD. In these cases, structured psychological interviews to assess social stress should be added [532] (LE: 1b).

Video-urodynamics may also be used as initial investigational tool in patients with suspicion of reflux. In this case reflux may be observed along with bladder dynamics. In the case of anatomical problems, such as posterior urethral valve (PUV) problems, syringocoeles, congenital obstructive posterior urethral membrane (COPUM) or Moormann’s ring, it may be necessary to perform cystoscopy with treatment. If neuropathic disease is suspected, MRI of the lumbosacral spine and medulla can help to exclude tethered cord, lipoma or other rare conditions.

3.10.3.Management

The treatment of LUTD involves a multimodal approach, involving strategies such as behavioural modification, and anticholinergic medication along with underlying and potentially complicating conditions such as constipation and UTIs.

Behavioural modification, mostly referred to as urotherapy, is a term which covers all non-pharmacological and non-surgical treatment modalities. It includes standardisation of fluid intake, bowel management; timed voiding and basic relaxed voiding education. The child and family are educated about normal bladder function and responses to urgency. Voiding regimens are instituted and UTIs and any constipation are treated. Treatment is aimed at optimising bladder emptying and inducing full relaxation of the urinary sphincter or pelvic floor prior to and during voiding.

Strategies to achieve these goals include:

1. Information and demystification, which includes explanation about normal LUT function and how a particular child deviates from normal function.
2. Instructions about what to do about the problem:
   • Regular voiding habits, sound voiding posture, pelvic floor awareness and training to relax pelvic floor and avoiding holding manoeuvres.
   • Lifestyle advice, regarding fluid intake, prevention of constipation, etc.
   • Registration of symptoms and voiding habits using bladder diaries or frequency-volume charts.
   • Support and encouragement via regular follow-up by the caregiver.

Recurrent UTIs and constipation should also be treated and prevented during the treatment period. In case of combined BBD it is advised to treat the bowel dysfunction first [512] as LUTS may disappear after successful management of bowel dysfunction.

Addition of other strategies, as below, may be needed:

• Pelvic floor muscle awareness practices with repeated sessions of biofeedback visualisation of uroflow curves and/or pelvic floor activity and relaxation.
• Clean intermittent self-catheterisation for large PVR volumes of urine.
• Antimuscarinic drug therapy if detrusor overactivity is present.
• If the bladder neck is associated with increased resistance to voiding, α-blocker drugs may be introduced.

Treatment efficacy can be evaluated by improvement in bladder emptying and resolution of associated symptoms. Controlled studies of the various interventions are needed. As with detrusor overactivity, the natural history of untreated dysfunctional voiding is not well delineated and optimum duration of therapy is poorly described. A high success rate has been described for urotherapy programmes, independent of the components of the programme. However, the evidence level is low as most studies of urotherapy programmes are retrospective and non-controlled [533]. A recent Cochrane analysis found very little evidence that can help to make evidene-based treatment decisions [534].

3.10.3.1.Specific interventions

As well as urotherapy, there are some specific interventions, including physiotherapy (e.g. pelvic floor exercises), biofeedback, alarm therapy and neuromodulation. Although good results with these treatment modalities have been reported, the level of evidence remains low, since only a few RCTs were published [535-541].

A systematic review reports that biofeedback is an effective, non-invasive method of treating dysfunctional voiding, and approximately 80% of children benefited from this treatment. However, most reports were of low level of evidence and studies of more solid design such as RCTs should be conducted [542].

A more recently published multicentre controlled trial of cognitive treatment, placebo, oxybutynin and bladder and pelvic floor training did not report better results with oxybutynin and pelvic floor training compared to standard urotherapy [532] (LE: 1b).

Two RCTs on underactive bladder without neurophatic disease have recently been published. Transcutaneous interferential electrical stimulation and animated biofeedback with pelvic floor exercise have been shown to be effective [543,544]. In some cases, pharmacotherapy may be added. Some studies on orthosympathicomimetics have been published with a low level of evidence [545].

Overactive bladder is common in the paediatric population. Although a stepwise approach starting with behavioural therapy is advised, antimuscarinic agents remain the mainstay of medical treatment for OAB. Oxybutynin is the most commonly used antimuscarinic in the paediatric population. The response to antimuscarinics varies and many children experience serious side effects. Although there have been reports about the use of tolterodine, fesoterodine, trospium, propiverine, and solifenacin in children, to date, most of them are off-label depending on age and national regulations. A few RCTs have been published, one on tolterodine showed safety but not efficacy [546], while another on propiverine showed both safety and efficacy [547] (LE:1). The recent study on solifenacin showed its efficacy with side effects like constipation and electrocardiogram changes [548].

The difference in results is probably due to study design. Despite the low level of evidence for the use of anticholinergics and antimuscarinics, their use is recommended because of the large number of studies reporting a positive effect on OAB symptoms. Although α-blocking agents are used occasionally, an RCT showed no benefit [549]. Botulinum toxin injection seems promising, but can only be used off-label [550].

A meta-analysis reports that neuromodulation therapy may lead to better partial improvement of non-neurogenic OAB; however, it may not render a definitive complete response. Office-based neuromodulation seems more efficacious than self-administered neuromodulation [551]. These new treatment modalities can only be recommended for standard therapy-resistant cases [552]. Despite early successful treatment, there is evidence that there is a high recurrence rate of symptoms in the long term which necessitates long-term follow-up [553]. In addition, many patients may present later in adulthood with different forms of LUTD [554].

3.10.4.Summary of evidence and recommendations for the management of day-time lower urinary tract conditions

Summary of evidence	LE
The term ‘bladder bowel dysfunction’ should be used rather than ‘dysfunctional elimination syndrome and voiding dysfunction’.	4
Day-time LUTS has a high prevalence (1% to 20%).	2

Recommendations	LE	Strength rating
Use two day voiding diaries and/or structured questionnaires for objective evaluation of symptoms, voiding drinking habits and response to treatment.	2	Strong
Use a stepwise approach, starting with the least invasive treatment in managing day-time lower urinary tract dysfunction in children.	4	Weak
Initially offer urotherapy involving bladder rehabilitation and bowel management.	2	Weak
If bladder bowel dysfunction is present, treat bowel dysfunction first, before treating the lower urinary tract condition.	2	Weak
Use pharmacotherapy (mainly antispasmodics and anticholinergics) as second line therapy in overactive bladder.	1	Strong
Use antibiotic prophylaxis if there are recurrent infections.	2	Weak
Re-evaluate in case of treatment failure; this may consist of (video) urodynamics MRI of lumbosacral spine and other diagnostic modalities, guiding to off-label treatment which should only be offered in highly experienced centres.	3	Weak

3.11.Monosymptomatic nocturnal enuresis - bedwetting

3.11.1.Epidemiology, aetiology and pathophysiology

Monosymptomatic nocturnal enuresis, also known as bedwetting, is defined as an intermittent nocturnal incontinence. It is a relatively frequent symptom in children, 5-10% at seven years of age and 1–2% in adolescents. With a spontaneous yearly resolution rate of 15% (at any age), it is considered as a relatively benign condition [530,555]. Seven out of 100 seven-year-old bedwetting children will continue to wet their bed into adulthood. Nocturnal enuresis is considered primary when a child has not yet had a prolonged period of being dry (six months). The term “secondary nocturnal enuresis” is used when a child or adult begins wetting again after having stayed dry.

Non-monosymptomatic nocturnal enuresis is defined as the condition of nocturnal enuresis in association with day-time lower urinary tracts symptoms (LUTS, recurrent UTIs and/or bowel dysfunction) [555,556].

Nocturnal enuresis has significant secondary stressful, emotional and social consequences for the child and their caregivers. Therefore treatment is advised from the age of six to seven years onwards considering mental status, family expectations, social issues and cultural background.

There is a clear hereditary factor in nocturnal enuresis. If none of the parents or their immediate relatives has suffered from bedwetting, the child has a 15% chance of wetting its bed. If one of the parents, or their immediate relatives have suffered from bedwetting, the chance of bedwetting increases to 44%, and if both parents have a positive history the chance increases to 77%. However, from a genetic point of view, enuresis is a complex and heterogeneous disorder. Loci have been described on chromosomes 12, 13 and 22 [556]. There is also a gender difference: two boys to one girl at any age.

High arousal threshold is the most important pathophysiological factor; the child does not wake up when the bladder is full. In addition to the high arousal threshold, there needs to be an imbalance between night-time urine output and night-time bladder capacity and activity [530,555,556]. Recently, attention has been given to the chronobiology of micturition in which the existence of a circadian clock in kidney, brain and bladder is postulated [557] (LE: 1).

A high incidence of comorbidity and correlation between nocturnal urine production and sleep disordered breathing, such as obstructive sleep apnoea, has been found and investigated. Symptoms such as habitual snoring, apnoeas, excessive sweating at night and mouth breathing in the patient history or via sleep questionnaires can lead to the diagnosis of adenotonsillar hypertrophy.

3.11.2.Diagnostic evaluation

The diagnosis is mainly obtained by history-taking. Focused questions to differentiate monosymptomatic vs. non-monosymptomatic, primary vs. secondary, comorbid factors such as behavioural or psychological problems and sleep disorder breathing, should be asked. In addition, a two day complete voiding and drinking diary, which records day-time bladder function and drinking habits will further exclude comorbid factors such as LUTS and polydipsia.

The night-time urine production should be registered by weighing the night-time diapers in the morning and adding the first morning voided volume [558]. The night-time urine production should be recorded over (at least) a two week period to diagnose an eventual differentiation between a high night-time production (more than 130% of the age expected bladder capacity) vs. a night-time OAB.

A physical examination should be performed with special attention to the external genitalia and surrounding skin as well as to the condition of the clothes (wet underwear or encopresis).

Urine analysis is indicated if there is a sudden onset of bedwetting, a suspicion or history of UTIs, or inexplicable polydipsia.

A uroflowmetry and US is indicated only if there is a history of previous urethral or bladder surgery, straining while voiding, interrupted voiding, an abnormal weak or strong stream, or a prolonged voiding time. If the comorbid factor of possible sleep disordered breathing occurs, a referral to an ear-nose-throat (ENT) specialist should be advised.

If the comorbid factor is developmental, attention or learning difficulties, family problems, parental distress and possible punishment of the child, a referral to a psychologist should be advised and followed-up.

3.11.3.Management

Before introducing any form of possible treatment, it is of utmost importance to explain the bedwetting condition to the child and the caregivers in order to demystify the problem.

3.11.3.1.Supportive treatment measures

Initially, supportive measures including normal and regular eating and drinking habits should be reviewed, stressing normal fluid intake during the day and reducing fluid intake in the hours before sleep. Keeping a chart depicting wet and dry nights, also called as basic bladder advice, has not been shown to be successful in the early treatment of nocturnal enuresis [559] (LE: 1a).

3.11.3.2.Conservative “wait and see” approach

If the child and its family is unable to comply with a treatment, if the treatment options are not possible for the family situation, and if there is no social pressure, a “wait and see” approach can be chosen. However, in this approach, it is important to emphasise the fact that the child should wear diapers at night to ensure a normal quality of sleep.

3.11.3.3.Nocturnal enuresis wetting alarm treatment

The nocturnal alarm treatment is the use of a device that is activated by getting wet. The goal is that the child wakes up by the alarm, which can be acoustic or tactile, either by itself or with the help of a caregiver. The method of action is to repeat the awakening and therefore change the high arousal to a low arousal threshold, specifically when a status of full bladder is reached. It is of utmost importance that the child is collaborating. Initial success rates of 80% are realistic, with low relapse rates, especially when night-time diuresis does not exceed age-expected bladder capacity [560]. Regular follow-up will improve the success.

3.11.3.4.Medical therapy

In the case of high night-time diuresis, success rates of 70% can be obtained with desmopressin (DDAVP), either as tablets (200-400 μg), or as sublingual DDAVP oral lyophilisate (120-240 μg). A nasal spray is no longer recommended due to the increased risk of overdose [561,562] (LE: 1). Relapse rates can be high after DDAVP discontinuation [555], however recently, structured withdrawal has shown lower relapse rates [563] (LE: 1).

In the event of desmopressin-resistant treatment for nocturnal enuresis or if a suspicion exists for night-time OAB, combination with antispasmodics or anticholinergics is safe and efficient [558]. Imipramine, which has been popular for treatment of enuresis, achieves only a moderate response rate of 50% and has a high relapse rate. Furthermore, cardiotoxicity and death from overdose are described, its use should therefore be discouraged as the first-line therapy [564] (LE: 1). Figure 6 presents stepwise assessment and management options for nocturnal enuresis.

Although several forms of neuromodulation and acupuncture have been investigated for nocturnal enuresis treatment, present data precludes their use because of its inefficiency, or at least no additional benefit.

Figure 6: A stepwise assessment and management options for nocturnal enuresis

ENT = ear, nose and throat.

3.11.4.Summary of evidence and recommendations for the management of monosymptomatic enuresis

Summary of evidence	LE
Chronobiology of micturition, in which the existence of a circadian clock has been proven in kidney, brain and bladder, and disturbances in this chronobiology play a major role in the pathophysiology of enuresis.	1

Recommendations	LE	Strength rating
Do not treat children less than five years of age in whom spontaneous cure is likely, but inform the family about the involuntary nature, the high incidence of spontaneous resolution and the fact that punishment will not help to improve the condition.	2	Strong
Use voiding diaries or questionnaires to exclude day-time symptoms.	2	Strong
Perform a urine test to exclude the presence of infection or potential causes such as diabetes insipidus.	2	Strong
Offer supportive measures in conjunction with other treatment modalities, of which pharmacological and alarm treatment are the two most important.	1	Strong
Offer desmopressin in proven night-time polyuria.	1	Strong
Offer alarm treatment in motivated and compliant families.	1	Strong

3.12.Management of neurogenic bladder

3.12.1.Epidemiology, aetiology and pathophysiology

Neurogenic detrusor-sphincter dysfunction (NDSD) can develop as a result of a lesion at any level in the nervous system. This condition contributes to various forms of LUTD, which may lead to incontinence, UTIs, VUR, and ultimately to renal scarring and renal failure requiring dialysis and/or transplantation. Conservative treatment starting in the first year of life is the first choice, however, surgery may be required at a later stage to establish adequate bladder storage, continence and drainage later on [565-567]. The main goals of treatment concerning the urinary tract are prevention of UTI’s, urinary tract deterioration, achievement of continence at an appropriate age and promoting as good a QoL as possible. With regard to the associated bowel dysfunction, stool continence, with evacuation at a social acceptable moment, is another goal as well as education and treatment of disturbance in sexual function. Due to the increased risk of development of latex allergy, latex-free products (e.g., gloves, catheters etc.) should be used from the very beginning whenever possible [568].

Neurogenic bladder in children with myelodysplasia presents with various patterns of Detrusor-Sphincter-Dyssynergia with a wide range of severity [569]. About 12% of neonates with myelodysplasia have no signs of neuro-urological dysfunction at birth [570]. Newborns with myelodysplasia and initially normal urodynamic studies are at risk for neurological deterioration secondary to spinal cord tethering, especially during the first six years of life. Close follow-up of these children is important for the early diagnosis and timely surgical correction of tethered spinal cord, and for the prevention of progressive urinary tract deterioration [570]. At birth, the majority of patients have normal UUTs, but up to 60% develop upper tract deterioration due to bladder changes, UTI and /or VUR, if not treated properly [571-574]. Even today in a contemporary series around 50% of the patients are incontinent and 15% have an impaired renal function at the age of 29 years [575]. A recent systematic review concerning the outcome of adult meningomyelocele patients demonstrated that around 37% (8-85%) are continent, 25% have some degree of renal damage and 1.3% end stage renal failure [576]. The term “continence” is used differently in the reports, and the definition of “always dry” was used in only a quarter of the reports [577].

The most common presentation at birth is myelodysplasia. The incidence of neural tube defects in Europe is 9.1 per 10,000 births and has not decreased in recent years, despite longstanding recommendations concerning folic acid supplementations [578]. The term myelodysplasia includes a group of developmental anomalies that result from defects in neural tube closure. Lesions include spina bifida aperta and occulta, meningocele, lipomyelomeningocele, or myelomeningocele. Myelomeningocele is by far the most common defect seen and the most detrimental.

With antenatal screening spina bifida can be diagnosed before birth with the possibility of intrauterine closure of the defect [579,580]. Traumatic and neoplastic spinal lesions of the cord are less frequent in children, but can also cause severe urological problems. Other congenital malformations or acquired diseases can cause a neurogenic bladder, such as total or partial sacral agenesis which can be part of the caudal regression syndrome [581]. In any child presenting with anorectal malformation (ARM) and cloacal malformations, the development of a neurogenic bladder is possible [582]. Patients with cerebral palsy may also present with varying degrees of voiding dysfunction, usually in the form of uninhibited bladder contractions (often due to spasticity of the pelvic floor and sphincter complex) and wetting. Finally, a “non-neurogenic neurogenic” bladder, such as Hinman or Ochoa syndrome, has been described, in which no neurogenic anomaly can be found, but severe bladder dysfunction as seen in neurogenic bladders is present [583,584].

3.12.2.Classification systems

As bladder sphincter dysfunction is poorly correlated with the type and spinal level of the neurological lesion, urodynamic and functional classifications are much more practical for defining LUT pathology and planning treatment in children.

The bladder and sphincter are two units working in harmony to act as a single functional unit. In patients with a neurogenic disorder, the storage and emptying phase of the bladder function can be disturbed. The bladder and sphincter may function either overactive or underactive and present in four different combinations. This classification system is based on urodynamic findings [585-587]:

• Overactive sphincter and overactive bladder.
• Overactive sphincter and underactive bladder.
• Underactive sphincter and overactive bladder.
• Underactive sphincter and underactive bladder.

3.12.3.Diagnostic evaluation

Today several guidelines and timetables are used [588-590]. The Panel advocate proactive management in children with spinal dysraphism. In those with a safe bladder during the first urodynamic investigation, the next urodynamic investigation can be delayed until one year of age.

3.12.3.1.History and clinical evaluation

History should include questions on clean intermittent catheterisation (CIC) frequency, urine leakage, bladder capacity, UTI, medication, bowel function as well as changes of neurological status. A thorough clinical evaluation is mandatory including the external genitalia and the back. A two day diary, recording drinking volume and times as well as CIC intervals, bladder volume and leakage can provide additional information about the efficacy of the treatment.

3.12.3.2.Laboratory and urinalysis

After the first week of life, the plasma creatinine level should be obtained, later in life; the cystatin level is more accurate [591,592]. If there is any sign of decreased renal function, physicians should be encouraged to optimise the treatment as much as possible. The criteria for urine analysis are the same as for UTI (refer to Chapter 3.9). However, it is much easier for caregivers or patients to obtain catheter urine in patients who are on CIC. They can also perform a dip stick analysis to screen for UTI at home. (For relevance see Section 3.12.4.5)

3.12.3.3.Ultrasound

At birth, US of the kidneys and bladder should be performed and then repeated at least annually. If there are any clinical changes in between, another US should be performed. Dilatation of the UUT should be reported according to the classification system of the Society of Foetal Urology [593], including the measurement of the caliceal dilatation and anterior posterior diameter of the renal pelvis. Residual urine and bladder wall thickness should also be mentioned. A dilated ureter behind the bladder should be recorded. Bladder wall thickness has been shown not to be predictive of high pressures in the bladder during voiding and storage and cannot be used as a non-invasive tool to judge the risk for the UUT [594].

3.12.3.4.Urodynamic studies/videourodynamic

Urodynamic studies (UD) are one of the most important diagnostic tools in patients with neurogenic bladders. In newborns with spina bifida aperta (failure of mesodermal in-growth over the developing spinal canal results in an open lesion most commonly seen in the lumbosacral area including an incomplete closure of the vertebral column and not covered by skin), the first UD should be performed after the phase of the spinal shock after closure, usually between the second and third months of life [595]. Especially in newborns, performing and interpretation of UD may be difficult, as no normal values exist. After that it should be repeated annually, depending on the clinical situation. During and after puberty bladder capacity, maximum detrusor pressure and detrusor leak point pressure increase significantly [596]. Therefore, during this time, a careful follow-up is mandatory.

3.12.3.4.1.Preparation before urodynamic studies

Before any UD a urine analysis should be undertaken. The first assessment should be done under antibiotic prophylaxis. A Cochrane analysis of nine randomised controlled trials showed, that the administration of prophylactic antibiotics compared to placebo reduced the risk of significant bacteriuria from 12% to 4% after UD studies. However, this was without significant difference for symptomatic UTI (20% vs. 28%), fever or dysuria [597]. If there is a significant bacteriuria, antibacterial treatment should be discussed; especially in older patients a single shot may be sufficient [598].

Generally UD-parameters should include:

• the bladder cystometric capacity;
• the intravesical filling pressure;
• detrusor compliance;
• the intravesical pressure at the moment of voiding or leakage;
• the presence or absence of overactive detrusor;
• the competence of the internal and external sphincter;
• the degree of synergy of the detrusor and sphincter during voiding;
• the PVR urine volume.

In infants, information on detrusor filling pressure and the pressure and bladder volume at which the child voids or leaks can be obtained [595]. Detrusor leak point pressure is more accurate than abdominal leak point pressure, but keeping the rectal probe in an infant in place can be challenging [595]. Addition of fluoroscopy (video-urodynamic study) will provide information about presence of VUR, at what pressures VUR starts and the configuration of the bladder neck during filling and leakage or voiding.

3.12.3.4.2.Uroflowmetry

Unlike in children with non-neurogenic voiding dysfunction, uroflowmetry can rarely be used since most affected patients do not void spontaneously. In those with cerebral palsy, non-neurogenic-neurogenic bladder or other neurological conditions allowing active voiding it may be a practical tool. It provides an objective way of assessing the efficiency of voiding, while recording of pelvic floor activity with electromyography (EMG) can be used to evaluate synergy between detrusor and the sphincter. The PVR urine is measured by US. The main limitation of uroflowmetry is a compliant child to follow instructions [599-602].

3.12.3.5.Urodynamic studies

The standards of the ICCS should be applied to UDs in patients with neurogenic bladders and accordingly reported [522,585]. Natural fill UD in children with neurogenic bladder detects more overactivity compared with diagnoses delivered by conventional UD [603,604]. It may be an option in patients where the findings in the normal UD are inconsistent with clinical symptoms and other clinical findings [604].

3.12.3.6.Voiding cystourethrogram

If video-urodynamic equipment is not available, a VCUG with UD is an alternative to confirm or exclude VUR and visualise the LUT including the urethra.

3.12.3.7.Renal scan

DMSA (Technetium Dimercapto-Succinic Acid) Renal scan is the gold standard to evaluate renal parenchyma. In contemporary series, renal scars can be detected in up to 46% as patients get older [605-607]. A positive DMSA-Scan correlates well with hypertension in adulthood, whereas US has a poor correlation with renal scars [607]. Therefore, a DMSA scan as a baseline evaluation in the first year of life is recommended.

3.12.4.Management

The medical care of children with neurogenic bladder requires an on-going multidisciplinary approach. There is some controversy about optimal timing of the management; proactive vs. expectant management [565-567]. Even with a close expectant management e.g. in one series 11 out of 60 need augmentation within a follow-up of 16 years and 7 out of 58 had a decrease in total renal function, which was severe in two [608]. During the treatment it should be also taken into account with spina bifida patients, that QoL is related to urinary incontinence independent from the type and level of spinal dysraphism and the presence or absence of a liquor shunt [609].

Foetal open and endoscopic surgery for meningomyelocele are performed to close the defect as early as possible to reduce the neurological, orthopaedic and urological problems [610]. In the MOMS-Trail, Brooks et al. found no difference between those closed in utero vs. those closed after birth concerning the need for CIC [580], but less trabeculation was found in the prenatal surgery group. Mean gestation age (28.3 vs. 35.2) seems to have no initial impact on bladder function in the first few years of life [611]. Despite some promising reports [611-614], caregivers need to be aware of the high risk of developing a neurogenic bladder as demonstrated by a Brazilian group [615]. Regular and close follow-up examinations including UD are indicated in all these patients.

3.12.4.1.Early management with intermittent catheterisation

Starting intermittent catheterisation (IC) soon after birth and closure of the defect by the neurosurgeon in all infants has shown to decrease renal complications and the need for later augmentation [616-618]. In infants without any clear sign of outlet obstruction, this may be delayed but only in very selected cases. These infants should be monitored very closely for UTIs and changes of the urinary tract with US and UD. The early initiation of IC in the newborn period makes it easier for caregivers to master the procedure and for children to accept it, as they grow older [619,620].

A Cochrane review as well as some recent studies showed, that there is a lack of evidence to state that the incidence of UTI is affected by use of sterile or clean technique, coated or uncoated catheters, single (sterile) or multiple use (clean) catheters, self-catheterisation or catheterisation by others, or by any other strategy [621-624]. Looking at the microbiological milieu of the catheter, there was a trend for reduced recovery of potentially pathogenic bacteria with the use of hydrophilic catheters. Also, a trend for a higher patient satisfaction with the use of hydrophilic catheters was seen [625]. Based on the current data, it is not possible to state that one catheter type, technique or strategy is better than another.

3.12.4.2.Medical therapy

Antimuscarinic/anticholinergic medication reduces/prevents detrusor overactivity and lowers intravesical pressure [626,627]. Effects and side effects depend on the distribution of the M1-M5 receptors [628]. In the bladder, the subtype M2 and M3 are present [627,629]. Oxybutynin is the most frequently used in children with neurogenic bladder with a success rate of up to 93% [630,631]. Dose-dependent side-effects (such as dry mouth, facial flushing, blurred vision heat intolerance etc.) limit its use. Intravesical administration has a significant higher bioavailability due to the circumvention of the intestinal first pass metabolism, as well as possible local influence on C-fiber-related activity and can be responsible for different clinical effect [632,633]. Intravesical administration should be considered in patients with severe side-effects, as long-term results demonstrated that it was well-tolerated and effective [634,635]. The transdermal administration leads also to a substantial lower ratio of N-desethyloxybutynin to oxybutynin plasma levels, however, there are treatment-related skin reactions in 12 out of 41 patients [636]. There are some concerns about central anticholinergic adverse effects associated with oxybutynin [637,638]. A double blinded cross-over trial, as well as a case control study, showed no deleterious effect on children’s attention and memory [639,640]. Tolterodine, solifenacin, trospium chloride and propiverine and their combinations can be also used in children [641-647]. The oral dosage for oxybutynin is up to 0.2 mg/kg/every 8 hours [627] given three times daily. The intravesical dosage can be up to 0.7 mg/kg/daily and transdermal 1.3-3.9 mg/daily. The dosage of the other drugs is: Tolterodine 0.5 – 4 mg/day divided in two doses, Solifenacin 1.25 up to 10 mg per day (single dose), Propiverin 0.8 mg/kg/day divided in two dosages and trospium chloride up to 3 times 15 mg starting with 3 times 5 mg. Except for oxybutynin, all other anticholinergic drugs are off-label use, which should be explained to the caregivers.

Early prophylactic treatment with anticholinergics showed a lower rate of renal deterioration as well as a lower rate of progression to bladder augmentation [616,618,648]. Beta-3 agonists like mirabegron may also be an alternative agent and may be effective in patients with neurogenic bladders. To date, there is almost no experience with this drug [649], therefore no recommendation can be made.

Alpha-adrenergic antagonists may facilitate emptying in children with neurogenic bladder [650]. Doxazosin with an initial dose of 0.5 to 1.0 mg or tamsulosin hydrochloride in a medium (0.0002-0.0004 mg/kg/day) or high dose (0.0004-0,0008 mg/kg/day) has been given to children with neurogenic bladders [650-652]. It was well tolerated but not effective at least in one study [651].

Botulinum toxin A injections: In neurogenic bladders that are refractory to anticholinergics, the off-label use of suburothelial or intramuscular injection of onabotulinum toxin A into the detrusor muscle is a treatment option [653,654]. In children, continence could be achieved in 32-100% of patients, a decrease in maximum detrusor pressure of 32% to 54%, an increase of maximum cystometric capacity from 27% to 162%, and an improvement in bladder compliance of 28%-176% [653]. Onabotulinum toxin A seems to be more effective in bladders with obvious detrusor muscle over-activity, whereas non-compliant bladders without obvious contractions are unlikely to respond [655,656]. Also, the injections into the trigone seems to be save in regard of reflux and upper tract damage; if it has some benefit is not further investigated [657].

The most commonly used dose of onabotulinum toxin A is 10 to 12 U/kg with a maximum dose between 200 U and 360 U [653]. However, in one study, 5 U/kg were used with comparable results [658]. To date, no randomised dose titration study has been published in children. The optimal dose in children as well as the time point when to inject which child is still unclear. Onabotolinum toxin A can be effective between three to twelve (0-25) months and repeated injections are effective up to ten years in one study [654,659,660].

Urethral sphincter onabotulinum toxin A injection has been shown to be effective in decreasing urethral resistance and improve voiding. The evidence is still too low to recommend its routine use in decreasing outlet resistance, but it could be considered as an alternative in refractory cases [661,662].

Neuromodulation

Intravesical electrical stimulation of the bladder [663-665], sacral nerve stimulation [666,667] and transcutaneous neuromodulation [668] are still experimental and cannot be recommended outside of clinical trials. The same is true for the intradural somatic-to-autonomic nerve anastomosis [669,670].

Urethral Dilatation

The aim is to lower the pop-off pressure by lowering the detrusor leak-point pressure by dilatation of the external sphincter under general anaesthesia up to 36 Charr. Some studies showed, that especially in females, the procedure is safe and in selected patients, effective [671-673].

Vesicostomy

Vesicostomy - preferably a Blocksom stoma [674] - is an option to reduce bladder pressure in children/newborns, if the caregivers are incompliant with IC and/or IC through the urethra is extremely difficult or impossible [675]. Especially in the young infant with severe upper tract dilatation or infections, a vesicostomy should be considered. Drawbacks are the difficulty fitting and maintaining a collecting appliance in older patients. A cystostomy button may be an alternative, with a complication rate (mostly UTI) of up to 34% within a mean follow-up of 37 months [676].

3.12.4.3.Management of faecal incontinence

Children with neurogenic bladder usually have also a neurogenic bowel function. Faecal incontinence may have an even greater impact on QoL, as the odour can be a reason for social isolation. The aim of each treatment is to obtain a smooth, regular bowel emptying and to achieve continence and impendence. The regime should be tailored to the patient’s need, which may change over time. Beside a diet with small portioned fibre food and adequate fluid intake to keep a good fluid balance [627], follow-up options should be offered to the patients and caregivers.

In the beginning, faecal incontinence is managed most commonly with mild laxatives, such as mineral oil, combined with enemas to facilitate removal of bowel contents. To enable the child to defecate once a day at a given time, rectal suppositories as well as digital stimulation by parents or caregivers can be used. Today, transanal irrigation is one of the most important treatments for patients with neurogenic bowel incontinence. Regular irrigations significantly reduce the risk for faecal incontinence and may have a positive effect on the sphincter tonus as well as the rectal volume [677]. The risk of irrigation induced perforation of the bowel is estimated as one per 50,000 [678]. During childhood, most children depend on the help of the caregivers. Later in some patients, transanal irrigation becomes difficult or impossible due to anatomic or social circumstances. In these patients antegrade irrigation using a MACE-stoma (Malone Antegrade Continence Enema) is an option, which can also be placed in the left abdomen [679,680]. In a long-term study of 105 patients, 69% had successful bowel management. They were started on normal saline, but were switched to GoLYTELY (PEG-3350 and electrolyte solution). Additives (biscodyl, glycerin etc.) were needed in 34% of patients. Stomal complications occurred in 63% (infection, leakage, and stenosis) of patients, 33% required surgical revision and 6% eventually required diverting ostomies [681]. In addition, patients need to be informed, that the antegrade irrigation is also time consuming taking at least 20-60 minutes..

3.12.4.4.Urinary tract infection

Urinary tract infections are common in children with neurogenic bladders. However, there is no consensus in most European centres, for prevention, diagnosing and treating UTIs in children with neurogenic bladders performing CIC [682]. Although bacteriuria is seen in more than half of children on CIC, patients who are asymptomatic do not need treatment [683,684]. Continuous antibiotic prophylaxis (CAP) creates more bacterial resistance as demonstrated by a randomised study. Those that stopped the prophylaxis had reduced bacterial resistance, however, 38 out of 88 started antibiotic prophylaxis again due to recurrent UTIs or the caregivers request [685]. A cohort study with 20 patients confirmed these findings. Continuous antibiotic prophylaxix was not protective against the development of symptomatic UTIs and new renal scarring, but increased the risk of bacterial resistance [686]. A randomised study in 20 children showed that cranberry capsules significantly reduced the UTI-rate as well as the rate of bacteriuria [687]. If VUR is present, prophylactic antibiotics should be started when patients experience recurrent UTIs [688,689].

3.12.4.4.1.Urinary tract infection and clean intermittent catherisation

The incidence of asymptomatic bacteriuria ranges between 42%-76% [619,627,690]. A cross-over study in 40 children with neurogenic bladder demonstrated, that the reuse of CIC-catheters for up to three weeks compared to one week increased the prevalence of bacteriuria from 34% to 74% (it was 60% at the start of the study). During the study-period of eighteen weeks, none of the patients developed a febrile UTI [691]. There is no medical benefit in performing CAP in children with neurogenic bladder, who perform CIC [627]. In those with recurrent UTI, intravesical instillation of gentamycin may be an option [692,693].

Reflux

Secondary reflux in patients with neurogenic bladder increases the risk for pyelonephritis. The treatment is primary related to bladder function including anticholinergic therapy, CIC and may be later augmentation [694]. Those with early and post-therapy persistent reflux during videourodynamic studies at low pressure have a higher risk of pyelonephritis [695]. Patients with a high-grade reflux before augmentation have a higher risk of persistent symptomatic reflux after the enterocystoplasty [696]. Therefore simultaneous ureteral re-implantation in high-grade symptomatic reflux especially in those with low-pressure high-grade reflux should be discussed with the patient/caregivers. Endoscopic treatment has a failure rate of up to 75% after a median follow-up of 4.5 years [697] which is in contrast to the open techniques with a higher success rate, but may have an increased risk of inducing obstruction [698].

3.12.4.5.Sexuality

Sexuality, while not an issue in childhood, becomes progressively more important as the patient gets older. This issue has historically been overlooked in individuals with myelodysplasia. However, patients with myelodysplasia do have sexual encounters [699]. The prevalence of precocious puberty is higher in girls with meningomyelocele [700]. Studies indicate that at least 15-20% of males are capable of fathering children and 70% of females can conceive and carry a pregnancy to term. It is therefore important to counsel patients about sexual development in early adolescence.

Women seem to be more sexually active than men in some studies from the USA and the Netherlands [699,701]; in an Italian study men were more active [701]. The level of the lesion was the main predictor to be sexually active [702,703]. Erectile function can be improved by sildenafil in up to 80% of the male patients [704,705]. Neurosurgical anastomosis between the inguinal nerve and the dorsal penile nerve in patients with a lesion below L3 and disturbed sensation is still to be considered as an experimental treatment [701,706]. Only 17% to one third of the patients talk to their doctors about sexuality, 25–68% were informed by their doctors about reproductive function [699]. Therefore, early discussion about sexuality in the adolescent is recommended and should be promoted by the paediatric urologist taking care of these patients.

3.12.4.6.Bladder augmentation

In patients where conservative treatment including onabotulinum toxin A (for indication see 3.12.4.3) fails to keep a low-pressure reservoir with a good capacity and compliance, bladder augmentation should be offered. For augmentation, ileal and colonic segments can be used [707]. Gastric segments are rarely used due to its associated complications like the haematuria-dysuria syndrome as well as secondary malignancies, which arise earlier than with other intestinal segments [708-711]. Enterocystoplasty increases bladder capacity, reduces storage pressure and can improve UUT drainage [712]. A good socially acceptable continence rate can be achieved with or without additional bladder outlet procedures [713]. In those, who are not able to perform CIC through the urethra, a continent cutaneous channel should be offered. Surgical complications and revision rate in this group of patients is high. The 30-day all over event rate in the American College of Surgeons’ National Surgical Quality Database is approximately 30% (23-33%) with a re-operation rate in this short time period of 13% [714,715]. In these patients with long-life expectancy the complication rate clearly increases with the follow-up period [714-717]. The ten-year cumulative complication incidence from the Paediatric Health Information System showed a rate of bladder rupture in up to 6.4%, small bowel obstruction in up to 10.3%, bladder stones in 36%, pyelonephritis in more than a third of the patients and a re-augmentation rate of up to 13% [718]. Bladder perforation, as one of the worst complications, occurs in 6-13% [719]. The rate of VP-shunt infections after gastrointestinal and urological procedures ranges between 0-22%. In a recent study, bowel preparation seems not to have a significant influence on the infection rate (10.5% vs. 8.3%) [720]. Not only surgical complications must be considered; also metabolic complications and consequences after incorporating bowel segments have to be taken into account, such as imbalance of the acid base balance, decrease in vitamin B12 levels and loss of bone density. Stool frequency can increase as well as diarrhoea after exclusion of bowel segments [721] and last, but not least, these patients have a lifelong increased risk to develop secondary malignancies [722,723]. Therefore, a lifelong follow-up of these patients is required including physical examination, US, blood gas analysis, (pH and base excess), renal function and vitamin B12 if Ileum is used. Endoscopic evaluation starting ten years after augmentation is not cost-effective [724,725], but may prevent some advanced cancer. Woodhouse et al. do not recommend cystoscopy within the first fifteen years after surgery [726]. The real value of annual cystoscopic evaluation has not been proven by any study. Urodynamic studies after bladder augmentation are only indicated, if upper tract dilatation and/or incontinence after the operation has not improved [727].

Adverse effects of intestinal cystoplasties can be avoided by the use of ureterocystoplasty. The combination of a small contracted bladder, associated with a severe dilation of the ureter of a non-functioning kidney is quite rare. The technique was first described in 1973 by Eckstein [728]; the success rate depends on patient selection and the re-augmentation rate can reach 73% [729,730].

Auto-augmentation with partial detrusorectomy or detrusormyotomy creating a diverticulum avoids metabolic complications with the use of intestinal segments. The reports are conflicting, therefore, it may be used in selected cases [731-734]. For a successful outcome, a pre-operative bladder capacity of 75-80% of the expected volume seems necessary [735,736]. Seromuscular cystoplasty has also not proven to be as successful as standard augmentation with intestine [737]. Tissue engineering, even if successful in vitro and some animal models, does not reach the results by using intestinal segments with a higher complication rate [738,739]. Therefore, these alternatives for bladder augmentation should be considered as experimental and should be used only in controlled trials.

3.12.4.7.Bladder outlet procedures

No available medical treatment has been validated to increase bladder outlet resistance. Alpha-adrenergic receptor stimulation of the bladder neck has not been effective [740-745]. Using fascial slings with autologous fascial strip or artificial material a continence rate between 40-100% can be achieved. In most cases this is achieved in combination with bladder augmentation [746, 747]. Catheterising through a reconstructed bladder neck or a urethra compressed by a sling may not be easy; many surgeons prefer to combine this approach with a catheterisable channel [565]. In contrast to the autologous slings, artificial slings in girls with CIC through the urethra have a high complication rate [748]. In males, it may be an option [749], however as long as long-term results are missing, this method has to be classified as experimental and should only be carried out in studies. Artificial urinary sphincters were introduced by Scott in 1973 [750]. The continence rates in the literature in selected patients can be up to 85% [751-754]. Post-pubertal patients, who can void voluntary are good candidates, if they are manually dexterous. In very selected patients, CIC through the sphincter in an augmented bladder is possible [755]. The erosion rate can be up to 29% and the revision rate up to 100% depending on the follow-up time [756].

Patients, who underwent a bladder neck procedure only, have a chance of > 30% for an augmentation later on; half of them developed new upper tract damage in that time [757, 758]. In patients with a good bladder capacity and bladder compliance without an indication for bladder augmentation, there is a risk of post-operative changes of the bladder function. Therefore, close follow-up of these patients with UD is required to avoid upper tract damage and chronic renal failure.

Bladder neck reconstruction is used mostly in exstrophy patients with acceptable results. However, in children with a neurogenic bladder the results are less favourable [759]. In most patients, the creation of a continent catheterisable stoma is necessary due to difficulties in performing the CIC via the urethra. In one series, 10% to a third still performed CIC via the urethra with a re-operation rates between 67% and 79% after a median follow-up between seven and ten years [760]. In patients who are still incontinent after a bladder outlet procedure, bladder neck closure with a continent catheterisable stoma is an option. The combination of a sling procedure together with a urethral lengthening procedure may improve the continence rates [761].

Bulking agents have a low success rate (10-40%), which is in most cases only temporary [762-764]. However, it does not adversely affect the outcome of further definite surgical procedures [762].

Bladder neck closure is often seen as the last resort to gain urinary continence in those patients with persistent urinary incontinence through the urethra. In girls, the transection is done between bladder neck and urethra and in boys above the prostate with preservation of the neurovascular bundle. It is an effective method to achieve continence together with a catheterisable cutaneous channel +/- augmentation as a primary or secondary procedure [765, 766]. A complication rate of up to a third and a vesicourethral/vesicovaginal fistula in up to 15% should be considered [767], together with a higher risk for bladder stones, bladder perforation and deterioration of the upper tract function, if the patient is not compliant with CIC and bladder irrigations [767, 768].

3.12.4.8.Catheterisable cutaneous channel.

In most patients with a neurogenic bladder IC is required. If this is not possible, or very time and/or resources consuming via the urethra, a continent cutaneous catheterisable channel should be offered as well as in those with bladder outlet procedures. It is especially beneficial to wheelchair-bound patients who often have difficulty with urethral catheterisation or are dependent on others to catheterise the bladder. In long-term studies the revision rate due to stenosis or incontinence can be as high as 50-60% depending on the type of channel [769,770].

The stoma can be placed at the umbilicus or in the lower right abdominal wall using a VQZ plasty [771]. It should be carefully evaluated pre-operatively: it is extremely important that the patient can reach the stoma easily. Sometimes it has to be placed in the upper abdominal wall due to sever scoliosis mostly associated with obesity.

3.12.4.9.Continent and incontinent cutaneous urinary diversion

Incontinent urinary diversion should be considered in patients who are not willing or able to perform a CIC and who need urinary diversion because of upper tract deterioration or gain urinary continence due to social reasons. In children and adolescents, the colonic conduit has shown to have less complications compared to the ileal conduit [772-775]. Total bladder replacement is extremely rare in children and adolescents, but may be necessary in some adults due to secondary malignancies or complications with urinary diversions. Any type of major bladder and bladder outlet construction should be performed in centres with sufficient experience in the surgical technique, and with experienced healthcare personnel to carry out post-operative follow-up [713,776,777].

Algorithms can be used for management of these patients (Figures 7 and 8).

3.12.5.Follow-up

Neurogenic bladder patients require lifelong follow-up including not only urological aspects but also neurological and orthopaedic aspects. Regular investigation of upper and lower urinary tract is mandatory. In patients with changes of the function of the upper and/or lower urinary tract, a complete neurological re-investigation should be recommended including a total spine MRI to exclude a secondary tethered cord or worsening of the hydrocephalus. In addition, if some neurological changes are observed a complete investigation of the urinary tract should be undertaken.

In those patients with urinary tract reconstruction using bowel segments, regulatory investigations concerning renal function, acid base balance and vitamin B12 status are mandatory to avoid metabolic complications. There is an increased risk for secondary malignancies in patients with a neurogenic bladder either with or without enteric bladder augmentations [723,778-785]. Therefore, patients need to be informed of this risk and possible signs like haematuria. Although there are poor data on follow-up schemes to discover secondary malignancies, after a reasonable follow-up time (e.g. ten to fifteen years), an annual cystoscopy can be considered.

3.12.6.Self-organisation of patients

As patients’ self-organisations can support the parents, caregivers and the patients in all aspects of their daily life, patients should be encouraged to join these organisations.

Figure 7a: Management of children with myelodysplasia with a neurogenic bladder Flowchart - First year of life

RBUS = Renal bladder ultrasound; UTI = urinary tract infection; VUD = videourodynamic; VCUG = voiding cystourethrography; CMG = cystometrogram; DMSA = dimercaptosuccinic acid; AB = antibiotics.

Figure 7b: Management of children with myelodysplasia with a neurogenic bladder Flowchart - 18 months - 4 years of age

RBUS = Renal bladder ultrasound; UTI = urinary tract infection; VUD = videourodynamic;

VCUG = voiding cystourethrography; CMG = cystometrogram; DMSA = dimercaptosuccinic acid; AB = antibiotics

Figure 7c: Management of children with myelodysplasia with a neurogenic bladder Flowchart - 5 years to adulthood

RBUS = Renal bladder ultrasound; UTI = urinary tract infection; VUD = videourodynamic; VCUG = voiding cystourethrography; CMG = cystometrogram; DMSA = dimercaptosuccinic acid.

Figure 8: Algorithm for the management of children with myelodysplasia with a neurogenic bladder

CAP = continuous antibiotic prophylaxis; CIC = clean intermittent catheterisation; US = ultrasound; VCUG = voiding cystourethrography; VUD = videourodynamic; VUR = vesicoureteric reflux.

3.12.7.Summary of evidence and recommendations for the management of neurogenic bladder

Summary of evidence	LE
Neurogenic detrusor-sphincter dysfunction (NDSD) may result in different forms of LUTD and ultimately result in incontinence, UTIs, VUR, and renal scarring.	2a
In children, the most common cause of NDSD is myelodysplasia (a group of developmental anomalies that result from defects in neural tube closure).	2
Bladder sphincter dysfunction correlates poorly with the type and level of the spinal cord lesion. Therefore, urodynamic and functional classifications are more practical in defining the extent of the pathology and in guiding treatment planning.	2a
Children with neurogenic bladder can have disturbances of bowel function as well as urinary function which require monitoring and, if needed, management.	2a
The main goals of treatment are prevention of urinary tract deterioration and achievement of continence at an appropriate age.	2a
Injection of botulinum toxin into the detrusor muscle in children who are refractory to anticholinergics, has been shown to have beneficial effects on clinical and urodynamic variables.	2a

Recommendations	LE	Strength rating
Urodynamic studies should be performed in every patient with spina bifida as well as in every child with high suspicion of a neurogenic bladder to estimate the risk for the upper urinary tract and to evaluate the function of the detrusor and the sphincter.	2	Strong
In all newborns, intermittent catheterisation (IC) should be started soon after birth. In those with a clear underactive sphincter and no overactivity starting IC may be delayed. If IC is delayed, closely monitor babies for urinary tract infections, upper tract changes (US) and the lower tract (UD).	3	Strong
Start early anticholinergic medication in the newborns with suspicion of an overactive detrusor.	2	Strong
The use of suburothelial or intradetrusoral injection of onabotulinum toxin A is an alternative and a less invasive option in children who are refractory to anticholinergics in contrast to bladder augmentation.	2	Strong
Treatment of faecal incontinence is important to gain continence and independence. Treatment should be started with mild laxatives, rectal suppositories as well as digital stimulation. If not sufficient transanal irrigation is recommended, if not practicable or feasible, a Malone antegrade colonic enema (MACE)/Antegrade continence enema (ACE) stoma should be discussed.	3	Strong
Ileal or colonic bladder augmentation is recommended in patients with therapy resistant overactivity of the detrusor, small capacity and poor compliance, which may cause upper tract damage and incontinence. The risk of surgical and non-surgical complications and consequences outweigh the risk of permanent damage of the upper urinary tract +/- incontinence due to the detrusor.	2	Strong
In patients with a neurogenic bladder and a weak sphincter, a bladder outlet procedure should be offered. It should be done in most patients together with a bladder augmentation.	3	Weak
Creation of a continent cutaneous catheterisable channel should be offered to patients who have difficulties in performing an IC through the urethra.	3	Weak