Long-term Outcomes and Adolescent Management of Epispadias, Exstrophy and Prune Belly Syndrome

Dan Wood and Christopher Woodhouse
University College London Hospitals

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Introduction

Babies who are born with the major anomalies of the genitourinary tract such as the exstrophy/epispadias complex and prune belly syndrome, will grow up with physical and psychological problems that have, perhaps, no equivalent in adult life. It is vital that comprehensive long-term care and follow up are arranged.

This need has been reinforced recently by the experience of a patient operated on elsewhere as a child who presented with severe metabolic derangement at the age of 60. Although she had had four children, she had never had any monitoring of the well known consequences of uretero-sigmoidostomy.

We have, at times, questioned whether these patients could be followed up at local hospitals and seen by us when problems arise. However, many have complex concerns or problems that require the support and help of a urologist familiar with their unusual conditions, their treatment and its consequences.

More important than this is the support of a multidisciplinary team which must include a nephrologist, radiologist and specialist nurses, amongst many others, and is the key to providing appropriate care. When one is treating patients affected by rare anomalies (1:30,000 live births for exstrophy or 1:100,000 for isolated epispadias) familiarity and expertise can only come from a central concentration of patients. This allows an experience to develop of both routine follow-up and the unexpected problems that arise in adult life – the net result being excellent patient care.

In this section the objective is to describe the current status of voiding, kidney and sexual function, and the long-term consequences of reconstruction.

Bladder Exstrophy and Epispadias

History  In the early part of the 20th century, bladder exstrophy resulted in 50% mortality by the age of 10 and 67 % by the age of 20. By the time of Megali’s report in 1973, this had fallen to below 5% (although 39 patients in his series were lost to follow-up so the potential rate may be as high as 31%) [1]. By 1983, the mortality directly attributable to exstrophy was 4 % [2]. This trend reflects a dramatic improvement in paediatric care in the 20th century. However, it is not enough just for patients to survive. Not surprisingly, they wish to be normal [10] and this depends on continuous improvement in reconstructive techniques. Adolescent and adult physicians have a responsibility to interact with paediatric carers – review of the patients that we see is the key to long-term data and outcome information, which itself informs future paediatric management.

It is very encouraging to see a change in expectations for patients with exstrophy (and perhaps other conditions). There are arguably two reasons for this:

1.  An increased understanding of anatomy has led to improved treatment and outcomes for major problems such as continence. Thus, huge progress in treatments has created a new threshold of expectation.

2.  The media and public perception of how we ‘should be’ has driven a higher population standard for our outward appearance of which the exstrophy population is well aware. Adolescents do not like to have scars. On the other hand, they do wish to have a belly button (which is absent with all standard bladder reconstructions) [10].

The psychological concerns of the exstrophy patient have been a source of interest in childhood. Data suggest an increasing vulnerability and anxiety level. Not surprisingly, as issues such as continence are resolved and adolescence looms, sexual anxiety features more prominently [3]. Other authors have found a higher than expected rate of suicidal ideation in male exstrophy patients – a different picture to the general population [4]. Despite this, patients express a determination to live a normal life equivalent to their peers and they develop a range of coping strategies in order to help them do so, such as trying to squeeze urine out in urinals to make their stream sound ‘normal’ to others. In addition, there have been a number of disclosures about bullying and of both positive and negative experiences in developing relationships [5]. Data from France has suggested that outcomes in females with exstrophy, however, are similar to the normal population [6].

The other factors that become notable with an improvement in initial treatment and thus long-term overall survival are an emergence of new disease processes. A recent paper from Johns Hopkins described a male exstrophy patient who developed prostate cancer. He safely underwent radical retropubic prostatectomy. Such experience emphasizes the need for shared care when adult conditions develop (Figure 1) [7]. Further examples of the importance of this arise in middle age with the increased risk of malignancy associated with exstrophy [8] or potentially associated with reconstructive surgery patients may have had [9]. Other problems such as metabolic disturbance or stones become more significant. In essence, when managing a group of patients such as these we must constantly adapt to shifting and expanding needs – where one problem is solved, new challenges will certainly follow.

It has been documented that there is a frequent association of classic bladder exstrophy with inguinal herniae [10]. They are frequently repaired at the time of infant reconstruction; however, occasionally inguinal hernia can be seen in adult exstrophy patients. The author has personal experience of one femoral hernia in bladder exstrophy.

Technical Developments  It is important to remember that bladder exstrophy is really a failure of pelvic development and thus bladder closure does not ‘fix’ the problem. It leaves the issue of the pelvic floor and continence unresolved.

The reconstruction of an infant with bladder is a subject of some debate in itself. Continence rates have steadily improved with refinement of surgical techniques. Most recently, the Kelly technique of full soft tissue mobilization is said to have continence rates in the region of 70 % at 10 years of age. Most patients will arrive in adult life continent of urine. The proportion that can void to completion is less clear. The remainder will be dry with self-catheterization and some will have had intestinal augmentations.

The concern from the Australian group has related to penile appearance [11]. The Kelly Technique was originally developed by Justin Kelly, however, it has been used most extensively at London’s Great Ormond Street Hospital, with data suggesting continence rates of 75% at 10 years of age and results that improve with age and data suggesting an improvement of penile appearance (Cuckow – personal communication). This compares favourably with other centres using different techniques (Table 1). Smaller series suggest that a variety and combination of approaches are needed to achieve credible outcomes [12].  The long-term outcome is dramatically worsened if the initial closure fails, with only an 18% continence rate in those who achieve closure at a subsequent attempt. Many may become dry (90%), but only following continent urinary diversion and the need for catheterization [13].

Table 1. Comparison of outcomes relating to type of exstrophy reconstruction.

Type of Repair	Continence Rate (%)
Kelly (Cuckow personal communication)	70
Complete Primary Repair [14]	37
Young Dees Leadbetter [15]	56
Failure of initial closure [13]	18

Voiding Function In the modern age of caring for bladder exstrophy patients, it becomes vital to consider both continence and voiding function. It is crude to say that purely because somebody is dry they are necessarily continent. The literature surrounding any form of reconstruction needs to be explicit about its definition of continence. Many subscribe to the view that this should include both the ability to voluntarily hold urine (without leakage) and void spontaneously. This is not to say that alternatives, in the form of urinary diversion are not acceptable – they are vital in some cases – but our results should reflect a true picture, not an enhanced view of surgical prowess.

Long-term data relating to ureterosigmoidostomy suggest that with a mean follow-up of 50 years, 52% still had their diversion in place and 60% had normal or mildly impaired renal function; however, 42 % of patients were not included in final follow-up [16].

Renal Function  Bladder exstrophy is largely regarded as an isolated disorder – most importantly, without a neurological or primary nephrological component. Data from the 1980s suggest that reconstruction does not have any significant effect on long-term renal function [17]. In fact, the literature makes very little comment about the renal function in these patients. The three most obvious surgical causes for renal damage are bladder neck reconstruction, reimplantation of ureters and, potentially, stone formation following augmentation or substitution cystoplasty. In our own group it is rare to find renal impairment and none that is attributable to primary disease. However, simply because of the degree of reconstruction, these patients are regularly monitored. If deterioration in renal function is detected, there should be a vigorous search for a ‘surgical’ cause.

One group for whom this can be a problem are those female patients who have undergone major urinary tract reconstruction and subsequently become pregnant. Renal function and serial ultrasonography of the upper tracts is our routine practice as patients can develop a significant hydronephrosis requiring percutaneous drainage – in a series of our patients we found an incidence of 15% for this complication (Figure 2) [18].

Sexual and Reproductive Function  Regardless of the outcome of bladder reconstruction, patients’ goals have shifted from being dry to other aspects related to quality of life. It is well established that deficient corporeal size and their attachment to the separated pubis leads to a shorter penis often with a greater girth [19, 20].

In female patients questions will arise about their ability to have sexual intercourse and fertility. Bladder exstrophy is not usually associated with abnormalities of the uterus or cervix, although rare exceptions do occur (Figure 3). The introitus is narrowed by a very prominent posterior fourchette which will usually prevent sexual intercourse. An introitoplasty is necessary in 34% of girls and a more formal vaginoplasty in a further 23% [21]. Anatomically, the cervix is inserted into the anterior wall of the vagina which tends to run parallel to the pelvic floor. In counseling patients, it should be emphasized that the cervix is often closer to their introitus than in normal women and may be a cause of dyspareunia. As fertility is normal, they must use contraception to avoid pregnancy [22].

Shared care of the pregnancy is important with a urologist involved from an early stage. In our own cohort those patients with a functioning bladder or artificial urinary sphincter in place have had a cesarean section. This should be set up to perform electively with a urologist available, if not present, to help with the initial dissection.

Female patients with bladder exstrophy are prone to uterine prolapse. Indications for surgery are prolapse when the woman has completed her family, or in a younger patient with intractable symptoms. The operation performed is a gortex wrap sacrocolpopexy [22].

Concerns about the hereditary patterns are understandable amongst exstrophy patients. The risk of having an affected child in the normal population is cited as 1:30,000 [23]. Historically, the risk of an affected adult having an affected child has been given as 1:70 [24]. More recent data suggest that it may be far less than that (<1 %). There is no identifiable gene locus – advanced parental age may be a risk and a female foetus may be protective [25].

Fertility in male patients is often assumed to be impaired – in one study looking at the long-term follow-up of 29 exstrophy/epispadias patients from Philadelphia, 63% of patients had normal semen analysis [26], and other similar studies appear to support this, but there is a much smaller group of patients in whom paternity has been established [27]. More recent data suggests 94% of men are able to ejaculate normally but that far fewer will have normal semen parameters [28]. For those who do not experience natural conception, testicular architecture and function is usually normal and assisted fertility techniques may be successful [29]. Other studies have suggested that fertility may be in more doubt [30]. In a review of a series including 134 male patients, it was noted that most men were able to have intercourse (some requiring prior correction of penile deformities) and 75% were able to ejaculate although volume was reduced [31].

The mechanism for normal ejaculation is necessarily disrupted, and this may be through:

• Direct damage to vasa or seminal vesicles in the course of multiple bladder neck operations
• No encircling prostate
• Reduced function of bulbospongiosus muscle [32]

Testes may be initially undescended, requiring orchidopexy [33, 34].

In the Philadelphia series all men had normal erections, 2/3 were straight, 1/3 had some curvature but all were capable of intercourse [26]. For those patients with concerns and who need evaluation, an artificial erection is our method of assessment. It is performed under general anaesthetic with large butterfly needles (one for each corpora as there is no cross circulation) (Figure 4).

Consequences of Reconstruction  Many patients with bladder exstrophy will have had urinary diversion. The associations with metabolic disturbance and stones are very well understood (Figure 5) [35,36].  Fears that enterocystoplasties would result in metabolic disturbance in children that would affect bone deposition and growth appear to be unfounded [37,38].

There is accumulating evidence that yearly endoscopy for the majority of patients with cystoplasties is unnecessary. The incidence of malignancy remains low and those detected were found on the basis of symptoms rather than surveillance [9,39]. There are data on a historical group of adult exstrophy patients that suggests an unexplained but significantly increased risk of malignancy in the exstrophy population – this does not appear to relate to previous treatment [8]. It remains a subject of debate as to the timing of cystoscopy in so-called higher risk groups. Logically, the fact that screening has failed to pick up problems suggests there is little justification for routine, regular endoscopy but a change in symptoms should be assessed completely, including cystoscopy and radiology.

Prune Belly Syndrome

Urological manifestations of prune belly syndrome are characterized by anomalies including an enlarged bladder, hydroureteronephrosis and renal dysplasia – the latter being the most important arbiter of survival. An absence of abdominal wall musculature creates the wrinkled or ‘prune’-like appearance of the abdominal skin and bilateral cryptorchidism is characteristic (Figure 6). The reported incidence ranges from 1:35,000 to 1:50,000 live births. All, by definition, are male, but a similar abnormality in the urinary tract is occasionally seen in girls. Genetic links have been difficult to establish on the basis of factors such as discordance with twins. Possible associations have been made with abnormalities on chromosomes 17 [40], 18 [41] and 21 [42] as well as other suggested patterns. Eleven cases of familial prune belly syndrome have been identified and a sex-linked autosomal pattern is suggested in these cases [43].

Renal Function  The most common scenario is that of a non-obstructed hydroureteronephrosis – there is no correlation between the degree of dilatation and the severity of renal failure. To that end, many patients will need little or no surgical intervention – with optimal medical management [44]. It must be ensured that there is no obstruction (performing a urethrotomy where necessary) and good bladder emptying. A policy of minimal surgical intervention has yielded good outcomes in 60% of patients [45]. Deterioration appears to occur once the urinary tract becomes infected – the risks of which increase with intervention.

Ureteric and Bladder Function  The ureters are grossly dilated with decreasing peristaltic function from proximal to distal [46]. The prune belly ureter also appears to have a greater collagen to smooth muscle ratio – with 62% collagen if they are refluxing [47]. Upper tract surgery will, at best, only stabilize a deteriorating situation and seldom improves it over and above that which can be achieved with a urethrotomy. For those with symptomatic residuals, self-catheterization may be needed, but the outcome is poor. The urinary tract quickly becomes chronically infected. In rare situations we have used tailored ureteric reduction and partial cystectomy as means of tackling urinary tract infections by reducing the dead space residual. This is an operation of last resort and an attempt to salvage quality of life for a desperate patient. For those with favourable urinary tracts, the outcome in later life is good [48]

Sexual Function  In a study of 41 boys with prune belly syndrome, following orchidopexy, long-term review showed that a majority of patients were able to undergo normal puberty and have normal sexual function without androgen supplementation [49]. Prune belly syndrome is acknowledged as having a strong association with infertility. There are anecdotal reports of natural conception but this would be a very rare exception rather than a rule [50].

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