Journal of Pediatric Surgery xxx (2014) xxx–xxx
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Management of bladder dysfunction in Wolfram syndrome with Mitrofanoff appendicovesicostomy: long-term follow-up☆ Sarah Mozafarpour, Abdol-Mohammad Kajbafzadeh ⁎, Ali Mojtahed, Mohammad Mojtahed, Hossein Mahboubi, Keivan Shalileh Pediatric Urology Research Center, Section of Tissue Engineering and Stem Cells Therapy, Children’s, Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran (IRI)
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Article history: Received 10 July 2014 Received in revised form 23 August 2014 Accepted 15 September 2014 Available online xxxx Key words: Wolfram (DIDMOAD) syndrome Mitrofanoff principle Diabetes mellitus Diabetes insipidus Bladder dysfunction
a b s t r a c t Purpose: To present the long-term outcomes of appendicovesicostomy using the Mitrofanoff principle for endstage Wolfram bladder dysfunction as an alternative to clean intermittent self-catheterization (CIC) per urethra mainly following blindness. Methods: Twelve Wolfram patients presenting with bilateral hydroureteronephrosis and advanced bladder dysfunction were included in this study. All patients were managed initially by CIC per urethra. All of these patients became blind during follow-up and were unable to perform urethral CIC independently. Out of these patients, six patients agreed to proceed to appendicovesicostomy. Appendicovesicostomy urinary diversion using the Mitrofanoff principle was performed in these six blind patients. The rest of the patients stopped CIC or performed CIC irregularly. Results: Severe hydroureteronephrosis and large bladders were found in all patients prior to intervention. All patients were able to conduct CIC independently through the stoma and maintained overnight bladder free drainage. In all patients with urinary diversion and CIC, the hydroureteronephrosis was reduced and renal function returned to normal. However, the non-intervention group ended with different degrees of progressive renal failure with three mortalities during the follow-up. Conclusions: We suggest appendicovesicostomy as a safe and lifesaving procedure for long-term management of bladder dysfunction in Wolfram syndrome particularly after progression to blindness © 2014 Elsevier Inc. All rights reserved.
Wolfram syndrome, also known as DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) is an autosomal-recessive dysmorphogenesis disorder with an implicated gene (WFS1) mutation located on chromosome 4p16 [1–4]. It is an uncommon condition with a prevalence ranging from 1 in 770,000 in the United Kingdom to 1 in 68,000 in Lebanon, and appears to be more common in countries with high prevalence of parental consanguinity [5,6]. Early onset non-autoimmune insulin dependent diabetes mellitus and progressive optic atrophy are the earliest presenting signs and essential features of Wolfram syndrome; however, due to genetic heterogeneity and later onset of some other manifestations including urological, neurological, psychiatric, and endocrine abnormalities, Wolfram syndrome may be diagnosed from fetal life to middle age [6–11]. A common component of the syndrome is urinary tract abnormalities mostly presenting with upper urinary tract dilatation which varies from mild hydronephrosis to megaureter, megacystis and atonic large ☆ No conflict of interest exists in relation to the submitted manuscript and there was no source of extra-institutional commercial funding or funding received from National Institutes of Health (NIH), Welcome Trust, Howard Hughes Medical Institute (HHMI) and others. ⁎ Corresponding author at: No. 62, Dr. Qarib’s Street, Keshavarz Boulevard, Tehran, Iran (IRI), 1419433151. Tel./fax: +98 21 66565400. E-mail address:
[email protected] (A.-M. Kajbafzadeh).
bladder [12–14]. Nevertheless, low-capacity, high-pressure bladder with sphincter dyssynergia is also reported in the literature [15]. Urinary tract abnormalities may be present at the time of diagnosis but remain undetected unless initial urological work up is done [15]. Two main theories have been suggested as the basis of urinary tract dilatation in these patients; one theory involves selective neuropathy of bladder and ureters while the second theory emphasizes more on the high urine flow rate and inadequate periodic bladder emptying causing functional urinary obstruction [13]. However, presence of hydronephrosis without diabetes insipidus in some patients supports nerve degeneration as the primary underlying etiology [16]. Regardless of the specific mechanism responsible for urinary tract abnormality, improving urinary drainage helps resolve hydronephrosis, prevent deterioration of renal function and more importantly enhance the patients’ quality of life and survival [17]. The management of voiding dysfunction in patients with Wolfram syndrome is similar to that of other causes, although when a patient presents with a large bladder, conservative managements, such as clean intermittent catheterization (CIC), are unlikely to control the problem adequately. CIC is sufficient to empty the bladder each time catheterization is performed, but overnight bladder drainage is mandatory for evacuation of nocturnal urine overproduction. Self-catheterization through urethra is difficult for patients who progress to blindness. Most teenagers refuse the catheterization by
http://dx.doi.org/10.1016/j.jpedsurg.2014.09.058 0022-3468/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Mozafarpour S, et al, Management of bladder dysfunction in Wolfram syndrome with Mitrofanoff appendicovesicostomy: long-term follow-up, J Pediatr Surg (2014), http://dx.doi.org/10.1016/j.jpedsurg.2014.09.058
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S. Mozafarpour et al. / Journal of Pediatric Surgery xxx (2014) xxx–xxx
their parents and consequently stop performing CIC and progress to renal failure [12]. Appendicovesicostomy using the Mitrofanoff principle has been shown to be an effective option in creating a catheterizable unit in incontinent children needing long-term urinary replacement [18,19]. There is no report on the efficacy of Mitrofanoff procedure in the management of cystopathy in Wolfram patients. In this study, we present the long-term outcomes of this surgical procedure in our Wolfram patients who were non-compliant to urethral CIC. 1. Methods Over a period of 10 years, 27 patients with Wolfram syndrome received multidisciplinary care at Children’s Hospital Medical Center, Tehran, Iran. All patients received endocrinologic, neurologic, ophthalmologic, otologic and urologic care. From September 1996 to October 2005, 12 of these patients were managed at our pediatric urology canter for bladder dysfunction and advanced bilateral hydroureteronephrosis. Patients underwent urologic evaluation including urinalysis, urine culture, renal function tests (serum creatinine), urinary tract ultrasound, voiding cystouretherography (VCUG), magnetic resonance urography and urodynamic studies. All patients were managed initially with regular CIC per urethra. They were trained to perform CIC through face-to-face education. An accompanying teaching CD was delivered to the parents or caregivers. The patients needed CIC every 1–3 h (depending on urine output) and remained on overnight bladder free drainage by use of a catheter connected to a urine bag attached to the patient’s thigh. This was necessary due to high overnight output in spite of desmopressin administration. For patients who initially refused CIC and had elevated serum creatinine levels, a suprapubic or Foley urethral catheter was placed in situ for 3–4 days in order to reverse renal failure, and CIC was then initiated after proper patient education. The boys catheterized per urethra without difficulty, however, the girls had to use a mirror to find the urethral orifice. Of these 12 patients, 6 had severe lower urinary tract symptoms and recurrent urinary tract infection and became unable to perform CIC independently because of blindness. These 6 patients consisted of 5 females and 1 male aged 7–17 years at the time of diagnosis (Table 1), with an average 24-h urine output of 7 L (4500–9000 mL). These patients were from two families with consanguineous parents (4 affected siblings in one family and 2 in another with 2 other healthy children), which made it impractical for their parents to perform CIC very often for several children. Based on the patients’ condition, appendicovesicostomy was offered as an alternative to urethral CIC. The principle of Mitrofanoff procedure and possible complications were explained to the patients and parents and informed written consent was obtained. One surgeon performed all the surgeries. The surgical methods of Mitrofanoff appendicovesicostomy and the techniques for construction of the abdominal stoma (VQ stoma) have been described elsewhere [20]. Three patients with vesicoureteral reflux and history of recurrent febrile urinary tract infections (UTIs) despite
receiving prophylactic antibiotics underwent endoscopic treatment of reflux with bulking agent before the operation (technique described elsewhere [21]. All patients underwent monthly urinalysis, urine culture and renal function tests. In case of recurrent UTIs, urinary tract ultrasound and VCUG were performed every 3 months and every 6 months, respectively up to one year. This survey was performed in accordance with the Helsinki Declaration and was approved by ethics committee of Tehran University of Medical Sciences, Tehran, Iran. 2. Results The postoperative recovery was uneventful in all patients. The catheter remained in place for 2 weeks and CIC per conduit was initiated immediately following the removal of the catheter every 2 h and overnight bladder free drainage due to high urine output. The mean cystometric bladder capacity was 1540 mL (range 950–1750 mL) initially. The upper tract dilation decreased dramatically in all patients. Four patients had initial creatinine level of more than 5.5 mg/dL which was reduced to 1.4 mg/dL (two patients), 1.5 mg/dL (one patient) and 2.5 mg/dL (one patient) three weeks after the operation (Table 2). During long-term follow-up (3–7 years), CIC through the Mitrofanoff channel reduced the degree of hydronephrosis as well as the frequency of recurrent UTIs and stabilized the serum creatinine level. All patients were able to perform CIC personally without further help from their parents in spite of blindness and were satisfied with the procedure. They found the abdominal stoma by palpation and inserted the catheter through it. They were able to maintain overnight free drainage by fixing the urine bag to the thigh. No early or late stoma-related complications such as retraction, vascular compromise, peristomal skin irritation/infection, abscess, fistula or parastomal herniation were observed in the patients during follow-up visits (Fig. 1). Patients had multiple hospital admissions since the time of operation for blood glucose level control, but not for urological problems. However, gradual progression of grade III bilateral hydroureteronephrosis was seen in 2 patients resulting from irregular CIC due to severe depression. These patients received special psychiatric support, which led to resumption of regular CIC and cessation of the progression of the hydroureteronephrosis. Recently, one patient presented with asymptomatic bacteriuria and mucous accumulation inside the bladder detected by routine ultrasound. This patient was managed by cystoscopic irrigation and evacuation of mucous, and no bacteriuria was detected thereafter. None of the patients undergoing Mitrofanoff procedure needed dialysis or kidney transplant. Most of the patients who refused to undergo Mitrofanoff procedure stopped CIC (4/6), and the remaining two performed CIC occasionally. All of them progressed to renal failure. One of them refused blood access for hemodialysis, three of them died due to renal failure, and two of them are on hemodialysis (Table 3).
Table 1 Pre-operative urologic work up of patients undergoing appendicovesicostomy. Patient no.
Gender
Age at diagnosis (Years)
M/F 1 2 3 4 5 6
F F F F F M
11 10 17 16 7 12
Lower urinary tract findings
Urodynamic findings
Uroradiology
U/C
VCUG
Ultrasonography
DMSA
MRU
Cystometry
Uroflowmetry
NL NL Recurrent Ec/Eb Recurrent Ec/K/P Ec Ec
BVUR NL BVUR BVUR BVUR BVUR
BHUN, PVRV =1050 BHUN, PVRV =1550 BHUN, PVRV =1050 BHUN, PVRV =1050 BHUN, PVRV =650 BHUN, PVRV =650
No scar No Scar Lt upper and lower pole scars Bilateral upper pole scars No scars No scars
BHUN, HB BHUN, HB BHUN, HB BHUN, HB BHUN, HB BHUN, HB
ALB, BC =950 LB, BC =950 LB, BC =1920 LB, BC =1920 LB, BC =1750 LB, BC =1750
ABN, PVRV =320 ABN, PVRV =320 ABN, PVRV =1120 ABN, PVRV =1120 ABN, PVRV =7020 ABN, PVRV =7020
F: female, M: male, ABN: abnormal, ABN uroflowmetry: low amplitude, prolonged voiding with staccato/interrupted patterns. NL: normal, U/C: urine culture, VCUG: voiding cystouretherography, LB: large bladder (N115% Expected Bladder Capacity = [age (years) + 1] × 30 ml), ALB: atonic large bladder, BC: bladder capacity, mL, MRU: Magnetic resonance urography, BHUN: bilateral hydroureteronephrosis, BVUR: bilateral vesico-ureteral reflux, Eb: Enterobacter spp, Ec: E. coli, HB: huge bladder, K: Klebsiella, P: Proteus, HUN: hydroureteronephrosis, PVRV: post-voiding residual volume, mL.
Please cite this article as: Mozafarpour S, et al, Management of bladder dysfunction in Wolfram syndrome with Mitrofanoff appendicovesicostomy: long-term follow-up, J Pediatr Surg (2014), http://dx.doi.org/10.1016/j.jpedsurg.2014.09.058
S. Mozafarpour et al. / Journal of Pediatric Surgery xxx (2014) xxx–xxx Table 2 Pre-operative, early post-operative (first creatinine level after the surgery) and last visit average serum creatinine levels in patients undergoing Mitrofanoff appendicovesicostomy. Patient no.
1 2 3 4 5 6
Average serum creatinine level (mg/dl) Pre-op
After the surgery
Last visit
1 1.2 5.5 5.5 5.6 5.6
1 1.5 1.4 2.5 1.5 1.4
1.1 1.1 1.5–2.4 2–2.8 1 1
3. Discussion Wolfram syndrome is estimated to be diagnosed in approximately 1 out of 150 patients presenting with early-onset diabetes [22]. Despite the prevalence of urologic problems in Wolfram syndrome, this issue has not been adequately addressed in the literature. Recognition of this disorder is vital as its management is different from that of patients with classic type I diabetes mellitus with much higher mortality rate [17]. Complication of urinary tract dilatation and infection is one of the most common causes of mortality and morbidity in Wolfram patients [17,23]. Urinary complications are mostly in the form of urinary tract dilatation [16,24], and have been reported to occur in up to 90% of patients, many of whom are asymptomatic [10,11]. Previous reports have mainly focused on description and etiological assessment of urinary tract dilatation [16]. Bladder dysfunction has been attributed to high diuresis associated with diabetes insipidus, a degenerative process affecting the central and peripheral nervous system, or overactive neurogenic bladder with sphincter dyssynergia [16,24,25]. Bladder dysfunction in wolfram syndrome and other disorders is generally managed with CIC per urethra. Nonetheless, performing CIC is associated with detrimental effects on the patient's quality of life [26]. According to Oh et al., [26] in patients using CIC following spinal cord injury, depression was closely related to female gender and the patient's ability to perform self-catheterization. The patient's ability to perform CIC had more significant impact on the severity of depressive symptoms rather than gender. However, in our opinion, the effect of gender on the severity of depression might be itself affected by the higher difficulty of self-catheterization in female patients. These difficulties are more prominent in children with Wolfram syndrome, who have to perform CIC several times a day due to diabetes insipidus while possible progression to blindness makes the whole psychological burden of CIC overwhelming and may consequently lead to irregular use of CIC and progression to renal failure. Moreover, urological manifestations in Wolfram patients
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usually present during teenage years when the reluctance in patients to seek help by a care-giver can further contribute to the child refusal. Ability to perform CIC is of utmost importance in Wolfram patients to prevent bladder over-distention and the progressive course of renal function decline. Wolfram patients need more frequent catheterization during the night due to exacerbated overnight urine production compared to patients with normal urine volume. Not performing urinary diversion has been previously shown to lead to chronic renal failure and finally to hemodialysis [24]. Kidney transplantation is also reported to result in aggravation of existing manifestations of Wolfram syndrome and thus is not a promising last chance remedy [27]. Using Mitrofanoff procedure, patients can attach a urine bag to the catheter inserted to the stoma; the urine bag is then fixed to the patient’s thigh and ensures the overnight urinary drainage while the patient is asleep. Our patients were able to fix the urine bag by themselves without any help. In our three female patients, placement of an abdominal stoma improved their ability to perform CIC despite blindness. They found the stoma by palpitation and performed CIC on their own. All patients were satisfied with the stomas, which helped them regain independence. In addition to improving the quality of life, this alternative method for CIC resulted in elimination of urinary symptoms, reduction in frequency of urinary UTIs and reversal of urinary dilatation. Additionally, there was no progression to renal failure during follow-up. The conduit also provided advantageous access to the bladder for siphonage in the patient with recurrent bacteriuria and intravesical mucus accumulation. All of the patients who refused to undergo the procedure progressed to renal failure. They did not perform CIC regularly and three of them finally died due to renal failure. Considering the high rate of consanguinity marriage in the Middle East, we suggest a high index of suspicion of Wolfram syndrome in juvenile onset diabetes mellitus especially with more than one affected child. Since renal function deterioration has a progressive course in Wolfram patients, initial urologic investigation is advised to detect possible asymptomatic abnormalities. Mitrofanoff procedure is suggested in the presence of bladder over-distention in cases where urethral self-catheterization is impracticable. 4. Conclusions In this study, appendicovesicostomy with the Mitrofanoff principle helped Wolfram patients perform CIC independently despite progression to blindness without any serious complication. Long-term follow-up revealed maintenance of renal function compared to patients who refused the surgery. We suggest this procedure as the first option in patients with Wolfram syndrome presenting with severe urinary problems. The goal is not only to improve their quality of life but also to help treat one of the major causes of mortality and morbidity in this disorder.
Fig. 1. (A) Photo of a patient’s abdomen showing no complications at the site of the VQ stoma (arrow). (B) The stoma with a urinary catheter in place. Solid arrow: VQ stoma, dashed arrow: umbilicus.
Please cite this article as: Mozafarpour S, et al, Management of bladder dysfunction in Wolfram syndrome with Mitrofanoff appendicovesicostomy: long-term follow-up, J Pediatr Surg (2014), http://dx.doi.org/10.1016/j.jpedsurg.2014.09.058
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S. Mozafarpour et al. / Journal of Pediatric Surgery xxx (2014) xxx–xxx
Table 3 Characteristics of patients with Wolfram syndrome who refused to undergo appendicovesicostomy and stopped CIC or performed CIC irregularly. Patient no.
Sex
Age at diagnosis (Years)
CIC per urethra
Nadir Creatinine level mg/dl (normal 1 mg/dl)
Renal failure
Hydroureteronephrosis
1 2 3 4 5 6
F F F M M F
10 11 17 16 17 12
1–3 days occasionally Refused Refused Refused Refused
2–3.8 stable 4.5 refused blood access for hemodialysis 6.7 2–3.3 stable 5.5 on hemodialysis 2.3–3.5 stable
+ Died Died on hemodialysis + Died +
Moderate Severe Severe Severe Severe Severe
CIC: Clean Intermittent Catheterization. F: female. M: male. Moderate hydronephrosis: anteroposterior pelvic diameter: 10–15 mm, Severe hydronephrosis: anteroposterior pelvic diameter greater than 15 mm.
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Please cite this article as: Mozafarpour S, et al, Management of bladder dysfunction in Wolfram syndrome with Mitrofanoff appendicovesicostomy: long-term follow-up, J Pediatr Surg (2014), http://dx.doi.org/10.1016/j.jpedsurg.2014.09.058