[Neurogenic bladder function disorders in patients with meningomyelocele: S2k guidelines on diagnostics and therapy]. / Neurogene Blasenfunktionsstörungen bei Patienten mit Meningomyelozele : S2k-Leitlinie zu Diagnostik und Therapie.

The treatment of children and adolescents with meningomyelocele has experienced a clear change in the last 30 years. The establishment of pharmacotherapy, clean intermittent catheterization (CIC) and infection prophylaxis have improved the prognosis for patients and have led to new therapeutic strategies. The interdisciplinary cooperation between neonatologists, neurosurgeons, pediatric neurologists, pediatric urologists, pediatric nephrologists, pediatric orthopedists and pediatric surgeons leads to optimization of individualized therapy. These guidelines present definitions and classifications, investigations and timing which are described in detail. The conservative and operative therapy options for neurogenic bladder function disorders are described and discussed with reference to the current literature. The brief overview provides in each case assistance for the treating physician in the care of this patient group and facilitates the interdisciplinary cooperation.

[Urological problems in patients with meningomyelocele. Diagnostic studies and management]. / Urologischer Erkrankungen bei Patienten mit Meningomyelozele. Diagnostik und Management.

Since the 1980s the management of children and adolescents with meningomyelocele has undergone major changes. The introduction of pharmacotherapy with antimuscarinic agents, clean intermittent catheterization (CIC) and antibacterial prophylaxis has revolutionized the management of children with neurogenic bladder. The co-operation between neonatologists, neurosurgeons, paediatric neurologists, paediatricians, paediatric urologists, paediatric nephrologists, paediatric orthopaedists and paediatric surgeons is necessary to achieve an optimized therapy in each individual patient. In this interdisciplinary consensus paper we provide definitions and classifications as well as a timetable for the appropriate investigations. The conservative and surgical options are explained in detail. A short review is given concerning orthopaedic management, incidence of latex allergy, options for bowel management, diagnosis and treatment of urinary tract infections, problems with sexuality and fertility as well as the long-term compliance of these patients and their relatives.

A screen for mutations in human homologues of mice exencephaly genes Tfap2alpha and Msx2 in patients with neural tube defects.

BACKGROUND: Very little is known about the identity of genetic factors involved in the complex etiology of nonsyndromic neural tube defects (NTD). Potential susceptibility genes have emerged from the vast number of mutant mouse strains displaying NTD. Reasonable candidates are the human homologues of mice exencephaly genes Tfap2alpha and Msx2, which are expressed in the developing neural tube. METHODS: A single-strand conformation analysis (SSCA) mutation screen of the coding sequences of TFAP2alpha and MSX2 was performed for 204 nonsyndromic NTD patients including cases of anencephaly (n = 10), encephalocele (n = 8), and spina bifida aperta, SBA (n = 183). A selected number of SBA patients was additionally tested for specific mutations in MTHFD, FRalpha, and PAX1 already shown to be related to NTD. RESULTS: Two TFAP2alpha point mutations in individual SBA patients were silent on the amino acid level (C308C, T396T). On nucleic acid level, these mutations change evolutionary conserved codons and thus may influence mRNA processing and translation efficiency. One SBA patient displayed an exonic 9-bp deletion in MSX2 leading to a shortened and possibly less functional protein. None of these mutations was found in 222 controls. Seven polymorphisms detected in TFAP2alpha and MSX2 were equally distributed in patients and controls. Patients with combined heterozygosity of an exonic MSX2 and an intronic TFAP2alpha polymorphism were at a slightly increased risk of NTD (OR 1.71; 95% CI 0.57-5.39). CONCLUSIONS: Although several new genetic variants were found in TFAP2 and MSX2, no statistically significant association was found between NTD cases and the new alleles or their combinations. Further studies are necessary to finally decide if these gene variants may have acted as susceptibility factors in our individual cases.

Assessment of brainstem function in Chiari II malformation utilizing brainstem auditory evoked potentials (BAEP), blink reflex and masseter reflex.

Brainstem dysfunction was evaluated in 67 patients with myelomeningocele and Chiari II malformation using brainstem auditory evoked potentials (BAEP), blink reflex (BR) and masseter reflex (MR). Signs and symptoms related to Chiari II malformation were observed in 18 patients while 49 patients had normal brainstem findings. BAEP and BR showed a higher sensitivity of brainstem involvement than MR (BAEP=1.0, BR=0.83, MR=0.50). BR, and in particular, MR were of higher accuracy (BR=0.52, MR=0.72) than BAEP (0.39) in separating patients with brainstem signs and symptoms related to Chiari II malformation. We feel that this is due to anatomic and physiologic peculiarities of the brainstem structures mediating BR and MR. Our results suggest that brainstem reflexes can support the decision of further treatment.

Urinary diversion and orthotopic bladder substitution in children and young adults with neurogenic bladder: a safe option for treatment?

PURPOSE: Combined pharmacotherapy, clean intermittent catheterization and infection prophylaxis is currently the gold standard of treatment for neurogenic bladder. However, as the adolescent gains independence from parental supervision, the intervals of clean intermittent catheterization compliance with medical treatment and regularity of followup examinations may decrease, and neurological and/or orthopedic status may change. This situation sometimes leads to failure of conservative treatment, resulting in incontinence and/or deterioration of the upper urinary tract. A multidisciplinary team was established at our institution 30 years ago to assess all aspects of care for patients with neurogenic bladder, of which urological function is just 1 aspect of the complex problem. Patient desires and essential medical goals, such as preservation of renal function, are considered by this team. An adequate compromise is sought and achieved in some cases by urinary diversion. We investigated the long-term safety of urinary diversion in these patients and its ability to protect the upper urinary tract. MATERIALS AND METHODS: Between 1967 and 1997 urinary diversion was performed in 149 patients with neurogenic bladder. Mean followup was 11.8 years (range 0.8 to 28.5) in 129 cases. Mean patient age at surgery was 12.1 years (range 0.8 to 20). A colonic conduit was created in 59 patients, mainly before the era of clean intermittent catheterization and continent diversion, while orthotopic bladder substitution was performed in 12 and continent urinary diversion (Mainz pouch I) in 58, of whom 50% were wheelchair bound. RESULTS: The upper urinary tract improved or remained stable in 97% of the renal units in patients with a colonic conduit or Mainz pouch I, and in 95% of the renal units in those with orthotopic bladder substitution. All patients with bladder substitution were continent during the day, 1 required occasional pads at night and 7 of 12 performed clean intermittent catheterization. Complete continence was achieved in 98% of those with a continent stoma. CONCLUSIONS: After failure of conservative treatment in patients with neurogenic bladder urinary diversion represents a safe long-term compromise. Daytime and nighttime continence is provided by the Mainz pouch bladder substitution and urinary diversion, while the upper urinary tract is protected by antireflux ureteral implantation.

Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects(NTD).

A number of studies have demonstrated that the common polymorphism 677C-->T in the gene encoding 5, 10-methylenetetrahydrofolate reductase (MTHFR) leads to a thermolabile variant with decreased enzyme activity and to mildly elevated plasma homocysteine. 677TT homozygosity was shown to be more frequent in NTD probands compared with controls in some studies. Recently, another polymorphism, 1298A-->C, in the MTHFR gene was described and combined heterozygosity 677CT/1298AC was suggested to be an additional risk factor for NTD. The present study examines the genotype and haplotype distribution of the two polymorphisms in the German population and evaluates the impact on NTD individuals and their relatives. To determine the haplotype of all individuals tested, we developed an easy-to-perform ARMS-RFLP test. Our data show that the two polymorphisms are in linkage disequilibrium in the general population and in NTD individuals. There was no statistically significant difference in allele and genotype frequency between probands (patients, fetuses) and controls (P > 0.10) and between observed and expected values for mother-child pairs (P > 0.80). Taking into account gender, an increased rate of 677CT heterozygotes was found in affected and unaffected males compared to affected and unaffected females. A family-based association study using a multiallelic transmission disequilibrium test (TDT) also shows that transmission rates do not deviate significantly from equilibrium (P > 0.50). Thus, our data provide no evidence for an association between NTD phenotype and MTHFR 677C/T-1298A/C genotypes and haplotypes.

Human transcription factor SLUG: mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the Slug subfamily-defining region.

Studies in mouse, chicken and Xenopus have shown that Slug is selectively expressed in the dorsal part of the developing neural tube. Ablation and antisense experiments in chicken suggest that Slug may be an important factor during neural tube closure. We therefore investigated the role of Slug as a possible candidate contributing to the aetiology of neural tube defects (NTD) in humans. We characterised the genomic structure of human SLUG including determination of the exon-intron boundaries. The coding sequence of SLUG was screened for mutations in 150 patients with NTD using single strand conformation analysis (SSCA). In one patient, we identified a missense mutation 1548C-->A in exon 2 causing an exchange of a conserved amino acid (D119E) in the Slug subfamily-defining region preceding the first zinc finger. This is the first description of a human mutation in the SLUG gene. In accordance with the findings in model organisms, the SLUG mutation may be causally related to the development of NTD in our patient and could be considered as a predisposing factor.

Evaluation of the MTHFR C677T allele and the MTHFR gene locus in a German spina bifida population.

UNLABELLED: A number of recent studies have demonstrated that the occurrence and recurrence risk of neural tube defects (NTD) is reduced by folic acid supplementation before and during pregnancy. Epidemiological studies have shown low plasma folate and raised plasma homocysteine in women with spina bifida aperta (SB) children suggesting an abnormal folate metabolism. The 5,10-methylenetetrahydrofolate reductase (MTHFR) variant C677T, resulting in a decreased activity of the enzyme, has been associated with the development of NTD. Several studies demonstrated that homozygosity for the C677T mutation occurs at a higher frequency in patients with SB phenotype than in control individuals. The SB risk is strongest if both the mother and her child have the mutation in the homozygous state. In the present study we compared the frequency of the C- and T-alleles in healthy German individuals (n = 153) with German SB patients (n = 137). Our study groups reveal no significant difference in C/T-allele frequencies and genotype distributions. A family based association study, the transmission disequilibrium test, confirms the absence of an association between T-allele and SB. In 9 of 40 families we were able to exclude linkage to the MTHFR locus (1p36.3) employing different inheritance models. CONCLUSION: Our data show no evidence for an association between the C677T mutation and the occurrence of the SB phenotype. Therefore we cannot support the hypothesis that the MTHFR variant does account for a significant genetic predisposition to the SB phenotype in the studied German patients.