[Desmopressin in the Treatment of Enuresis: Is Lyophilisate Superior to Tablets?] / Desmopressin in der Behandlung der Enuresis: Ist das Lyophilisat den Tabletten überlegen?

Background: Prognosis of MNE is good when adequate treatment starts in a timely manner. First-line treatment for monosymptomatic nocturnal enuresis (MNE) includes desmopressin (Grade A/Level 1 recommendation from the ICI). Missing or insufficient response to pharmacological treatment can be caused by incomplete compliance, but might also be associated with differences in bioavailability from the tablet form. This prospective, non-interventional study was designed to compare desmopressin tablets to the newer ,,melt'' formulation, also known as lyophilisate or orally disintegrating tablet (ODT). The primary endpoint of this study was the patients'/parents' acceptance; the secondary end point was a decrease in the number of wet nights. Materials and Methods: Each of the scheduled 100 participating doctors had to recruit two MNE candidates, one for each treatment group, with a planned total of 200 participants. At the end of the treatment period, treatment satisfaction, difficulties in taking the medication, forgotten doses and treatment success were reported. Results: In total, 134 patients were included (49 on tablet and 84 on melt). Difficulties in taking the medication and forgotten doses were significantly less with the melt than with the tablet formulation. Treatment satisfaction was better with melt. After the 3 months study, the number of wet nights was considerably reduced in both groups. With lyophilisate, a statistically significant greater reduction in wet nights was recorded as early as 2 weeks after starting the treatment. Conclusion: Desmopressin as orally disintegrating tablets is an effective treatment and is associated with improved patient compliance.

Intensive playing leads to non-monosymptomatic enuresis in children with low prepulse inhibition.

AIM: Parents of children suffering from non-monosymptomatic enuresis (nmE) report their child wetting itself during intensive playing. As children with enuresis are characterized by reduced bladder control (measured as prepulse inhibition (PPI) of startle reflex), the hypothesis suggests that intensive playing leads to further decrease in control and consecutive wetting. Two questions are important: Does PPI change while concentrating? Is this difference more explicit in children with daytime incontinence? METHODS: Forty-four healthy children, 40 children with nmE and 37 with monosymptomatic enuresis (mE) were examined. PPI was measured while watching DVD and while playing Nintendo's Wii(®) , and calculated as percentage of the native startle response. RESULTS: All probands showed a relevant decrease in PPI: in relaxed state, the PPI of the controls was 54%; when concentrating, it fell to 34.5% (p = 0.014). The decrease in PPI in mE was from 66% to 51% (p = 0.008), and the decrease in PPI in nmE was from 29% to 21% (p = 0.125). CONCLUSION: While the decrease in PPI when playing was smallest in the group with nmE, overall PPI level was by far the lowest. The findings confirm the aetiology of enuresis through impaired 'sensori-motor gating' in children with nmE and provide a neurophysiologic correlate for wetting while playing.

Maturation of prepulse inhibition (PPI) in childhood.

It is known that sensorimotor gating measured by the prepulse inhibition of the startle reflex (PPI) matures during childhood. Since certain disorders in children, for example, enuresis, show a significant loss in PPI, the PPI as a tool for investigating brainstem reflex control mechanism gains in importance. Therefore, it is crucial to know the natural course of PPI maturation in childhood. A total of 122 healthy children aged from 3-10 years and 10 healthy adults were examined. PPI was initiated by a 120 ms and a 60 ms prepulse and was measured by the EMG of M. orbicularis oculi. For the respective prepulse intervals, the PPI level in each age group increased from 3 to 9 or 10 years and showed a similar course. The findings confirm and extend knowledge about the maturation of PPI during childhood and emphasize the importance of age-dependent standard values when investigating PPI in children.

Effects of desmopressin on the sleep of children suffering from enuresis.

AIM: To evaluate the effect of 1-desamino-8-D-Arginine Vasopressin (DDAVP) on sleep architecture and arousal reactions in children with primary monosymptomatic nocturnal enuresis (PME). METHODS: A prospective, placebo-controlled, randomized, double-blind, cross-over study was performed on children suffering from bed-wetting. Placebo and DDAVP were given for 7 days each after which an unattended home polysomnography (PSG) was recorded. After lifting the blinding, the PSGs were compared. RESULTS: A total of 20 children with PME, aged 6-15 years, were enrolled in the study. The number of wet nights decreased significantly with DDAVP treatment. Delta power, distribution of sleep stages, number of arousals, arousal index and the effect of arousals on sleep stages did not differ significantly. Bed-wetting occurred within each sleep stage and did not follow any particular pattern. In most cases, it was preceded by an arousal reaction, but no awakening occurred. CONCLUSION: DDAVP has no effect on the sleep architecture of children with PME when analysed by classical PSG, which is determined by collecting the electric activity of cortical neurons. Taking recent research findings into account, this supports the thesis that the disturbances causing PME occur at brain stem level and do not reach consciousness.

Enuresis in hyperthyroidism: a temporary lack of central control mechanism leads to nocturnal enuresis.

UNLABELLED: We report on a 9-year-old boy who suffered from hyperthyroidism and a new appearance of enuresis. Bedwetting ceased and prepulse inhibition (PPI) - measured as a parameter of central control - increased during the course of therapy. CONCLUSION: The increase in PPI is an indication that enuresis in hyperthyroidism could be as a result of a temporary loss of central control on brainstem reflexes. The case conveys new insights into the correlation between thyroid hormones and micturition patterns and the aetiology of enuresis.

Long-term desmopressin response in primary nocturnal enuresis: open-label, multinational study.

BACKGROUND: Primary nocturnal enuresis (PNE) is a distressing condition, particularly in severe cases (> or = 3 wet nights/week). A prevalent pathophysiological mechanism, especially in monosymptomatic PNE (PMNE), is commonly believed to be an insufficient increase in night-time release of antidiuretic hormone. Desmopressin, a synthetic analogue of antidiuretic hormone, has been shown to reduce the number of wet nights experienced by PMNE patients in several controlled trials. AIM: This study was performed to evaluate desmopressin treatment in the real-life clinical setting and was a large-scale, 6-month investigation of efficacy and safety in patients with severe PNE. Predictive factors for desmopressin response were also evaluated. A total of 744 children aged 5 years and above from four countries were involved in the study. RESULTS: At baseline, patients had a median of 6 wet nights/week; at 6 months, 41% of patients had experienced > or = 50% reduction in the mean number of wet nights. Long-term desmopressin treatment was consistently well-tolerated across all ages, with 5% of patients experiencing any treatment-related adverse events. The strength of treatment response was associated with nocturnal diuresis (p < 0.0001) and age (p = 0.0167) in logistic regression analyses. Compliance and dosage were also associated with response and more patients experienced > or = 50% reduction in wet nights after 6 months' treatment than earlier in the study, suggesting the value of persistent treatment. CONCLUSION: This study shows that long-term desmopressin treatment in the clinical setting is effective and well-tolerated in PNE patients of 5 years and upwards. Early improvements in bedwetting of any appreciable magnitude may be rewarding, may facilitate compliance and enable good long-term response.

[On the inferior quality of renal sonograms in patients with lumbar meningomyelocele]. / Uber die mindere Qualität von Nierensonogrammen bei Patienten mit lumbaler Meningomyelozele.

AIM: Many examiners complain about the inferior quality of renal sonograms in patients with lumbar, meningomyelocele (MMC), especially about the insufficient contrast. The study was carried out in order to scrutinize these reports and to test the hypothesis that this effect might be caused by the increased echogenicity of the abnormally innervated musculature in these patients. METHODS: In 17 "matched pairs" of patients with lumbar MMC and healthy controls the echogenicity and the contrast of the sonograms of the kidneys, the biceps muscle and the rectus femoris muscle were measured and compared. RESULTS: Echogenicity and contrast of the renal sonograms were significantly lower in patients with MMC (p = 0.004). Sonography of the musculature of the upper extremities revealed no differences, the echogenicity of the rectus femoris muscle, however, was significantly higher (p = 0.001) in patients with MMC. CONCLUSION: The results presented support the hypothesis that the elevated echogenicity of the abdominal wall and trunk musculature in patients with MMC reduce the effective ultrasound signal.

The effect of desmopressin on short-term memory in children with primary nocturnal enuresis.

PURPOSE: The use of desmopressin in patients with primary nocturnal enuresis is based on the hypothesis of a nocturnal lack of endogenous arginine vasopressin. However, in addition to the kidney, other targets of desmopressin are known. Therefore, we examined whether the administration of desmopressin influences central nervous function in children with primary nocturnal enuresis. MATERIALS AND METHODS: Our prospective, randomized, double-blind, placebo controlled cross-over study was performed on 40 children with nocturnal enuresis. Patients were randomly assigned to receive either 20 microg. desmopressin intranasally or 0.9% saline solution. Each group comprised 19 and 21 to children, respectively. After 2 weeks the groups were switched. The children were tested for short-term memory and reaction time to both treatments. Statistical analysis was done using the Wilcoxon matched pairs test. RESULTS: Median patient age was 8.0 years (range 6 to 13). During desmopressin treatment children in both groups had a significant decrease of wet nights (5.3 to 3.2 per week). In contrast to reaction time, short-term memory was significantly different between both groups (p <0.05). CONCLUSIONS: Our results demonstrate an increase in short-term memory after desmopressin treatment in children with nocturnal enuresis. This finding indicates the central nervous system as a target involved in the pathogenesis of nocturnal enuresis as well as the therapeutic benefit of desmopressin treatment.

Prolonged dietary calcium restriction: a diagnostic approach in idiopathic hypercalciuria.

BACKGROUND: Although frequently observed, the etiology of idiopathic hypercalciuria (IHC) remains largely unknown. A common hypothesis postulates intestinal hyperabsorption and/or a primary renal leak as the pathophysiological basis. The aim of our study was to investigate the regulation pattern of calcium homeostasis in patients with IHC by using a prolonged period of calcium restriction. METHODS: Twenty-seven patients with IHC were investigated. After a 3-week run-in period (dietary calcium content 700-1,000 mg/24 h), a standard calcium reduced diet (300 mg/24 h) was given for 4 weeks. Thereafter, the participants received again a normal calcium-containing diet. Values for urinary calcium, PTH and calcitriol levels of all participants were obtained at different phases of the study. Forty-three healthy persons served as controls. RESULTS: During calcium restriction, two distinct groups were identified. One group displayed an increase (n = 12) in urinary calcium excretion, the second (n = 15) a marked reduction, respectively. In both groups, the values during calcium restriction were significantly different from baseline (p < 0.01). In the first group, the increase of urinary calcium excretion was accompanied by an increase of PTH and calcitriol. These values were also significantly different from baseline values (p < 0.01). The control group showed decreasing calcium excretion during oral restriction (p < 0.01). CONCLUSION: Prolonged calcium restriction proved to be useful in distinguishing apparently two major forms of IHC. The fact that one group displayed the same excretion pattern as the control group raises the question if this group just represents the upper limit of a physiological range. These findings may shed new light on diagnosis, pathogenesis and treatment of patients with IHC.

[Age- and weight-related dosage of dDAVP in the treatment of primary nocturnal enuresis]. / Alters- und gewichtsbezogene Dosierung von dDAVP in der Therapie der primären Enuresis nocturna.

BACKGROUND: In treating primary nocturnal enuresis the dosages recommended for an intranasal application of dDAVP are 20, 30 or 40 microgram depending on the response. Dosages that take the patient's weight or age into account are not commonly used until now. PATIENTS AND METHODS: In the present prospective study including 43 children therapeutic success was therefore evaluated on the basis of the dosage that was standardized according to both age and weight of the patients. The patients' weight ranged from 16.5 to 98 kg, their age from 6 to 14.9 years. RESULTS: The dDAVP dosages that were applied ranged from 0.3 and 2.4 microgram/kg and 3.74 and 15.3 microgram x age/kg respectively. Therapeutic efficacy was at 63 %. CONCLUSIONS: The results suggest an ideal weight-related dosage of 1 microgram x weight or rather an age- and weight-related dosage of 8 microgram x weight/age. A higher dosage evidently is of little use since there was a significant difference between the non-responders and the responders (p < 0.01) with the non-responders not even reacting to higher dosages.

Early tubular proteinuria and the development of nephritis in Henoch-Schönlein purpura.

The prognosis of Henoch-Schonlein purpura (HSP) is mainly determined by the involvement of the kidney, but prognostic markers have not been established. To study the extent of tubular involvement in HSP and its relationship to the development of HSP nephritis, we measured the urinary excretion of two tubular marker proteins in 36 children with HSP. After admission, urinary N-acetyl-beta-D-glucosaminidase (NAG) was determined in 20 children and alpha1-microglobulin (alpha1-MG) in 16 children respectively. These values were compared with the biochemical data on admission, 1 month, 6 months, and 12 months later. A total of 198 24-h urine samples from healthy children were used for the establishment of reference data for NAG and alpha1-MG (mean+/-2 SD). Twenty-one patients had elevated excretion of either NAG (>mean+2 SD, n=12) or alpha1-MG (>mean+2 SD, n=9). The highest values (>mean+4 SD) were found in patients with early kidney involvement. Normal values were accompanied by a benign further clinical course. Children with intermediate high values (>mean+2 SD,

Molecular cloning, tissue distribution, and chromosomal mapping of the human epithelial Ca2+ channel (ECAC1).

Functional and morphological analyses indicated that the epithelial Ca2+ channel (ECaC), which was recently cloned from rabbit kidney, exhibits the defining properties for being the gatekeeper in transcellular Ca2+ (re)absorption. Its human homologue provides, therefore, a molecular basis for achieving a better understanding of Ca2+ mal(re)absorption. By applying the RACE technique, the full-length cDNA of human ECaC (HGMW-approved symbol ECAC1) was obtained. It consisted of 2,772 bp with an open reading frame of 2,187 bp encoding a protein of 729 amino acids with a predicted molecular mass of 83 kDa. Phylogenetic analysis indicated that this highly selective Ca2+ channel exhibits a low level of homology (<30%) to other Ca2+ channels, suggesting that it belongs to a new family. hECaC was highly expressed in kidney, small intestine, and pancreas, and less intense expression was detected in testis, prostate, placenta, brain, colon, and rectum. These ECaC-positive tissues also expressed the 1,25-dihydroxyvitamin D3-sensitive calcium-binding proteins, calbindin-D9K and/or calbindin-D28K. The human ECaC gene mapped to chromosome 7q31.1-q31.2. Taken together, the conspicuous colocalization of hECaC and calbindins in organs that are not prime regulators of plasma Ca2+ levels could illustrate new pathways in cellular Ca2+ homeostasis.

Influence of hyperfiltration on the measurement of urinary N-acetyl-beta-D-glucosaminidase.

The measurement of urinary enzymes in patients with diabetes mellitus has become a useful additional test for the early detection of nephropathy. Controversy persists concerning methods of measurement since during early stages of insulin-dependent diabetes mellitus children develop the so-called hyperfiltration syndrome. This study was performed to determine whether elevated levels of excreted creatinine influence the determination of the enzyme N-acetyl-beta-D-glucosaminidase (NAG). Reference values for NAG in single-spot urines (units NAG/mmol creatinine) and in 24-h collections (units NAG/l urine) were established in two different groups of 105 and 111 healthy children. NAG was then measured in single-spot urines (as NAG/mmol creatinine) and in collection urines of 30 diabetic children within the same 24-h period and compared with the reference population. These results were compared with hemoglobin (Hb)A1(a-c) and fructosamine values as well as creatinine clearance of the diabetic patients. There was a direct correlation between the NAG levels in single-spot and 24-h urine collections of diabetic patients. However, the NAG/creatinine ratio in the single-spot urines did not correlate with the HbA1(a-c) or fructosamine level. When 24 h collections (expressed as NAG/l) were used, the results correlated well with HbA1(a-c) and fructosamine. There was an inverse correlation between the creatinine clearance and the NAG/creatinine ratio, i.e., a high creatinine clearance correlated with a low NAG/creatinine ratio. This was not the case for 24 h collections (expressed as units/l). Hence, in children with insulin-dependent diabetes mellitus 24-h urine collections should be used for urinanalysis. Parameters should not be related to creatinine, since the ratio of urinary protein and creatinine is unreliable because of the high urinary creatinine during the hyperfiltration state.

Tubulointerstitial nephritis and uveitis in association with Epstein-Barr virus infection.

The case of a 13.5-year-old girl with acute tubulointerstitial nephritis and uveitis (TINU syndrome) is presented. The etiology of this rare syndrome, which in most cases involves female adolescents and usually regresses spontaneously, is still unknown. An infection-triggered pathological immune reaction has been considered to play a role in the pathogenesis of this disorder. Here we report for the first time the association of TINU syndrome and Epstein-Barr virus infection.

Effect of DDAVP on nocturnal enuresis in a patient with nephrogenic diabetes insipidus.

The case of an 8 year old boy with both nocturnal enuresis and nephrogenic diabetes insipidus is presented. Diagnosis of nephrogenic diabetes insipidus was based on a typical medical history, the characteristic result of a fluid restriction test, the lack of an effect of 1-desamino-8-D-arginine (DDAVP) on both urine osmolality and plasma coagulation factors and, finally, the detection of a hemizygous missense mutation within the arginine vasopressin (AVP) receptor gene. Hydrochlorothiazide treatment and dietary measures reduced the patient's urine volume to one third of its original volume. However, this had no effect on enuresis. The daily intranasal application of DDAVP did not further reduce urine output but dramatically decreased the frequency of bed wetting. This observation contradicts the common notion that the therapeutic effect of DDAVP in nocturnal enuresis is the result of compensation for a nocturnal AVP deficit. Rather, it points to a different mode of action of DDAVP in patients with enuresis. It is hypothesised that central AVP receptors are a target of DDAVP and that they might play an important role in the pathogenesis of nocturnal enuresis.

Regulation of arginine vasopressin in enuretic children under fluid restriction.

BACKGROUND: Treatment of primary nocturnal enuresis using 1-deamino-8-D-arginine-vasopressin is based on the hypothesis that antidiuretic hormone (arginine vasopressin [AVP]) secretion is insufficient during the night. Persisting doubts about the theoretical background of this treatment and first results pointing to a different AVP regulation in children with nocturnal enuresis were the motives for the present study. OBJECTIVE: To determine if children with primary nocturnal enuresis have different AVP levels during fluid restriction when compared with normal controls. METHODS: Twenty-three children with nocturnal enuresis (median age, 11 years) were compared with a corresponding control group of 18 healthy children. Plasma osmolality, urine osmolality, and plasma AVP concentrations were determined before and after a defined fluid restriction. RESULTS: Regarding plasma and urine osmolality, no differences were found between the two groups. AVP levels after fluid restriction, however, showed significant differences. To maintain osmolality, the plasma AVP concentrations of the controls rose to a median value of 5.7 pg/mL (range: 0.9-29.0 pg/mL) in comparison to a median of 14.0 pg/mL (range: 3.5-64.0 pg/mL, P =. 015) for the enuretic children. CONCLUSION: The results are consistent with the established fact that AVP secretion is a function of plasma osmolality. They contradict the hypothesis that enuretic children have a AVP deficiency that has to be supplemented. Rather, the results point to a defect at the AVP receptor level or of the signal transduction pathway.

Nephrocalcinosis in three siblings with idiopathic hypercalciuria.

Idiopathic hypercalciuria (IH) associated with nephrocalcinosis was found in three of six siblings. After the three affected children were maintained on a low-calcium diet, they demonstrated increasing hypercalciuria, parathyroid hormone, and vitamin D3 levels. An oral calcium loading test was not necessary to diagnose renal IH. During treatment with hydrochlorothiazide, the calcium excretion was normalized. These patients are remarkable because nephrocalcinosis is generally regarded as a rare complication of renal IH. Moreover, the fact that three of six siblings are affected raises the question of whether the renal form of IH is genetically distinct from other forms of IH.

Immunohistological studies on an Onchocerca volvulus ankyrin (EI).

The distribution of an Onchocerca volvulus ankyrin, designated E1, was studied in different O. volvulus stages and other helminths by immunohistochemistry using rabbit antibodies raised against the recombinant E1 protein. In adult O. volvulus the protein designated E1 was localized to the extracellular clefts as well as to the cytoplasm adjacent to the cell membrane in the area of the basal labyrinth in hypodermis, intestine and uterus and to a lesser extent in oviduct and vas deferens. Neuronal cell bodies were also labelled. No labelling of the basal laminae, muscles or epithelia of ovary or testis was observed. Detection of the E1 protein was associated with embryonic development. Germ cells and early morulae showed no reaction; labelling was first seen in late morulae, corresponding to the stage of gastrulation, and increased in the following embryonic stages. In microfilariae the nerve ring and the cephalic space, which represents the anterior nerve-enriched portion of the body, were labelled. In third-stage larvae of O. volvulus labelling was associated with the hypodermis, and in those of Anisakis sp. the cytoplasm adjacent to the membrane of the excretory gland cell and the basal labyrinth of the hypodermis were labelled. Following anthelminthic treatment a disruption of the labelling pattern of the E1 protein was observed in adult O. volvulus with leakage of the protein into neighbouring areas. Damage to the worm was associated with reduction and finally loss of E1 protein labelling. No E1 protein was detected in dead adult worms, embryos or microfilariae. Labelling of the same organs was observed in 8 other Onchocerca species and in several other nematodes, but no reaction was seen in trematodes. The results indicate that the EI protein is associated with neuronal structures of O. volvulus, that its presence is developmentally regulated and that it has cross-reactive homologues in other nematodes. The results suggest that E1 is a functional protein. It may be useful for the assessment of parasite damage and death as well as in the characterization of the filarial nervous system.

Physiological bowlegs or infantile Blount's disease. Some new aspects on an old problem.

The differentiation between physiological bowlegs and infantile Blount's disease in patients aged 11-30 months is very difficult. Nevertheless, diagnosis is deemed important because treatment of infantile Blount's disease is recommended. Fourteen patients with severe bowing of the legs seen in our outpatient clinic were investigated retrospectively. We examined them and measured the tibiofemoral and metaphyseal/diaphyseal angles in radiographs taken at their first presentation. The finding that the tibiofemoral angle is not helpful in differential diagnosis could be confirmed but, contrary to reports by other authors, neither was the metaphyseal/diaphyseal angle. In view of the spontaneous recovery of all investigated patients, it must be doubted whether a diagnosis of infantile tibia vara can be made in early infancy, and whether infantile Blount's disease is a diagnosis in its own right.