Effect of alarm therapy on conditioning of central reflex control in nocturnal enuresis: pilot study on changes in prepulse inhibition (PPI).

BACKGROUND: Alarm therapy is a long-established first-line therapy for nocturnal enuresis (NE). Desamino-arginine vasopressin (dDAVP) as alternative first-line therapy was shown to increase the prepulse inhibition (PPI) of startle reflexes, thus supporting the hypothesis of a maturational delay of reflex inhibition in NE. Effects of alarm therapy on PPI have not yet been investigated. METHODS: The PPI of startle reflexes was measured in 20 children with NE (13 boys, 7 girls, median age 8.5 years, range 5-13) before and after at least 6 weeks of alarm treatment and compared with repeated PPI measurements in 11 healthy controls (7 boys, 4 girls, median age 8 years, range 6-13). RESULTS: In the NE patients, PPI increased from a median baseline of 20-46% under alarm therapy (p = 0.005), with a reduction from a median of 7 to 2 wet nights per week (p = 0.002). The controls showed no difference in PPI (52% median at first, 40% at second measurement, p = 0.966). CONCLUSIONS: The increase of PPI trough alarm therapy was comparable with that under dDAVP, suggesting an analogous method of action and explaining the alternative or synergistic effect of both therapies. In addition, it further substantiates the hypothesis of a maturational delay of reflex control in NE.

Prepulse inhibition of acoustic startle and the influence of methylphenidate in children with ADHD.

OBJECTIVE: ADHD is common among children with comorbidity of enuresis. Findings concerning prepulse inhibition (PPI) of startle reflexes are controversial. Although PPI is improved through desamino-arginine vasopressin (dDAVP) in enuresis, some patients also improve concomitant ADHD through dDAVP. This study aims to evaluate whether methylphenidate (MPH) also improves PPI in ADHD. METHOD: Nineteen ADHD patients were investigated in a prospective, double-blind, crossover study with MPH versus placebo. PPI was measured as a reduction of acoustic startle reflexes. Subgroups of gender, ADHD subtype, and baseline PPI were analyzed. RESULTS: Median baseline PPI of ADHD patients (51.7%) was below the value of age-matched normal controls (73%, p = .090). MPH showed no improvement in the whole group, or the subgroups gender or subtype. Reduced baseline PPI was significantly improved (22.5%-39.3%, p = .039). CONCLUSION: Heterogeneity of ADHD is confirmed with a wide range of baseline PPI. The improvement of reduced baseline PPI through MPH suggests impaired sensorimotor gating in this subgroup.

Simultaneous EMG-fMRI during startle inhibition in monosymptomatic enuresis--an exploratory study.

Evidence is growing that monosymptomatic enuresis (ME) is a maturational disorder of the central nervous system with a lack of arousal and lacking inhibition of the micturition reflex. Previous studies have shown a significant reduction of prepulse inhibition (PPI) of startle in children with enuresis. However, it is still unclear whether the abnormal PPI in enuresis is based on an inhibitory deficit at brainstem or cortical level. Nine children with ME and ten healthy children were investigated using simultaneous recording of EMG from the M. orbicularis oculi and functional MRI. The experimental paradigm consisted of acoustic startle stimulation, with startle-alone stimuli and prepulse-startle combinations. Functional MRI data were processed using multiple regression and parametric modulation with startle amplitudes as a parameter. Neither patients with enuresis nor healthy children revealed measurable PPI in the MRI scanner. Startle stimuli caused equal hemodynamic changes in the acoustic cortex, medial prefrontal and orbitofrontal cortex in both groups. The amplitude of startle correlated with more prominent BOLD signal changes in the anterior cingulate cortex in healthy subjects than in patients with ME. This pronounced frontal activation in healthy controls was related to the PPI condition, indicating that the prefrontal cortex of healthy children was activated more strongly to inhibit startle than in patients with ME. In conclusion, apart from the possibility that recordings of PPI inside the MRI scanner may be compromised by methodological problems, the results of this study suggest that high cortical control mechanisms at the prefrontal level are relevant for the pathogenesis of ME.

Intracellular ATP production in CD4+ T cells as a predictor for infection and allograft rejection in trough-level guided pediatric liver transplant recipients under calcineurin-inhibitor therapy.

BACKGROUND: The assessment of cell-mediated immune responses through the measurement of intracellular adenosine-tri-phosphate (iATP) production (Cylex ImmuKnow) as a pharmacodynamic biomarker of immune function represents a potential tool to optimize individual immunosuppressive therapy independent of drug dosage or trough levels. This study aims to investigate the correlations between iATP and adverse events, immunosuppression, calcineurin-inhibitor-trough levels, and age. METHODS: In this prospective trial, 31 nontransplant pediatric subjects and 50 consecutive children were included after they underwent liver transplantation (LTX). During the study period, 4 allograft rejections and 3 acute infections occurred. The patients were treated with cyclosporine, tacrolimus, mycophenolate mofetil, and everolimus either as monotherapy or in combinations. The reactivity of the immune system was measured as iATP concentration in CD4+ T-cells after in vitro stimulation by phytohemagglutinin. RESULTS: The iATP concentrations in patients with intercurrent, clinically significant infections were in the low immune response range (median iATP 181 versus 251 ng/mL, P = 0.308), whereas the patients with incidental allograft rejection had significantly higher iATP concentrations as compared with the event-free group (median iATP 444 versus 251 ng/mL, P = 0.017). However, there was a wide range of iATP concentrations in both nontransplant and LTX patient groups, and no clear iATP cut-off values for an increased risk of infection or rejection could be defined. Post LTX, stable-phase patients showed a significantly lower iATP compared with respective controls (median iATP 297 versus 384 ng/mL, P = 0.013). No significant correlation between calcineurin-inhibitor-trough concentrations and iATP was found. iATP was not correlated with age, but was inversely correlated with time after transplantation. CONCLUSIONS: The observed correlation between clinical events and iATP concentrations is similar to the findings previously reported in adult patients who underwent transplantation. The lack of correlation of iATP with trough drug concentrations suggests that the ImmuKnow assay provides independent information that may be useful to guide immunosuppressive therapy in pediatric (liver) transplant patients. However, the wide range of iATP levels in event-free patients suggests that serial iATP measurements will be necessary to assess and guide the individual immunosuppressive therapy. Further investigations are needed to evaluate and extend these findings.

Effect of 1-desamino-8-D-arginine vasopressin on prepulse inhibition of startle supports a central etiology of primary monosymptomatic enuresis.

OBJECTIVE: To test the hypothesis that 1-desamino-8-D-arginine vasopressin (dDAVP) has an effect on prepulse inhibition (PPI) of startle in patients with primary monosymptomatic enuresis (PME), thus indicating a central effect. STUDY DESIGN: Patients with PME (n = 21, age 6 to 12 years) were enrolled in a prospective, randomized, double-blinded, cross-over study. Startle reflexes and PPI were measured under dDAVP treatment versus placebo. RESULTS: The data show that dDAVP has a significant effect on PPI, raising it from 38.88% under placebo to the age-related normal level of 62.6% with dDAVP treatment (P = .0127). CONCLUSIONS: Our findings revive the concept of a central pathophysiology of PME and offer a different explanation for the effects of dDAVP, which not only acts on the kidney, but also is (as is AVP) a central neurotransmitter with a signal cascade on relevant reflex mechanisms.