Long-Term Follow-Up of Pediatric Patients with Dyskinetic Cerebral Palsy and Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare. OBJECTIVES: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP. METHODS: The STIM-CP trial was a prospective, single-arm, multicenter study in which patients from the parental trial agreed to be followed-up for up to 36 months. Assessments included motor and non-motor domains. RESULTS: Of the 16 patients included initially, 14 (mean inclusion age 14 years) were assessed. There was a significant change in the (blinded) ratings of the total Dyskinesia Impairment Scale at 36 months. Twelve serious adverse events (possibly) related to treatment were documented. CONCLUSION: DBS significantly improved dyskinesia, but other outcome parameters did not change significantly. Investigations of larger homogeneous cohorts are needed to further ascertain the impact of DBS and guide treatment decisions in DCP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Quality of Life After Deep Brain Stimulation of Pediatric Patients with Dyskinetic Cerebral Palsy: A Prospective, Single-Arm, Multicenter Study with a Subsequent Randomized Double-Blind Crossover (STIM-CP).

BACKGROUND: Patients with dyskinetic cerebral palsy are often severely impaired with limited treatment options. The effects of deep brain stimulation (DBS) are less pronounced than those in inherited dystonia but can be associated with favorable quality of life outcomes even in patients without changes in dystonia severity. OBJECTIVE: The aim is to assess DBS effects in pediatric patients with pharmacorefractory dyskinetic cerebral palsy with focus on quality of life. METHODS: The method used is a prospective, single-arm, multicenter study. The primary endpoint is improvement in quality of life (CPCHILD [Caregiver Priorities & Child Health Index of Life with Disabilities]) from baseline to 12 months under therapeutic stimulation. The main key secondary outcomes are changes in Burke-Fahn-Marsden Dystonia Rating Scale, Dyskinesia Impairment Scale, Gross Motor Function Measure-66, Canadian Occupational Performance Measure (COPM), and Short-Form (SF)-36. After 12 months, patients were randomly assigned to a blinded crossover to receive active or sham stimulation for 24 hours each. Severity of dystonia and chorea were blindly rated. Safety was assessed throughout. The trial was registered at ClinicalTrials.gov, number NCT02097693. RESULTS: Sixteen patients (age: 13.4 ± 2.9 years) were recruited by seven clinical sites. Primary outcome at 12-month follow-up is as follows: mean CPCHILD increased by 4.2 ± 10.4 points (95% CI [confidence interval] -1.3 to 9.7; P = 0.125); among secondary outcomes: improvement in COPM performance measure of 1.1 ± 1.5 points (95% CI 0.2 to 1.9; P = 0.02) and in the SF-36 physical health component by 5.1 ± 6.2 points (95% CI 0.7 to 9.6; P = 0.028). Otherwise, there are no significant changes. CONCLUSION: Evidence to recommend DBS as routine treatment to improve quality of life in pediatric patients with dyskinetic cerebral palsy is not yet sufficient. Extended follow-up in larger cohorts will determine the impact of DBS further to guide treatment decisions in these often severely disabled patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A randomised controlled multicentre investigator-blinded clinical trial comparing efficacy and safety of surgery versus complex physical decongestive therapy for lipedema (LIPLEG).

BACKGROUND: Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT. METHODS/DESIGN: LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0-10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction. The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher's exact test in a hierarchical test strategy. DISCUSSION: LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema. TRIAL REGISTRATION: ClinicalTrials.gov NCT04272827. Registered on February 14, 2020. TRIAL STATUS: Protocol version is 02_0, December 17, 2019.

Thalamic deep brain stimulation for Tourette Syndrome: A naturalistic trial with brief randomized, double-blinded sham-controlled periods.

BACKGROUND: There is still a lack of controlled studies to prove efficacy of thalamic deep brain stimulation for Tourette's Syndrome. OBJECTIVES: In this controlled trial, we investigated the course of tic severity, comorbidities and quality of life during thalamic stimulation and whether changes in tic severity can be assigned to ongoing compared to sham stimulation. METHODS: We included eight adult patients with medically refractory Tourette's syndrome. Bilateral electrodes were implanted in the centromedian-parafascicular-complex and the nucleus ventro-oralis internus. Tic severity, quality of life and comorbidities were assessed before surgery as well as six and twelve months after. Short randomized, double-blinded sham-controlled crossover sequences with either active or sham stimulation were implemented at both six- and twelve-months' assessments. The primary outcome measurement was the difference in the Yale Global Tic Severity Scale tic score between active and sham stimulation. Adverse events were systematically surveyed for all patients to evaluate safety. RESULTS: Active stimulation resulted in significantly higher tic reductions than sham stimulation (F = 79.5; p = 0.001). Overall quality of life and comorbidities improved significantly in the open-label-phase. Over the course of the trial two severe adverse events occurred that were resolved without sequelae. CONCLUSION: Our results provide evidence that thalamic stimulation is effective in improving tic severity and overall quality of life. Crucially, the reduction of tic severity was primarily driven by active stimulation. Further research may focus on improving stimulation protocols and refining patient selection to improve efficacy and safety of deep brain stimulation for Tourette's Syndrome.

Protocol update for the SABATO trial: a randomized controlled trial to assess early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection.

BACKGROUND: SABATO (Staphylococcus aureus bacteremia antibiotic treatment options) is a randomized, parallel-group, clinical non-inferiority trial designed to examine the efficacy and safety of early oral switch therapy in low-risk Staphylococcus aureus infection. The original trial protocol was published in Trials (accessible at https://doi.org/10.1186/s13063-015-0973-x ). Here we describe final amendments to the study protocol and discuss the underlying rationale. METHODS/DESIGN: Three major changes were introduced into the study protocol: (1) the inclusion and exclusion criteria were refined so that patients with certain comorbidities (end-stage renal disease, severe liver disease) and uninfected foreign bodies (orthopedic prosthesis, pacemaker, implanted cardiac cardioverter-defibrillator) became eligible for enrollment under certain conditions; (2) the target sample size was decreased by choosing a conventional non-inferiority margin of 10% and converting the interim analysis (215 patients) into the final analysis; and (3) an additional follow-up visit after 30 days was introduced to allow for a closer follow-up of patients. CONCLUSION: Changes to the study protocol were introduced to improve the enrollment and follow-up of patients. Furthermore, the decrease of the sample size will facilitate completion of the trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01792804. Registered on 13 February 2013. German Clinical trials register, DRKS00004741. Registered on 4 October 2013, EudraCT 2013-000577-77.

Early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection (SABATO): study protocol for a randomized controlled trial.

BACKGROUND: Current guidelines recommend that patients with Staphylococcus aureus bloodstream infection (SAB) are treated with long courses of intravenous antimicrobial therapy. This serves to avoid SAB-related complications such as relapses, local extension and distant metastatic foci. However, in certain clinical scenarios, the incidence of SAB-related complications is low. Patients with a low-risk for complications may thus benefit from an early switch to oral medication through earlier discharge and fewer complications of intravenous therapy. The major objective for the SABATO trial is to demonstrate that in patients with low-risk SAB a switch from intravenous to oral antimicrobial therapy (oral switch therapy, OST) is non-inferior to a conventional course of intravenous therapy (intravenous standard therapy, IST). METHODS/DESIGN: The trial is designed as randomized, parallel-group, observer-blinded, clinical non-inferiority trial. The primary endpoint is the occurrence of a SAB-related complication (relapsing SAB, deep-seated infection, and attributable mortality) within 90 days. Secondary endpoints are the length of hospital stay; 14-day, 30-day, and 90-day mortality; and complications of intravenous therapy. Patients with SAB who have received 5 to 7 full days of adequate intravenous antimicrobial therapy are eligible. Main exclusion criteria are polymicrobial bloodstream infection, signs and symptoms of complicated SAB (deep-seated infection, hematogenous dissemination, septic shock, and prolonged bacteremia), the presence of a non-removable foreign body, and severe comorbidity. Patients will receive either OST or IST with a protocol-approved antimicrobial and are followed up for 90 days. Four hundred thirty patients will be randomized 1:1 in two study arms. Efficacy regarding incidence of SAB-related complications is tested sequentially with a non-inferiority margin of 10 and 5 percentage points. DISCUSSION: The SABATO trial assesses whether early oral switch therapy is safe and effective for patients with low-risk SAB. Regardless of the result, this pragmatic trial will strongly influence the standard of care in SAB. TRIAL REGISTRATION: ClinicalTrials.gov NCT01792804 registered 13 February 2013; German Clinical trials register DRKS00004741 registered 4 October 2013, EudraCT 2013-000577-77 . First patient randomized on 20 December 2013.

Indicators of overweight and cardiovascular disease risk factors among 11- to 17-year-old boys and girls in Germany.

OBJECTIVE: We analyzed the magnitude of the association between cardiovascular disease (CVD) risk factors and various measures of overweight among adolescents, to determine which indicator of overweight is most relevant for risk assessment. METHODS: 5,546 boys and girls aged 11-17 years participating in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were studied. Overweight was assumed when different anthropometric variables exceeded age- and sex-specific 90th percentiles. Blood pressure was measured and blood samples were analyzed for serum total cholesterol, lipoproteins, high-sensitivity C-reactive protein, and glycosylated hemoglobin (HbA1c). RESULTS: In both sexes, overweight was significantly associated with adverse levels of CVD risk factors, except HbA1c. These associations were most pronounced for overweight as defined by waist circumference (WC), waist-to-height ratio (WHtR), or BMI. Between 11% and 37% of the overweight children exceeded the defined cut-offs for individual CVD risk factors, with age- and puberty-adjusted significant odds ratios (95% confidence interval (CI)) in comparison to normal-weight age mates ranging from 1.7 (1.0-3.0) to 6.1 (4.5-8.2). CONCLUSIONS: The findings of this population-based survey suggest that, among adolescents, WC, WHtR, and BMI are easily applicable measures of overweight that appear to be relevant for CVD risk assessment.

Relation of isoflavones and fiber intake in childhood to the timing of puberty.

BACKGROUND: It has been suggested that phytoestrogens and dietary fiber can affect puberty timing. OBJECTIVE: We examined whether intake of isoflavone and fiber in healthy white children before their pubertal growth spurt [age at take-off (ATO)] was associated with puberty timing. DESIGN: Multivariate regression analyses were performed in 227 DONALD (DOrtmund Nutritional and Anthropometric Longitudinally Designed) Study participants with 3-d weighed dietary records and information on potential confounders at baseline (1 and 2 y before ATO). In a subsample (n = 111), urinary isoflavones were determined in 24-h urine samples by gas chromatography-mass spectrometry analysis. Puberty timing was examined by using ATO and chronologic ages at pubertal stage 2 for breast development (B2) or gonadal development, peak height velocity (PHV), and menarche or voice break. RESULTS: Girls whose diet was in the highest dietary isoflavone tertile experienced Tanner stage 2 for breast development ap 0.7 y later and reached PHV ap 0.6 y later than did girls whose diet was in the lowest isoflavone tertile [age (95% CI) at B2: 10.7 y (10.4, 10.9 y) compared with 10.0 y ( 9.7, 10.3 y), respectively; P for trend = 0.04; age at PHV: 11.9 y (11.6, 12.2 y) compared with 11.3 y (11.0, 11.6 y), respectively; P for trend = 0.04; adjusted for body mass index z score and fiber intake]. In boys, dietary isoflavones were not associated with pubertal markers. Urinary isoflavone and dietary fiber intakes were not associated with pubertal markers. CONCLUSIONS: Girls, but not boys, with higher prepubertal isoflavone intakes appear to enter puberty at a later age. Fiber intake in this sample of healthy white girls and boys was not relevant for puberty timing.

Potential determinants of obesity among children and adolescents in Germany: results from the cross-sectional KiGGS Study.

BACKGROUND: Obesity among children and adolescents is a growing public health problem. The aim of the present paper is to identify potential determinants of obesity and risk groups among 3- to 17-year old children and adolescents to provide a basis for effective prevention strategies. METHODS: Data were collected in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), a nationally representative and comprehensive data set on health behaviour and health status of German children and adolescents. Body height and weight were measured and body mass index (BMI) was classified according to IOTF cut-off points. Statistical analyses were conducted on 13,450 non-underweight children and adolescents aged 3 to 17 years. The association between overweight, obesity and several potential determinants was analysed for this group as well as for three socio-economic status (SES) groups. A multiple logistic regression model with obesity as the dependent variable was also calculated. RESULTS: The strongest association with obesity was observed for parental overweight and for low SES. Furthermore, a positive association with both overweight (including obesity) and obesity was seen for maternal smoking during pregnancy, high weight gain during pregnancy (only for mothers of normal weight), high birth weight, and high media consumption. In addition, high intakes of meat and sausages, total beverages, water and tea, total food and beverages, as well as energy-providing food and beverages were significantly associated with overweight as well as with obesity. Long sleep time was negatively associated with obesity among 3- to 10-year olds. Determinants of obesity occurred more often among children and adolescents with low SES. CONCLUSION: Parental overweight and a low SES are major potential determinants of obesity. Families with these characteristics should be focused on in obesity prevention.

Supplementation with a multivitamin containing 800 microg of folic acid shortens the time to reach the preventive red blood cell folate concentration in healthy women.

BACKGROUND: The lowest risk of having a child with a neural tube defect (NTD) was related to red blood cell (RBC) folate concentrations of >906 nmol/L. For NTD prevention, it is recommended that women use periconceptional supplementation of 400 microg/day folic acid. Using this dose previous studies indicate that RBC folate >906 nmol/L was not reached within four weeks of supplementation. OBJECTIVE: The effectiveness of a multivitamin/multimineral supplement containing 800 microg folic acid (verum) was evaluated using RBC folate concentration exceeding 906 nmol/L as primary endpoint. In addition, the time frame of achieving the threshold level was established as well as the effect of supplementation of other B vitamins on folate metabolism. SUBJECTS AND METHODS: 46 healthy females received 800 microg/day of folic acid or placebo for 16 weeks. Blood samples were collected in four-week intervals. Plasma and RBC folate were measured with the microbiological method. RESULTS: Mean (+/-SED) RBC folate increased over time to 1430+/-53 nmol/L, but did not reach a steady state after 16 weeks of intervention. Mean time to reach the target level was 4.2 +/- 3.5 weeks in the verum group. Intake of verum also led to an increase over time of plasma folate. CONCLUSIONS: Preventive RBC folate concentration of more than 906 nmol/L can be reached within four weeks of supplementation with daily intake of 800 microg folic acid. With respect to NTD prevention, we suggest the re-evaluation of the current recommendation of folic acid supplementation.

Calculation of red blood cell folate steady state conditions and elimination kinetics after daily supplementation with various folate forms and doses in women of childbearing age.

BACKGROUND: A maternal red blood cell (RBC) folate concentration > 906 nmol/L is thought to be optimal for lowering the risk of neural tube defects (NTDs) in pregnancy. Whereas the appearance of folate in RBCs has been followed during folic acid supplementation, data on elimination kinetics are not yet available. OBJECTIVE: The aim of our investigation was to estimate the steady state conditions and elimination kinetics of folate in RBCs. DESIGN: Data from 2 randomized, placebo-controlled, double-blind intervention trials were used for kinetic modeling. These studies were performed to investigate the appearance of folate in RBCs in healthy women of childbearing age after different supplementation strategies (study 1: n = 69; 400 microg folic acid/d and 416 microg [6S]-5-methyltetrahydrofolate/d for 24 wk; study 2: n = 21; 800 microg folic acid/d for 16 wk). RESULTS: For RBC folate concentrations, steady state conditions were not reached after 24 (study 1) and 16 (study 2) wk of folate supplementation. However, with the use of these data, we calculated the biological half-life (t(1/2)) of RBC folate to be approximately 8 wk. With the application of pharmacokinetic principles, steady state conditions for RBC folate should be reached after 40 wk (t(1/2) x 5). CONCLUSION: With the use of pharmacokinetic principles, the appearance and elimination kinetics of RBC folate can be calculated on the basis of this t(1/2) value.

Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age.

BACKGROUND: For the primary prevention of neural tube defects (NTDs), public health authorities recommend women of childbearing age to take 400 mug folic acid/d 4 wk before conception and during the first trimester. The biologically active derivate [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) could be an alternative to folic acid. OBJECTIVE: We investigated the effect of supplementation with [6S]-5-MTHF compared with that of folic acid on red blood cell folate concentration, an indicator of folate status. DESIGN: The study was designed as a double-blind, randomized, placebo-controlled intervention trial. Healthy women (n = 144) aged 19-33 y received 400 microg folic acid, the equimolar amount of [6S]-5-MTHF (416 microg), 208 microg [6S]-5-MTHF, or placebo as a daily supplement for 24 wk. Red blood cell and plasma folate concentrations were measured at baseline and at 4-wk intervals. RESULTS: The increase in red blood cell folate over time was significantly higher in the group receiving 416 microg [6S]-5-MTHF/d than in the groups receiving 400 microg folic acid/d or 208 microg [6S]-5-MTHF/d (P < 0.001). No plateau was reached in red blood cell folate concentration in the 3 treatment groups during 24 wk of intervention; however, plasma folate plateaued after 12 wk. CONCLUSIONS: We showed that administration of [6S]-5-MTHF is more effective than is folic acid supplementation at improving folate status. In addition, the study indicates that the recommended period for preconceptional folic acid supplementation should be extended to >4 wk for maximal prevention of NTDs based on folate concentrations. [6S]-5-MTHF might be an efficient and safe alternative to folic acid.

Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women.

BACKGROUND: Increased plasma total homocysteine (tHcy) is a risk factor for vascular disease and adverse pregnancy outcomes. Health authorities recommend periconceptional supplementation with 400 micro g folic acid to prevent neural tube defects. Several countries have implemented food fortification with folic acid. However, excessive intake of folic acid could mask an undiagnosed vitamin B-12 deficiency. The biologically active [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) may be an alternative to folic acid because it is unlikely to mask vitamin B-12 deficiency symptoms. OBJECTIVE: We compared the tHcy-lowering potential of 2 dosages of [6S]-5-MTHF with that of 400 micro g folic acid during 24 wk of supplementation. DESIGN: In this double-blind, randomized, controlled intervention trial, 144 female participants were supplemented daily with 400 micro g folic acid, 416 micro g [6S]-5-MTHF, 208 micro g [6S]-5-MTHF, or placebo. Concentrations of tHcy and plasma folate were measured at baseline and at 4-wk intervals. RESULTS: After supplementation, there was a significant interaction between time and treatment with respect to changes in tHcy and plasma folate (both P < 0.001 by two-factor repeated-measures analysis of variance). The decrease in tHcy did not differ significantly between the 3 supplemented groups (P > 0.05; Tukey's post hoc test). The increase in plasma folate in the group receiving 208 micro g [6S]-5-MTHF was significantly lower than that in the groups receiving 400 micro g folic acid (P < 0.001) or 416 micro g [6S]-5-MTHF (P < 0.05). CONCLUSIONS: [6S]-5-MTHF was shown to be an adequate alternative to folic acid in reducing tHcy concentrations. Supplementation with 416 micro g [6S]-5-MTHF was no more effective than that with 208 micro g [6S]-5-MTHF.

5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women.

BACKGROUND: Elevated plasma total homocysteine (tHcy) is a risk factor for vascular disease and neural tube defects. The polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (FADH(2)) (MTHFR) influences the tHcy concentration and the response to tHcy-lowering therapy. Supplementation with folic acid (FA) decreases plasma tHcy, but limited data are available on the effect of 5-methyltetrahydrofolate (MTHF). OBJECTIVE: We evaluated the tHcy-lowering potential of low-dose FA and of MTHF with respect to the MTHFR genotype. DESIGN: In this randomized, placebo-controlled, double-blind study, 160 women received 400 microg FA, the equimolar amount of MTHF (480 microg, racemic mixture), or a placebo daily during an 8-wk treatment period. Blood samples were collected at baseline and at 4 and 8 wk. RESULTS: Changes in plasma tHcy concentration depended on the supplemented folate derivative and the MTHFR genotype. Supplementation with FA significantly decreased tHcy concentrations by > or = 13% in women of all 3 genotypes after both 4 and 8 wk. The greatest decrease was 20% (P < 0.05) in the women with the TT genotype after 4 wk. MTHF supplementation also decreased tHcy, but only the women with the CT genotype had a significant decrease after 4 wk (7%; P < 0.05). The largest nonsignificant reduction (15%) occurred in the women with the TT genotype after 4 wk of MTHF supplementation. CONCLUSIONS: The response to tHcy-lowering therapy is influenced by MTHFR genotype. Women with the TT genotype seem to benefit the most from supplementation with either FA or MTHF. In women with the CT or CC genotype, FA is more effective than MTHF in lowering plasma tHcy.

Folate status in Germany 1997-2000.

Data about folate intake and blood values of the German population, published between 1997 and 2000, have been reviewed. Median folate intake is about 250 micrograms/day in the adult population, which indicates a high likelihood of inadequate intake when compared to the Estimated Average Requirement (EAR) of 320 micrograms/day. Only a few studies have evaluated serum and erythrocyte folate or plasma homocysteine as a marker of folate status. The most representative data show that 25% of German women of childbearing age have an inadequate recent folate intake. Only 13.3% of the women have red blood cell folate values above the critical value of 400 micrograms/day established by Daly et al (1995). Folic acid fortification of food is shown to be responsible for about 25% of folate intake in the German child and adolescent population in one study. If we extrapolate these data to the general population, folic acid fortification could be the explanation for the differences observed between folate intake and blood values. The discrepancy might also be explained by slight inaccuracies in food composition tables. Folate intake from fortified food or from supplements is not taken into account in most of the studies, which is a variable that can lead to confusion. Nutrition surveys should adapt official composition tables for local food patterns, and include fortified commercial foods, in order to make folate intake data more accurate. However, representative serum and erythrocyte folate values are lacking for most age groups. Before taking public health measures concerning folate fortification of food, the real folate status of the German population should be established.