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Background: Vestibular migraine (VM) is the most frequent cause of recurrent spontaneous attacks of vertigo causally related to migraine. The objective of the Prophylactic treatment of vestibular migraine with metoprolol (PROVEMIG) trial was to demonstrate that metoprolol succinate is superior to placebo in the prevention of episodic vertigo- and migraine-related symptoms in patients with VM., Methods: This phase III, two-arm, parallel-group, double-blind, randomized placebo-controlled trial was designed to be conducted at tertiary referral centres at neurology and ear, nose and throat departments of eight German university hospitals. The planned sample size was a total of 266 patients to be allocated. Adults aged 18 years or above diagnosed with probable or definitive VM according to the Neuhauser criteria 2001 were randomly assigned 1:1 to 6 months blinded metoprolol (maintenance dosage of 95 mg daily) or placebo. The primary efficacy outcome was the self-reported number of vertiginous attacks per 30 days documented by means of a paper-based daily symptom diary. The pre-specified time period of primary interest was defined as months 4 to 6. Secondary outcomes included the patient-reported number of migraine days and vertigo days, the Dizziness Handicap Inventory, and clinical assessments. Adverse events were reported throughout the whole 9-month study period., Results: At the time of trial termination, no evidence for a difference in the incidence of vertiginous attacks between groups was detected. For the full analysis set, the incidence rate ratio was 0.983 (95% confidence interval (CI) 0.902-1.071) for metoprolol versus placebo. In both groups, there was a significant decline over time in the overall monthly vertigo attacks by a factor of 0.830 (95% CI 0.776-0.887). Results were consistent for all subjective and objective key measures of efficacy. The treatment was well tolerated with no unexpected safety findings., Conclusions: After randomizing 130 patients PROVEMIG had to be discontinued because of poor participant accrual not related to the tolerability of the study medication or safety concerns; no treatment benefit of metoprolol over placebo could be established. Additional preparatory work is much needed in the development, psychometric evaluation and interpretation of clinically meaningful end points in trials on episodic syndromes like VM taking into consideration the complexity of this disease entity comprising two domains (vertigo- and headache-related disability)., Trial Registration: EudraCT, 2009-013701-34. Prospectively registered on 8 April 2011.

Background: Cerebellar ataxia (CA) is a frequent and often disabling condition that impairs motor functioning and impacts on quality of life (QoL). No medication has yet been proven effective for the symptomatic or even causative treatment of hereditary or non-hereditary, non-acquired CA. So far, the only treatment recommendation is physiotherapy. Therefore, new therapeutic options are needed. Based on three observational studies, the primary objective of the acetyl-DL-leucine on ataxia (ALCAT) trial is to examine the efficacy and tolerability of a symptomatic therapy with acetyl-DL-leucine compared to placebo on motor function measured by the Scale for the Assessment and Rating of Ataxia (SARA) in patients with CA., Methods/design: An investigator-initiated, multicenter, European, randomized, double-blind, placebo-controlled, 2-treatment 2-period crossover phase III trial will be carried out. In total, 108 adult patients who meet the clinical criteria of CA of different etiologies (hereditary or non-hereditary, non-acquired) presenting with a SARA total score of at least 3 points will be randomly assigned in a 1:1 ratio to one of two different treatment sequences, either acetyl-DL-leucine (up to 5 g per day) followed by placebo or vice versa. Each sequence consists of two 6-week treatment periods, separated by a 4-week wash-out period. A follow-up examination is scheduled 4 weeks after the end of treatment. The primary efficacy outcome is the absolute change in the SARA total score. Secondary objectives are to demonstrate that acetyl-DL-leucine is effective in improving (1) motor function measured by the Spinocerebellar Ataxia Functional Index (SCAFI) and SARA subscore items and (2) QoL (EuroQoL 5 dimensions and 5 level version, EQ-5D-5 L), depression (Beck Depression Inventory, BDI-II) and fatigue (Fatigue Severity Score, FSS). Furthermore, the incidence of adverse events will be investigated., Discussion: The results of this trial will inform whether symptomatic treatment with the modified amino-acid acetyl-DL-leucine is a worthy candidate for a new drug therapy to relieve ataxia symptoms and to improve patient care. If superiority of the experimental drug to placebo can be established it will also be re-purposing of an agent that has been previously used for the symptomatic treatment of dizziness., Trial Registration: The trial was prospectively registered at www.clinicaltrialsregister.eu (EudraCT no. 2015-000460-34) and at https://www.germanctr.de (DRKS-ID: DRKS00009733 ).

Background: Gestational weight gain (GWG) has been shown to be a risk factor for overweight in offspring.Aim of this study was to quantify the contributions of trimester-specific and total GWG on offspring's BMI and waist circumference (WC). This is of interest for the design of interventions targeted at women showing a high GWG in early pregnancy., Methods: In a retrospective cohort study data on GWG (total and by trimester, exposure), a number of potential confounders, and children's BMI z-scores and WC (outcomes) were analyzed using structural equation models to disentangle the trimester-specific direct effects of GWG and indirect effects mediated via total GWG., Results: 7313 mother child pairs with a children's mean age of 5.81 years were analyzed. Total effects (indirect + direct) of GWG (kg/week) on children's BMI z-score and WC (cm) were observed in all trimesters, most prominently in the second. The longitudinal effect of GWG is a composite of trimester-specific direct effects (on BMI: 0.105, 0.255, 0.002, on WC: 0.538, 1.64, 0.308) and total GWG (on BMI 0.608, on WC: 1.03) at the end of pregnancy., Conclusions: Both trimester-specific priming and total GWG explained offspring's anthropometrics. The results indicate, that reversal from additional weight gain attained early in pregnancy resulting in normal total GWG at the end of pregnancy might still contribute to a substantial reduction of offspring's BMI and WC.

Background: The original Logistic Organ Dysfunction Sore (LODS) excluded cardiac surgery patients from its target population, and the suitability of this score in cardiac surgery patients has never been tested. We evaluated the accuracy of the LODS and the usefulness of its daily measurement in cardiac surgery patients. The LODS is not a true logistic scoring system, since it does not use β-coefficients., Methods: This prospective study included all consecutive adult patients who were admitted to the intensive care unit (ICU) after cardiac surgery between January 2007 and December 2008. The LODS was calculated daily from the first until the seventh postoperative day. Performance was assessed with Hosmer-Lemeshow (HL) goodness-of-fit test (calibration) and receiver operating characteristic (ROC) curves (discrimination) from ICU admission day until day 7. The outcome measure was ICU mortality., Results: A total of 2801 patients (29.6% female) with a mean age of 66.4 ± 10.7 years were included. The ICU mortality rate was 5.2% (n = 147). The mean stay on the ICU was 4.3 ± 6.8 days. Calibration of the LODS was good with no significant difference between expected and observed mortality rates on any day (p ≥ 0.05). The initial LODS had an area under the ROC curve (AUC) of 0.81. The AUC was best on ICU day 3 with a value of 0.93, and declined to 0.85 on ICU day 7., Conclusions: Although the LODS has not previously been validated for cardiac surgery patients it showed reasonable accuracy in prediction of ICU mortality in patients after cardiac surgery.

Background: Outcome prediction scoring systems are increasingly used in intensive care medicine, but most were not developed for use in cardiac surgery patients. We compared the performance of four intensive care outcome prediction scoring systems (Acute Physiology and Chronic Health Evaluation II [APACHE II], Simplified Acute Physiology Score II [SAPS II], Sequential Organ Failure Assessment [SOFA], and Cardiac Surgery Score [CASUS]) in patients after open heart surgery., Methods: We prospectively included all consecutive adult patients who underwent open heart surgery and were admitted to the intensive care unit (ICU) between January 1st 2007 and December 31st 2008. Scores were calculated daily from ICU admission until discharge. The outcome measure was ICU mortality. The performance of the four scores was assessed by calibration and discrimination statistics. Derived variables (Mean- and Max- scores) were also evaluated., Results: During the study period, 2801 patients (29.6% female) were included. Mean age was 66.9 ± 10.7 years and the ICU mortality rate was 5.2%. Calibration tests for SOFA and CASUS were reliable throughout (p-value not < 0.05), but there were significant differences between predicted and observed outcome for SAPS II (days 1, 2, 3 and 5) and APACHE II (days 2 and 3). CASUS, and its mean- and maximum-derivatives, discriminated better between survivors and non-survivors than the other scores throughout the study (area under curve ≥ 0.90). In order of best discrimination, CASUS was followed by SOFA, then SAPS II, and finally APACHE II. SAPS II and APACHE II derivatives had discrimination results that were superior to those of the SOFA derivatives., Conclusions: CASUS and SOFA are reliable ICU mortality risk stratification models for cardiac surgery patients. SAPS II and APACHE II did not perform well in terms of calibration and discrimination statistics.

Background: Vertigo and dizziness are symptoms which are reported frequently in clinical practice. We aimed to develop diagnostic indices for four prevalent vertiginous diseases: benign paroxysmal positional vertigo (BPPV), Menière's disease (MD), vestibular migraine (VM), and phobic postural vertigo (PPV)., Methods: Based on a detailed questionnaire handed out to consecutive patients presenting for the first time in our dizziness clinic we preselected a set of seven questions with desirable diagnostic properties when compared with the final diagnosis after medical workup. Using exact logistic regression analysis diagnostic scores, each comprising of four to six items that can simply be added up, were built for each of the four diagnoses., Results: Of 193 patients 131 questionnaires were left after excluding those with missing consent or data. Applying the suggested cut-off points, sensitivity and specificity were 87.5 and 93.5% for BPPV, 100 and 87.4% for MD, 92.3 and 83.7% for VM, 73.7 and 84.1% for PPV, respectively. By changing the cut-off points sensitivity and specificity can be adjusted to meet diagnostic needs., Conclusions: The diagnostic indices showed promising diagnostic properties. Once further validated, they could provide an ease to use and yet flexible tool for screening vertigo in clinical practice and epidemiological research.

Background: Co-morbidities of vertiginous diseases have so far not been investigated systematically. Thus, it is still unclear whether the different vertigo syndromes (e.g. benign paroxysmal positional vertigo (BPPV), Meniere's disease (MD), vestibular migraine and phobic vertigo (PPV)) have also different spectrums of co-morbidities., Methods: All patients from a cohort of 131 participants were surveyed using a standardised questionnaire about the co-morbidities hypertension, diabetes mellitus, BMI (body mass index), migraine, other headache, and psychiatric diseases in general and the likelihood of a depression in particular., Results: We noted hypertension in 29.0% of the cohort, diabetes mellitus in 6.1%, migraine in 8.4%, other headache in 32.1%, psychiatric diseases in 16.0%, overweight and obesity in 33.6% and 13.7% respectively, as well as a clinical indication for depression in 15.9%., Conclusion: In general, we did not detect an increased prevalence of the co-morbidities diabetes mellitus, arterial hypertension, migraine, other headache and obesity compared to the general population. There was an increased prevalence of psychiatric co-morbidity in patients with PPV, and the prevalence of hypertension was elevated in patients with MD.