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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 Autologous progenitor cell therapy comprising granulocyte-colony stimulating factor (G-CSF) for mobilization of bone-marrow derived progenitor cells (BMPCs) into peripheral blood and inhibition of dipeptidylpeptidase-IV by sitagliptin for enhanced myocardial recruitment of circulating BMPCs has been shown to improve survival after acute myocardial infarction (MI) in preclinical studies. In the SITAGRAMI trial we found that during short-term follow-up G-CSF plus sitagliptin (GS) failed to show a beneficial effect on cardiac function and clinical events in patients with acute MI that underwent successful PCI. The objective of the present analysis was to assess the impact of GS versus placebo treatment on long-term clinical outcomes of the SITAGRAMI trial patient population. Methods In the randomized, prospective, double-blind, placebo-controlled SITAGRAMI trial, 174 patients with acute MI were assigned to GS or placebo in a 1:1 ratio. The primary outcome for the present long-term analysis was the composite of death, MI or stroke on long-term follow-up. Results The median [IQR] follow-up duration was 4.50 [3.56–5.95] years. The primary outcome occurred in 12.8% of patients assigned to placebo and 9.2% assigned to GS (HR 0.69, 95% CI 0.28–1.69; p=0.42). The incidence of the combined cardiovascular outcome was 47.7% in the placebo- and 41.4% in the GS-group (HR 0.75, 95% CI 0.48–1.18; p=0.21). Overall, there was no significant difference in MACCE rates between both treatment groups (p=0.41). Conclusion These long-term follow-up data indicate that GS therapy does not improve clinical outcomes of patients with acute MI.

Convergent strabismus is a common diagnosis in early childhood, when it is mostly considered benign. If it develops later in life, strabismus can, however, be a sign of neurological disease. In these cases the underlying pathophysiological mechanisms are largely unknown. In this retrospective case–control study we analyzed the neuro-ophthalmological examination reports of 400 adult patients who presented at the German Center for Vertigo and Balance Disorders to determine an association between ocular misalignment and cerebellar dysfunction. Patients with cerebellar signs (i.e., cerebellar ataxia and/or cerebellar ocular motor signs) had a 4.49 (95 % CI [1.60; 13.78]) times higher frequency of ocular misalignment and specifically a 13.3 (95 % CI [3.80; 55.73]) times increased frequency of esophoria/esotropia (ESO) during distant gaze than patients without cerebellar dysfunction. ESO when looking into the distance was associated with saccadic smooth pursuit, dysmetria of saccades, and downbeat nystagmus (DBN) (χ 2 test, p

Background Patients with acquired brain injury who have been discharged from inpatient neurological rehabilitation often continue to suffer from limited independence, participation, and quality of life. Participation-focused outpatient treatment (in German: teilhabeorientierte ambulan. Methods In a randomized, controlled trial, 53 patients who had sustained an acquired brain injury approximately four years earlier were allotted to two different sequences of treatment (26 TEAM/control, 27 control/TEAM). The primary endpoint was the achievement of an individual participation goal one month after the start of treatment. The secondary endpoints included independence in everyday activities, health-related quality of life, participation, and need for nursing care. The intervention was four weeks long and was carried out on an outpatient basis (19.4 ± 1.3 hours per week). Patients in the control group were treated in a manner resembling usual current care. All endpoints were evaluated in a per-protocol (PP) analysis of data from 47 patients. For confirmation, an intention-to-treat (ITT) analysis was also carried out for the primary endpoint and for independence in everyday activities. Results According to the PP analysis, TEAM patients achieved their individual participation goals at 1 month more frequently than control patients receiving standard treatment (61% vs. 21%; p = 0.008) and improved more with respect to independence in everyday activities. The difference between TEAM and standard treatment was +7.3 points on the FIM (Functional Independence Measure) scale (95% confidence interval [2.8; 11.8]; p = 0.0024). The superiority of TEAM was confirmed by the ITT analysis (achievement of the participation goal, TEAM vs. standard treatment: 54% vs. 19%, p = 0.0103). Moreover, improvements were seen at 12 months in quality of life, participation, and the need for nursing care. Conclusion The TEAM rehabilitation program can help patients in the chronic phase of acquired brain injury achieve participation goals that are relevant to everyday life. An adjustment of the care structure in Germany to include such intensive goal-oriented rehabilitation programs would lead to a more effective mobilization of these patients' potential for long-term rehabilitation.

Background: A high percentage of patients with vestibular migraine (VM) were reported to have central ocular motor dysfunctions (COMD) in the symptom-free interval. Since VM is a chronic disorder, it is of interest if COMD worsen over time. Methods: Thirty VM patients and 11 control patients participated in an 8-year-long observational study with follow-up. All patients underwent standardized neuro-ophthalmological and neuro-otological examinations at the initial presentation and at follow-up. The primary outcome measure was change in COMD at follow-up. Results: In general, COMD in the symptom-free interval were subtle, consisting of a saccadic horizontal and/or vertical pursuit. At follow-up, significantly more patients with VM had COMD (p = 0.015). The prevalence of COMD increased from 20 to 63% in VM patients. Further, the presence of COMD at follow-up had a positive predictive value of 90.5% for the diagnosis of VM. Successful treatment with prophylactic migraine medication seems to prevent the development and worsening of COMD (p = 0.008). Conclusion: Mild COMD occur in a large percentage of VM patients during the course of the disease. The presence of COMD is predictive of VM in patients with recurrent attacks of vertigo. Prophylactic migraine medication seems to attenuate the development and progression of COMD.

Objective: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus. Methods: After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis. Results: The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 ( p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP ( p = 0.08). The VDADL score decreased from 6.00 to 1.50 ( p = 0.02). 4AP was well-tolerated. Conclusions: This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. Level of evidence: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.

The objective of this study was to evaluate the clinical benefit and the side effects of high dosages of betahistine dihydrochloride (288-480 mg/day) in patients with severe Menière's disease (MD). In this case series 11 patients with MD who had not responded sufficiently to a dosage of 144 mg/day of betahistine dihydrochloride were treated on an individual basis with daily dosages between 288 and 480 mg of betahistine dihydrochloride. The number of attacks per month and the side effects were monitored. Non-parametric tests were used for statistical analysis. As a result, the frequency and the severity of vertigo were significantly reduced in all patients. The side effects were mild, self-limiting, and did not require any change in the treatment strategy. Despite the considerable limitations of an observational study--in particular in MD--high dosages of betahistine dihydrochloride between 288 and 480 mg/day seem to be effective in patients who do not sufficiently respond to lower dosages. Moreover, such dosages are well tolerated.

Objective In animal models, G-CSF based progenitor cell mobilization combined with a DPP4 inhibitor leads to increased homing of bone marrow derived progenitor cells to the injured myocardium via the SDF1/CXCR4 axis resulting in improved ejection fraction and survival after acute myocardial infarction (AMI). Research design and methods After successful revascularization in AMI, 174 patients were randomized 1:1 in a multi-centre, prospective, placebo-controlled, parallel group, double blind, phase III efficacy and safety trial to treatment with G-CSF and Sitagliptin (GS) or placebo. Diabetic and non-diabetic patients were included in our trial. The primary efficacy endpoint hierarchically combined global left and right ventricular ejection fraction changes from baseline to 6months of follow-up (Δ LVEF , Δ RVEF ), as determined by cardiac MRI. Results At follow-up Δ LVEF as well as Δ RVEF did not differ between the GS and placebo group. Patients in the placebo group had a similar risk for a major adverse cardiac event within 12months of follow-up as compared to patients under GS. Conclusion Progenitor cell therapy comprising the use of G-CSF and Sitagliptin after successfully revascularized acute myocardial infarction fails to show a beneficial effect on cardiac function and clinical events after 12months. (EudraCT: 2007–003,941-34; ClinicalTrials.gov: NCT00650143, funding: Heinz-Nixdorf foundation).

To investigate and compare several quantification methods of myocardial perfusion measurements, paying special attention to the relation between the techniques and the required measurement duration.Seven patients underwent contrast-enhanced rest and stress cardiac perfusion measurements at 3T. Three slices were acquired in each patient and were divided into 16 segments, leading to 112 rest and stress data curves, which were analyzed using various tracer kinetic models as well as a model-free deconvolution. Plasma flow, plasma volume, and myocardial perfusion reserve were analyzed for the complete acquisition as well as for the first pass data only.Deconvolution analysis yielded stable results for both rest and stress analysis, while Fermi and one compartment models agree well for first pass data (rest measurements only) and prolonged data acquisition (stress measurements only). More complex models do not yield satisfactory results for the short measurement times investigated in this study.When performing MRI-based quantification of myocardial perfusion, care must be taken that the method used is appropriate for the time frame under investigation. When a numerical deconvolution is used instead of tracer kinetic models, more stable results are obtained.

Purpose. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. Methods. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. Results. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to population-based control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. Conclusions. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.

PURPOSE. To evaluate the role of fellow eye status in determining progression of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). METHODS. A total of 300 eyes with GA of 193 patients from the prospective, longitudinal, natural history FAM Study were classified into three groups according to the AMD manifestation in the fellow eye at baseline examination: (1) bilateral GA, (2) early/intermediate AMD, and (3) exudative AMD. GA areas were quantified based on fundus autofluorescence images using a semiautomated image-processing method, and progression rates (PR) were estimated using two-level, linear, mixed-effects models. RESULTS. Crude GA-PR in the bilateral GA group (mean, 1.64 mm(2)/y; 95% CI, 1.478-1.803) was significantly higher than in the fellow eye early/intermediate group (0.74 mm(2)/y, 0.146-1.342). Although there was a significant difference in baseline GA size (P = 0.0013, t-test), and there was a significant increase in GA-PR by 0.11 mm(2)/y (0.05-0.17) per 1 disc area (DA; 2.54 mm(2)), an additional mean change of -0.79 (-1.43 to -0.15) was given to the PR beside the effect of baseline GA size. However, this difference was only significant when GA size was ≥1 DA at baseline with a GA-PR of 1.70 mm(2)/y (1.54-1.85) in the bilateral and 0.95 mm(2)/y (0.37-1.54) in the early/intermediate group. There was no significant difference in PR compared with that in the fellow eye exudative group. CONCLUSIONS. The results indicate that the AMD manifestation of the fellow eye at baseline serves as an indicator for disease progression in eyes with GA ≥ 1 DA. Predictive characteristics not only contribute to the understanding of pathophysiological mechanisms, but also are useful for the design of future interventional trials in GA patients.

PURPOSE To determine the degree of concordance for progression rate, size of atrophy, and visual acuity in patients with bilateral geographic atrophy (GA) due to age-related macular degeneration (AMD). METHODS Analysis was performed in 156 eyes of 78 patients with bilateral GA. Best corrected visual acuity was determined with ETDRS charts. GA was quantified in digital fundus autofluorescence images (excitation, 488 nm; emission, >500 nm) by semiautomated imaging analysis. A linear, two-level, random-effects model was used to assess the natural course of disease. The concordance correlation coefficient (CCC) was calculated to assess the degree of agreement between disease characteristics of the left and right eyes. Bland-Altman plots were applied to compare measurements in the eyes. RESULTS CCC between the eyes was 0.310 (95% CI, 0.097-0.495) for visual acuity, 0.706 (95% CI, 0.575-0.801) for GA size, and 0.756 (95% CI, 0.644-0.837) for GA progression rate. Although Bland-Altman plots revealed high concordance for the progression rate, there was considerable discrepancy between both eyes for GA size. [corrected] CONCLUSIONS GA progression in bilateral atrophic AMD is a symmetrical process; however, GA size may differ substantially between the eyes. High concordance in intraindividual disease progression in the presence of a high degree of interindividual variability indicates an influence by genetic and/or environmental factors rather than nonspecific ageing changes. The relatively small concordance of GA size in this cohort may indicate asymmetric evolution of the disease in affected individuals. The results may be useful in the design of future clinical trials designed to slow the rate of GA progression (Clinical Trials.gov number, NCT00393692).

Background Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown. Methodology/Principal Findings Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6×10−9, 3.2×10−3, and P = 2.6×10−12, respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm2/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13). Conclusions/Significance This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression.

Background: Vestibular paroxysmia (VP), which is attributed to neurovascular cross-compression (NVCC), leads to vertiginous spells. Although VP was described more than 30 years ago by Jannetta and colleagues, we still need more reliable data on its diagnostic features and the efficacy of medical treatment. Methods: A follow-up study of 32 patients with recurrent short spells of vertigo and with diagnosis of VP by published criteria was performed using medical records and patient consultation (mean follow-up time 31.3 months). Results: In 28% of patients the attacks occurred exclusively when at rest, whereas in 22% they were regularly precipitated by a certain action, most frequently a head turn (60%). The most common accompanying symptom was unsteadiness of stance or gait (75%). Constructive interference in steady state magnetic resonance imaging (n = 23) demonstrated at least one site of NVCC in all but one patient. Caloric testing disclosed a mild increase in vestibular deficit over time, and a hyperventilation-induced nystagmus was found in 70% of the tested patients (n = 23). The majority of patients were treated with carbamazepine (mean dose 568 mg/d) or oxcarbazepine (mean dose 870 mg/d). Treatment led to a significant reduction in the attack frequency to 10% of baseline (95% CI 6.69–14.96%), in attack intensity to 15% (95% CI 11.57–19.63%), and a reduction in attack duration to 11% (95% CI 6.72–17.40), after adjusting for time effects. Conclusion: This follow-up proves the usefulness of the diagnostic criteria, especially constructive interference in steady state magnetic resonance imaging, and the therapeutic efficacy of medical treatment.