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Background and ObjectivesAlzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of β-amyloid (Aβ) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aβ and tau pathology.MethodsOne hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, 18F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB− (less than Centiloid [CL] 20) and then expanded to include PiB+ individuals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aβ (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time.ResultsSteeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those CL40).DiscussionEarly, Aβ-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aβ and tau pathology. Composites of these measures may help determine whether anti-Aβ or anti-tau therapies administered at the first signs of pathology might preserve cognitive function.Classification of EvidenceThis study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.

Background and Purpose: High-serum glucose on admission is a predictor of poor outcome after stroke. We assessed the association between glucose concentrations and clinical outcomes in patients who underwent endovascular treatment. Methods: From the MR CLEAN Registry, we selected consecutive adult patients with a large vessel occlusion of the anterior circulation who underwent endovascular treatment and for whom admission glucose levels were available. We assessed the association between admission glucose and the modified Rankin Scale score at 90 days, symptomatic intracranial hemorrhage and successful reperfusion rates. Hyperglycemia was defined as admission glucose ≥7.8 mmol/L. We evaluated the association between glucose and modified Rankin Scale using multivariable ordinal logistic regression and assessed whether successful reperfusion (extended Thrombolysis in Cerebral Infarction 2b-3) modified this association. Results: Of 3637 patients in the MR CLEAN Registry, 2908 were included. Median admission glucose concentration was 6.8 mmol/L (interquartile range, 5.9–8.1) and 882 patients (30%) had hyperglycemia. Hyperglycemia on admission was associated with a shift toward worse functional outcome (median modified Rankin Scale score 4 versus 3; adjusted common odds ratio, 1.69 [95% CI, 1.44–1.99]), increased mortality (40% versus 23%; adjusted odds ratio, 1.95 [95% CI, 1.60–2.38]), and an increased risk of symptomatic intracranial hemorrhage (9% versus 5%; adjusted odds ratio, 1.94 [95% CI, 1.41–2.66]) compared with nonhyperglycemic patients. The association between admission glucose levels and poor outcome (modified Rankin Scale score 3–6) was J -shaped. Hyperglycemia was not associated with the rate of successful reperfusion nor did successful reperfusion modify the association between glucose and functional outcome. Conclusions: Increased admission glucose is associated with poor functional outcome and an increased risk of symptomatic intracranial hemorrhage after endovascular treatment.

Background: Microvascular dysfunction (MVD) contributes to stroke, dementia, depression, retinopathy and chronic kidney disease. However, the determinants of MVD are incompletely understood. Greater blood pressure variability (BPV) may be one such determinant.Methods and results: We used cross-sectional data of The Maastricht Study (n = 2773, age 59.9 years; 51.9% men) to investigate whether greater very short- to mid-term BPV is associated with various MVD measures. We standardized and averaged within-visit, 24-h and 7-day BPV into a systolic and a diastolic BPV composite score. MVD measures included a composite score of MRI cerebral small vessel disease (CSVD) features (total brain parenchymal volume, white matter hyperintensity volume, lacunar infarcts and cerebral microbleeds), a composite score of flicker light-induced retinal arteriolar and venular dilation response, albuminuria, heat-induced skin hyperemia and a composite score of plasma biomarkers of MVD (sICAM-1, sVCAM-1, sE-selectin and von Willebrand Factor). We used linear regression adjusted for age, sex, glucose metabolism status, mean 24-h systolic or DBP, cardiovascular risk factors and antihypertensive medication. We found that higher systolic and diastolic BPV composite scores (per SD) were associated with higher albuminuria [higher ratio, 1.04 (95% CI 1.00–1.08) and 1.07 (1.03–1.11), respectively], but not with other measures of MVD tested.Conclusion: Greater systolic and diastolic BPV was associated with higher albuminuria, but not with CSVD features, flicker light-induced retinal arteriolar and venular dilation response, heat-induced skin hyperemia and plasma biomarkers of MVD. This suggests that the microvasculature of the kidneys is most vulnerable to the detrimental effects of greater BPV.

Contains fulltext : 219370.pdf (Publisher’s version ) (Closed access) Background: Comorbid personality disorders are assumed to negatively interfere with the treatment outcome of affective disorders. Data on late-life panic disorder remain unknown. We examined the association of personality pathology and treatment outcome related to age and treatment modality. Methods: An observational study on the effectiveness of cognitive-behavioral therapy (CBT) for panic disorder with agoraphobia among patients 18 to 74 years of age and randomized controlled comparison of paroxetine and CBT in older patients (60 y of age or older) were performed. The diagnosis of panic disorder was confirmed by the Anxiety Disorder Interview Schedule-Revised (ADIS-IV) and personality features were assessed with the Personality Diagnostic Questionnaire. The impact of personality features on either agoraphobic cognitions (Agoraphobic Cognitions Questionnaire) or avoidance behavior (Mobility Inventory Avoidance Scale) was examined by multiple linear regression analyses adjusted for sex, level of education, duration of illness, comorbid psychopathology, and baseline severity. The interaction between personality and age was examined among those treated with CBT (n=90); the interaction between personality and treatment modality was examined among the older subgroup (n=34). Results: Cluster B personality pathology (evaluated on the basis of either Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria depending on the date of assessment) was negatively associated with outcomes of CBT in both younger and older adults with panic disorder and agoraphobia. Older adults with a higher number of features of any personality pathology or cluster A pathology had worse treatment outcomes when treated with paroxetine compared with CBT. Conclusions: Cluster B pathology had a detrimental effect on CBT treatment outcome for panic disorder in both age groups. In late-life panic disorder with comorbid personality pathology, CBT may be preferred over treatment with paroxetine. 11 p.

Background and Purpose— Patients with acute ischemic stroke treated with endovascular thrombectomy may be treated with repeat endovascular thrombectomy (rEVT) in case of recurrent large vessel occlusion. Data on safety and efficacy of these interventions is scarce. Our aim is to report on frequency, timing, and outcome of rEVT in a large nation-wide multicenter registry. Methods— In the Netherlands, all patients with endovascular thrombectomy have been registered since 2002 (MR CLEAN Pretrial registry, MR CLEAN Trial [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], and MR CLEAN Registry). We retrospectively reviewed these databases for anterior circulation rEVT cases. Patient characteristics, procedural data, and functional outcome (modified Rankin Scale at 90 days) were analyzed. Results— Of 3928 patients treated between 2002 and 2017, 27 (0.7%) underwent rEVT. Median time between first and second procedure was 78 (1–1122) days; 11/27 patients were re-treated within 30 days. Cardioembolism was the most common etiology (18 patients [67%]). In 19 patients (70%), recurrent occlusion occurred ipsilateral to previous occlusion. At 90 days after rEVT procedure, 44% of the patients had achieved functional independence (modified Rankin Scale score of 0–2), and 33% had died. Adverse events were 2/27 (7.4%) intracranial hemorrhage, 1/27 (3.7%) stroke progression, and 1/27 (3.7%) pneumonia. Conclusions— In this large nationwide cohort of patients with acute ischemic stroke treated with endovascular thrombectomy, rEVT was rare. Stroke cause was mainly cardio-embolic, and most recurrent large vessel occlusions in which rEVT was performed occurred ipsilateral. Although there probably is a selection bias on repeated treatment in case of recurrent large vessel occlusion, rEVT appears safe, with similar outcome as in single-treated cases.

Background and ObjectivesThe clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity.MethodsWe used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors.ResultsFor validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort.DiscussionmEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, also in countries outside the Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America.Classification of EvidenceThis study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in patients with GBS.Trial Registration InformationNCT01582763.

Background and ObjectivesOculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Disease progression is known to be slow, but details on the natural history remain unknown. We aimed to examine the natural history of OPMD in a large nationwide cohort to determine clinical outcome measures that capture disease progression and can be used in future clinical trials.MethodsPatients invited by their treating physicians or identified from the national neuromuscular database and invited family members were examined twice 20 months apart with fixed dynamometry; Medical Research Council (MRC) grading; maximum bite force and isometric tongue strength; Motor Function Measure (MFM); 10-step stair test; maximum swallowing, chewing, and speech tasks; and quality of life assessments.ResultsDisease progression was captured by 8 of 18 measures over 20 months in 43 patients with genetically confirmed OPMD. The largest deterioration was seen in deltoid muscle strength (−27% [range −17% to −37%]), followed by the quadriceps (−14% [range −6 to −23%]), iliopsoas (−12.2%), tongue (−9.9%), and MRC sum score (−2.5%). The 10-step stair test (−12.5%), MFM part D1 (−7.1%), and maximum repetition rate of /pa/ (−5.3%) showed a significant decrease as well (all p < 0.05). The Physical Functioning domain of the Short Form-36 Health Survey significantly deteriorated (p = 0.044). No relationship was found between disease progression and genotype or disease duration (p > 0.05).DiscussionDespite the slow disease progression of OPMD, this study showed that several outcome measures detected progression within 20 months. Deltoid muscle strength, measured by fixed dynamometry, showed the greatest decline. These longitudinal data provide clinical outcome measures that can be used as biomarkers in future clinical trials.

ObjectiveTo compare how structural MRI, fluorodeoxyglucose (FDG), and flortaucipir (FTP) PET signals predict cognitive decline in high-amyloid vs low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials.MethodsIn this prospective cohort study, we analyzed data from clinically normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and Pittsburgh compound B (PiB)-PET acquired within a year and prospective cognitive evaluations over a mean 3-year follow-up. We focused analyses on predefined regions of interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed with the Preclinical Alzheimer's Cognitive Composite. We evaluated the association between biomarkers and cognitive decline using linear mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials.ResultsData from 131 participants (52 women, age 73.98 ± 8.29 years) were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high PiB.DiscussionIn preclinical Alzheimer disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials.Classification of EvidenceThis study provides Class II evidence that in people with preclinical Alzheimer disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.

OBJECTIVE: In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS.METHODS: Eligible patients with RRMS treated with SC interferon-β-1a (IFN-β-1a) 44 μg 3 times weekly and serum 25(OH)D levels RESULTS: At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035).CONCLUSIONS: SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-β-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS.CLINICALTRIALSGOV IDENTIFIER: NCT01285401.CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS treated with SC IFN-β-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.

Introduction Iodine-124 positron emission tomography/computed tomography (I-124 PET/CT) is increasingly being used in the absorbed dose estimation in the radioiodine treatment of differentiated thyroid cancer (DTC). However, the produced prompt gamma coincidences (PGCs) associated with the I-124 decay result in a bias in the absorbed dose estimation. The impact of a sinogram-based PGC correction approach on the absorbed dose estimation in I-124 PET/CT DTC imaging is investigated. Methods I-124 phantom and patient measurements were performed on a Siemens Biograph mCT PET/CT system. All images were reconstructed with (PGC(on)) and without PGC correction (PGC(off)). The phantom contained seven spheres (diameters: 6.6-37 mm). The spheres and background compartment were filled with a I-124 solution, resulting in a low (9.4 : 1) and a high sphere-to-background activity concentration ratio (750 : 1). Sphere recovery coefficient (RC) values were determined. In addition, the impact of PGC correction on measured lesion uptake and calculated lesion-absorbed dose was assessed for 66 lesions identified in 24 DTC patients. Results PGC correction systematically increased sphere RC values up to 71% for the smallest spheres. For the patient data, PGC correction significantly increased both the measured I-124 uptake (P

Plastic and reconstructive surgery : global open 9(2), e3394 (2021). doi:10.1097/GOX.0000000000003394, Published by Lippincott Williams & Wilkins, Philadelphia, Pa.

Background: Fibromuscular dysplasia (FMD) and atherosclerotic renal artery stenosis (ARAS) are the most common causes of renovascular hypertension. So far, FMD is believed to cause hypertension via similar mechanisms as in ARAS, that is, a decrease in renal blood flow, which subsequently leads to increased renin secretion. However, given the differences in the blood pressure (BP)-lowering effect of revascularization between patients with ARAS and FMD, we questioned whether this is true.Methods: We measured renal blood flow (133 Xenon washout method) and renin secretion per kidney and their relationship to BP in a cohort of 64 patients with multifocal FMD and 110 patients with ARAS (off medication, prior to revascularization).Results: We found that renal blood flow is significantly higher in FMD as compared with ARAS. In patients with unilateral ARAS, renin secretion was increased in the affected kidney as compared with the unaffected kidney. This lateralization in renin secretion, however, was not found in unilateral FMD. After correction for differences in baseline characteristics, we found that systemic renin levels and local renin secretion was lower in FMD as compared with ARAS. Moreover, the relationship between BP and renin secretion in FMD was inverse to that in ARAS.Conclusion: These findings argue against the hypothesis that FMD induces hypertension via similar pathophysiological mechanism as in ARAS.

Objective:As blood–brain barrier (BBB) dysfunction may occur in normal aging but may also play a pivotal role in the pathophysiology of cerebral small vessel disease (cSVD), we used dynamic contrast-enhanced (DCE)–MRI to quantify the rate and the spatial extent of BBB leakage in patients with cSVD and age- and sex-matched controls to discern cSVD-related BBB leakage from aging-related leakage.Methods:We performed structural brain MRI and DCE-MRI in 80 patients with clinically overt cSVD and 40 age- and sex-matched controls. Using the Patlak pharmacokinetic model, we calculated the leakage rate. The mean leakage rate and relative leakage volume were calculated using noise-corrected histogram analysis. Leakage rate and leakage volume were compared between patients with cSVD and controls for the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter.Results:Multivariable linear regression analyses adjusting for age, sex, and cardiovascular risk factors showed that the leakage volume of the NAWM, WMH, and CGM was significantly larger in patients with cSVD compared with controls. No significant difference was found for leakage rate in any of the tissue regions.Conclusion:We demonstrated a larger tissue volume with subtle BBB leakage in patients with cSVD than in controls. This was shown in the NAWM, WMH, and CGM, supporting the generalized nature of cSVD.

Background: Early-onset dementia (EOD) is a rare condition, with an often atypical clinical presentation, and it may therefore be challenging to diagnose. Specialized memory clinics vary in the type of patients seen, diagnostic procedures applied, and the pharmacological treatment given. The aim of this study was to investigate quality-of-care indicators in subjects with EOD from 3 tertiary memory clinics in 3 European countries.Methods: We included 1325 newly diagnosed EOD patients, ages 65 years or younger, between January 1, 2007 and December 31, 2013, from the Danish Dementia Registry (Rigshospitalet, Copenhagen), the Swedish Dementia Registry ("SveDem", Karolinska University Hospital, Stockholm), and the Amsterdam Dementia Cohort (VU University Medical Center).Results: The frequency of EOD among all dementia patients was significantly lower in Copenhagen (410, 20%) and Stockholm (284, 21%) compared with Amsterdam (631, 48%). Not all quality indicator targets were met, such as the time to diagnosis, the mini-mental state examination score available, and the prescription of cholinesterase inhibitors. Cerebrospinal fluid sampling, registered in 2 sites, was performed in over 80% of the subjects.Conclusions: In tertiary referral centers in Copenhagen, Stockholm, and Amsterdam, quality indicators were not always met for patients with EOD. Results partly reflect differences in referral pattern, the application of diagnostic criteria, and local best practices. Standardized international procedures for patients with EOD may reduce this variability.

Background and Purpose— A high clot burden score (CBS) is associated with favorable outcome after intravenous treatment for acute ischemic stroke. The added benefit of intra-arterial treatment might be less in these patients. The aim of this exploratory post hoc analysis was to assess the relation of CBS with neurological improvement and endovascular treatment effect. Methods— For 499 of 500 patients in the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the CBS was determined. Ordinal logistic regression models with and without main baseline prognostic variables were used to assess the association between CBS (continuous or dichotomized at CBS of 6) and a shift toward better outcome on the modified Rankin Scale. The model without main baseline prognostic variables only included treatment allocation and CBS. Models with and without a multiplicative interaction term of CBS and treatment were compared using the χ 2 test to assess treatment effect modification by CBS. Results— Higher CBS was associated with a shift toward better outcome on the modified Rankin Scale; adjusted common odds ratio per point CBS was 1.12 (95% confidence interval, 1.04–1.20]. Dichotomized CBS had an adjusted common odds ratio of 1.67 (95% confidence interval, 1.12–2.51). Both effect estimates were slightly attenuated by adding baseline prognostic variables. The addition of the interaction terms did not significantly improve the fit of the models. There was a small and insignificant increase of intra-arterial treatment efficacy in the high CBS group. Conclusions— A higher CBS is associated with improved outcome and may be used as a prognostic marker. We found no evidence that CBS modifies the effect of intra-arterial treatment. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR1804. URL: http://www.controlled-trials.com . Unique identifier: ISRCTN10888758.

ObjectiveTo determine the long-term association of hemoglobin levels and anemia with risk of dementia, and explore underlying substrates on brain MRI in the general population.MethodsSerum hemoglobin was measured in 12,305 participants without dementia of the population-based Rotterdam Study (mean age 64.6 years, 57.7% women). We determined risk of dementia and Alzheimer disease (AD) (until 2016) in relation to hemoglobin and anemia. Among 5,267 participants without dementia with brain MRI, we assessed hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion.ResultsDuring a mean follow-up of 12.1 years, 1,520 individuals developed dementia, 1,194 of whom had AD. We observed a U-shaped association between hemoglobin levels and dementia (p = 0.005), such that both low and high hemoglobin levels were associated with increased dementia risk (hazard ratio [95% confidence interval (CI)], lowest vs middle quintile 1.29 [1.09–1.52]; highest vs middle quintile 1.20 [1.00–1.44]). Overall prevalence of anemia was 6.1%, and anemia was associated with a 34% increased risk of dementia (95% CI 11%–62%) and 41% (15%–74%) for AD. Among individuals without dementia with brain MRI, similar U-shaped associations were seen of hemoglobin with white matter hyperintensity volume (p = 0.03), and structural connectivity (for mean diffusivity, p < 0.0001), but not with presence of cortical and lacunar infarcts. Cerebral microbleeds were more common with anemia. Hemoglobin levels inversely correlated to cerebral perfusion (p < 0.0001).ConclusionLow and high levels of hemoglobin are associated with an increased risk of dementia, including AD, which may relate to differences in white matter integrity and cerebral perfusion.

A 4-year-old boy with macrocephaly (+3 SD) was evaluated with MRI, which showed a subdural hygroma secondary to rupture of a left temporal arachnoid cyst and triventricular enlargement. Two years later, we repeated imaging to explore the possibility of a third ventriculostomy. There was a flow void across the floor of the third ventricle (figure). By using 3D cardiac-gated dynamic imaging, we demonstrated that a spontaneous ventriculostomy had already occurred (video, [links.lww.com/WNL/B217][1]). Spontaneous third ventriculostomy is rare and can occur in children and adults with chronic hydrocephalus.1 [1]: http://links.lww.com/WNL/B217

Item does not contain fulltext OBJECTIVES: To investigate whether a squelch effect occurs in the first 3 years after simultaneous bilateral cochlear implantation and to investigate whether this effect increases during follow-up. STUDY DESIGN: Prospective study as part of a multicenter randomized controlled trial that compares simultaneous bilateral cochlear implantation to sequential and unilateral cochlear implantation. SETTING: Tertiary referral center. PATIENTS: Nineteen postlingually deafened adults. INTERVENTION: Simultaneous bilateral cochlear implantation. MAIN OUTCOME MEASURE: The squelch effect, measured yearly with a speech-intelligibility-in-noise test with spatially separated sources. Bilateral results were compared to unilateral results in which the cochlear implant at the noise side was turned off. The squelch effect was investigated for the patients' best performing ear and for the left and right ears separately. RESULTS: In 13 individual patients, a squelch effect was present after 1 year. This number increased during follow-up years. On group level, a squelch effect was present in patients' best performing ear after 2 and 3 years (1.9 dB). A squelch effect was present in both ears after 3 years (AS: 1.7 dB, AD: 1.3 dB). CONCLUSION: Patients who underwent simultaneous bilateral cochlear implantation developed a measurable benefit from the squelch effect after 2 years in their best performing ear and after 3 years in both ears. These observations suggest that the brain learns to use interaural differences to segregate sound from noise after simultaneous bilateral cochlear implantation. The squelch effect increased over time which suggests a growth in cortical integration and differentiation of inputs from bilateral CIs due to brain plasticity. TRIAL REGISTRATION: Dutch Trial Register NTR1722. LEVEL OF EVIDENCE: 1b.

Objectives: To define CSF β-amyloid 1–42 (Aβ42) cutpoints to detect cortical amyloid deposition as assessed by 11C-Pittsburgh compound B ([11C]PiB)-PET and to compare these calculated cutpoints with cutpoints currently used in clinical practice.Methods: We included 433 participants (57 controls, 99 with mild cognitive impairment, 195 with Alzheimer disease [AD] dementia, and 82 with non-AD dementia) from 5 European centers. We calculated for each center and for the pooled cohort CSF Aβ42 and Aβ42/tau ratio cutpoints for cortical amyloid deposition based on visual interpretation of [11C]PiB-PET images.Results: Amyloid-PET–based calculated CSF Aβ42 cutpoints ranged from 521 to 616 pg/mL, whereas existing clinical-based cutpoints ranged from 400 to 550 pg/mL. Using the calculated cutpoint from the pooled sample (557 pg/mL), concordance between CSF Aβ42 and amyloid-PET was 84%. Similar concordance was found when using a dichotomized Aβ42/tau ratio. Exploratory analysis showed that participants with a positive amyloid-PET and normal CSF Aβ42 levels had higher CSF tau and phosphorylated tau levels and more often had mild cognitive impairment or AD dementia compared with participants who had negative amyloid-PET and abnormal CSF Aβ42 levels.Conclusions: Amyloid-PET–based CSF Aβ42 cutpoints were higher and tended to reduce intercenter variability compared with clinical-based cutpoints. Discordant participants with normal CSF Aβ42 and a positive amyloid-PET may be more likely to have AD-related amyloid pathology than participants with abnormal CSF Aβ42 and a negative amyloid-PET.Classification of evidence: This study provides Class II evidence that an amyloid-PET–based CSF Aβ42 cutpoint identifies individuals with amyloid deposition with a sensitivity of 87% and specificity of 80%.

Objective: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS). Methods: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II). Results: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a. Conclusions: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS. ClinicalTrials.gov identifier: NCT00530348 and NCT00548405. Classification of evidence: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.

Background and Purpose— The capillary index score (CIS) is based on the hypothesis that areas lacking capillary blush on pretreatment cerebral digital subtraction angiograms correspond to nonviable cerebral tissue. Methods— Pretreatment digital subtraction angiograms and post-treatment noncontrast enhanced computed tomographic scans from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) trial were evaluated for areas lacking capillary blush and with tissue hypodensity, respectively. Because the superior and middle zones of the CIS correspond to the 7 cerebral cortex regions of the Alberta Stroke Program Early CT (ASPECT) score, capillary blush was scored in these 2 zones (0–2), called sub-CIS, and compared with the ASPECT score in these 7 regions (0–7), called hypodensity score. The presence and extent of hypodensity were compared between sub-CIS zones with contingency tables and nonparametric comparisons between groups, respectively. Results— On the basis of a sample size of 50 subjects, 100% with sub-CIS P =0.004). The extent of hypodensity (numeric hypodensity score) was significantly lower for sub-CIS=2 than 0 or 1 ( P =0.02). For 42 subjects with revascularization data, the presence and extent of hypodensity were significantly lower for sub-CIS=2 plus good revascularization than for other combinations of sub-CIS and revascularization ( P =0.02 and 0.01, respectively). Conclusions— The absence of capillary blush on pretreatment digital subtraction angiogram seems to correspond to nonviable cerebral tissue. Successful revascularization reduces the chance of tissue hypodensity (infarction), when capillary blush is present. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR number 1804. URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758.

Background and Purpose— Intra-arterial treatment by means of retrievable stents has been proven safe and effective. In MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the choice of the type of thrombectomy device was left to the discretion of the interventionist. The aim of this study was to explore the differences in functional outcome, neurological recovery, reperfusion, extent of infarction, and adverse events according to stent type and make. Methods— The primary outcome was functional outcome at 90 days, assessed with the modified Rankin Scale (mRS). Neuroimaging outcomes included occlusion on computed tomographic angiography at 24 hours, infarct volume at 5 to 7 days, and modified thrombolysis in cerebral infarction scores. Safety outcomes included death within 90 days and any symptomatic intracerebral hemorrhage. We analyzed possible interactions between stent type and treatment with multiple regression models. Treatment effects were adjusted for patient age, stroke severity, and collateral score. Results— Of the 500 patients included in the trial, 233 were allocated to intervention. Of these, 124 (53%) were first treated with Trevo (adjusted common odds ratio for shift on the mRS [acOR, 1.98; 95% confidence interval, 1.30–2.92]), 31 (13%) with Solitaire (acOR, 1.90; 95% confidence interval, 0.97–3.73), 40 (17%) with other retrievable stents or mechanical devices (acOR, 0.96; 95% confidence interval, 0.51–3.93], and 38 (16%) could not be treated. There was no interaction between device and treatment effect on functional outcome and all other secondary and safety outcomes. Conclusions— We found no evidence for a differential effect of thrombectomy for acute ischemic stroke by type of stent. Clinical Trial Registration— URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758.

OBJECTIVE To investigate the efficacy of medical honey as topical treatment of chronically discharging open mastoid cavities in comparison with conventional eardrops. STUDY DESIGN Single-center, prospective, randomized controlled, double-dose trial of 12 weeks. PATIENTS AND INTERVENTION Twenty-eight patients diagnosed as having a chronically discharging open mastoid cavity underwent medical honey gel (intervention) or conventional eardrops (control) treatment. Treatment interventions were repeated after 4 weeks. MAIN OUTCOME MEASURES Visual analogue scale of ear complaints, cavity inflammation, and bacterial infection. RESULTS Most patients had a cavity with localized granulation. After treatment, inflammation score decreased in both groups (p < 0.05), with more pronounced inflammation-free cavities in the honey group. Honey treatment resulted in less discomfort (p < 0.001) and otorrhea (p < 0.001), even after correction for additional medication use (p < 0.05, p < 0.01). This decrease was not seen in the control group. Pain and itching did not change on treatment. Most cavities were infected with Pseudomonas species and Staphylococcus aureus. After treatment, a 23% increase of negative culture was seen with honey compared with 30% in the control group (nonsignificant). No serious adverse reactions were found. CONCLUSION Medical honey gel is a safe alternative treatment option for patients with a chronically discharging open mastoid cavity and beneficial in reducing discomfort, otorrhea, and inflammation with a bactericidal effect.

Research on tinnitus suppression by intracochlear electrical stimulation has gained interest over the past few decades and it has become easier to apply since the introduction of cochlear implants (CI). This study attempted to gain more insight into optimal stimulation characteristics for tinnitus suppression.Eleven subjects with unilateral CI and tinnitus were recruited from our CI clinic. Electrical stimulation, independent of acoustic sounds, was generated using their CI. The current prospective (single blinded) experimental study systematically assessed two stimulation parameters, namely current level and the anatomical stimulation site inside the cochlea and their short-term effect on tinnitus.Approximately one-third of the tested conditions were successful in which case tinnitus loudness was reduced by at least 30%. At least one successful condition was achieved for nine subjects (82%). Complete suppression was achieved in 6 out of 107 tested conditions (6%). The effect of subthreshold electrical stimulation on tinnitus suppression did not differ significantly from above threshold electrical stimulation. However, a positive relation between mean percentage tinnitus suppression and current level was observed. Pitch-matched electrical stimulation did not appear to suppress tinnitus better than other tested conditions.The majority of the subjects were able to experience tinnitus reduction through intracochlear electrical stimulation independent of acoustic sounds. Tinnitus can be reduced with audible or even inaudible, subthreshold stimuli. Clear trends in optimal stimulation characteristics were not found. Optimal stimulus characteristics for tinnitus reduction therefore appear to be highly subject-specific.

Abstract— Previous trials have shown that in patients with resistant hypertension device-based baroreflex activation therapy (BAT) can substantially reduce blood pressure. However, the fact that electrodes had to be implanted bilaterally may be a drawback for further development of the technique. In this study, we explored whether unilateral stimulation would produce comparable results as bilateral stimulation. In the Pivotal trial, treatment-resistant hypertensive patients were randomized to receive either immediate BAT or deferred BAT, that is, 6 months after implantation. We adjusted stimulation parameters individually so as to provide optimal baroreflex activation. Unilateral stimulation was applied unless bilateral stimulation resulted in a greater blood pressure reduction. When we pooled the 6-month data for the group with immediate BAT and the 12-month data for the group with deferred BAT, a total of 215 patients had been stimulated on one side only (127 at the right side and 88 at the left side), whereas 80 patients had been stimulated bilaterally. Although blood pressure and heart rate did not differ between the 2 groups at baseline, all these variables were significantly lower in the unilateral than in the bilateral group after the 6-month period. When we compared the effect of right-sided stimulation with those of either left-sided or bilateral stimulation, we found right-sided stimulation to be the most effective. We conclude that unilateral and in particular right-sided BAT has a more profound effect on blood pressure than bilateral or left-sided BAT. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00442286.

Introduction: Sedentary time has been associated with detrimental health effects, so in some countries, guidelines to reduce sedentary time have been developed. As reducing sedentary time inevitably results in more nonsedentary time, effects of this reduction may depend on the activity with which it is replaced. Purpose: This study aimed to examine associations of theoretical reallocations of sedentary time to standing or stepping with cardiometabolic outcomes and type 2 diabetes. Methods: We included 2213 participants (51% men, mean +/- SD age = 60.0 +/- 8.1 yr) of the Maastricht Study who were asked to wear an accelerometer 24 h.d(-1) for a week. We calculated daily sedentary, standing, and stepping time. An isotemporal substitution modeling approach was applied to examine effects on waist circumference; body mass index; cholesterol, triacylglycerol, glucose, and insulin levels; metabolic syndrome; and type 2 diabetes. Results: Replacement of sedentary time (30 min.d(-1)) with stepping was associated with lower odds for metabolic syndrome (odds ratio [OR] = 0.72, 95% confidence interval [CI] = 0.66-0.78) and type 2 diabetes (OR = 0.79, 95% CI = 0.72-0.87), more favorable waist circumference (B = -1.42, 95% CI = -1.78 to -1.06), and body mass index (B = -0.48, 95% CI = -0.62 to -0.35) and improved cholesterol, triacylglycerol, glucose, and insulin levels. Replacing sedentary time with standing was associated with lower odds for metabolic syndrome and type 2 diabetes and favorable outcomes in waist circumference, cholesterol, triacylglycerol, and insulin levels. Conclusion: Theoretical replacements of sedentary time with nonsedentary time (both standing and stepping) were associated with lower odds for metabolic syndrome, type 2 diabetes, and beneficial metabolic outcomes. These results could be important for the general population, including those who cannot meet physical activity guidelines. Consideration should be given to developing recommendations for daily reallocating sedentary time. This study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant no. 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), the Cardiovascular Center (CVC, Maastricht, the Netherlands), CARIM School for Cardiovascular Diseases (Maastricht, the Netherlands), CAPHRI School for Public Health and Primary Care (Maastricht, the Netherlands), NUTRIM School for Nutrition and Translational Research in Metabolism (Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands), and Health Foundation Limburg (Maastricht, the Netherlands) and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands), and Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands). A Koster has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2011-CIG) under grant agreement PCIG09-GA-2011-293621.

Previous studies on the relationship between subjective cognitive failures (SCF) and objective cognitive function have shown inconsistent results. In addition, research on the association between SCF and imaging markers of cerebral small vessel disease is limited. We investigated whether SCF in patients with essential hypertension, who are at high risk of cerebral small vessel disease, are associated with objective cognitive function and magnetic resonance imaging manifestations of cerebral small vessel disease. We included 109 patients with hypertension who underwent extensive neuropsychological assessment, including questionnaires measuring SCF and symptoms of anxiety and depression. Brain magnetic resonance imaging was performed to rate the presence of lacunes, cerebral microbleeds, and perivascular spaces, as well as white matter hyperintensities volume. Results showed significant associations between SCF and objectively measured overall cognition ( B =−0.02; 95% confidence interval=−0.03 to −0.005), memory ( B =0.02; 95% confidence interval=−0.03 to −0.004), and information processing speed ( B =−0.02; 95% confidence interval=−0.03 to −0.001) after adjustment for patient characteristics and vascular risk factors. In addition, SCF were associated with the presence of cerebral microbleeds (odds ratio=1.12; 95% confidence interval=1.02–1.23) after adjustment for patient characteristics and vascular risk factors but not with other imaging markers of cerebral small vessel disease. Our study demonstrates that attention for SCF in patients with hypertension is needed because these may point to lower objective cognitive function, which might be as a result of the presence of cerebral microbleeds. Accordingly, this study emphasizes that neuropsychological assessment and brain imaging need to be considered when patients with hypertension report SCF.

The main objectives of this expert consensus are to raise awareness about fibromuscular dysplasia, which is more frequent and more often systemic than previously thought and can sometimes have devastating consequences; to provide up-to-date recommendations for the diagnosis, evaluation, and management of the disease; and to identify research priorities. The emphasis has been put on recommendations for daily practice. The main topics covered include definition, classification, diagnosis, and management of fibromuscular dysplasia in adult patients with symptomatic involvement of the renal arteries, supra-aortic trunks, and digestive and peripheral arteries.

An 88-year-old woman with chronic hypertension was seen in the internal/geriatric medicine outpatient clinic. She had been treated for high blood pressure (BP) for ≈20 years with a low-dose thiazide, to which an angiotensin-converting enzyme-inhibitor had been added 5 years ago. In addition, after a possible transient ischemic attack 10 years ago, aspirin, omeprazole, and simvastatin had been added. She is known with mild cognitive impairment, which is stable with a mini-mental state examination score of 25, and a mild depression for which fluoxetine has been prescribed. In addition, she experienced 2 falls in the past 2 years; calcium/vitamin D and alendronate were started for the management of osteoporosis. On physical examination, she appears vital with a normal fluent gait and no signs of hemiparesis. Her BP is 165/75 mm Hg in the sitting position. Immediately after standing up from her chair, she feels dizzy for ≈10 seconds, but after 1 and 3 minutes, no orthostatic hypotension is found. Estimated glomerular filtration rate is 50 mL/min per 1.73 m2. Should antihypertensive treatment be intensified, left unaltered, or reduced? The oldest old, that is, persons aged ≥80 years, will be the fastest growing segment of the population for the next 40 years. By 2050, more than one quarter of all men and women aged ≥65 years in the Western world will be in the oldest old group.1 Despite longer life expectancy, the prevalence of various chronic diseases and functional impairment increases with age. As a result, populations of older individuals are often highly heterogeneous and individuals with same chronological age vary widely in health and functional ability. In other words, there is substantial heterogeneity in their biological age, and those at the higher end of biological age are often referred to as vulnerable or frail. BP rises with …

Objective: To review and evaluate the effectiveness and methodological quality of available treatment methods for unawareness of deficits after acquired brain injury (ABI). Methods: Systematic literature search for treatment studies for unawareness of deficits after ABI. Information concerning study content and reported effectiveness was extracted. Quality of the study reports and methods were evaluated. Results: A total of 471 articles were identified; 25 met inclusion criteria. 16 were uncontrolled or single-case studies. Nine were of higher quality: 2 randomized controlled trials, 5 single case experimental designs, 1 single-case design with pre- and posttreatment measurement, and 1 quasi-experimental controlled design. Overall, interventions consisted of multiple components including education and multimodal feedback on performance. Five of the 9 high-quality studies reported a positive effect of the intervention on unawareness in patients with some knowledge of their impairments. Effect sizes ranged from questionable to large. Conclusion: Patients with ABI may improve their awareness of their disabilities and possibly attain a level at which they personally experience problems when they occur. At present, because of lack of evidence, no recommendation can be made for treatment approaches for persons with severe impairment of self-awareness in the chronic phase of ABI. We recommended developing and evaluating theory-driven interventions specifically focused on disentangling the components of treatment that are successful in improving awareness. High-quality intervention studies are urgently needed using controlled designs (eg, single-case experimental designs, randomized controlled trials) based on a theoretic perspective with a detailed description of the content of the intervention and suitable outcome measures.

Objective: Achieving long-term remission after a limited more intense treatment period would prevent prolonged use of corticosteroids or IV immunoglobulin (IVIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In this prospective cohort study we present long-term follow-up data on patients included in a multicenter randomized controlled trial comparing 6 monthly pulses of dexamethasone with 8 months of daily prednisolone. Methods: Treatment effect was assessed with the Inflammatory Neuropathy Cause and Treatment disability scale and the Rivermead Mobility Index and was categorized using the CIDP Disease Activity Status (CDAS) scale. Results: By March 2011, 39 out of 40 patients were included with a median follow-up of 4.5 years. Cure (>5 years off treatment) or remission according to the CDAS criteria after 1 or 2 courses of pulsed dexamethasone or daily prednisolone was achieved in 10 out of 39 patients (26%). Half of the patients who were in remission after initial treatment experienced a relapse (median treatment-free interval: 17.5 months for dexamethasone, 11 months for prednisolone). Alternative diagnosis was made in 7 out of 12 (58%) who did not respond to any therapy and in none of the treatment-responsive patients. Conclusions: Cure or long-term remission can be achieved in about one-quarter of patients with CIDP after 1 or 2 courses of pulsed dexamethasone or 8-month daily prednisolone. In treatment-nonresponsive patients, the diagnosis CIDP should be reconsidered. Classification of Evidence: This study provides Class IV evidence that pulsed dexamethasone or 8-month daily prednisolone can lead to long-term remission in CIDP. Neurology (R) 2012;78:1079-1084

Background and Purpose— Cerebral small vessel disease (CSVD) may be caused by endothelial dysfunction, whereas endothelial progenitor cells (EPC) may attenuate endothelial dysfunction. Their vitality is lower in CSVD. A subset of lymphocytes, angiogenic T-cells, is capable to stimulate EPC function. The purpose of our study was to explore the relation between CSVD manifestations, angiogenic T-cells, and EPC in hypertensive patients with CSVD. Methods— We compared 32 essential hypertensive patients with CSVD (white matter lesions, asymptomatic lacunar infarcts, or microbleeds on 1.5-Tesla MRI) to 29 age-matched and sex-matched hypertensive controls. We counted angiogenic T-cells (CD3 + /CD31 + /CD184 + ) and putative EPC (CD31 + /CD34 + /CD45 - /KDR + ) by flow cytometry and determined EPC vitality by in vitro cluster formation. Results— Putative EPC numbers were lower in hypertensive individuals with CSVD than in those without (10±7 . 10 3 /mL versus 13±6 . 10 3 /mL [median±interquartile range]; P =0.011). Angiogenic T-cell numbers were also lower in hypertensive individuals with CSVD than in those without (0.56±0.25 . 10 9 /mL versus 0.78±0.50 . 10 9 /mL; P =0.008). Higher angiogenic T-cell numbers independently related to absence of CSVD (odds ratio, 0.088; 95% confidence interval, 0.012–0.627). Conclusions— Our data suggest that angiogenic T-cells and putative EPC independently relate to radiological CSVD manifestations in hypertensive patients.

Fingolimod (FTY720, Gilenya, Novartis Pharma AG, Basel, Switzerland) is an oral disease-modifying therapy (DMT) approved for relapsing multiple sclerosis (MS) that acts via modulation of the sphingosine-1-phosphate (S1P) receptor.1 Fingolimod also targets the cardiovascular system, frequently causing reduced heart rate after the first dose.2 We describe a patient with MS who developed paroxysmal atrial fibrillation (PAF) after initiating fingolimod therapy.