Showing papers by "Luciano A. Sposato published in 2017"

Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016

Abstract: Summary Background Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level. Methods We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development. Findings Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs. Interpretation Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services. Funding Bill & Melinda Gates Foundation.

Subcutaneous versus intravenous immunoglobulin for chronic autoimmune neuropathies: A meta-analysis

Abstract: Introduction: High-dose intravenous immunoglobulin (IVIg) is an evidence-based treatment for multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). Recently, subcutaneous immunoglobulin (SC-Ig) has received increasing attention. Methods: We performed a meta-analysis of reports of efficacy and safety of SC-Ig versus IVIg for inflammatory demyelinating polyneuropathies. Results: A total of 8 studies comprising 138 patients (50 with MMN and 88 with chronic CIDP) were included in the meta-analysis. There were no significant differences in muscle strength outcomes in MMN and CIDP with Sc-Ig (MMN: ES-effect size=0.65, 95%CI-confidence interval=-0.31 to 1.61; CIDP: ES=0.84, 95%CI=-0.01 to 1.69). Additionally SC-Ig had a 28% reduction in relative risk (RR) of moderate and/or systemic adverse effects (95%CI = 0.11 to 0.76). Conclusion: The efficacy of SC-Ig is similar to IVIg for CIDP and MMN and has a significant safety profile. This article is protected by copyright. All rights reserved.

The complexity of atrial fibrillation newly diagnosed after ischemic stroke and transient ischemic attack: advances and uncertainties.

Abstract: Purpose of reviewAtrial fibrillation is being increasingly diagnosed after ischemic stroke and transient ischemic attack (TIA). Patient characteristics, frequency and duration of paroxysms, and the risk of recurrent ischemic stroke associated with atrial fibrillation detected after stroke and TIA (A

Therapeutic Strategies and Drug Development for Vascular Cognitive Impairment

Abstract: Dementia is a large and growing health problem in developed and developing countries, with total costs approaching 1% of global gross domestic product, threatening the sustainability of healthcare systems.1 There are currently no disease‐modifying treatments for the most common cause of dementia, Alzheimer disease (AD). The second most common contributor to dementia risk is cerebrovascular disease.2 In contrast to AD, there is greater hope that vascular contributions to cognitive impairment can be prevented and treated. Recent evidence that the incidence of dementia is declining has prompted speculation, not yet confirmed, that this decline may be partly attributable to improved vascular care.3, 4 In this article, we review trial design and drug development for vascular cognitive impairment (VCI), focusing on symptomatic patients with vascular mild cognitive impairment (MCI) or dementia. First, we review axes along which vascular components of cognitive impairment can be addressed, including choice of trial population, trial intervention, and type of outcome. Second, we briefly review the pathophysiology of VCI, introducing the concept that trials may focus on disease modification, improving resilience, or enhancing cognition. Third, we systematically review prior drug trials for VCI patients according to drug class and trial size. Finally, we offer suggestions for methodological improvements for future trials.

Population-based stroke and dementia incidence trends: Age and sex variations

Abstract: Introduction We discovered a concomitant decline in stroke and dementia incidence rates at a whole population level in Ontario, Canada. This study explores these trends within demographic subgroups. Methods We analyzed administrative data sources using validated algorithms to calculate stroke and dementia incidence rates from 2002 to 2013. Results For more than 12 years, stroke incidence remained unchanged among those aged 20 to 49 years and decreased for those aged 50 to 64, 65 to 79, and 80+ years by 22.7%, 36.9%, and 37.9%, respectively. Dementia incidence increased by 17.3% and 23.5% in those aged 20 to 49 and 50 to 64 years, respectively, remained unchanged in those aged 65 to 79 years, and decreased by 15.4% in those aged 80+ years. Discussion The concomitant decline in stroke and dementia incidence rates may depict how successful stroke prevention has targeted shared risk factors of both conditions, especially at advanced ages where such risk factors are highly prevalent. We lend support for the development of an integrated system of stroke and dementia prevention.

Cost-effectiveness of cerebrospinal biomarkers for the diagnosis of Alzheimer’s disease

Abstract: Accurate and timely diagnosis of Alzheimer’s disease (AD) is important for prompt initiation of treatment in patients with AD and to avoid inappropriate treatment of patients with false-positive diagnoses. Using a Markov model, we estimated the lifetime costs and quality-adjusted life-years (QALYs) of cerebrospinal fluid biomarker analysis in a cohort of patients referred to a neurologist or memory clinic with suspected AD who remained without a definitive diagnosis of AD or another condition after neuroimaging. Parametric values were estimated from previous health economic models and the medical literature. Extensive deterministic and probabilistic sensitivity analyses were performed to evaluate the robustness of the results. At a 12.7% pretest probability of AD, biomarker analysis after normal neuroimaging findings has an incremental cost-effectiveness ratio (ICER) of $11,032 per QALY gained. Results were sensitive to the pretest prevalence of AD, and the ICER increased to over $50,000 per QALY when the prevalence of AD fell below 9%. Results were also sensitive to patient age (biomarkers are less cost-effective in older cohorts), treatment uptake and adherence, biomarker test characteristics, and the degree to which patients with suspected AD who do not have AD benefit from AD treatment when they are falsely diagnosed. The cost-effectiveness of biomarker analysis depends critically on the prevalence of AD in the tested population. In general practice, where the prevalence of AD after clinical assessment and normal neuroimaging findings may be low, biomarker analysis is unlikely to be cost-effective at a willingness-to-pay threshold of $50,000 per QALY gained. However, when at least 1 in 11 patients has AD after normal neuroimaging findings, biomarker analysis is likely cost-effective. Specifically, for patients referred to memory clinics with memory impairment who do not present neuroimaging evidence of medial temporal lobe atrophy, pretest prevalence of AD may exceed 15%. Biomarker analysis is a potentially cost-saving diagnostic method and should be considered for adoption in high-prevalence centers.

Milder Alzheimer's disease pathology in heart failure and atrial fibrillation

Abstract: Introduction Heart failure (HF) and atrial fibrillation (AF) have been associated with a higher risk of Alzheimer's disease (AD). Whether HF and AF are related to AD by enhancing AD neuropathological changes is unknown. Methods We applied network analyses and multiple logistic regression models to assess the association between HF and AF with severity of AD neuropathology in patients from the National Alzheimer's Coordinating Center database with primary neuropathological diagnosis of AD. Results We included 1593 patients, of whom 129 had HF and 250 had AF. HF and AF patients were older and had milder AD pathology. In the network analyses, HF and AF were associated with milder AD neuropathology. In the regression analyses, age (odds ratio [OR] 0.94, 95% confidence interval [CI] 0.93–0.95 per 1-year increase in age, P P = .014) were inversely related to severe AD pathology, whereas APOE e4 genotype showed a direct association (OR 1.68, 95% CI 1.31–2.16). Vascular neuropathology was more frequent in patient with HF and AF patients than in those without. Discussion HF and AF had milder AD neuropathology. Patients with milder AD lived longer and had more exposure to vascular risk factors. HF and AF patients showed a higher frequency of vascular neuropathology, which could have contributed to lower the threshold for clinically evident dementia.

Decision-making interventions to stop the global atrial fibrillation-related stroke tsunami.

Abstract: Atrial fibrillation affects 33.5 million people worldwide and its prevalence is expected to double by 2050 because of the aging population. Atrial fibrillation confers a 5-fold higher risk of ischemic stroke compared to sinus rhythm. We present our view of the role of shared medical decision-making to combat global underutilization of oral anticoagulation for stroke prevention in atrial fibrillation patients. Oral anticoagulation underuse is widespread as it is present within atrial fibrillation patients of all risk strata and in countries across all income levels. Reasons for oral anticoagulation underuse include but are probably not limited to poor risk stratification, over-interpretation of contraindications, and discordance between physician prescription preferences and actual administration. By comparing a catastrophic event to the consequences of atrial fibrillation related strokes, it may help physicians and patients understand the negative outcomes associated with oral anticoagulation under-utilization and the magnitude to which oral anticoagulations neutralize atrial fibrillation burden.

Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE): A Translational, Integrated, and Transdisciplinary Approach

Abstract: Background It has been hypothesized that ischemic stroke can cause atrial fibrillation. By elucidating the mechanisms of neurogenically mediated paroxysmal atrial fibrillation, novel therapeutic strategies could be developed to prevent atrial fibrillation occurrence and perpetuation after stroke. This could result in fewer recurrent strokes and deaths, a reduction or delay in dementia onset, and in the lessening of the functional, structural, and metabolic consequences of atrial fibrillation on the heart. Methods The Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE) study is an investigator-driven, translational, integrated, and transdisciplinary initiative. It comprises 3 complementary research streams that focus on atrial fibrillation detected after stroke: experimental, clinical, and epidemiological. The experimental stream will assess pre- and poststroke electrocardiographic, autonomic, anatomic (brain and heart pathology), and inflammatory trajectories in an animal model of selective insular cortex ischemic stroke. The clinical stream will prospectively investigate autonomic, inflammatory, and neurocognitive changes among patients diagnosed with atrial fibrillation detected after stroke by employing comprehensive and validated instruments. The epidemiological stream will focus on the demographics, clinical characteristics, and outcomes of atrial fibrillation detected after stroke at the population level by means of the Ontario Stroke Registry, a prospective clinical database that comprises over 23,000 patients with ischemic stroke. Conclusions PARADISE is a translational research initiative comprising experimental, clinical, and epidemiological research aimed at characterizing clinical features, the pathophysiology, and outcomes of neurogenic atrial fibrillation detected after stroke.

The Incidence and Characteristics of Stroke in Urban-Dwelling Iranian Women.

Abstract: Background Population-based data regarding stroke among women are scarce in developing countries. This study was designed to determine whether sex differences exist in stroke incidence, mortality, and recurrence. Methods The Mashhad Stroke Incidence Study is a population-based cohort study in Iran. For a period of 1 year, all patients with stroke in 3 geographical regions in Mashhad were recruited and then followed up for 5 years. Age- and sex-specific crude incidence rates were standardized to the World Health Organization New World Population. Male-to-female incidence rate ratios were assessed for all age groups and all subtypes of first-ever stroke (FES). Results The annual crude incidence rate of FES (per 100,000 population) was similar in men (144; 95% confidence interval [CI]: 129-160) and women (133; 95% CI: 119-149). Standardized FES annual incidence rates were 239 (95% CI: 213-267) for men and 225 (95% CI 200-253) for women, both greater than in most western countries. There were no significant differences in stroke recurrence or case-fatality between women and men during early and long-term follow-up. Conclusion The similar incidence of stroke between men and women highlights the importance of equally prioritizing adequate preventive strategies for both sexes. The greater relative incidence of stroke in women in Mashhad compared with other countries warrants improvement of primary and secondary stroke prevention.

Right insular cortex involvement is consistently associated with death after ischaemic stroke.

Abstract: Involvement of the insular cortex in patients with ischaemic stroke is frequent and has been associated with increased risk of death after stroke [1], albeit with some controversy [2]. The main source of dispute is that insular strokes are usually more severe [2,3] and associated with larger brain infarcts [2], meaning that stroke severity or infarct size should be considered as potential confounders to be included in regression models for death. Notably, outcomes of left and right insular cortex strokes may differ due to the laterality of autonomic representation in the brain [4]. Indeed, there is dispute regarding whether left, right or both insular strokes are associated with higher mortality [1,2]. In this issue of European Journal of Neurology, in an initiative based on the cohort of the 1000 Plus study conducted by researchers from the University of Berlin and Helmholtz Association of German Research Centres, Hanne et al. [5] report an association between right insular cortex involvement and increased risk of death at 90 days. The 1000 Plus is a magnetic resonance imaging (MRI) study enrolling consecutive patients with stroke or transient ischaemic attack seen in the emergency department at Charit e Campus Benjamin Franklin (Berlin, Germany) within 24 h of symptoms onset, between 1 September 2008 and 11 November 2012. The main outcome was death, ascertained at 90 days by telephone interviews. 3 T diffusion-weighted imaging (DWI) MRI comprising 50 axial slices with a thickness of 2.5 mm without gaps allowed for a highly accurate identification of ischaemic strokes involving the insular cortex. Although the baseline 1000 Plus cohort included patients presenting clinically with transient symptoms, this study is solely based on 736 patients with identifiable ischaemic stroke in DWI MRI with complete follow-up data. In Cox regression analyses adjusted for lesion volume and stroke severity, right insular cortex involvement but not infarct volume or left insular involvement was associated with death (hazard ratio 2.60). Stroke severity and age were also associated with increased case fatality. A secondary analysis using the Stroke Lesion Atlas, an in-house software that creates overlap images of lesion topographies of patients sharing specific outcomes (e.g. death), showed that the maximum lesion overlap was registered in the insula both for patients alive and for dead patients at 90 days. However, maximum overlap was greater amongst those who were dead at the end of the follow-up period, further supporting that right insular involvement is related to death. Similarly to this study, we recently found that right insular involvement was independently associated with increased death 6 months after ischaemic stroke in the cohort of the Third International Stroke Trial (IST-3) after adjusting for lesion size and stroke severity amongst other variables [6]. Furthermore, right insular infarcts were also independently associated with disability and combined death or dependence. Together, the study by Hanne et al. [5] and ours [6] contribute to highlight that ischaemic damage to the right insula is independently related to increased risk of death after stroke, ensuring the need to elucidate the underlying pathophysiology. Unfortunately, in neither study was the cause of death ascertained. Regardless, and as hypothesized by the authors, a handful of mechanisms comprising cardiac arrhythmias, pneumonia and hyperglycaemia could be regarded as potential causes of more death after right insular infarction. Amongst them, neurogenically mediated cardiac arrhythmias and/or sudden death emerge as the most likely mechanisms. Accordingly, cardiac arrhythmias are triggered by autonomic imbalances [7] and lesions to the right insula can result in increased sympathetic tone, cardiac arrhythmias and sudden death [1,8]. Handedness may reflect different brain organizations for autonomic control. Right-handers are five times as likely to die from sudden death after a transient ischaemic attack or minor stroke as left-handers or ambidextrous patients [9]. Future research should assess whether death after right insular ischaemic stroke is truly caused by fatal cardiac arrhythmias and sudden death and how cardiac arrhythmias are initiated by brain lesions. It will be important to determine the type of arrhythmias. If a lesion causes parasympathetic predominance, one would expect death resulting from bradycardia and eventual asystole. If sympathetic tone prevails, death

Response by Sposato et al to Letter Regarding Article, "Effect of Right Insular Involvement on Death and Functional Outcome After Acute Ischemic Stroke in the IST-3 Trial (Third International Stroke Trial)".

Abstract: In Response: We appreciate Alves et al for their comments on our article, Effect of Right Insular Involvement on Death and Functional Outcome After Acute Ischemic Stroke in the IST-3 Trial.1 Insular involvement after ischemic stroke has been associated with worse outcomes. However, until recently, results were conflicting because most studies failed to adjust their analyses for variables known to impact on stroke death and functional outcome such as stroke severity or the volume of infarcted brain tissue.2 Furthermore, the role of laterality has been rarely addressed. We showed an association between right insular involvement and higher odds of death and worse functional outcome at 6 months after adjustment for age, stroke severity, lesion size, atrial fibrillation, treatment with intravenous recombinant …

Visual Aids for Improving Patient Decision Making in Severe Symptomatic Carotid Stenosis

Abstract: Background Because of the large amount of information to process and the limited time of a clinical consult, choosing between carotid endarterectomy (CEA) and carotid angioplasty with stenting (CAS) can be confusing for patients with severe symptomatic internal carotid stenosis (ICA). Goal We aim to develop a visual aid tool to help clinicians and patients in the decision-making process of selecting between CEA and CAS. Materials and Methods Based on pooled analysis from randomized controlled trials including patients with symptomatic and severe ICA (SSICA), we generated visual plots comparing CEA with CAS for 3 prespecified postprocedural time points: (1) any stroke or death at 4 months, and (2) any stroke or death in the first 30 days and ipsilateral stroke thereafter at 5 years and (3) at 10 years. Results A total of 4574 participants (2393 assigned to CAS, and 2361 to CEA) were included in the analyses. For every 100 patients with SSICA, 6 would develop any stroke or death in the CEA group compared with 9 undergoing CAS at 4 months (hazard ratio [HR] 1.53; 95%CI 1.20-1.95). At 5 years, 7 patients in the CEA group would develop any periprocedural stroke or death and ipsilateral stroke thereafter versus 12 undergoing CAS (HR 1.72; 95%CI 1.24-2.39), compared with 10 patients in the CEA and 13 in the CAS groups at 10 years (HR 1.17; 95%CI 0.82-1.66). Conclusion Visual aids presented in this study could potentially help patients with severe symptomatic internal carotid stenosis to better weigh the risks and benefits of CEA versus CAS as a function of time, allowing for the prioritization of personal preferences, and should be prospectively assessed.

Letter by Sposato et al Regarding Article, “Stroke as the Initial Manifestation of Atrial Fibrillation: The Framingham Heart Study”

Abstract: We read with interest the study by Lubitz et al1 on stroke as the initial manifestation of atrial fibrillation (AF) in the Framingham Heart Study. Stroke occurred as the initial clinical expression of AF among 1.7% of patients on the same day, in 3.4% within 30 days before, in 3.7% within 90 days before, and among 4.8% within the first year before AF detection. There are 2 possible ways of understanding these results. First, as acknowledged by the authors, stroke occurring at different time points within a year before AF detection could be regarded as the first clinically evident consequence of AF. In contrast, AF could be the consequence of the index stroke among some participants. The inflammatory response and impairment of the autonomic regulation of …

Stroke rates vary substantially across cohorts of patients with atrial fibrillation

Abstract: Commentary on: Quinn GR, Severdija ON, Chang Y, et al . Wide variation in reported rates of stroke across cohorts of patients with atrial fibrillation. Circulation 2017;135:208–19.[OpenUrl][1][Abstract/FREE Full Text][2] Oral anticoagulants (OACs) substantially reduce stroke risk in patients with atrial fibrillation (AF); however, they remain globally underused.1 One of the main reasons is the difficulty in stratifying AF-related ischaemic stroke risk at the individual patient level.1 ,2 Among scores stratifying AF-related stroke risk, CHA2-DS2-Vasc prevails in most recent international AF guidelines.3 ,4 Still, it remains unknown whether AF-related stroke risk is stable across regions, international cohorts or within specific CHA2-DS2-Vasc score strata. This systematic review included only studies reporting ischaemic stroke rates for patients with AF not on OACs, and assessed … [1]: {openurl}?query=rft.jtitle%253DCirculation%26rft_id%253Dinfo%253Adoi%252F10.1161%252FCIRCULATIONAHA.116.024057%26rft_id%253Dinfo%253Apmid%252F27799272%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=circulationaha&resid=135/3/208&atom=%2Febmed%2F22%2F3%2F110.atom