Anti- #ganglioside #antibodies in patients with #Zika virus #infection-associated #GBS in #Brazil (PLoS Negl Trop Dis., abstract)

[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Anti-ganglioside antibodies in patients with Zika virus infection-associated Guillain-Barré Syndrome in Brazil

Juan Rivera-Correa, Isadora Cristina de Siqueira, Sabrina Mota, Mateus Santana do Rosário, Pedro Antônio Pereira de Jesus, Luiz Carlos Junior Alcantara, Joel D. Ernst, Ana Rodriguez

Published: September 17, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007695 / This is an uncorrected proof.

 

Abstract

Zika virus infection is associated with the development of Guillain-Barré syndrome (GBS), a neurological autoimmune disorder caused by immune recognition of gangliosides and other components at nerve membranes. Using a high-throughput ELISA, we have analyzed the anti-glycolipid antibody profile, including gangliosides, of plasma samples from patients with Zika infections associated or not with GBS in Salvador, Brazil. We have observed that Zika patients that develop GBS present higher levels of anti-ganglioside antibodies when compared to Zika patients without GBS. We also observed that a broad repertoire of gangliosides was targeted by both IgM and IgG anti-self antibodies in these patients. Since Zika virus infects neurons, which contain membrane gangliosides, antigen presentation of these infected cells may trigger the observed autoimmune anti-ganglioside antibodies suggesting direct infection-induced autoantibodies as a cause leading to GBS development. Collectively, our results establish a link between anti-ganglioside antibodies and Zika-associated GBS in patients.

 

Author summary

Zika virus infection can trigger the development of Guillain Barré syndrome (GBS), a neurological autoimmune disorder mediated by antibodies recognizing gangliosides in nerve membranes. Mechanisms such as molecular mimicry have been identified as a cause for GBS development in certain infections, such as Campylobacter jejuni, but the broad self reactivity observed during GBS suggests a role for alternative mechanisms. Our finding that Zika patients with GBS present higher levels of anti-ganglioside antibodies compared to uncomplicated Zika patients in Brazil points to these auto-antibodies as a trigger for GBS in these patients. These findings further support infection-induced autoantibodies as a factor contributing to GBS development, adding novel mechanisms for GBS development beyond molecular mimicry.

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Citation: Rivera-Correa J, de Siqueira IC, Mota S, do Rosário MS, Pereira de Jesus PA, Alcantara LCJ, et al. (2019) Anti-ganglioside antibodies in patients with Zika virus infection-associated Guillain-Barré Syndrome in Brazil. PLoS Negl Trop Dis 13(9): e0007695. https://doi.org/10.1371/journal.pntd.0007695

Editor: Rebecca C. Christofferson, Louisiana State University, UNITED STATES

Received: March 18, 2019; Accepted: August 7, 2019; Published: September 17, 2019

Copyright: © 2019 Rivera-Correa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files

Funding: AR and JRC received funding for this project from New York University School of Medicine Internal Funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Zika Virus; Immunopathology; GBS; Neurology; Brazil.

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Chronic #dengue virus #encephalitis in a patient with progressive #dementia with extrapyramidal features (Ann Neurol., abstract)

[Source: Annals of Neurology, full page: (LINK). Abstract, edited.]

Chronic dengue virus encephalitis in a patient with progressive dementia with extrapyramidal features

Tory P. Johnson Ph.D.,  H. Benjamin Larman Ph.D.,  Myoung‐Hwa Lee Ph.D.,  Stephen S. Whitehead Ph.D., Jeffrey Kowalak Ph.D., Camilo Toro M.D., C. Christopher Lau Ph.D., Juyun Kim

First published: 28 August 2019 / DOI:  https://doi.org/10.1002/ana.25588

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ana.25588.

 

Abstract

Objective

To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program.

Methods

Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing and the phage‐display assay, VirScan, for viral immune responses. An etiological diagnosis was established post‐mortem.

Results

Using VirScan, enrichment of dengue viral antibodies were detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but post‐mortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situhybridization, quantitative polymerase chain reaction and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months ante‐mortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency and sequencing of the virus demonstrated wild‐type dengue virus in the central nervous system.

Interpretation

Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self‐limiting and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Further, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiologies.

This article is protected by copyright. All rights reserved.

Keywords: Dengue Fever; Encephalitis; Dementia; Neurology.

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Early Gross #Motor #Development Among Brazilian #Children with #Microcephaly Born Right After #Zika Virus #Infection #Outbreak (J Dev Behav Pediatr., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Dev Behav Pediatr. 2019 Aug 22. doi: 10.1097/DBP.0000000000000722. [Epub ahead of print]

Early Gross Motor Development Among Brazilian Children with Microcephaly Born Right After Zika Virus Infection Outbreak.

A Ventura P1,2, C Lage ML1, L de Carvalho A2, S Fernandes A2, B Taguchi T2, Nascimento-Carvalho CM1,3.

Author information: 1 Post-graduation Program in Health Sciences, Federal University of Bahia School of Medicine, Salvador, Brazil. 2 SARAH Network of Rehabilitation Hospital, Salvador, Brazil. 3 Department of Paediatrics, Federal University of Bahia School of Medicine, Salvador, Brazil.

 

Abstract

OBJECTIVE:

To assess the gross motor development of children with presumed congenital Zika virus (ZIKV) infection over the first 2 years of their lives.

METHODS:

Seventy-seven children were assessed at the median ages of 11, 18, and 24 months, using the evaluative instrument Gross Motor Function Measure (GMFM-66). At the third assessment, the children with diagnoses of cerebral palsy (CP) were classified by severity through the Gross Motor Function Classification System (GMFCS) and stratified by topography indicating the predominantly affected limbs. With these instruments in combination and using the motor development curves as reference, the rate of development and functional ability were estimated.

RESULTS:

At 2 years of age, all children had the diagnosis of CP. Seventy-four (96.1%) presented gross motor skills similar to those of children aged 4 months or younger, according to the World Health Organization’s standard. The GMFM-66 median score among the 73 (94.8%) children with quadriplegia and GMFCS level V showed significant change between 11 and 18 months (p < 0.001) and between 11 and 24 months (p < 0.001). No significant difference (p = 0.076) was found between 18 and 24 months.

CONCLUSION:

Despite showing some gross motor progress during the initial 18 months of life, these children with presumed congenital ZIKV infection and CP experienced severe motor impairment by 2 years of age. According to the motor development curves, these children with quadriplegia have probably already reached about 90% of their motor development potential.

PMID: 31453893 DOI: 10.1097/DBP.0000000000000722

Keywords: Zika Virus; Zika Congenital Syndrome; Neurology; Pediatrics; Brazil.

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#Molecular and #Clinical #Comparison of #Enterovirus D68 #Outbreaks among Hospitalized #Children, #Ohio, #USA, 2014 and 2018 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 11—November 2019 / Research

Molecular and Clinical Comparison of Enterovirus D68 Outbreaks among Hospitalized Children, Ohio, USA, 2014 and 2018

Huanyu Wang, Alejandro Diaz, Katherine Moyer1, Maria Mele-Casas2, Maria Fatima Ara-Montojo3, Isabel Torrus2, Karen McCoy, Asuncion Mejias, and Amy L. Leber

Author affiliations: Nationwide Children’s Hospital, Columbus, Ohio, USA (H. Wang, A. Diaz, K. Moyer, M. Mele-Casas, M.F. Ara-Montojo, I. Torrus, K. McCoy, A. Mejias, A.L. Leber); The Ohio State University, Columbus, Ohio, USA (H. Wang, A. Mejias, A.L. Leber).

 

Abstract

Enterovirus D68 (EV-D68) causes respiratory tract infections and neurologic manifestations. We compared the clinical manifestations from 2 EV-D68 outbreaks in 2014 and 2018 and a low-activity period in 2016 among hospitalized children in central Ohio, USA, and used PCR and sequencing to enable phylogenetic comparisons. During both outbreak periods, infected children had respiratory manifestations that led to an increase in hospital admissions for asthma. The 2018 EV-D68 outbreak appeared to be milder in terms of respiratory illness, as shown by lower rates of pediatric intensive care unit admission. However, the frequency of severe neurologic manifestations was higher in 2018 than in 2014. During the same period in 2016, we noted neither an increase in EV-D68 nor a significant increase in asthma-related admissions. Phylogenetic analyses showed that EV-D68 isolates from 2018 clustered differently within clade B than did isolates from 2014 and are perhaps associated with a different EV-D68 subclade.

Keywords: Enterovirus; EV-D68; Neurology; Pediatrics; Ohio; USA.

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#Isavuconazole diffusion in #infected #human #brain (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Isavuconazole diffusion in infected human brain

Claire Rouzaud, Vincent Jullien, Anne Herbrecht, Bruno Palmier, Simona Lapusan, Marjolaine Morgand, Romain Guéry, Amélie Dureault, François Danion, Stéphanie Puget, Lauriane Goldwirt,Fanny Lanternier, Olivier Lortholary

DOI: 10.1128/AAC.02474-18

 

ABSTRACT

We report cases of a 39-year-old woman with chronic lymphocytic leukemia and of 21-year-old man with chronic granulomatous disease treated for cerebral aspergillosis. Patients required radical surgery respectively for infection progression despite adequate isavuconazole plasma concentration or neurological complication. We thus decided to measure brain isavuconazole concentration. These results suggest that the concentrations of isavuconazole obtained clearly differ in the infected brain tissue from those obtained in the normal brain tissue and the cerebrospinal fluid.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Aspergillus spp.; Isavuconazole; Neurology.

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Association Between #Statin Use and #Risk of #Dementia After a #Concussion (JAMA Neurol., abstract)

[Source: JAMA Neurology, full page: (LINK). Abstract, edited.]

Original Investigation / May 20, 2019

Association Between Statin Use and Risk of Dementia After a Concussion

Donald A. Redelmeier, MD, MSHSR 1,2,3,4,5; Fizza Manzoor, BHSc 1,2,3; Deva Thiruchelvam, MSc 3

Author Affiliations: 1 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 2 Evaluative Clinical Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; 3 Institute for Clinical Evaluative Sciences in Ontario, Toronto, Ontario, Canada; 4 Division of General Internal Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; 5 Center for Leading Injury Prevention Practice Education & Research, Toronto, Ontario, Canada

JAMA Neurol. 2019;76(8):887-896. doi:10.1001/jamaneurol.2019.1148

 

Key Points

  • Question   – Is statin use associated with an increased or decreased risk of subsequent dementia after a concussion?
  • Findings   – In this large extended population-based double cohort study following 28 815 patients after a concussion, the 5-year incidence of dementia was substantial and statin use was associated with a significantly reduced risk of subsequent dementia.
  • Meaning  – Concussions are associated with an increased long-term risk of dementia, which is modestly reduced for patients receiving a statin.

 

Abstract

Importance  

Concussions are an acute injury that may lead to chronic disability, while statin use might improve neurologic recovery.

Objective  

To test whether statin use is associated with an increased or decreased risk of subsequent dementia after a concussion.

Design, Setting, and Participants  

Large extended population-based double cohort study in Ontario, Canada, from April 1, 1993, to April 1, 2013 (enrollment), and continued until March 31, 2016 (follow-up). Dates of analysis were April 28, 2014, through March 21, 2019. Participants were older adults diagnosed as having a concussion, excluding severe cases resulting in hospitalization, individuals with a prior diagnosis of dementia or delirium, and those who died within 90 days.

Exposure  

Statin prescription within 90 days after a concussion.

Main Outcome and Measure  

Long-term incidence of dementia.

Results  

This study identified 28 815 patients diagnosed as having a concussion (median age, 76 years; 61.3% female), of whom 7058 (24.5%) received a statin, and 21 757 (75.5%) did not receive a statin. A total of 4727 patients subsequently developed dementia over a mean follow-up of 3.9 years, equal to an incidence of 1 case per 6 patients. Patients who received a statin had a 13% reduced risk of dementia compared with patients who did not receive a statin (relative risk, 0.87; 95% CI, 0.81-0.93; P < .001). The decreased risk of dementia associated with statin use applied to diverse patient groups, remained independent of other cardiovascular medication use, intensified over time, was distinct from the risk of subsequent depression, and was not observed in patients after an ankle sprain.

Conclusions and Relevance  

In this study, older adults had a substantial long-term risk of dementia after a concussion, which was associated with a modest reduction among patients receiving a statin.

Keywords: Concussion; Statins; Neurology.

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Association of #Blood and #CSF #Tau Level and Other #Biomarkers With #Survival Time in Sporadic #CJD (JAMA Neurol., abstract)

[Source: JAMA Neurology, full page: (LINK). Abstract, edited.]

Original Investigation / May 6, 2019

Association of Blood and Cerebrospinal Fluid Tau Level and Other Biomarkers With Survival Time in Sporadic Creutzfeldt-Jakob Disease

Adam M. Staffaroni, PhD 1; Abigail O. Kramer, MS 1,2; Megan Casey, BS1; et al Huicong Kang, MD 1,3; Julio C. Rojas, MD, PhD 1; Christina D. Orrú, PhD 4; Byron Caughey, PhD 4; I. Elaine Allen, PhD 5; Joel H. Kramer, PsyD 1; Howard J. Rosen, MD 1; Kaj Blennow, MD, PhD 6,7; Henrik Zetterberg, MD, PhD 6,7,8,9; Michael D. Geschwind, MD, PhD 1

Author Affiliations: 1 UCSF Memory and Aging Center, Department of Neurology, University of California, San Francisco; 2 Department of Psychology, Palo Alto University, Palo Alto, California; 3 Department of Neurology, Tongji Hospital affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 4 Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana; 5 Department of Biostatistics and Epidemiology, University of California, San Francisco; 6 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 7 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden; 8 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; 9 UK Dementia Research Institute, University College London, London, United Kingdom

JAMA Neurol. 2019;76(8):969-977. doi:10.1001/jamaneurol.2019.1071

 

Key Points

  • Question  – Can fluid biomarkers improve prediction of survival time in sporadic Creutzfeldt-Jakob disease (sCJD) above and beyond demographic and genetic biomarkers?
  • Findings  – In this longitudinal cohort study including 188 participants with probable or definite sCJD and codon 129 genotyping, in addition to polymorphisms of prion protein gene codon 129 and baseline functional status, several cerebrospinal fluid–based and blood-based biomarkers were associated with survival in patients with sCJD. Total tau concentrations in the blood and cerebrospinal fluid appear to be the most promising.
  • Meaning  – This study provides evidence that blood-based biomarkers can be used to predict survival in patients with sCJD, potentially improving clinical care and our ability to power treatment trials.

 

Abstract

Importance  

Fluid biomarkers that can predict survival time in sporadic Creutzfeldt-Jakob disease (sCJD) will be critical for clinical care and for treatment trials.

Objective  

To assess whether plasma and cerebrospinal fluid (CSF) biomarkers are associated with survival time in patients with sCJD.

Design, Setting, and Participants  

In this longitudinal cohort study, data from 193 patients with probable or definite sCJD who had codon 129 genotyping referred to a tertiary national referral service in the United States were collected from March 2004 to January 2018. Participants were evaluated until death or censored at the time of statistical analysis (range, 0.03-38.3 months). We fitted Cox proportional hazard models with time to event as the outcome. Fluid biomarkers were log-transformed, and models were run with and without nonfluid biomarkers of survival. Five patients were excluded because life-extending measures were performed.

Main Outcomes and Measures  

Biomarkers of survival included sex, age, codon 129 genotype, Barthel Index, Medical Research Council Prion Disease Rating Scale, 8 CSF biomarkers (total tau [t-tau] level, phosphorylated tau [p-tau] level, t-tau:p-tau ratio, neurofilament light [NfL] level, β-amyloid 42 level, neuron-specific enolase level, 14-3-3 test result, and real-time quaking-induced conversion test), and 3 plasma biomarkers (t-tau level, NfL level, and glial fibrillary acidic protein level).

Results  

Of the 188 included participants, 103 (54.8%) were male, and the mean (SD) age was 63.8 (9.2) years. Plasma t-tau levels (hazard ratio, 5.8; 95% CI, 2.3-14.8; P < .001) and CSF t-tau levels (hazard ratio, 1.6; 95% CI, 1.2-2.1; P < .001) were significantly associated with survival after controlling for codon 129 genotype and Barthel Index, which are also associated with survival time. Plasma and CSF t-tau levels were correlated (r = 0.74; 95% CI, 0.50-0.90; P < .001). Other fluid biomarkers associated with survival included plasma NfL levels, CSF NfL levels, t-tau:p-tau ratio, 14-3-3 test result, and neuron-specific enolase levels. In a restricted subset of 23 patients with data for all significant biomarkers, the hazard ratio for plasma t-tau level was more than 40% larger than any other biomarkers (hazard ratio, 3.4; 95% CI, 1.8-6.4).

Conclusions and Relevance  

Cerebrospinal fluid and plasma tau levels, along with several other fluid biomarkers, were significantly associated with survival time in patients with sCJD. The correlation between CSF and plasma t-tau levels and the association of plasma t-tau level with survival time suggest that plasma t-tau level may be a minimally invasive fluid biomarker in sCJD that could improve clinical trial stratification and guide clinical care.

Keywords: CJD; Prions; Neurology.

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