Encephalitis Related research January 2014

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1 Study title Lead Institution and lead investigator Abstract or further info on study Funder Funding awarded Start date (or date of award) Proposed end date ES Coapplicant status 1 Informal study of Encephalitis Angela VINCENT Suhkvir Wright and Yael Hacohen, Oxford; Ming Lim, London 2 Faciobrachial dystonic seizures a prodrome to LGI1-antibody encephalitis 3 Faciobrachial dystonic seizures: an immunotherapy responsive syndrome whose treatment may prevent encephalitis 4 Audit of children/adolescents following encephalitis seen for neuropsychological assessment 5 Understanding and Improving the Outcome of Encephalitis Oxford, Prof A Vincent London, Mike Johnson and Oxford, Sarosh Irani Paediatric Neuropsychology Service, Nottingham University Hospitals NHS Trust Dr Arleta Starza-Smith, Dr and Dr Emily Talbot in collaboration with Dr Rachel Kneen & Dr Vicky Gray at Alder Hey in Liverpool Prof. Tom Solomon, Brain Infections Group, University of Liverpool Presence of antibodies to neuronal antigens in sera from children with autoimmune encephalitis. Retrospective study on children from five UK centres (Hacohen et al 2012). Two other pediatric cohort studies in progress Preliminary results published : Irani et al Ann Neurol May;69(5): A prospective study to understand whether immunotherapy for Faciobrachial dystonic seizures prevents encephalitis Looking to audit children/adolescents who had encephalitis and been seen for neuropsychological assessment across two centres Study the clinical predictors of Encephalitis, and of poor outcome Better understand those outcomes in terms of cognitive function, quality of life, and cost Develop the means of intervening to Wellcome Trust NIHR Oxford Biomedical NIHR Oxford Biomedical NIHR Oxford Biomedical Within NHS Trusts WT clinical training fellowship to Suhkvir Wright Oxford Biomedical training fellowship to Yael Hacohen NIHR fellowship to Sarosh Irani April 1 st 2012 March 31 st /2007 indefinite On going indefinite n/a 2013 End 2013 NIHR 2 million

2 improve the outcome 6 Understanding the role of Inflammation in Encephalitis 7 Enhanced diagnostic and management strategies to improve the identification and outcome of individuals with encephalitis 8 Cognitive dysfunction in autoimmune limbic encephalitis and its implications for the neuroscience of remote memory. Dr Benedict Michael, Brain Infections Group, University of Liverpool Dr Julia Granerod/HPA University of Oxford; Dr. Christopher Butler and Dr Thomas Miller In humans, which of these protein molecules causes the inflammation in HSV encephalitis and are they more closely related to a poor outcome than the amount of virus? Aims 1. To devise a standard diagnostic algorithm for the laboratory investigation of encephalitis across the UK; 2. To establish how improved access to intrathecal and autoantibody testing will contribute to better management of cases; 3. To ensure consistent high-level molecular diagnostics are available across the England; 4. To establish a communications strategy for general physicians, general practitioners (GPs) and the general public to raise awareness of encephalitis and contribute to rapid referral; 5. To establish a bio-bank for further work on the aetiology of encephalitis cases; 6. To define the role of scans in early management of encephalitis cases; 7. To define and quantify sequelae postencephalitis. Limbic encephalitis (LE) is a disease in which amnesia and seizures arise from inflammation of the medial temporal lobes (MTL), a region critical for memory. Many cases of LE are due to autoimmune disease where antibodies against proteins in the cell membrane of neurons, NIHR 456, DoH 413,840 January 2013 The Encephalitis Society Patrick Berthould Charitable Trust 2 years with total of 150,000 January /1/ /1/2015

3 9 Intravenous Immunoglobulin in the management of Encephalopathy University of Oxford and Professor Andrew J Pollard especially the voltage-gated potassium channel complex (VGKC-LE). Patients with VGKC-LE usually improve with treatment, but some develop lasting problems with their memory, probably as a result of permanent brain damage. Very little is known about the cause of patients memory difficulties or how they can be prevented. VGKC-LE was first described in Oxford, and there is a large number of people in the region who have been treated for it. We will perform memory testing and detailed brain scans in these people, and in a group of newly-diagnosed patients, in order to understand how VGKC-LE causes memory impairment and improve the management of this condition. VGKC-LE also offers unique opportunities for understanding how the brain processes memories. Many scientists think that, although the MTL is important for memory, it is not involved in remembering events that occurred long ago ( remote memory ). However, our preliminary work suggests that patients with VGKC-LE, who have damage to the MTL, are unable to remember events even from their childhood. We now need to check this finding in a large number of patients using detailed tests of remote memory and state-of-the-art brain scanning. If true, it will have important implications for our understanding of how memories are laid. To determine whether early treatment with intravenous immunoglobulin (IVIG) additional to standard care for children presenting with symptoms and signs of acute encephalitis EME 2,360,932 1/9/ /8/2016

4 improves outcome when compared to standard care alone. 10 Neuropsychological Outcome of Encephalitis in Children - a better understanding to develop improved services Rachel Kneen Arleta Starza Smith Ava Easton Dr Marta García- Fiñana Michael Kopelman Tom Solomon We will study the neuropsychological outcome of encephalitis in children & adolescents (<18 years). We will do this by studying children and adolescents enrolled in a previous Health Protection Agency (HPA) study of encephalitis (funded by Department of Health) and those enrolled in the NIHR programme grant. The research is led by Alder Hey Children s NHS Foundation Trust in partnership with the Liverpool Brain Infections Group, the Encephalitis Society, the HPA and other experts in this area.?? 11 Mechanism and Efficacy of Corticosteroids in Herpes simplex virus Encephalitis in Adults Tom Solomon Test the primary hypothesis that treatment with the corticosteroid dexamthasone, rather than placebo, is associated with a reduction in the swelling of the temporal lobe measured by magnetic resonance imaging at 2 weeks, without an associated in detectable virus in the CSF. The aims are: 1. is to set up a randomised placebo controlled trial of dexamethasone versus placebo in adults with HSV encephalitis 2. to perform MRI scanning at admission, and 2 weeks later, to allow examination of the effect of dexamethasone on brain swelling in the temporal lobe 3. to see whether dexamethasone treatment affects the proportion of EME 1,154,637??

5 patients who have HSV still detectable in the routine CSF examination which is performed at 2 weeks into treatment. 12 Acute encephalitis in children- Which outcomes are important Prof Tom Solomon and Dr Rachel Kneen (supervisors), Dr Jennifer Lemon (research fellow) We will also address these additional questions: 1. How do MRI scans at 6 months compare for patients treated with or without corticosteroids 2. What is the effect of corticosteroid treatment on host response patterns in the CSF and blood for patients with HSV encephalitis 3. How do clinical outcomes at 2 weeks and at 6 months compare for patients treated with or without corticosteroids. A need has been identified by researchers to standardise which outcomes are measured in clinical trials. The Core Outcomes Measurement in Effectiveness Trials (COMET) initiative suggests that this can be achieved by developing a Core Outcome Set (COS) which should be developed with stakeholder groups. A COS is a list of the minimum that should be measured and reported in all clinical trials of a specific condition. Encephalitis is a complex disease with a wide variety of different outcomes and can have a huge impact on the lives of patients and their families. There is currently no COS for paediatric encephalitis and this research aims to undertake the first steps towards development of this list by 1) Assessing what outcomes have been measured previously in clinical trials involving patients with acute Institute of Infection and Global health. The qualitative study is a sub study of the UK ChiMES study n/a Aug 2013 Dec 2014

6 13 Examining host response in viral encephalitis: towards developing novel immunomodulatory therapies Jeoffrey Segura encephalitis by means of a systematic review 2) Exploring via interviews with parents which outcomes matter most to children with encephalitis and their families, how perspectives on any problems experienced have changed over time and future expectations. To study the mechanisms of host damage in viral encephalitis we have a range of models, including a blood brain barrier model, cardiomyocyte model and neuronal cell model. These allow us to examine the effect of viral infection and of serum and cerebrospinal fluid from infected patients on host tissues, and to interrogate the host response through collaboration with Prof Neil Hall of Liverpool s Centre for Genomic Research. In this project we will thus determine the effects of the relevant host markers, and importantly explore the role of putative treatment to reverse these effects. In recent years antibodies against IL-6, IL-1Ra, and G-CSF have become available in clinical practise. This PhD project will determine which of these compounds might be suitable as development as treatment for viral encephalitis, as well as identifying possible new therapeutic targets. The Encephalitis Society/Kirkby Foundation/Univ ersity of Liverpool PhD Fellowship 17,859 per year for three years July

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