Anti-N-Methyl-D-Aspartate Receptor Encephalitis, Autoimmune Encephalitis
Conditions
Keywords
Magnetic resonance imaging (MRI), Magnetic resonance spectroscopy (MRS), Resting-state functional MRI, Cognition, Ultra-high field MRI
Brief summary
Autoimmune encephalitis is brain inflammation caused by the immune system mistakenly reacting against proteins in the brain. The commonest form is called NMDAR-antibody encephalitis (N-methyl-D-aspartate receptor antibody encephalitis), a rare condition which mainly affects children and young people and causes difficulties in memory, thinking and mental health which can have significant long-term impacts on education, employment and quality of life. In this project we will use advanced magnetic resonance imaging (MRI) to measure changes in the structure, function and chemistry of the brains of children and young people who are in early recovery from NMDAR-antibody encephalitis and other forms of immune-mediated encephalitis. We will investigate if MRI measurements in patients differ from those in healthy people, and if they can help predict patient outcome one year later, assessed by tests of memory, thinking, mental health and functioning in daily life.
Detailed description
This study aims to develop non-invasive, in vivo measures of neurobiological dysfunction derived from the overarching hypothesis that dysfunction of inhibitory interneurons alters the cerebral concentrations of gamma-aminobutyric acid (GABA) and glutamate (Glu) and underlies T2 changes and deficient connectivity in functional networks in early recovery from NMDAR-antibody encephalitis. Our ambition is to identify the best potential prognostic biomarkers from these neurometabolite measurements and structural and functional MRI. Our primary objective is to test the following specific hypotheses in children and young people with NMDAR-antibody encephalitis: * Hypothesis 1: GABA is decreased, and Glu increased, on MR spectroscopy of the medial temporal lobe and medial prefrontal cortex in NMDAR-antibody encephalitis. * Hypothesis 2: Local GABA and Glu are correlated with (i) resting-state functional MRI (fMRI) based functional connectivity and (ii) parameter map-based microstructural changes. Specifically, we hypothesise that (i) GABA is positively correlated and Glu inversely correlated with functional connectivity, assessed by whole-brain mapping of the default mode network and seed-based analysis of hippocampal-frontal connectivity; and (ii) Glu is positively correlated and GABA inversely correlated with median T2 values within the hippocampus. * Hypothesis 3: Local neurometabolites, network measures and microstructural changes predict cognitive, psychiatric and functional outcome at one year. Specifically, we hypothesise that medial temporal Glu, GABA and hippocampal T2 predict memory performance, and prefrontal Glu and GABA predict attention, executive function and fluid intelligence.
Interventions
OTHERNot applicable - non-interventional study
Not applicable - non-interventional study
Sponsors
Guy's and St Thomas' NHS Foundation Trust
Action Medical Research
King's College London
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
8 Years to 24 Years
Healthy volunteers
Yes
Inclusion criteria
NMDAR-antibody encephalitis group: 1. Age 8-24 years at study enrollment. 2. Disease onset in the last 12 months before study enrollment. 3. Meets consensus diagnostic criteria (Graus et al., 2016) for either probable anti-NMDAR encephalitis OR definite anti-NMDAR encephalitis. Antibody-negative autoimmune encephalitis group: 1. Age 8-24 years at study enrollment. 2. Disease onset in the last 12 months before study enrollment. 3. Meets consensus diagnostic criteria (Graus et al., 2016) for either autoantibody-negative but probable autoimmune encephalitis OR definite autoimmune limbic encephalitis. Healthy control group: 1\. Age 8-24 years at study enrollment.
Exclusion criteria
All participants: 1\. Any clear contra-indication for an MRI scan. In particular this would be due to the presence of any implanted devices or metal from previous surgery or accident. Healthy control group: 1\. A known neurological or neurodevelopmental disorder. NMDAR-antibody encephalitis and antibody-negative autoimmune encephalitis groups: 1. Alternative more likely cause of neurological symptoms than autoimmune encephalitis, i.e. reasonable exclusion of other diagnoses as per consensus criteria (Graus et al., 2016). 2. Severe movement disorder/uncontrolled epilepsy/dysautonomia. 3. Previous infective encephalitis with major destructive brain lesions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebral concentrations of GABA and glutamate at the prefrontal cortex and left medial temporal lobe | Baseline | Measured with MR spectroscopy - stimulated echo acquisition mode (STEAM) sequence |
| Structural MRI | Baseline | Quantitative MRI parameter maps including measurement of median T2 values in the hippocampus |
| Resting-state fMRI | Baseline | Whole-brain mapping of the default mode network and seed-based analysis of hippocampal-frontal connectivity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CANTAB (Cambridge Cognition, UK): Paired Associates Learning | Baseline (all groups), 1 year (patients) | Cognitive test (higher score indicating better outcome) |
| CANTAB (Cambridge Cognition, UK): Rapid Visual Information Processing | Baseline (all groups), 1 year (patients) | Cognitive test (higher score indicating better outcome) |
| CANTAB (Cambridge Cognition, UK): Spatial Span | Baseline (all groups), 1 year (patients) | Cognitive test (higher score indicating better outcome) |
| CANTAB (Cambridge Cognition, UK): Intra-Extra Dimensional Set Shift | Baseline (all groups), 1 year (patients) | Cognitive test (higher score indicating better outcome) |
| CANTAB (Cambridge Cognition, UK): Stockings of Cambridge | Baseline (all groups), 1 year (patients) | Cognitive test (higher score indicating better outcome) |
| CANTAB (Cambridge Cognition, UK): Stop Signal Task | Baseline (all groups), 1 year (patients) | Cognitive test (higher score indicating better outcome) |
| Wechsler Abbreviated Scale of Intelligence 2nd Edition (WASI-II) | Baseline (all groups), 1 year (patients) | Cognitive test (higher score indicating better outcome) |
| Patient Health Questionnaire (PHQ-9) | Baseline (all groups), 1 year (patients) | Questionnaire-based psychiatric symptom score (lower score indicating better outcome) |
| Generalized Anxiety Disorder 7-item Scale (GAD-7) | Baseline (all groups), 1 year (patients) | Questionnaire-based psychiatric symptom score (lower score indicating better outcome) |
| Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales | Baseline (all groups), 1 year (patients) | Questionnaire-based functional outcome score (higher score indicating better outcome) |
| PedsQL Multidimensional Fatigue Scale | Baseline (all groups), 1 year (patients) | Questionnaire-based functional outcome score (higher score indicating better outcome) |
| Behaviour Rating Inventory of Executive Function (BRIEF) | Baseline (all groups), 1 year (patients) | Questionnaire-based functional outcome score (lower score indicating better outcome) |
| Conners 3 Short Form / Conners' Adult ADHD Rating Scale | Baseline (all groups), 1 year (patients) | Questionnaire-based functional outcome score (lower score indicating better outcome) |
| Prodromal Questionnaire Brief Version (PQ-B) | Baseline (all groups), 1 year (patients) | Questionnaire-based psychiatric symptom score (lower score indicating better outcome) |
| Rey Auditory Verbal Learning Test (RAVLT) | Baseline (all groups), 1 year (patients) | Cognitive test (higher score indicating better outcome) |
| Doors & People Test | Baseline (all groups), 1 year (patients) | Cognitive test (higher score indicating better outcome) |
Countries
United Kingdom
Contacts
Primary ContactMichael R Eyre, MBBS MRes
Backup ContactDavid W Carmichael, PhD MSci
Outcome results
None listed