Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis

Conditions
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Anti-N-Methyl-D-Aspartate Receptor Encephalitis, Autoimmune Encephalitis

Intervention / Treatment
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* Other: Not applicable - non-interventional study


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: NMDAR-antibody encephalitis group: Age 8-24 years at study enrollment. Disease onset in the last 12 months before study enrollment. Meets consensus diagnostic criteria (Graus et al., 2016) for either probable anti-NMDAR encephalitis OR definite anti-NMDAR encephalitis. Antibody-negative autoimmune encephalitis group: Age 8-24 years at study enrollment. Disease onset in the last 12 months before study enrollment. 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: 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). Severe movement disorder/uncontrolled epilepsy/dysautonomia. Previous infective encephalitis with major destructive brain lesions.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| NMDAR-antibody encephalitis<br>Children and young people (ages 8-24 years) with a diagnosis of NMDAR-antibody encephalitis. | Other: Not applicable - non-interventional study<br>* Not applicable - non-interventional study<br>|
| Antibody-negative autoimmune encephalitis<br>Children and young people (ages 8-24 years) with a diagnosis of autoantibody-negative but probable autoimmune encephalitis or definite autoimmune limbic encephalitis. | Other: Not applicable - non-interventional study<br>* Not applicable - non-interventional study<br>|
| Healthy control<br>Healthy children and young people (ages 8-24 years). | Other: Not applicable - non-interventional study<br>* Not applicable - non-interventional study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebral concentrations of GABA and glutamate at the prefrontal cortex and left medial temporal lobe | Measured with MR spectroscopy - stimulated echo acquisition mode (STEAM) sequence | Baseline | 
| Structural MRI | Quantitative MRI parameter maps including measurement of median T2 values in the hippocampus | Baseline | 
| Resting-state fMRI | Whole-brain mapping of the default mode network and seed-based analysis of hippocampal-frontal connectivity | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wechsler Abbreviated Scale of Intelligence 2nd Edition (WASI-II) | Cognitive test (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| Rey Auditory Verbal Learning Test (RAVLT) | Cognitive test (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| Doors & People Test | Cognitive test (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| CANTAB (Cambridge Cognition, UK): Paired Associates Learning | Cognitive test (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| CANTAB (Cambridge Cognition, UK): Rapid Visual Information Processing | Cognitive test (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| CANTAB (Cambridge Cognition, UK): Spatial Span | Cognitive test (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| CANTAB (Cambridge Cognition, UK): Intra-Extra Dimensional Set Shift | Cognitive test (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| CANTAB (Cambridge Cognition, UK): Stockings of Cambridge | Cognitive test (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| CANTAB (Cambridge Cognition, UK): Stop Signal Task | Cognitive test (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| Prodromal Questionnaire Brief Version (PQ-B) | Questionnaire-based psychiatric symptom score (lower score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| Patient Health Questionnaire (PHQ-9) | Questionnaire-based psychiatric symptom score (lower score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| Generalized Anxiety Disorder 7-item Scale (GAD-7) | Questionnaire-based psychiatric symptom score (lower score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales | Questionnaire-based functional outcome score (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| PedsQL Multidimensional Fatigue Scale | Questionnaire-based functional outcome score (higher score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| Behaviour Rating Inventory of Executive Function (BRIEF) | Questionnaire-based functional outcome score (lower score indicating better outcome) | Baseline (all groups), 1 year (patients) | 
| Conners 3 Short Form / Conners' Adult ADHD Rating Scale | Questionnaire-based functional outcome score (lower score indicating better outcome) | Baseline (all groups), 1 year (patients) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Magnetic resonance imaging (MRI), Magnetic resonance spectroscopy (MRS), Resting-state functional MRI, Cognition, Ultra-high field MRI