Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis

King's College London75 enrolled

Overview

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.

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.

Study Type

Eligibility

Sex: ALLMin age: 8 YearsMax age: 24 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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

Time frame: Baseline

Structural MRI

Quantitative MRI parameter maps including measurement of median T2 values in the hippocampus

Time frame: Baseline

Resting-state fMRI

Whole-brain mapping of the default mode network and seed-based analysis of hippocampal-frontal connectivity

Time frame: Baseline