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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05280600
Other study ID # KCL21-018
Secondary ID GN2835IRAS 29779
Status Recruiting
Phase
First received
Last updated
Start date May 19, 2022
Est. completion date February 28, 2026

Study information

Verified date October 2023
Source King's College London
Contact Michael R Eyre, MBBS MRes
Phone +44 207 1887188
Email michael.eyre@kcl.ac.uk
Is FDA regulated No
Health authority
Study type Observational

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 75
Est. completion date February 28, 2026
Est. primary completion date February 28, 2024
Accepts healthy volunteers Accepts Healthy Volunteers
Gender All
Age group 8 Years to 24 Years
Eligibility 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.

Study Design


Related Conditions & MeSH terms


Intervention

Other:
Not applicable - non-interventional study
Not applicable - non-interventional study

Locations

Country Name City State
United Kingdom Guy's and St Thomas' NHS Foundation Trust London Greater London

Sponsors (3)

Lead Sponsor Collaborator
King's College London Action Medical Research, Guy's and St Thomas' NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016 Apr;15(4):391-404. doi: 10.1016/S1474-4422(15)00401-9. Epub 2016 Feb 20. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary 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
Primary Structural MRI Quantitative MRI parameter maps including measurement of median T2 values in the hippocampus Baseline
Primary Resting-state fMRI Whole-brain mapping of the default mode network and seed-based analysis of hippocampal-frontal connectivity Baseline
Secondary Wechsler Abbreviated Scale of Intelligence 2nd Edition (WASI-II) Cognitive test (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary Rey Auditory Verbal Learning Test (RAVLT) Cognitive test (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary Doors & People Test Cognitive test (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary CANTAB (Cambridge Cognition, UK): Paired Associates Learning Cognitive test (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary CANTAB (Cambridge Cognition, UK): Rapid Visual Information Processing Cognitive test (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary CANTAB (Cambridge Cognition, UK): Spatial Span Cognitive test (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary CANTAB (Cambridge Cognition, UK): Intra-Extra Dimensional Set Shift Cognitive test (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary CANTAB (Cambridge Cognition, UK): Stockings of Cambridge Cognitive test (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary CANTAB (Cambridge Cognition, UK): Stop Signal Task Cognitive test (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary Prodromal Questionnaire Brief Version (PQ-B) Questionnaire-based psychiatric symptom score (lower score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary Patient Health Questionnaire (PHQ-9) Questionnaire-based psychiatric symptom score (lower score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary Generalized Anxiety Disorder 7-item Scale (GAD-7) Questionnaire-based psychiatric symptom score (lower score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary 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)
Secondary PedsQL Multidimensional Fatigue Scale Questionnaire-based functional outcome score (higher score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary Behaviour Rating Inventory of Executive Function (BRIEF) Questionnaire-based functional outcome score (lower score indicating better outcome) Baseline (all groups), 1 year (patients)
Secondary 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)
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