Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis

Autoimmune Encephalitis Clinical Trial

— DANCE-AE  

Official title:

Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05280600
• Other study ID #: KCL21-018
• Secondary ID: GN2835IRAS 29779
• Status: Recruiting
• 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
• 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.

Related Conditions & MeSH terms

• Anti-N-Methyl-D-Aspartate Receptor Encephalitis
• Autoimmune Diseases of the Nervous System
• Autoimmune Encephalitis
• Encephalitis
• Hashimoto Disease

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)