Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis (DANCE-AE)

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.

Study Overview

• Status: Recruiting
• Conditions: Autoimmune Encephalitis; Anti-N-Methyl-D-Aspartate Receptor Encephalitis
• Intervention / Treatment: Other: Not applicable - non-interventional study

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.

• Study Type: Observational
• Enrollment (Estimated): 75

Contacts and Locations

• Study Contact: Name: Michael R Eyre, MBBS MRes; Phone Number: 56322 +44 207 1887188; Email: michael.eyre@kcl.ac.uk
• Study Contact Backup: Name: David W Carmichael, PhD MSci; Email: david.carmichael@kcl.ac.uk

Study Locations

• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, SE1 7EH
      • Recruiting
      • Guy's and St Thomas' NHS Foundation Trust
      • Contact: Michael R Eyre, MBBS MRes; Email: michael.eyre@kcl.ac.uk
      • Contact: Ming J Lim, MBBS PhD; Email: ming.lim@gstt.nhs.uk
      • Principal Investigator: Ming J Lim, MBBS PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 24 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

All participants will be recruited in the United Kingdom.

NMDAR-antibody encephalitis and antibody-negative autoimmune encephalitis groups: Identified by neurologists/paediatric neurologists in secondary/tertiary healthcare settings, or by self-referral via the Encephalitis Society.

Healthy control group: Identified from King's College London volunteer databases, friends and siblings of autoimmune encephalitis cases, or recruited from local schools and colleges.

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
NMDAR-antibody encephalitis; Children and young people (ages 8-24 years) with a diagnosis of NMDAR-antibody encephalitis.	Other: Not applicable - non-interventional study; Not applicable - non-interventional study
Antibody-negative autoimmune encephalitis; 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; Not applicable - non-interventional study
Healthy control; Healthy children and young people (ages 8-24 years).	Other: Not applicable - non-interventional study; Not applicable - non-interventional study

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: Guy's and St Thomas' NHS Foundation Trust; Action Medical Research
• Investigators: Principal Investigator: David W Carmichael, PhD MSci, King's College London

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2022
• Primary Completion (Estimated): February 28, 2024
• Study Completion (Estimated): February 28, 2026

Study Registration Dates

• First Submitted: February 10, 2022
• First Submitted That Met QC Criteria: March 14, 2022
• First Posted (Actual): March 15, 2022

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Cognition; Magnetic resonance imaging (MRI); Magnetic resonance spectroscopy (MRS); Resting-state functional MRI; Ultra-high field MRI
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases; Neoplasms by Site; Endocrine System Diseases; Thyroid Diseases; Neurodegenerative Diseases; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Thyroiditis, Autoimmune; Thyroiditis; Neuroinflammatory Diseases; Encephalitis; Autoimmune Diseases of the Nervous System; Hashimoto Disease; Anti-N-Methyl-D-Aspartate Receptor Encephalitis
• Other Study ID Numbers: KCL21-018; GN2835 (Other Grant/Funding Number: Action Medical Research); IRAS 297793 (Other Identifier: Health Research Authority)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Consent will be requested from participants to share imaging data and summary clinical and demographic data. Where participants consent, imaging data will be de-identified, removing facial features from the magnetic resonance images and all identifying information will be removed from the image header (the part of the file that describes how the image data was acquired). The resulting data will be shared together with anonymised clinical data at the request of other researchers.
• IPD Sharing Time Frame: To be confirmed
• IPD Sharing Access Criteria: Requests for data access from researchers at accredited research institutions will be considered. Any requests for data sharing may require a formal agreement to be put in place between the Sponsors and the recipient.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No