Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	Yes
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Observational
Eligible Ages	8 Years - 24 Years
Gender	All

More Inclusion & Exclusion Criteria

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.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05280600
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	King's College London
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	David W Carmichael, PhD MSci
Principal Investigator Affiliation	King's College London
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	United Kingdom
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Anti-N-Methyl-D-Aspartate Receptor Encephalitis, Autoimmune Encephalitis

Additional Details

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.

Arms & Interventions

Arms

: NMDAR-antibody encephalitis

Children and young people (ages 8-24 years) with a diagnosis of NMDAR-antibody encephalitis.

: 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.

: Healthy control

Healthy children and young people (ages 8-24 years).

Interventions

Other: - Not applicable - non-interventional study

Not applicable - non-interventional study

Contact a Trial Team

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International Sites

London, Greater London, United Kingdom

Status

Recruiting

Address

Guy's and St Thomas' NHS Foundation Trust

London, Greater London, SE1 7EH

Site Contact

Michael R Eyre, MBBS MRes

[email protected]

+44 207 1887188

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