Clinical trial NCT05280600: Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis
Official title: Developing Advanced Neuroimaging for Clinical Evaluation of Autoimmune Encephalitis
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Anti-N-Methyl-D-Aspartate Receptor Encephalitis
Autoimmune Encephalitis
Keywords: Magnetic resonance imaging (MRI)
Magnetic resonance spectroscopy (MRS)
Resting-state functional MRI
Cognition
Ultra-high field MRI
Lead sponsor: King's College London
Sponsor class: OTHER
Collaborators: name: Guy's and St Thomas' NHS Foundation Trust
name: Action Medical Research
First posted: 2022-03-15
Enrollment: 75
Sex: ALL
Minimum age (years): 8
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief 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.

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.

Eligibility 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.

Primary outcomes:
measure: Cerebral concentrations of GABA and glutamate at the prefrontal cortex and left medial temporal lobe
timeFrame: Baseline
measure: Structural MRI
timeFrame: Baseline
measure: Resting-state fMRI
timeFrame: Baseline
Secondary outcomes:
measure: Wechsler Abbreviated Scale of Intelligence 2nd Edition (WASI-II)
timeFrame: Baseline (all groups), 1 year (patients)
measure: Rey Auditory Verbal Learning Test (RAVLT)
timeFrame: Baseline (all groups), 1 year (patients)
measure: Doors & People Test
timeFrame: Baseline (all groups), 1 year (patients)
measure: CANTAB (Cambridge Cognition, UK): Paired Associates Learning
timeFrame: Baseline (all groups), 1 year (patients)
measure: CANTAB (Cambridge Cognition, UK): Rapid Visual Information Processing
timeFrame: Baseline (all groups), 1 year (patients)
measure: CANTAB (Cambridge Cognition, UK): Spatial Span
timeFrame: Baseline (all groups), 1 year (patients)
measure: CANTAB (Cambridge Cognition, UK): Intra-Extra Dimensional Set Shift
timeFrame: Baseline (all groups), 1 year (patients)
measure: CANTAB (Cambridge Cognition, UK): Stockings of Cambridge
timeFrame: Baseline (all groups), 1 year (patients)
measure: CANTAB (Cambridge Cognition, UK): Stop Signal Task
timeFrame: Baseline (all groups), 1 year (patients)
measure: Prodromal Questionnaire Brief Version (PQ-B)
timeFrame: Baseline (all groups), 1 year (patients)
measure: Patient Health Questionnaire (PHQ-9)
timeFrame: Baseline (all groups), 1 year (patients)
measure: Generalized Anxiety Disorder 7-item Scale (GAD-7)
timeFrame: Baseline (all groups), 1 year (patients)
measure: Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales
timeFrame: Baseline (all groups), 1 year (patients)
measure: PedsQL Multidimensional Fatigue Scale
timeFrame: Baseline (all groups), 1 year (patients)
measure: Behaviour Rating Inventory of Executive Function (BRIEF)
timeFrame: Baseline (all groups), 1 year (patients)
measure: Conners 3 Short Form / Conners' Adult ADHD Rating Scale
timeFrame: Baseline (all groups), 1 year (patients)
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
state: Greater London
Study officials:
affiliation: King's College London
name: David W Carmichael, PhD MSci
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.