Antibody-mediated NMDA Receptor Encephalitis: Symptoms, Biomarkers, and Mechanisms of the Prolonged Recovery Stage

Study Overview
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Brief Summary
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The encephalitis mediated by antibodies against the NMDA receptor (NMDARe) predominantly affects young adults and children resulting in severe neurologic and psychiatric deficits. After overcoming the acute stage, patients are left with long-lasting behavioral, cognitive, and psychiatric alterations with important socio-family-economical implications. Here investigators postulate that a better knowledge of this stage will improve treatment decisions and outcome. In Aim 1, the post-acute stage will be clinically characterized, tools to remotely follow cognitive, behavioral and psychiatric deficits will be provided, and the impact of cognitive rehabilitation will be assessed. In Aim 2, biomarkers (autoimmune, inflammatory, neuronal injury) will be identified as signatures of the acute and post-acute stages. In Aim 3, a mouse model of NMDARe will be used to determine the underlying mechanisms and treatment of the postacute stage.

Official Title
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Antibody-mediated NMDA Receptor Encephalitis: Symptoms, Biomarkers, and Mechanisms of the Prolonged Recovery Stage

Conditions
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Anti-NMDA Receptor Encephalitis

Intervention / Treatment
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* Behavioral: Remote cognitive rehabilitation program


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥12 years old with NMDARe in the post-acute stage of the disease; ≤6 months from hospital discharge (acute phase) Exclusion Criteria (one of the following): Inability to obtain informed consent; inability to travel to the center.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-NMDARe patients with remote cognitive rehabilitation<br>Participants of a prospective cohort in post-acute phase of the Antibody-mediated NMDA Receptor Encephalitis that will received a behavioral treatment. | Behavioral: Remote cognitive rehabilitation program<br>* Remote cognitive rehabilitation program will be performed through an online validated platform (Guttmann NeuroPersonalTrainer: https://gnpt.es/) run by the psychologists team. This is a Sanitary Product with CE certification (Sanitary Product RPS/430/2014; International Patent [PCT/ES2008/00677]) and here will be used within its approved indications. The rehabilitation program will increase in difficulty and decrease in frequency during the first year of follow-up (V1-V3).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Age | Age measured in years | 18 months | 
| Gender | Male or female | 18 months | 
| Vision condition | Studied by optometer | 18 months | 
| Handedness | Right- or Left-handed | 18 months | 
| General medical history | Description of the most important issues compiled in the general medical history of the participant | 18 months | 
| Allergies | List of allergies of each participant | 18 months | 
| Symptoms related to NMDARe | Detailed description of symptoms experienced before, during and after the post-acute phase of NMDARe. | 18 months | 
| Treatments | All treatments in which the participant is being involved. | 18 months | 
| Functional status | Functional status according to Modified Rankin Scale (mRS) Modified Rankin Scale: - Range: from 0 points (no symptoms) to 6 points (dead). | 18 months | 
| Intelligence Quotient | Estimated through General Ability Index (GAI; from Weschler Adult Intelligence Scale - IV (WAIS-IV). This index is obtained through Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI). Range of GAI: from 40 to 160. Higher is better. Range of VCI: from 50 to 150. Higher is better. Range of PRI: from 50 to 150. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Verbal working memory | Verbal Working Memory: Working Memory Index (WMI) from WAIS-IV. - Range of WMI: from 50 to 150. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Phonological loop | Assessed by Forward order span of Digit span subtest from WAIS-IV. - Range: from 0 to 9 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Visual working memory | Visual Working Memory: Spatial location subtest from Weschler Memory Scale - IV (WMS-IV). - Range of Spatial Location subtest: from 0 to 32. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Verbal learning | Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI) - Total learning: range: from 0 to 80. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Proactive interference verbal memory | Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI) - Interference list: range: 0 to 15. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Short-term verbal memory | Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI) - Short-term memory free recall: range: 0 to 15. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Long-term verbal memory | Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI) - Long-term memory free recall: range: 0 to 15. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Verbal recognition memory | Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI) - Word-list Recognition: range: 0 to 15. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Verbal discrimination memory | Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI) Discrimination index of word-list: False positives + omissions of recognition between 44 total words to recognize. Higher is better. Retention index: percentatge of Long-term memory free recall between Short-term memory free recall. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Verbal retention memory | Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI) - Retention index: percentatge of Long-term memory free recall between Short-term memory free recall. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Immediate visual memory | Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R) - Immediate visual memory: range: from 0 to 36. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Delayed visual memory | Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R) - Delayed visual memory: range: from 0 to 12. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Visual retention memory | Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R) - Retention index: percentatge of Long-term memory free recall between the Higher punctuation at Trial 2 or 3. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Visual recognition memory | Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R) - Figure Recognition: range: from 0 to 6. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Visual discrimination memory | Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R) - Discrimination index: figure recognized minus false positives. Range: from -6 to 6. Higher is better. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Processing speed | Processing speed Index (PSI; from Weschler Adult Intelligence Scale - IV (WAIS-IV). Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| TMT-A | Trail Making Test part A (TMT-A): - Time in seconds: from 0 to infinity. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| TMT-B | Trail Making Test part B (TMT-B): - Time in seconds: from 0 to infinity. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Naming | Assessed by: Boston Naming Test (BNT) - Total correct: from 0 to 60 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Naming with cues | Assessed by: Boston Naming Test (BNT) - Total correct with phonemic cue: from 0 to 60 | 18 months | 
| Latency in naming | Assessed by: Boston Naming Test (BNT) - Time to complete test in seconds | 18 months | 
| Semantic fluency | Number of name of animals recalled in 1 minute: range: from 0 to infinity. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Phonemic fluency | Number of words started by letter M recalled in 1 minute: - Range: from 0 to infinity. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Visuospatial skills | Number location subtest of the Visual-Object Spatial and Perceptual battery. - Range: from 0 to 10 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Visuospatial skills - children | Assessed by Arrows subtest of NEPSY-2 battery - Range: from 0 to 20 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Stroop test - word subtest | - Words: words read in 45 seconds Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Stroop test - color subtest | - Colour: colours distinguished in 45 seconds. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Stroop test - word-color subtest | - Word-colour: colours distinguished in 45 seconds. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Detectability - CPT3 | Assessed by Continuous Performance Test - 3rd Version. Measures the respondent's ability to differentiate non-targets (i.e. the letter X) from targets (i.e. all other letters). Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Omissions - CPT3 | Assessed by Continuous Performance Test - 3rd Version. Result from a failure to respond to targets. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Comissions - CPT3 | Assessed by Continuous Performance Test - 3rd Version. Comissions are made when responses are given to non-targets. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| HRT - CPT3 | Assessed by Continuous Performance Test - 3rd Version. Hit Reaction Time (HRT) is the mean response speed of correct responses from the whole administration. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| HRT-SD - CPT3 | Assessed by Continuous Performance Test - 3rd Version. Hit Reaction Time Standard Deviation (HRT-SD) is a measure of response speed consistency during the entire administration. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Variability- CPT3 | Assessed by Continuous Performance Test - 3rd Version. The amount of variability that the patient showed in 18 separate segments of the administration in relation to their own overall Hit Reaction Time Standard Deviation (HRT-SD). It is a measure of response consistency and a within respondent measure. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| HRT Block Change - CPT3 | Assessed by Continuous Performance Test - 3rd Version. Hit Reaction Time Block Change indicates the change in mean response speed across blocks. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| HRT ISI Change - CPT3 | Assessed by Continuous Performance Test - 3rd Version. Hit Reaction Time Inter-Stimulus Interval Change (HRT ISI Change) indicates the change in mean response speed at various ISIs. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Prensence of psychiatric symptoms or disorders in presential assessments | Number of participants with psychiatric symptoms/disorders following DSM-IV-TR guidelines (psychotic symptoms, symptoms of depression, symptoms of mania, global functioning). | 18 months | 
| Sleep microstructure - Total study time | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Total sleep time: minutes | 18 months | 
| Sleep microstructure - Total sleep time | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Total sleep time: minutes | 18 months | 
| Sleep microstructure - Sleep efficiency | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Sleep efficiency: based on total study time and total sleep time | 18 months | 
| Sleep microstructure - Time to sleep onset | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Time to sleep onset: minutes | 18 months | 
| Sleep microstructure - Time in stage N1 | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Time in stage N1: minutes | 18 months | 
| Sleep microstructure - Time in stage N2 | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Time in stage N2: minutes | 18 months | 
| Sleep microstructure - Time in stage N3 | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Time in stage N3: minutes | 18 months | 
| Sleep microstructure - Time in stage R | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Time in stage R: minutes | 18 months | 
| Sleep microstructure - First epoch of N1 | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - First epoch of N1: minutes | 18 months | 
| Sleep microstructure - First epoch of N2 | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - First epoch of N2: minutes | 18 months | 
| Sleep microstructure - First epoch of N3 | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - First epoch of N3: minutes | 18 months | 
| Sleep microstructure - First epoch of REM | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - First epoch of REM: minutes | 18 months | 
| Sleep microstructure - REM/NREM time ratio | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - REM/NREM time ratio | 18 months | 
| Sleep microstructure - Number of arousals | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Number of arousals (total) | 18 months | 
| Sleep microstructure - Arousal Index | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Arousal Index | 18 months | 
| Sleep microstructure - Confusional arousals | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Confusional arousals: Yes or No | 18 months | 
| Sleep microstructure - Direct transition from N3 to W | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Direct transition from N3 to W: yes or no | 18 months | 
| Sleep microstructure - Delta arousals | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Delta arousals?: yes, no or unknown | 18 months | 
| Sleep microstructure - Wake after sleep | It will be adapted to patient's sleep habits ( 23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported. Parameters: - Wake after sleep: hour | 18 months | 
| Adherence to cognitive treatment - 6 months | Number of sessions performed in 6 months | 6 months | 
| Adherence to cognitive treatment - 9 months | Number of sessions performed in 9 months | 9 months | 
| Adherence to cognitive treatment - 12 months | Number of sessions performed in 12 months | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune/inflammatory signaling-target gene expression pathways | Whole blood/CSF will be collected using PAXgene® Blood RNA Tubes (Qiagen) shipped to the centers. Blood from healthy subjects and CSF from patients with normal pressure hydrocephalus will serve as controls. Total RNA will be extracted using PAXgene® Blood RNA Kit (Qiagen). RNA samples are quantified using Qubit 2.0 Fluorometer (Life Technologies) and RNA integrity is determined with Agilent 2100 Bioanalyzer (Agilent Technologies). Expression levels of 44 genes related to immune/inflammatory (or cytokine) pathways will be measured with the nCounter® Digital Analyzer (NanoString). The raw copy number of mRNA transcripts of each gene will be standardized (stdGene) using the geometric mean of the 4 housekeeping genes for each subject. | 18 months | 
| Neurofilament light chain (NfL) levels in acute stage | Signature of molecular biomarkers in the acute stage | 18 months | 
| Neurofilament light chain (NfL) levels in post-acute stage | Signature of molecular biomarkers in the post-acute stages | 18 months | 
| Cell immunophenotyping - proportion of CD4 | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD4. | 18 months | 
| Cell immunophenotyping - proportion of CD8 | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD8. | 18 months | 
| Cell immunophenotyping - proportion of CD8+CD45RA+ | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD8+CD45RA+. | 18 months | 
| Cell immunophenotyping - proportion of CD8+CD45RO+ | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD8+CD45RO+. | 18 months | 
| Cell immunophenotyping - proportion of iNKT | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of iNKT. | 18 months | 
| Cell immunophenotyping - proportion of CD19 | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD19. | 18 months | 
| Cell immunophenotyping - proportion of B naive (IgM+IgD+CD27-) | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of B naive (IgM+IgD+CD27-). | 18 months | 
| Cell immunophenotyping - proportion of B memory (IgD-) | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of B memory (IgD-). | 18 months | 
| Cell immunophenotyping - proportion of regulatory B cells | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of regulatory B cells. | 18 months | 
| Cell immunophenotyping - proportion of plasmablasts | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of plasmablasts. | 18 months | 
| Cell immunophenotyping - proportion of NK cells | Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of NK cells. | 18 months | 
| MRI | It will be conducted on a 3 Tesla Prisma scanner using a 32-channel head coil. Scanning takes  50 min including 3D T1-weighted in sagittal plane; T2*axial EPI; axial diffusion weighted EPI; 3D sagittal FLAIR; resting state functional MRI and glutamate and H2O univoxel spectroscopy in dorsolateral prefrontal cortex and hippocampus. There is no contrast used for the MRI scans Outcome for MRI is normal or abnormal. Investigators will review all MRI sequences and determine if the MRI is abnormal and then describe the abnormality or abnormalities seen. | 18 months | 
| EEG: normalcy | It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). - Normalcy: yes or no. | 18 months | 
| EEG: time awake | It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Parameters: - Time awake: percentage | 18 months | 
| EEG: time in drowsiness | It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Parameters: - Time in drowsiness: percentage | 18 months | 
| EEG: time asleep | It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Parameters: - Time asleep: percentage | 18 months | 
| EEG: epileptiform activity | It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Parameters: - Epileptiform activity: yes or no | 18 months | 
| EEG: seizures | It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Parameters: - Seizures: yes or no | 18 months | 
| EEG: slowing | It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Parameters: - EEG slowing: yes or no | 18 months | 
| EEG: Changes with Intermittent Light Stimulation | It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Parameters: - Changes with Intermittent Light Stimulation: yes or no | 18 months | 
| EEG: Changes with hyperventilation | It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases). Parameters: - Changes with hyperventilation: yes or no | 18 months | 
| Verbal working memory - remote assessment | Assessed by: Digit subtest from WAIS-IV: obtained by Forward order, indirect order, increasing order subtests. - Range: 0 - 48 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Verbal learning - remote assessment | Assessed by: Total learning List A subtest from Rey Auditory Verbal Learning Test (RAVLT) - Range: 0 - 75 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Proactive interference verbal memory - remote assessment | Assessed by: List B subtest from Rey Auditory Verbal Learning Test (RAVLT) - Range: 0 - 15 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Short-term verbal memory - remote assessment | Assessed by: Short-term verbal memory subtest from Rey Auditory Verbal Learning Test (RAVLT) - Range: 0 - 15 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Long-term verbal memory - remote assessment | Assessed by: Long-term verbal memory subtest from Rey Auditory Verbal Learning Test (RAVLT) - Range: 0 - 15 Orientation: temporal and spatial orientation Psychomotor speed: 5 digit test Executive functions: 5 digit test, CANTAB, Verbal fluency test. Selective and sustained attention: 5 digit test Language: Boston Naming Test (BNT) Visuospatial: Benton Judgment of Line Orientation Test (JLO) Social cognition: CANTAB Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Verbal recognition memory - remote assessment | Assessed by: Verbal recognition memory list subtest from Rey Auditory Verbal Learning Test (RAVLT) - Range: 0 - 15 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Verbal discrimination memory - remote assessment | Assessed by: Verbal discrimination memory subtest from Rey Auditory Verbal Learning Test (RAVLT) - Range: 0 - 1 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Complex figure copy - remote assessment | Assessed by: Precision in the copy of the Rey-Osterrieth Complex Figure: - Range: 0-36 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Time - Complex figure copy - remote assessment | Assessed by: Time to perform the copy of the Rey-Osterrieth Complex Figure: seconds Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Type - Complex figure copy - remote assessment | Assessed by: Type of copy of the Rey-Osterrieth Complex Figure: - Range: 1 to 4 | 18 months | 
| Short-term visual memory - remote assessment | Assessed by: Short term memory subtest of the Rey-Osterrieth Complex Figure: - Range: 0 - 36 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Long-term visual memory - remote assessment | Assessed by: Long-term memory subtest of the Rey-Osterrieth Complex Figure: - Range: 0 - 36 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Orientation in time - remote assessment | Assessed by: Orientation in time subtest from Test Barcelona - Revised. - Range: 0 -5 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Orientation in space - remote assessment | Assessed by: Orientation in space subtest from Test Barcelona - Revised. - Range: 0 -5 Orientation: temporal and spatial orientation Psychomotor speed: 5 digit test Executive functions: 5 digit test, CANTAB, Verbal fluency test. Selective and sustained attention: 5 digit test Language: Boston Naming Test (BNT) Visuospatial: Benton Judgment of Line Orientation Test (JLO) Social cognition: CANTAB Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| 5DT Lecture - remote assessment | Assessed by: Lecture subtest from 5 digit test: time Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| 5DT counting - remote assessment | Assessed by: Counting subtest from 5 digit test: time Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| 5DT Choosing - remote assessment | Assessed by: Choosing subtest from 5 digit test: time Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| 5DT Switching - remote assessment | Assessed by: Switching subtest from 5 digit test: time Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| 5DT Inhibition - remote assessment | Assessed by: Inhibition subtest from 5 digit test: time Executive functions: 5 digit test, CANTAB, Verbal fluency test. Selective and sustained attention: 5 digit test Language: Boston Naming Test (BNT) Visuospatial: Benton Judgment of Line Orientation Test (JLO) Social cognition: CANTAB Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| 5DT Flexibility - remote assessment | Assessed by: Flexibility subtest from 5 digit test: time Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Perceptual reasoning CANTAB - remote assessment | Assessed by: Intra-Extra Dimensional test from CANTAB battery. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Visuospatial Working Memory CANTAB - remote assessment | Assessed by: Spatial Working Memory test from CANTAB battery Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Emotion Recognition CANTAB - remote assessment | Assessed by: Emotion Recognition Task from CANTAB battery. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Semantic fluency - remote assessment | Assessed by: Semantic fluency test: Produce names of fruits and vegetables in 1 minute Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Phonemic fluency - remote assessment | Assessed by: Phonemic fluenct test: Produce words that start with letter M. Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Naming - remote assessment | Assessed by: Boston Naming Test (BNT): - Range: from 0 to 60 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Naming with cues - remote assessment | Assessed by: Boston Naming Test (BNT) - Total correct with phonemic cue: from 0 to 60 | 18 months | 
| Time in Naming - remote assessment | Assessed by: Boston Naming Test (BNT): time to complete | 18 months | 
| Visuospatial skills - remote assessment | Assessed by: Benton Judgment of Line Orientation Test (JLO): - Range: 0 to 30 Raw scores were transformed into standard T-scores (mean 50 ± standard deviation [SD] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased. | 18 months | 
| Psychiatric symptoms/disorders in remote assessments | Number of participants with psychiatric symptoms/disorders following DSM-IV-TR guidelines (psychotic symptoms, symptoms of depression, symptoms of mania, global functioning). | 18 months | 
| Serial bias in working memory | This is quantified from the participant responses in the working memory task. Errors in the report of memorized locations are multiplied by the sign of the difference in locations in the previous and current trials and then averaged over the whole session to obtain the index of serial bias. We expect increases in this index as patients improve clinically. | 18 months | 
| EEG reactivations in working memory | This is quantified by training decoders of memorized locations on EEG signals acquired over several electrodes during the working memory task. Reactivations are the average strength of the decoders during the fixation period of the next trial. We expect that EEG reactivations increase as patients improve clinically and correlate with the serial bias index. | 18 months | 
| Slow-wave rate of growth during slow-wave sleep period | This is quantified from EEG recorded during sleep, by detecting individual slow-waves and estimating their strength, and then computing the rate of growth of this strength in the first slow-wave periods in the night. We expect the rate of growth of slow waves to increase as patients improve. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognitive Impairment, Encephalitis, Autoimmune, Cognitive rehabilitation