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

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.

Study Overview

• Status: Recruiting
• Conditions: Anti-NMDA Receptor Encephalitis
• Intervention / Treatment: Behavioral: Remote cognitive rehabilitation program

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Josep Dalmau, MD,PhD; Phone Number: 34 93 227 1738; Email: jdalmau@clinic.cat

Study Locations

• Spain
  • Cataluña
    • Barcelona, Cataluña, Spain, 08036
      • Recruiting
      • Hospital Clinic de Barcelona
      • Contact: Josep Dalmau, MD, PhD; Phone Number: +34 93 227 1738; Email: jdalmau@clinic.cat
      • Contact: Victor Patricio, MS; Phone Number: +34 93 227 1738; Email: vpatricio@recerca.clinic.cat
      • Principal Investigator: Josep Dalmau, MD, PhD
      • Principal Investigator: Thais Armanguè, MD, PhD
      • Sub-Investigator: Mar Guasp, MD, PhD
      • Sub-Investigator: Eugenia Martínez-Hernández, MD, PhD
      • Sub-Investigator: Víctor Patricio, MS
      • Sub-Investigator: Amaia Muñoz, MD
      • Sub-Investigator: Laia Prades, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Anti-NMDARe patients with remote cognitive rehabilitation; 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; 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).

What is the study measuring?

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 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
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
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. 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	Number of name of animals recalled in 1 minute: range: from 0 to infinity. (Test Barcelona - Revised) (for ADULTS) Number of name of animals recalled in 1 minute + number of name of food and drinks recalled in 1 minute: from 0 to infinity (NEPSY - II) (for CHILDREN) 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. (Test Barcelona-Revised) (for ADULTS) Number of words started by letter "P" recalled in 1 minute + number of words started by letter "M" in 1 minute: range: from 0 to infinity (NEPSY-II) (for CHILDREN). 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

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
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
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 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
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
Long-term verbal memory - remote assessment	Assessed by: Long-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
Orientation in space - remote assessment	Assessed by: Orientation in space subtest from Test Barcelona - Revised. - Range: 0 -5	18 months
5DT Inhibition - remote assessment	Assessed by: Inhibition 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
Semantic fluency - remote assessment	Assessed by: Semantic fluency test: Produce names of fruits and vegetables in 1 minute (Test Barcelona - Revised) (for ADULTS); Number of name of animals recalled in 1 minute + number of name of food and drinks recalled in 1 minute: from 0 to infinity (NEPSY - II) (for CHILDREN) 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 in 1 minute: range from 0 to infinity (Test Barcelona - Revised) (for ADULTS); Number of words started by letter "P" recalled in 1 minute + number of words started by letter "M" in 1 minute: range: from 0 to infinity (NEPSY-II) (for CHILDREN). 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 Higher is better.	18 months
IEDEEDS - remote assessment	IED EDS Errors: The number of times that the subject failed to select the stimulus compatible with the current rule on the stage where the extra-dimensional shift occurs. This is a measure of the subject's ability to shift attentional set. Assessed by: Intra-Extra Dimensional test from CANTAB battery. - Raw score range: 0 - 50. Lower 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
IEDYERTA - remote assessment	IED Total Errors (Adjusted): The total number of times that the subject chose a wrong stimulus - i.e. one incompatible with the current rule, adjustment for every stage that was not reached. Lower is better. Total Errors Adjusted = Total Errors (problems reached) + [(number of unreached problems) * (25)] This is a measure of the subject's efficiency in attempting the test. Subjects failing at any stage of the test will have had less opportunity to make errors. The adjustment is carried out to compensate for this missing data, and provide a more comparable error score to subjects completing all stages of the test.. Assessed by: Intra-Extra Dimensional test from CANTAB battery. - Raw score range: 0 - 402. Lower 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
IEDYCOST - remote assessment	IED Stages Completed: This is the total number of stages the subject completed successfully. There are nine stages to be completed. Higher is better. Assessed by: Intra-Extra Dimensional test from CANTAB battery. - Range: 0 - 9. Higher is better.	18 months
SWM Total Errors - remote assessment	SWM Total Errors: The total number of times a box is selected that is certain not to contain a token and therefore should not have been visited by the subject, i.e. between errors + within errors - double errors. Calculated across all assessed four, six and eight token trials. Assessed by: Spatial Working Memory test from CANTAB battery. - Range: 0 - 157. Lower is better	18 months
SWM Between Errors - remote assessment	SWM Between Errors: The number of times the subject incorrectly revisits a box in which a token has previously been found. Calculated across all assessed four, six and eight token trials. Assessed by: Spatial Working Memory test from CANTAB battery: - Raw score range: 0 - 153. Lower 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
SWM Within Errors - remote assessment	SWM Within Errors: The number of times a subject revisits a box already shown to be empty during the same search. Calculated across all assessed four, six and eight token trials. Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 0 - 153. Lower is better.	18 months
SWM Double Errors - remote assessment	SWM Double Errors: The number of times a subject commits an error that is both a within error and a between error. Calculated across all assessed four, six and eight token trials. Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 0 - 147. Lower is better.	18 months
SWMS - remote assessment	SWM Strategy (6-8 boxes): The number of times a subject begins a new search pattern from the same box they started with previously. If they always begin a search from the same starting point we infer that the subject is employing a planned strategy for finding the tokens. Therefore a low score indicates high strategy use (1 = they always begin the search from the same box), a high score indicates that they are beginning their searches from many different boxes. Calculated across assessed trials with 6 tokens or 8 tokens. Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 2 - 14. Lower 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
SWMSX - remote assessment	SWM Strategy (6-12 boxes): The number of times a subject begins a new search pattern from the same box they started with previously. If they always begin a search from the same starting point we infer that the subject is employing a planned strategy for finding the tokens. Therefore a low score indicates high strategy use (1 = they always begin the search from the same box), a high score indicates that they are beginning their searches from many different boxes. Calculated across assessed trials with 6 tokens or more. Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 3 - 26. Lower is better.	18 months
SWMPR - remote assessment	SWM Problem Reached: This measure reports the problem number that the subject reached, but did not necessarily complete. Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 2 - 6. Higher is better.	18 months
ERTTH - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total Hits: The total number of times the subject selected the correct emotion. Calculated across all assessed trials. - Range: 0 - 90. Higher is Better	18 months
ERTTHH - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total Hits Happiness: The total number of times the subject correctly selected the emotion 'Happiness'. Calculated across all assessed trials. - Range: 0 - 15 . Higher is Better	18 months
ERTTHS - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total Hits Sadness: The total number of times the subject correctly selected the emotion 'Sadness'. Calculated across all assessed trials. - Range: 0 - 15 . Higher is Better	18 months
ERTTHF - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total Hits Fear: The total number of times the subject correctly selected the emotion 'Fear'. Calculated across all assessed trials. - Range: 0 - 15 . Higher is Better	18 months
ERTTHA - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total Hits Anger: The total number of times the subject correctly selected the emotion 'Anger'. Calculated across all assessed trials. - Range: 0 - 15 . Higher is Better	18 months
ERTTHSU - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery ERT Total Hits Surprise: The total number of times the subject correctly selected the emotion 'Surprise'. Calculated across all assessed trials. - Range: 0 - 15 . Higher is Better.	18 months
ERTTHD - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total Hits Disgust: The total number of times the subject correctly selected the emotion 'Disgust'. Calculated across all assessed trials. - Range: 0 - 15 . Higher is Better.	18 months
ERTTFAH - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total False Alarms Happiness: The total number of times the subject incorrectly selected the emotion 'Happiness'. Calculated across all assessed trials. - Range: 0 - 75 . Lower is Better.	18 months
ERTTFAS - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total False Alarms Sadness: The total number of times the subject incorrectly selected the emotion 'Sadness'. Calculated across all assessed trials. - Range: 0 - 75 . Lower is Better.	18 months
ERTTFAF - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total False Alarms Fear: The total number of times the subject incorrectly selected the emotion 'Fear'. Calculated across all assessed trials. - Range: 0 - 75 . Lower is Better.	18 months
ERTTFAA - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total False Alarms Anger: The total number of times the subject incorrectly selected the emotion 'Anger'. Calculated across all assessed trials. - Range: 0 - 75 . Lower is Better.	18 months
ERTTFASU - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total False Alarms Surprise: The total number of times the subject incorrectly selected the emotion 'Surprise'. Calculated across all assessed trials. - Range: 0 - 75 . Lower is Better.	18 months
ERTTFAD - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Total False Alarms Disgust: The total number of times the subject incorrectly selected the emotion 'Disgust'. Calculated across all assessed trials. - Range: 0 - 75 . Lower is Better.	18 months
ERTUHRH - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Unbiased Hit Rate Happiness: The unbiased hit rate ensures that recognition accuracy of the Happiness emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Happiness trials only. - Range: 0 to 1. Higher is better.	18 months
ERTUHRS - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Unbiased Hit Rate Sadness: The unbiased hit rate ensures that recognition accuracy of the Sadness emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Sadness trials only - Range: 0 to 1. Higher is better.	18 months
ERTUHRF - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Unbiased Hit Rate Fear: The unbiased hit rate ensures that recognition accuracy of the Fear emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Fear trials only. - Range: 0 to 1. Higher is better.	18 months
ERTUHRA - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Unbiased Hit Rate Anger: The unbiased hit rate ensures that recognition accuracy of the Anger emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Anger trials only. - Range: 0 to 1. Higher is better.	18 months
ERTUHRSU - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Unbiased Hit Rate Surprise: The unbiased hit rate ensures that recognition accuracy of the Surprise emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Anger trials only. - Range: 0 to 1. Higher is better.	18 months
ERTUHRSD - remote assessment	Assessed by: Emotion Recognition Task from CANTAB battery. ERT Unbiased Hit Rate Disgust: The unbiased hit rate ensures that recognition accuracy of the Disgust emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Disgust trials only. - Range: 0 to 1. Higher is better.	18 months

Collaborators and Investigators

• Sponsor: Fundacion Clinic per a la Recerca Biomédica
• Collaborators: Hospital Sant Joan de Deu
• Investigators: Principal Investigator: Josep Dalmau, MD, PhD, Hospital Clinic

Publications and helpful links

General Publications

• Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013 Feb;12(2):157-65. doi: 10.1016/S1474-4422(12)70310-1. Epub 2013 Jan 3.
• Guasp M, Rosa-Justicia M, Munoz-Lopetegi A, Martinez-Hernandez E, Armangue T, Sugranyes G, Stein H, Borras R, Prades L, Arino H, Planaguma J, De-La-Serna E, Escudero D, Llufriu S, Sanchez-Valle R, Santamaria J, Compte A, Castro-Fornieles J, Dalmau J; Spanish anti-NMDAR Encephalitis Study Group. Clinical characterisation of patients in the post-acute stage of anti-NMDA receptor encephalitis: a prospective cohort study and comparison with patients with schizophrenia spectrum disorders. Lancet Neurol. 2022 Oct;21(10):899-910. doi: 10.1016/S1474-4422(22)00299-X.
• Arino H, Munoz-Lopetegi A, Martinez-Hernandez E, Armangue T, Rosa-Justicia M, Escudero D, Matos N, Graus F, Sugranyes G, Castro-Fornieles J, Compte A, Dalmau J, Santamaria J. Sleep disorders in anti-NMDAR encephalitis. Neurology. 2020 Aug 11;95(6):e671-e684. doi: 10.1212/WNL.0000000000009987. Epub 2020 Jun 23.
• Finke C, Kopp UA, Scheel M, Pech LM, Soemmer C, Schlichting J, Leypoldt F, Brandt AU, Wuerfel J, Probst C, Ploner CJ, Pruss H, Paul F. Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2013 Aug;74(2):284-96. doi: 10.1002/ana.23932. Epub 2013 Jul 8.
• Heine J, Kopp UA, Klag J, Ploner CJ, Pruss H, Finke C. Long-Term Cognitive Outcome in Anti-N-Methyl-D-Aspartate Receptor Encephalitis. Ann Neurol. 2021 Dec;90(6):949-961. doi: 10.1002/ana.26241. Epub 2021 Oct 21.
• Armangue T, Titulaer MJ, Malaga I, Bataller L, Gabilondo I, Graus F, Dalmau J; Spanish Anti-N-methyl-D-Aspartate Receptor (NMDAR) Encephalitis Work Group. Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr. 2013 Apr;162(4):850-856.e2. doi: 10.1016/j.jpeds.2012.10.011. Epub 2012 Nov 16.

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2023
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): November 30, 2025

Study Registration Dates

• First Submitted: May 19, 2023
• First Submitted That Met QC Criteria: December 13, 2023
• First Posted (Actual): December 28, 2023

Study Record Updates

• Last Update Posted (Actual): May 6, 2024
• Last Update Submitted That Met QC Criteria: May 3, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Cognitive Impairment; Encephalitis; Cognitive rehabilitation; Autoimmune
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Neoplasms by Site; Neurodegenerative Diseases; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuroinflammatory Diseases; Encephalitis; Anti-N-Methyl-D-Aspartate Receptor Encephalitis
• Other Study ID Numbers: HR22-00221

Drug and device information, study documents

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