Antibody-mediated LGI1 Encephalitis: Symptoms, Biomarkers, and Mechanisms of the Chronic Phase of the Disease
NCT Number: NCT06515106
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Limbic Encephalitis With LGI1 Antibodies
Interventions: BEHAVIORAL: Remote cognitive rehabilitation program
Sponsor: Fundacion Clinic per a la Recerca Biomédica
Sex: ALL
Age: CHILD, ADULT, OLDER_ADULT
Enrollment: 20
Study Design: Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: SUPPORTIVE_CARE
Start Date: 2023-12-18
Completion Date: 2026-12-31
Locations: Hospital Clínic de Barcelona, Barcelona, Cataluña, 08036, Spain

Summary:
The encephalitis mediated by antibodies against Leucine-rich, glioma inactivated 1 protein (anti-LGI1 encephalitis) predominantly affects men (M:F, 6:4) and mostly older than 60 years. The disease has two distinct clinical phases: The acute phase in which the majority of patients develop severe short-term memory deficits (unable to remember events or experiences that occurred a few minutes earlier). This memory impairment can be preceded or accompanied by one or more of the following: hyponatremia (60% of patients), a highly distinctive type of seizures called facio-brachial dystonic seizures (\~40% of patients), along with confusion, irritability and other types of focal seizures or less frequently, generalized seizures. In addition, many patients at this stage have symptoms of REM sleep behavior disorder. In this stage, the CSF may show pleocytosis or mild increase of proteins, the EEG is usually abnormal, and in \~60% of the patients the MRI shows typical increased FLAIR signal in medial temporal lobes (11). There is a clinical sub-phenotype (\~13% of patients) in which the disease presents as a rapidly progressive cognitive decline without the indicated FLAIR MRI changes. About 70% of patients improve rapidly with corticosteroids and immunotherapy (eg, intravenous immunoglobulins and/or plasma exchange), but the improvement is often partial. After the acute phase, there is a chronic or residual phase which represents the interval from improvement of initial symptoms until the disease is considered no longer active and the remaining symptoms are thought to be irreversible. This chronic phase may take several months (it has been less well studied), and is characterized by the absence of CSF pleocytosis and inflammatory MRI changes (albeit this may show residual hippocampal atrophy), and very low or undetectable titers of serum antibodies. Most patients are unable to return to their job or previous activities due to residual (irreversible) memory or cognitive deficits accompanied by signs of moderate brain atrophy. In addition, we and others have shown that about 27-35% of patients have relapsing symptoms after improving from the acute phase (. Although acute symptomatic seizures (facio-brachial dystonic and others) occur in \~90% of patients during the acute phase of the disease, less than 10% of patients develop chronic epilepsy often associated with hippocampal sclerosis. Therefore, the prevailing concept on this disease suggests a syndrome and clinical course in which the acute phase shows rapid, albeit partial, response to immunotherapy, and the symptoms of the chronic phase represent a burnout or irreversible process, in which the disease is no longer active, and the potential improvement of remaining symptoms is uncertain.

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.

In Aim 2, the impact of cognitive rehabilitation will be assessed.

In Aim 3, a mouse model of anti-LGI1 encephalitis will be used to determine the underlying mechanisms and treatment of the postacute stage.

Primary Outcome Measures: Age, Age measured in years, 12 months|Gender, Male or female, 12 months|Handedness, Right- or Left-handed, 12 months|General medical history, Description of the most important issues compiled in the general medical history of the participant, 12 months|Allergies, List of allergies of each participant, 12 months|Symptoms related to anti-LGI1 encephalitis, Detailed description of symptoms experienced before, during and after the post-acute phase of anti-LGI1 encephalitis., 12 months|Treatments, All treatments in which the participant is being involved., 12 months|Functional status, Functional status according to Modified Rankin Scale (mRS).

Modified Rankin Scale:

- Range: from 0 points (no symptoms) to 6 points (dead)., 12 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., 12 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., 12 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., 12 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., 12 months|Verbal learning, Assessed by:

Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC

- 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., 12 months|Proactive interference verbal memory, Assessed by:

Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC).

- 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., 12 months|Short-term verbal memory, Assessed by:

Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC).

- 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., 12 months|Long-term verbal memory, Assessed by:

Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC):

- 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., 12 months|Verbal recognition memory, Assessed by:

Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC).

- 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., 12 months|Verbal discrimination memory, Assessed by:

Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC)

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., 12 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., 12 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., 12 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., 12 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., 12 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., 12 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., 12 months|Processing speed, Symbol Search subtest (WAIS-IV)

- Total (correct answers less incorrect answers): 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., 12 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., 12 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., 12 months|Naming with cues, Assessed by: Boston Naming Test (BNT)

- Total correct with phonemic cue: from 0 to 60, 12 months|Latency in naming, Assessed by: Boston Naming Test (BNT)

- Time to complete test in seconds, 12 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., 12 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., 12 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., 12 months|Symbolic gesture right hand - order, Symbolic gesture right hand - order subtest from Test Barcelona - Revised

- 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., 12 months|Symbolic gesture left hand - order, Symbolic gesture left hand - order subtest from Test Barcelona - Revised

- 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., 12 months|Symbolic gesture right hand - imitation, Symbolic gesture right hand - imitation subtest from Test Barcelona

- 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., 12 months|Symbolic gesture left hand - imitation, Symbolic gesture left hand - imitation subtest from Test Barcelona - Revised

- 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., 12 months|Bilateral ideomotor praxis - imitation, Bilateral ideomotor praxis imitation subtest from Test Barcelona

- 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., 12 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., 12 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., 12 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., 12 months|Prensence of psychiatric symptoms or disorders, Number of participants with psychiatric symptoms/disorders following DSM-IV-TR guidelines (psychotic symptoms, symptoms of depression, symptoms of mania, global functioning)., 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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), 12 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, 12 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, 12 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, 12 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, 12 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, 12 months|Adherence to cognitive treatment - 6 months, Percentage of sessions performed in 6 months out of 48 (sessions performed out of 48 x 100), 6 months|Adherence to cognitive treatment - 9 months, Percentage of sessions performed in 9 months (sessions performed out of 54 x 100), 9 months|Adherence to cognitive treatment - 12 months, Percentage of sessions performed in 9 months out of 60 (sessions performed out of 60 x 100), 12 months|Cardiovagal evaluation. (Composite autonomic scoring scale), Continuous electrocardiogram heart rate changes during deep breathing and postural changes (beats per minute).Composite autonomic scoring scale minimun 0, maximum 3, higher scores mean a worse outcome., 12 months|Valsava ratio, Continuous electrocardiogram heart rate changes during Valsalva manoeuvre (ratio)., 12 months|Sympathetic evaluation (Composite autonomic scoring scale), Beat-to-beat blood pressure changes to isometric exercise, Valsalva manoeuvre and postural changes, (mmHg). Composite autonomic scoring scale minimun 0, maximum 4, higher scores mean a worse outcome, 12 months|Composite Autonomic Symptom Score (Compass-31), Self-scoring Compass 31 autonomic assessment. Minimum 0, maximum 100, higher scores mean a worse outcome., 12 months|Electromyography (EMG), Needle recording electrode will be inserted into different muscles (orbicularis oris, extensor indicis propius, tibialis anterior).Presence of abnormal discharges will be recorded (0 none to 4 maximum)., 12 months|Brainstem reflex, Trigeminal blink reflex, mediated by trigemino-facial ponto-medullary -circuits will be assessed. Surface recording electrodes will be attached over the orbicularis oculi in both sides with active electrode over the middle part of the lower eyelid and the reference at the lateral cantus of the eye . Stimulating electrodes will be placed over the supraorbital nerve. Ipsilateral (R1, R2) and contralateral responses (R2c) latencies measured in ms will be analyzed, 12 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., 12 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., 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 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, 12 months
Secondary Outcome Measures: LGI-1 antibodies, Determined with brain tissue immunohistochemistry and cell - based assays, 12 months|HLA genotyping, performed by standard techniques based on DNA - PCR and polymorphism identification by reverse hybridization with specific probes and fluorescence labelling of hybridized fragments (PCR - SSOP) (Immucor GTI Diagnostics Inc.Waukesha USA) in combination with genomic DNA sequencing by Sanger methodology (PCRSBT)., 12 months|Immune/inflammatory signaling-target gene expression pathways, RNA/NanoString analysis of targeted gene expression related to activation/function of B cells, T cells, microglia, and other interleukin/ chemokine signaling. Whole blood/CSF will be collected using PAXgene® Blood RNA tubes (Qiagen) shipped to the centers. 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 immunological pathways and cytokines (Annex,Table) will be measured with the nCounter® Digital Analyzer (NanoString), as reported (Armangue et al., Mol Genet Metab 2017;122:134-9). Twenty healthy participants will serve as controls (single evaluation)., 12 months|NfL levels, determined in serum and CSF using the SiMoA Quanterix technique, as reported (Guasp et al., Neurology 2022;98:e1489 - 98). Age-and sex-matched healthy participants from previous studies will serve as controls., 12 months