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or residual phase which represents the interval from improvement of initial symptoms until the disease is considered no longer active and the remaining symptoms are thought to be irreversible.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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
20
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).
Hospital Clínic de Barcelona
Barcelona, Catalonia, Spain
RECRUITINGAge
Age measured in years
Time frame: 12 months
Gender
Male or female
Time frame: 12 months
Handedness
Right- or Left-handed
Time frame: 12 months
General medical history
Description of the most important issues compiled in the general medical history of the participant
Time frame: 12 months
Allergies
List of allergies of each participant
Time frame: 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.
Time frame: 12 months
Treatments
All treatments in which the participant is being involved.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 12 months
Naming with cues
Assessed by: Boston Naming Test (BNT) \- Total correct with phonemic cue: from 0 to 60
Time frame: 12 months
Latency in naming
Assessed by: Boston Naming Test (BNT) \- Time to complete test in seconds
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 6 months
Adherence to cognitive treatment - 9 months
Percentage of sessions performed in 9 months (sessions performed out of 54 x 100)
Time frame: 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)
Time frame: 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.
Time frame: 12 months
Valsava ratio
Continuous electrocardiogram heart rate changes during Valsalva manoeuvre (ratio).
Time frame: 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
Time frame: 12 months
Composite Autonomic Symptom Score (Compass-31)
Self-scoring Compass 31 autonomic assessment. Minimum 0, maximum 100, higher scores mean a worse outcome.
Time frame: 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).
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 12 months
LGI-1 antibodies
Determined with brain tissue immunohistochemistry and cell - based assays
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 12 months
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