Antibody-mediated LGI1 Encephalitis: Symptoms, Biomarkers, and Mechanisms of the Chronic Phase of the Disease

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or residual phase which represents the interval from improvement of initial symptoms until the disease is considered no longer active and the remaining symptoms are thought to be irreversible.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 Overview

• Status: Recruiting
• Conditions: Limbic Encephalitis With LGI1 Antibodies
• 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 Clínic 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
      • 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
      • Principal Investigator: Lorena Rami, PhD
      • Sub-Investigator: Thais Armanguè, MD, PhD
      • Sub-Investigator: Elianet Fonseca, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients with Antibody-mediated LGI-1 encephalitis in the post-acute stage of the disease;
• Patients has been discharged from hospital (acute phase).

Exclusion Criteria:

• 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: Antibody-mediated LGI1 encephalitis patients; 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; 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	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

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Fundacion Clinic per a la Recerca Biomédica
• Investigators: Principal Investigator: Josep Dalmau, MD, PhD, Hospital Clínic; Principal Investigator: Lorena Rami, PhD, Fundacion Clinic per a la Recerca Biomédica

Publications and helpful links

General Publications

• Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D, Cunningham R, Zuckerman M, Mutton KJ, Solomon T, Ward KN, Lunn MP, Irani SR, Vincent A, Brown DW, Crowcroft NS; UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010 Dec;10(12):835-44. doi: 10.1016/S1473-3099(10)70222-X. Epub 2010 Oct 15. Erratum In: Lancet Infect Dis. 2011 Feb;11(2):79.
• 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.
• Dalmau J, Graus F. Antibody-Mediated Encephalitis. N Engl J Med. 2018 Mar 1;378(9):840-851. doi: 10.1056/NEJMra1708712. No abstract available.
• Dalmau J, Geis C, Graus F. Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System. Physiol Rev. 2017 Apr;97(2):839-887. doi: 10.1152/physrev.00010.2016.
• Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, Parsons TD, Lynch DR, Dalmau J, Balice-Gordon RJ. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010 Apr 28;30(17):5866-75. doi: 10.1523/JNEUROSCI.0167-10.2010.
• Planaguma J, Leypoldt F, Mannara F, Gutierrez-Cuesta J, Martin-Garcia E, Aguilar E, Titulaer MJ, Petit-Pedrol M, Jain A, Balice-Gordon R, Lakadamyali M, Graus F, Maldonado R, Dalmau J. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain. 2015 Jan;138(Pt 1):94-109. doi: 10.1093/brain/awu310. Epub 2014 Nov 11.
• Petit-Pedrol M, Sell J, Planaguma J, Mannara F, Radosevic M, Haselmann H, Ceanga M, Sabater L, Spatola M, Soto D, Gasull X, Dalmau J, Geis C. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain. 2018 Nov 1;141(11):3144-3159. doi: 10.1093/brain/awy253.
• van Sonderen A, Petit-Pedrol M, Dalmau J, Titulaer MJ. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat Rev Neurol. 2017 May;13(5):290-301. doi: 10.1038/nrneurol.2017.43. Epub 2017 Apr 18.
• Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012 Apr;54(7):899-904. doi: 10.1093/cid/cir1038. Epub 2012 Jan 26.
• Armangue T, Spatola M, Vlagea A, Mattozzi S, Carceles-Cordon M, Martinez-Heras E, Llufriu S, Muchart J, Erro ME, Abraira L, Moris G, Monros-Gimenez L, Corral-Corral I, Montejo C, Toledo M, Bataller L, Secondi G, Arino H, Martinez-Hernandez E, Juan M, Marcos MA, Alsina L, Saiz A, Rosenfeld MR, Graus F, Dalmau J; Spanish Herpes Simplex Encephalitis Study Group. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018 Sep;17(9):760-772. doi: 10.1016/S1474-4422(18)30244-8. Epub 2018 Jul 23.
• Lai M, Huijbers MG, Lancaster E, Graus F, Bataller L, Balice-Gordon R, Cowell JK, Dalmau J. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010 Aug;9(8):776-85. doi: 10.1016/S1474-4422(10)70137-X. Epub 2010 Jun 28.
• Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang B, Vincent A. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain. 2010 Sep;133(9):2734-48. doi: 10.1093/brain/awq213. Epub 2010 Jul 27.
• Munoz-Sanchez G, Planaguma J, Naranjo L, Couso R, Sabater L, Guasp M, Martinez-Hernandez E, Graus F, Dalmau J, Ruiz-Garcia R. The diagnosis of anti-LGI1 encephalitis varies with the type of immunodetection assay and sample examined. Front Immunol. 2022 Dec 15;13:1069368. doi: 10.3389/fimmu.2022.1069368. eCollection 2022.
• van Sonderen A, Thijs RD, Coenders EC, Jiskoot LC, Sanchez E, de Bruijn MA, van Coevorden-Hameete MH, Wirtz PW, Schreurs MW, Sillevis Smitt PA, Titulaer MJ. Anti-LGI1 encephalitis: Clinical syndrome and long-term follow-up. Neurology. 2016 Oct 4;87(14):1449-1456. doi: 10.1212/WNL.0000000000003173. Epub 2016 Sep 2.
• Arino H, Armangue T, Petit-Pedrol M, Sabater L, Martinez-Hernandez E, Hara M, Lancaster E, Saiz A, Dalmau J, Graus F. Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome. Neurology. 2016 Aug 23;87(8):759-65. doi: 10.1212/WNL.0000000000003009. Epub 2016 Jul 27.
• Iranzo A, Graus F, Clover L, Morera J, Bruna J, Vilar C, Martinez-Rodriguez JE, Vincent A, Santamaria J. Rapid eye movement sleep behavior disorder and potassium channel antibody-associated limbic encephalitis. Ann Neurol. 2006 Jan;59(1):178-81. doi: 10.1002/ana.20693.
• de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, Bastiaansen AEM, Schreurs MWJ, Rouhl RPW, van Donselaar CA, Majoie MHJM, Neuteboom RF, Sillevis Smitt PAE, Thijs RD, Titulaer MJ. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology. 2019 May 7;92(19):e2185-e2196. doi: 10.1212/WNL.0000000000007475. Epub 2019 Apr 12.
• Ramberger M, Berretta A, Tan JMM, Sun B, Michael S, Yeo T, Theorell J, Bashford-Rogers R, Paneva S, O'Dowd V, Dedi N, Topia S, Griffin R, Ramirez-Franco J, El Far O, Baulac S, Leite MI, Sen A, Jeans A, McMillan D, Marshall D, Anthony D, Lightwood D, Waters P, Irani SR. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain. 2020 Jun 1;143(6):1731-1745. doi: 10.1093/brain/awaa104.
• Ohkawa T, Fukata Y, Yamasaki M, Miyazaki T, Yokoi N, Takashima H, Watanabe M, Watanabe O, Fukata M. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci. 2013 Nov 13;33(46):18161-74. doi: 10.1523/JNEUROSCI.3506-13.2013.
• Irani SR, Stagg CJ, Schott JM, Rosenthal CR, Schneider SA, Pettingill P, Pettingill R, Waters P, Thomas A, Voets NL, Cardoso MJ, Cash DM, Manning EN, Lang B, Smith SJ, Vincent A, Johnson MR. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain. 2013 Oct;136(Pt 10):3151-62. doi: 10.1093/brain/awt212. Epub 2013 Sep 6.
• Diaz Baquero AA, Franco-Martin MA, Parra Vidales E, Toribio-Guzman JM, Bueno-Aguado Y, Martinez Abad F, Perea Bartolome MV, Asl AM, van der Roest HG. The Effectiveness of GRADIOR: A Neuropsychological Rehabilitation Program for People with Mild Cognitive Impairment and Mild Dementia. Results of a Randomized Controlled Trial After 4 and 12 Months of Treatment. J Alzheimers Dis. 2022;86(2):711-727. doi: 10.3233/JAD-215350.

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 26, 2024
• First Submitted That Met QC Criteria: July 18, 2024
• First Posted (Actual): July 23, 2024

Study Record Updates

• Last Update Posted (Actual): July 23, 2024
• Last Update Submitted That Met QC Criteria: July 18, 2024
• Last Verified: July 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; Infections; Neoplasms; Neoplasms by Site; Central Nervous System Viral Diseases; Central Nervous System Infections; Neurodegenerative Diseases; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuroinflammatory Diseases; Encephalitis; Limbic Encephalitis
• Other Study ID Numbers: PI23/00858

Drug and device information, study documents

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