Home Ultra-long Term EEG Monitoring for Rare Epilepsies and Developmental and Epileptic Encephalopathies

Initial screening of the subjects.

Subjects with DEE or rare epilepsies with uncontrolled seizures and previously investigated in outpatients epilepsy clinics and in the Epilepsy Monitoring Unit (EMU) will be evaluated by review of the medical records.

The aim is to select subjects in whom assessment of seizure frequency is extremely relevant for their clinical management, including adjustment of medicines and need of support measures in their daily life. The indication to recruit also patients with epilepsy and intellectual disabilities is supported by the evidence that in these patients, either when living at home or in institutions, it is particularly difficult to have an objective assessment of their seizure frequency and of the response to treatment or to treatment adjustments. The use of sqEEG in this group of patients is therefore expected to provide extremely valuable information on the disease severity (i.e. seizure frequency) and the epilepsy modification following treatment changes.

The subjects will be selected regardless of a diagnosis of focal or generalized epilepsy, and regardless previous surgical treatments.

Recruitment and consent. The written consent form will be presented and discussed with the subject/legal guardians; all questions related to the informed consent will be answered. In all cases patients will receive detailed information regarding the procedure and purposes.

Study plan The project design includes two sequential parts, 'Part 1' which is a short-term study evaluating sqEEG compared to standard EEG monitoring. 'Part 2' represent the core of the project and consists of the ultra-longterm sqEEG monitoring at home for at least 12 weeks (up to 24 weeks).

Study Part 1:

• Subjects selection and recruitment
• Implantation of subcutaneous EEG electrodes by a surgeon/neurosurgeon. The implantation procedure will take care to place subcutaneously the electrode contacts over the site of the seizure focus as defined by a previous epilepsy data of the patients. The implantation will be unilateral in case of documented unilateral ictal epileptic discharges, or generalized epilepsies. In patients with independent bilateral seizure onset the implant will be bilateral.
• Earliest 10 days after the surgical procedure, the subjects will be admitted to the EMU as part of clinical practice activity at the investigational site, with the aim of recording their seizures both with video-EEG and sqEEG. This will allow the Neurologist:

1. to test the sensitivity of sqEEG to detect seizures as compared to video-EEG (standard procedure);
2. to assess the rate of false positives (FP) and false negatives (FN) detections
3. to test the tolerability of sqEEG in the short term;
4. to test the algorithm for automatic seizure detection in this initial set of EEG data;
5. to test the safety of the sqEEG in the short term;

• Admission in EMU will last from 2 days to 2 weeks based on the number of seizures recorded (one electrographic or electroclinical seizure recorded on scalp EEG is advisable). At the end of EMU admission, seizure identification and quantification will be performed independently by the personnel of EMU and by the reviewer of sqEEG data. Both will be blinded of each other's results. Then the results will be compared.

Study Part 2:

The subject will proceed to the home-monitoring study. Aim of the extended study is to assess sensitivity of seizure detection of sqEEG in comparison to subject's diary in the daily environment, and the tolerability and safety of sqEEG in a period of at least 3 months.

Study protocol of the extended part:

• The subject will be discharged at home after EMU admission with the device and all the necessary information on how to handle it.
• Data on usage times for each participant will be derived from the time stamps and duration of the recorded EEGs as saved by the ELD.
• Adjustment of the anti-seizure medicines will be allowed whenever the clinical conditions will require it. Any changes in the treatment will be noted in the subjects' seizure diary. Data on the use of ASMs will be collected at every study visit.
• Adverse Device Effects (ADEs) will be defined as any unintended or unfavorable response to the system during the study period possibly related to the use of the device or related procedures. ADEs will be classified according to severity based on their impact on daily life as the following: mild (does not interfere with everyday activities), moderate (interferes with some everyday activities), and severe (prevents some everyday activities) (Weisdorf et al., 2019). Serious ADEs will be defined as ADEs requiring hospitalization, leading to death (or would have done so in the absence of treatment) or lasting disability. These definitions will follow the guidance provided in ISO 14155:2011 Clinical investigation of medical devices for human subjects - Good clinical practice.
• Participants will be requested to document all events that they believed to be seizures in a seizure diary. Collection of the time and date will be integrated with the registration of each event. In the paper form, participants have to note time and date by themselves. Participants will be instructed also to provide a seizure description as detailed as possible by using a specific form. Family members or caregivers will be allowed to fill out the seizure description forms. Upon collection, the participants will have the opportunity to comment on the entries to the seizure diary and the seizure descriptions.
• Based on all the information available, self-reported events will be classified following two steps: (1) classification of each event as epileptic or non-epileptic; (2) evaluation of each epileptic seizure and adding a further semiology label as "focal aware seizure (FAS)," "focal impaired awareness seizure (FIAS)," or "uncertain." This distinction will be made by an experienced epileptologist.

At every week after discharge, a review by visual inspection of one week EEG data will be performed, and assessment of the reportability of the sqEEG in comparison to subject's diary, tolerability and safety of the device will be evaluated.

Evaluation of the EEG data by the algorithm for automatic seizure detection will be performed blinded from the results of the visual analysis. In addition, an evaluation of the potential individual clinical impact of the data obtained will be performed.

Visual review of the EEG: a neurophysiology technician trained in reading the sqEEG data will review the raw data from EpiSight (the software for the visualization of sqEEG data, who is part of the device) to identify seizure events blinded from the subject's seizure diary. The detected events will be validated by a supervision of an expert clinical neurophysiologist.

Assessment of tolerability and safety: eventual complaints about tolerability will be collected from the subject and the diary. Side-effects, reported by the subject and in the diary will be analyzed as classified as described above.

Evaluation of the algorithm for automatic seizure detection (ASD): the sqEEG data will be analyzed by the ASD algorithm; the results of the ASD algorithm will be reviewed by investigators blinded from the results of the visual analysis.

Assessment of potential clinical impact: the results of the 3-6 months sqEEG monitoring will be evaluated in terms of their possible impact on patient's management by evaluating its usefulness:

• to evaluate the actual seizure frequency with the ongoing treatment at the time of implantation and compare it with the seizure frequency reported in the diary;
• to prompt of adjustments of the medical treatment and evaluate their effects (the time "before treatment changes" and the time "after treatment changes" should possibly be of comparable length);
• to identify and define patterns of seizure occurrence (circadian occurrence, clustering of seizures) that can be communicated to the subject to eventually counsel him/her on how to behave in the more vulnerable situations;
• in assessing whether support measures (for instance, nocturnal supervision, specialized personnel, safer accommodations) are advised (for example, in cases of seizure frequency being higher than expected in subjects living alone).
• other factors not considered, but suggested by subject or PI to provide a clinical impact.

After 12 weeks of home sqEEG monitoring, subjects will terminate the clinical study and the subscalp electrode is removed. A further follow-up visit will be planned per clinical practice in the months after study termination.

If the doctor and patient judge the device useful an extension study period of other 12 weeks is allowed (to reach 24 weeks).