Intracranial CArtography of Cortical Contribution to Respiratory Load Compensation in Epilepsy

Overview

30% of patients with epilepsy suffer from drug-resistant seizures and have a greater risk of premature mortality than the general population. Among all causes of death, the most frequent is SUDEP, for sudden and unexpected death in epilepsy patients. SUDEP typically occurs after a nocturnal seizure, and primarily results from a postictal central respiratory dysfunction in patients with generalized convulsive seizure (GCS), suggesting the critical role of seizure-related impairment of breathing control, and underscoring the importance of monitoring and preventive interventions during the post-ictal phase. Most of patients with drug-resistant seizures demonstrate transient peri-ictal apnea and hypoxemia especially in the aftermath of a GCS. Experimental and clinical data suggest that most SUDEP primarily result from a fatal seizure-related respiratory arrest 5. Apnea was the primary cause of death in several epilepsy models. In patients whose SUDEP had occurred during long-term video-EEG monitoring, we observed fatal postictal central apnea after a nocturnal GCS in all SUDEP. Accordingly, it is currently hypothesized that in a subgroup of patients, repetition of seizures may contribute to chronic alteration of respiratory regulation which may increase the risk of fatal postictal central respiratory arrest. Central regulation of autonomic function is ensured by the so-called Central Autonomic Network (CAN), which anatomy in humans has primarily been investigated in neuroimaging studies or using intraEEG (iEEG) data in patients with drug-resistant focal epilepsy undergoing presurgical evaluation with intracerebral electrodes. Central regulation of breathing primarily rely on brainstem, especially the preBötzinger complex for rhythm generation and the retrotrapezoid nucleus and dorsal raphe for chemoreception, especially ventilatory response to hypercapnia. However, through an intricated structures connecting these regions, this respiratory signal projects to a network of cortical and subcortical regions mainly including the limbic and sensorimotor cortical areas. Studies in patients undergoing iEEG reinforced the role of limbic and paralimbic structures, with transient central apnea elicited by direct electrical stimulation of amygdala, hippocampus, anterior parahippocampal, and antero-mesial fusiform gyri. However, our group also reported transient hypoxemia could be elicited by cortical direct electrical stimulation outside the temporo-limbic structures, most commonly after stimulation of the perisylvian cortex. Importantly, our group recently showed that involvement of this perisylvian cortex in the epileptogenic zone is a strong risk factor of SUDEP, reinforcing the importance of further studying its integration in the cortical control of respiration. The involvement of cortical control of ventilation is particularly important to ensure expiratory load compensation, a typical situation after GCS, which is associated with airway obstruction, especially when the face is positioned into the pillow. This cortical component of the physiological response to experimental expiratory loads was investigated in healthy subjects through the study of EEG activity during an expiratory load compensation protocol. Accordingly, EEGs were processed by ensemble averaging expiratory time-locked segments and examined for pre-expiratory EEG potentials, defined as a slow negative shift from the baseline signal preceding expiration, and suggestive of cortical preparation of expiration. Expiratory load compensation was associated with EEG premotor potential presumably involving the supplementary motor area. However, because of the limited spatial resolution of scalp EEG, the organization of cortical neural sources involved in this expiratory load compensation or during response to hypercapnia, especially the interaction between the premotor cortex, the sensorimotor cortical areas and the perisylvian cortex is unknown.

Interventions

• Procedure SEEG monitoring
  Patients will be recruited among adult patients suffering from drug-resistant focal epilepsy who undergo SEEG monitoring at the Epilepsy Department of the Neurological Hospital. The study will be offered to patients during the hospitalization.
• Procedure Comprehensive respiratory monitoring
  In addition to SEEG monitoring, all participants will undergo comprehensive respiratory monitoring in order to collect respiratory data (tidal volume, VE, and respiratory rate) and gas exchange (PETO2 and PETCO2).
• Procedure Cardio-respiratory monitoring
  In addition to SEEG channels, cardio-respiratory monitoring consisting of pulse oximetry, respiratory efforts (thoracic and abdominal) and EKG recordings will be performed.
• Procedure Expiratory load compensation
  Expiratory load compensation will be assessed in the patient's room in the epilepsy monitoring unit. Patients will breathe through a facemask connected in series to a bidirectional pneumotach and a three-way T-shaped valve. The second port on the three-way valve will be open to room air, and third port will be connected to a CE-marked PEEP valve (PEEP 20 valve, Ambu A/S Denmark) allowing to adjust airflow resistance during expiration from 0.15-2.0 kPa (1.5-20 cmH2O). Respired air will be continu
• Procedure Hypercapnic challenge
  The patient breathes through the mouth, using a mouthpiece and a nose clip, through a device fitted with a hermetically sealed bag that measures the various parameters of his/her breathing. At the start of the test, the patient breathes ambient air and his or her breathing is measured. Then, after a few minutes, the patient is connected to the bag, breathing in a closed circuit. This causes a gradual increase in carbon dioxide (CO2) in the inspired air. During this time, breathing parameters wil
• Other Questionnaires
  Caffeine intake Self-report the degree of "breathlessness" during Expiratory load compensation using a visual analogue scale Self-report the degree of "breathlessness

Primary outcome measures

• Cortical localization of pre-expiratory potentials (via SEEG) during HETL (20 cmH₂O) in drug-resistant epilepsy [Time frame: Through study completion, an average of 1 year]

Secondary outcome measures (8)

• dentification of cortical SEEG contacts showing pre-expiratory potentials under 10 cmH₂O low expiratory threshold load (LETL) in drug-resistant epilepsy [Time frame: Through study completion, an average of 1 year]
• Cortical localization of SEEG contacts exhibiting pre-expiratory potentials during a hypercapnic challenge (HyperCO₂) in patients with drug-resistant epilepsy. [Time frame: Through study completion, an average of 1 year]
• Latency (ms) of the pre-expiratory potentials in each condition (HETL, LETL, HyperCO2) [Time frame: Through study completion, an average of 1 year]
• Value of hypercapnic ventilatory response (HCVR)* in each condition (HETL, LETL, HyperCO2) [Time frame: Through study completion, an average of 1 year]
• Number of focal to bilateral tonic-clonic seizures during the 18 months preceding the SEEG [Time frame: Inclusion visit]
• Localization of the SEEG contacts included in the epileptogenic zone (EZ) [Time frame: Inclusion visit]
• Current and past mean daily intake of caffeine (mg/day) [Time frame: Inclusion visit]
• Respiratory discomfort of the experiment during each condition (HETL, LETL, HyperCO2) [Time frame: Immediately after the respiratory challenges.]

Eligibility criteria

Inclusion criteria

• Written informed consent obtained from study subject and ability for study subject to comply with the requirements of the study
• Aged 18 to 55 years old
• Diagnosis of drug-resistant focal epilepsy, as defined by the International League Against Epilepsy 20
• Patients undergoing SEEG as part of presurgical evaluation
• At least one SEEG electrode localized in the perisylvian cortex
• At least one SEEG electrode localized in the premotor cortex

Exclusion criteria

1\. Ongoing or chronic respiratory and/or cardiac insufficiency and/or ischemic cardiac disease 2. History of stroke in the last 5 years 3. Intracranial hypertension related to space-occupying lesion in the brain 4. Pregnant, parturient, or breastfeeding women 5. Individuals receiving psychiatric care 6. Individuals deprived of their liberty by judicial or administrative decision 7. Adults subject to legal protection measures (guardianship, curatorship) 8. Individuals not affiliated with a social security scheme or beneficiaries of a similar scheme

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Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Prevention

Study locations

France · 1 center

• Service de Neurologie Fonctionne et d'Epileptologie Hôpital Neurologique Pierre WERTHEIMER — Bron

Identifiers

NCT: NCT07599150 · 69HCL26_0383

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗