Abstracts

Rationale: Sudden Death in Epilepsy (SUDEP) is the most important epilepsy-related life-threatening event in people with chronic epilepsy. SUDEP is associated with ictal-related cardio-respiratory dysfunction which may be caused by convulsive activity spreading from the cerebrum to the brainstem. Clinical evidence suggests that respiratory arrest or prolonged apnea may be the initial cause of SUDEP. Methods: 9 rats had chronic microelectrode implantation for intracranial iEEG. An assembly of six microwires (Plastics-1 Inc., Roanoke, VA, USA) was implanted into the right brainstem (lateral and medial solitary tract, nucleus tractus solitarus) of 7 rats stereotactically. Also, these rats had a right hippocampus bipolar electrode with a cannula and a cortical bipolar electrode. Among these 7 rats, 3 rats were controls, who had weekly baseline iEEG recordings for 2-3 months. The other 4 rats received an intrahippocampal dose of 4-AP (1 µL to 5 µL at 40 mM) after a 1 week recovery period. The intrahippocampal 4-AP injection experiments were repeated in 2 rats without brainstem implantation, to test the consistency of rats' seizure-related experiences without local damage to the cardio/respiratory centres. Similarly, these rats received an intrahippocampal dose of 4-AP (5 µL at 40 mM). Also, we have recorded iEEG from a 14 year old girl during her epilepsy presurgical evaluation, during which she experienced a SUDEP episode with successful resuscitation. The iEEG was recorded using depth and grid electrodes from her left frontal lobe. Results: The basal iEEG recordings from control experiments indicated long-term stability of the recording system. Of the four rats with brainstem electrodes who received an 4-AP injection, 3 received low dose of 4-AP (1 µL) and demonstrated several electrographic seizures with or without class I to brief (<25 sec) class IV seizures for 3-4 hours, but no spread of epileptiform activity into the brainstem. The fourth rat which received a higher intrahippocampal dose of 4-AP (5 µL), had several electrographic seizures with class I and II behaviors for the first 15 minutes. About 25 minutes after the 4-AP intrahippocampal injection, a 70 sec tonic clonic seizure occurred, followed by cortical and brainstem EEG flattening, simultaneous respiratory difficulties and subsequent respiratory arrest,. Similar seizure-related respiratory difficulties due to the higher 4-AP dose (5 µL) occurred in the 2 rats without brainstem implantation. Also, the human SUDEP episode demonstrated similar cortical electrographic flattening before the respiratory arrest. Conclusions: These studies show that brainstem epileptiform activity is a necessary concomitant for respiratory arrest in a hippocampal originating model of secondarily generalized seizures. Also cortical EEG flattening could be a marker for subsequent respiratory arrest as noted in both the animal model and human case.