Abstracts

Rationale: We investigated how prolonged seizure activity impacts on cardiorespiratory function and leads to sudden death in an acute rat model. Methods: Urethane-anaesthetized female Long-Evans rats were implanted with: nasal thermocouple, venous and arterial cannulae, and electrodes for ECG, hippocampal, cortical and brainstem recording. Kainic acid injection into the ventral hippocampus induced status epilepticus. Results: Seizures led to hypertension, tachycardia and tachypnoea punctuated by recurrent transient apnoeas. Most cases appeared to be obstructive. Nasal airflow ceased, while efforts to breathe persisted as continued rhythmic activity of: respiratory pre-Bötzinger neurons, inspiratory EMG, and excursions of chest wall and abdomen. Blood pressure oscillated in time with respiratory efforts. This pattern also occurred in a minority of cases of incomplete apnoea, but not in rare cases of transient central apnoeas. During transient obstructive apnoeas the frequency of all inspiratory efforts decreased abruptly by ~30% suggesting a re-setting of the central respiratory rhythm generator. Twenty-two of thirty-two rats died spontaneously typically after 2 hours of status. The cause of death was either an obstructive apnoea (12) or central apnoea following progressive slowing of respiration (10). Most rats dying of central had previously experienced several transient obstructive apnoeas. Negative DC field potential shifts of the brainstem followed the final breath, consistent with previous work on spreading depolarization in mouse models. Timing suggests the DC shift is a consequence rather than cause of respiratory collapse. Cardiac activity continues, with a rapid decrease in heartrate with no consistent relationship with the DC shift. Conclusions: Seizure activity in forebrain induces pronounced autonomic activation disrupts activity in medullary respiratory centres, resulting in death from either obstructive or central apnoea. These results directly inform mechanisms of death in status epilepticus, and indirectly provide clues to mechanisms of SUDEP. Funding: This work was supported by a grant from the James Lewis Foundation through Epilepsy Research UK