Brainstem activity, apnea, and death during seizures induced by intrahippocampal kainic acid in anaesthetized rats

Abstract

Objective: To investigate how prolonged seizure activity affects cardiorespiratory function and activity of pre-Bötzinger complex, leading to sudden death. Methods: Urethane-anesthetized female Long-Evans rats were implanted with nasal thermocouple; venous and arterial cannulae; and electrodes for electrocardiography (ECG) and hippocampal, cortical, and brainstem recording. Kainic acid injection into the ventral hippocampus induced status epilepticus. Results: Seizures caused hypertension, tachycardia, and tachypnea punctuated by recurrent transient apneas. Salivation increased considerably: in 11 of 12 rats, liquid with alkaline pH consistent with saliva was expelled from the mouth. Most transient apneas were obstructive: nasal airflow ceased, while, in 83%, efforts to breathe persisted as continued rhythmic activity of respiratory pre-Bötzinger neurons, inspiratory electromyography (EMG), and excursions of the chest wall and abdomen. Blood pressure oscillated in time with respiratory efforts. This pattern also occurred in a minority of cases (16%) of incomplete apnea, but not in rare cases (1%) of transient central apneas. During transient obstructive apneas, the frequency of all inspiratory efforts decreased abruptly by ~30%, suggesting a resetting of the central respiratory rhythm generator. Twenty-two of thirty-one rats died, due either to obstructive apnea (12) or central apnea following progressive slowing of respiration (10). Most rats dying of central apnea had experienced several transient obstructive apneas.Negative DC field potential shifts of the brainstem followed the final breath, consistent with previous reports on spreading depolarization in mouse models. Timing suggests that the DC shift is a consequence rather than cause of respiratory collapse.Cardiac activity continued for tens of seconds. Significance: Seizure activity in forebrain induces pronounced autonomic activation and disrupts activity in medullary respiratory centers, resulting in death from either obstructive or central apnea. These results directly inform mechanisms of death in status epilepticus, and indirectly provide clues to mechanisms of sudden unexpected death in epilepsy (SUDEP). K E Y W O R D SHeart rate, obstructive apnea, status epilepticus, SUDEP | 2347 JEFFERYS Et al.

Cardiac effects of repeated focal seizures in rats induced by intrahippocampal tetanus toxin: Bradyarrhythmias, tachycardias, and prolonged interictal QT interval

“…None of the rats die unexpectedly in the present study, so we do not have evidence for a model of SUDEP, but it does provide a useful means to study the manner in which repeated self‐limiting seizures can affect cardiac function. In acute rat models that induce SE, animals do die, but the brain is challenged excessively 17,34 . In the present study, only a proportion of seizures were convulsive (Racine stages 4‐5) and, apart from experiencing seizures, the animals were in good health.…”

“…In addition to its effect on the heart, vagus activation during increased sympathetic drive has been shown to predispose to periods of apnea 37 . Although we did not measure respiration in the chronic model in this study, it is interesting that acute SE induced by systemic or intrahippocampal injection of kainic acid also induces intense sympathoactivation punctuated by apneas, which were often lethal in these models 17,34,39 …”

“…The most commonly used animal models of chronic epilepsy rely on systemic injection of epileptogenic agents 13 . Direct actions on peripheral or central (eg, brainstem) sites 7,14–16 may induce cardiac and respiratory changes independently of seizures, complicating interpretation of results 17 . These models reveal prolongation of QTc (QT corrected to a standardized heart rate) following chronic epilepsy 7,8 .…”

Causes and Effects Contributing to Sudden Death in Epilepsy and the Rationale for Prevention and Intervention

“…Occasionally laryngospasm is sufficient to cause OA ( 34 , 52 ). OA is associated with intense effort to inspire, rapid desaturation, and a significant “second level” autonomic co-activation to protect core blood flow.…”

“…The work on brainstem depolarization ( 92 ) demonstrates that this form of spreading depression likely accounts for the development of respiratory failure after reaching the point of respiratory arrest. The time to develop, the time of occurrence, and the time that would be necessary for resolution all point to brainstem depolarization occurring as a result of hypoxemia and after the point of respiratory arrest ( 52 , 93 ).…”