Acute and chronic cardiorespiratory consequences of focal intrahippocampal administration of seizure-inducing agents. Implications for SUDEP
Abstract
The risk factors for SUDEP are undoubtedly heterogenous but the main factor is the frequency of generalized tonic-clonic seizures with apnoea and/or cardiac abnormalities likely precipitating the lethal event. By its very nature modelling SUDEP experimentally is challenging, yet insights into the nature of the lethal event and precipitating factors are vital in order to understand and prevent fatalities.
Acute animal models, which induce status epilepticus (SE), can be used to help understand pathophysiological processes during and following seizures, which sometimes lead to death. The most commonly used method to induce seizures and status epilepticus is systemic administration of an ictogenic agent.
Microinjection of such agents into restricted regions within the brain induces a more localised epileptic focus and circumvents the risk of direct actions on cardiorespiratory control centres. Both approaches have revealed substantial cardiovascular and respiratory consequences, including death as a result of apnoea, which may be of central origin, obstructive due to laryngospasm or, at least in genetically modified mice, a result of spreading depolarisation to medullary respiratory control centres.
SUDEP is by definition a result of epilepsy, which in turn is diagnosed on the basis of two or more unprovoked seizures. The incidence of tonic-clonic seizures is the main risk factor, raising the possibility that repeated seizures cause cumulative pathological and/or pathophysiological changes that contribute to the risk of SUDEP.
Chronic experimental models, which induce repeated seizures that in some cases lead to death, do show progressive development of pathophysiological changes in the myocardium, e.g. prolongation of QT the interval of the ECG or, over longer periods, ventricular hypertrophy. However, the currently available evidence indicates that seizure-related deaths are primarily due to apnoeas, but cardiac factors, particularly cumulative cardiac pathophysiologies due to repeated seizures, are potential contributing factors.