Clinical Pharmacology: Drugs as a Benefit and/or Risk in Sudden Unexpected Death in Epilepsy?

Abstract

Death may be the consequence of natural or unnatural causes, such as accidents, homicide, and suicide, which have no relationship to the disease of epilepsy. Direct causes of death include status epilepticus, and indirect causes may be head trauma or drowning subsequent to a seizure. When death occurs suddenly and without explanation, the term sudden unexpected unexplained death is used. Unexplained is a term that clinicians and research scientists are working to clarify. Numerous preclinical animal studies have been conducted as models for sudden death and have led to clinical studies in persons with epilepsy. These studies show that sympathetic nerve stimulation, ouabain, or coronary occlusion increased temporal dispersion of recovery of ventricular excitability and led to an underlying electrical instability that predisposed the ventricularmyocardium to arrhythmia. Cardiac arrhythmias in an animal model for ouabain-induced toxicity were associated with neural autonomic dysfunction. Neural discharges were characterized by increases, decreases, or no change in the discharge of postganglionic cardiac sympathetic nerves monitored simultaneously, predisposing to cardiac arrhythmia. Stimulation of the sympathetic ventrolateral cardiac nerve produced a shift in the origin of the pacemaker and tachyarrhythmias because the nerve is not uniformly distributed to the various regions of the heart but is localized to the atrioventricular junctional and ventricular regions. Such nonuniform distribution of sympathetic nerves would also contribute to initiation of arrhythmia as a nonuniform neural discharge occurred. Studies examining the physiology and pharmacology of this finding in multiple animal models found that subconvulsant, interictal discharge was associated with autonomic cardiac neural non-uniform discharge and cardiac arrhythmias. As a result of further investigations, Lathers and Schraeder edited a book in 1990 that summarized the clinical problem of sudden unexpected death and epilepsy (SUDEP). The contributors concluded that there was a paucity of clinical data addressing the mechanism of death. Regulatory response resulting from the consequent increased awareness of SUDEP occurred in 1993, when the FDA focused attention of practitioners and pharmaceutical manufacturers on the question of whether use of anticonvulsant drugs contributes to or prevents sudden unexpected death in epileptic persons. The FDA-convened panel of scientists considered the prevalence of sudden unexpected death in patients involved in studies associated with developing new anticonvulsant drugs and reviewed data on the risk of sudden unexpected death in patients taking lamotrigine. The risk of SUDEP was no different from thatfound in the young epilepsy population in general. Estimated SUDEP rates in patients receiving the new anticonvulsant drugs lamotrigine, gabapentin, topiramate, tigabine, and zonisamide were found to be similar to those in patients receiving standard anticonvulsant drugs, suggesting that SUDEP rates reflect population ...

Quantification of respiratory parameters in patients with temporal lobe epilepsy

“…No association between seizure frequency, AED and altered pulmonary function was found. discussion Potential mechanisms of SUDEP comprise cardiac arrhythmia, autonomic imbalance, hypoxia, arrhyth-mogenic drugs or central or obstructive apnoea 4,[20][21][22] . We analyzed respiratory parameters in patients with TLE during the interictal period and found no significant alterations in respiratory function tests.…”

Trends in suicide by drowning in the elderly in England and Wales 1979–2001

“…Cardiac arrest and subsequent drowning in bathtubs were attributed to sudden reduction in blood pressure and cardiac arrhythmia and not due to fatal self harm (Yoshioka et al, 2003). Drowning has also been attributed to Sudden Unexpected Death in Epilepsy (SUDEP) either subsequent to a seizure or occurring suddenly without explanation (Lathers and Schraeder, 2002). It may be relevant to note that in a local study (Salib et al, 2004) bathroom drowning accounted for 7% of all elderly drowning suicide, some of who may have in fact died suddenly, but naturally, in water in Figure 7.…”

Methods for ECG Evaluation of Indicators of Cardiac Risk, and Susceptibility to Aconitine-induced Arrhythmias in Rats Following Status Epilepticus

“…In addition to SE, patients experiencing spontaneously recurring seizures, i.e. epilepsy, are at risk of premature sudden and unexpected death associated with epilepsy (SUDEP) 18 . As with SE, the precise mechanisms mediating SUDEP are not known.…”

“…As with SE, the precise mechanisms mediating SUDEP are not known. It has been proposed that ventricular abnormalities and resulting arrhythmias make a significant contribution [18][19][20][21][22] .…”

“…As with SE, the precise mechanisms mediating SUDEP are not known. It has been proposed that ventricular abnormalities and resulting arrhythmias make a significant contribution [18][19][20][21][22] .To investigate the mechanisms of seizure-related cardiac death, and the efficacy of cardioprotective therapies, it is necessary to obtain both ECG-derived indicators of risk and evaluate susceptibility to cardiac arrhythmias in animal models of seizure disorders [23][24][25] . Here we describe methods for implanting ECG electrodes in the Sprague-Dawley laboratory rat (Rattus norvegicus), following SE, collection and analysis of ECG recordings, and induction of arrhythmias during iv infusion of aconitine.…”