SUDEP Mechanisms

Monday, July 20, 2015

While the exact mechanisms for sudden unexpected death in epilepsy (SUDEP) are not well understood, over the past decade, a more accurate understanding of the sequence of events following a seizure that leads to death has emerged from observations made in epilepsy monitoring units. These terminal seizures are associated with significant abnormalities in breathing, heart rate, and heart rhythm. Even when not fatal, seizures can lead to impaired oxygenation and decreased blood pressure. Control of these essential cardiac, respiratory, and autonomic functions lies in the brainstem, and it is hypothesized that spread of seizure activity into the brainstem from the cerebral cortex is necessary for most SUDEPs.

Study on Cardiopulmonary Depression

In a recent study by Aiba and Noebels, the authors explored brainstem activity following a seizure in genetically engineered mice prone to SUDEP. Mice missing the Kv1.1 potassium channel or expressing an abnormal SCN1A gene encoding a sodium channel subunit (a mouse model of Dravet syndrome) have been previously shown to have spontaneous seizures and premature death. The authors recorded electrical activity from the cortex and dorsal medulla as well as respiration and ECG during experimentally evoked seizures under anesthesia. They found the following.

  • Many of the SUDEP-prone mice, but not wild type mice, exhibited spreading depression in the dorsal medulla following seizures. This spreading depression, a phenomenon associated with slow and long lasting depolarization of neurons and glia leading to regional brain shutdown, was associated with fatal respiratory and ECG abnormalities in the mice.
  • Direct injection of potassium chloride into the dorsal medulla of mutant and wild type mice to trigger spreading depression in the absence of cortical seizures lead to apnea, bradycardia, and. if prolonged, cardiopulmonary arrest. The induced spreading depression was also associated with a transient suppression of cortical activity, similar to what is seen after tonic-clonic seizures and has been linked to SUDEP risk.
  • SUDEP-prone Kv1.1 knockout and SCN1A mutant mice had lower thresholds for evoking spreading depression when tested in brainstem slices compared to wild-type littermates. This lowered threshold was normalized when the mice also had the gene MapT, which encodes for the microtube-associated protein tau, knocked out. MapT gene knock out has previously been shown by this group to reverse premature mortality in these SUDEP prone mice.

Promising Avenue Found for SUDEP Prevention

This study is important because it provides a key mechanistic link between seizures and cardiopulmonary failure in SUDEP. Further studies are needed to see if these findings generalize to other seizure and SUDEP models. Developing treatments targeting brainstem spreading depression may be a promising avenue for SUDEP prevention.

Authored by: Daniel Friedman MD | SUDEP Editor on 7/2015

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