Why Is Animal Research Important in SUDEP?

Sudden unexpected death in epilepsy (SUDEP) is a devastating possibility for patients with epilepsy and their families. Currently, there is no proven method for preventing SUDEP, which occurs without warning to patients. Possible causes of SUDEP have been proposed based on the rare instances when SUDEP was observed. These possible causes include:

Heart

Several research groups have used animals with abnormal genes that cause them to have seizures and also show heart problems. They are using these animal models to try to understand how these heart problems could contribute to SUDEP.

Breathing Problems

The most common problem that has been seen in cases of SUDEP and near-SUDEP is severe breathing problems that occur after seizures. It has been shown that when people have seizures, breathing problems can occur, but in most patients the problems go away quickly after the seizure. However, the breathing problem in a few patients may become severe, and it appears to have the potential of leading to SUDEP.

In order to find treatments that might prevent this, animal models are being used to study the effect of seizures on breathing. Some animals, including two types of mice named DBA/1 and DBA/2, have an inherited form of epilepsy that is associated with death after a seizure. It has been shown that death after seizures in these mice can be prevented if their breathing is supported using a respirator. These mice can be used to model SUDEP that is caused by breathing problems.

Previous research has shown that certain brain chemicals control breathing in animals and in humans. It has also been shown that several of these chemicals are released into the brain during seizures. Some of these brain chemicals can stimulate breathing and others can depress breathing.

Using the DBA mice as models of SUDEP, we are investigating whether drugs that increase the action of the brain chemicals that stimulate breathing can prevent death in these mice.

We are also investigating whether drugs that block the action of brain chemicals that depress respiration can prevent death after seizures in these animals.

1. Experiments so far suggest that fluoxetine, a drug that is commonly used to treat clinical depression and is known to increase the action of brain chemical serotonin, which stimulates breathing, can block seizure-induced death in DBA mice. This action may involve stimulation of breathing.

2. Not all of the similar drugs are as effective as fluoxetine in blocking death, however. There is some very early evidence in patients with epilepsy that this type of drug may also improve breathing after seizures, but this needs to be confirmed.

3. There is another brain chemical called adenosine that is also released during seizures and is known to depress breathing. Drugs that block the action of this brain chemical are available and are similar to caffeine.

4. Experiments are currently being done to evaluate if drugs that modify the action of brain chemicals can explain why these mouse or rat models of SUDEP have a high risk of death following seizures. The use of these animal models can help to determine if brain chemicals are potential sources for developing medications or procedures for preventing SUDEP in humans.

If the drugs tested prevent death in these SUDEP animal models, the drugs can be tested in humans to see if they can improve the breathing problems that occur after seizures. Therefore, animal models of SUDEP are vital to developing treatments for preventing SUDEP in humans.

Suggested Readings:

1. S. Tupal and C. L. Faingold. Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice. Epilepsia 47 (1):21-26, 2006.

2. L. M. Bateman, C. S. Li, T. C. Lin, and M. Seyal. Serotonin reuptake inhibitors are associated with reduced severity of ictal hypoxemia in medically refractory partial epilepsy. Epilepsia 51 (10):2211-2214, 2010.