Biochemistry of Epilepsy

        There are two main kinds of brain cells, neurons and glia.  Neurons are nerve cells that pass messages from one to another to take information in from our senses, and control our thoughts and bodies.  Glial cells are their helpers.
         One neuron's axons connect to many other neurons in many ways.  For an example try this activity : First find someone else to help you.  Take one finger and touch the person's head, then take another finger and touch the person's hair, then take another finger and touch the person's hand.  Each body part represents a neuron.  Your arm is a neuron's axon, your fingers are the terminal buds, and the person you are touching is all the other neurons you connect with.  That is how neurons connect.
        Neurons don't really touch each other, they stay seperated by a little space called a synapse.  To send a message, the sending neuron takes in calcium and releases a chemical messenger called a neurotransmitter.  This chemical messenger travels to the next neuron and goes to a special spot called a receptor.  If the amount of chemical messenger is enough, the neuron receiving the message lets in lots of sodium, which changes the electrical charge in the neuron, producing an electrical wave called an action potential.  This is called "firing".  Once a neuron fires, it sends the message along to all the neurons it is in contact with.
    One neuron passes a message onto the next like a game of telephone.  Only they don't whisper, and they always get the message right!  It's also like freeze tag.  Some chemical messengers (and some of the glial cells) stop the neuron from sending on the message.  They are like the person who is "it" in freeze tag.   They freeze the neurons to stop them from passing the message on.  Then the other neurons "tag" the neurons to unfreeze them so they can "run" to pass on the message.  Freeze messengers are useful because they prevent the brain from having too much activity to handle.  They also help you get used to the feeling of your clothes, rather than having them bug you all day.  This is called accomodation.  Accomodation could not happen without "freeze" messengers.  Freeze messengers are called inhibitory neurotransmitters.  Unfreeze messengers are called excitatory neurotransmitters.
    When the messenger reaches its' receptor at the next neuron, it causes an ion channel to open.  Inhibitory neurotransmitters allow chloride to enter the ion channel which freezes the next neuron, and makes it harder to excite.  Excitatory neurotransmitters allow sodium to enter the ion channel, which excites the neuron and makes it "fire" or pass on the message.
    Neurotransmitters don't stay around in the synapse for long, they are either broken apart into pieces that can be put back together later in the neuron, or they are captured and recycled.  Being captured and recycled is called "reuptake".
    In the animation below, freeze messengers (inhibitory neurotransmitters) are blue dots, run messengers (excitatory neurotransmitters) are red dots, and the red wave is the electrical energy caused by sodium ions entering the neuron.

        It's important for there to be a balance between freeze messengers and unfreeze messengers.  If there are not enough freeze messengers, a seizure can happen.  A seizure happens when too many messages are going around the brain at once, all at the same time.  It's as if two different messages are going around the circle at once during a game of telephone.  This makes it very likely that the messages are going to get mixed up.  During a seizure, the neurons send mixed up messages to your body, so the body does things that you don't want it to.  Anything the brain or body can do it can do as the result of a seizure.
        Some seizures start in the whole brain at once, these are called generalized seizures.  Generalized seizures include absence seizures, tonic-clonic seizures, atonic seizures.  Some seizures start in a small part of the brain and stay there.  These are called partial seizures.  There are two kinds of partial seizures, complex partials where consciousness is changed or lost, and simple partials when you are conscious for the whole thing.  Partial seizures can also spread to the whole brain, causing a secondarily generalized seizure.  In this case, the partial seizure is then called an aura, because it is warning that a bigger seizure is coming.  People whose seizures start out generalized do not have any warning that they are about to have a seizure.
 
 

Medicines:

Carbamazepine blocks ion channels and reduces the amount of sodium that can enter neurons.  It is helpful for partial and secondarily generalized seizures but can make absence seizures worse.

Diazepam and similar medicines work by attaching to the GABA receptor and increasing the amount of freeze messages in the brain.  There is a special form of this medicine that can be used to stop seizures that go on too long (status epilepticus).  It works for all kinds of seizures, but can cause sleepiness.

Ethosuximide works only on absence seizures.  It blocks a certain type of calcium ion channel in neurons.

Felbamate is used as a last resort medicine because it can damage the liver or bone marrow.  Scientists are not sure how it works.  It seems to be safer for children with a very severe seizure disorder called Lennox-Gastaut syndrome.

Gabapentin might increase the freeze messenger GABA in the brain, or it might affect ion channels.  It works for partial seizures and secondarily generalized seizures.  It does not work for generalized seizures like absence seizures.

Lamotrigine blocks ion channels, and prevents sodium from entering into neurons that are already rapidly firing.  This reduces their ability to send more messages, and prevents seizures from an overload of messages.  Lamotrigine works for all kinds of seizures, both partial and generalized.

Oxcarbazepine is similar to carbamazepine, but is broken down in the body very differently.  This prevents most of the side effects that people taking carbamazepine can suffer.  It works best for partial and secondarily generalized seizures, and seems to work by affecting ion channels.

Phenobarbitol reduces neuron activity by blocking the special attachment place (receptor) for the excitatory neurotransmitter glutamate.  This means that the "run" or "fire" message cannot get to the next neuron.  It works for partial seizures and tonic-clonic seizures, but can make absence seizures worse.

Phenytoin blocks sodium ion channels.  It works best for partial seizures and generalized tonic-clonic seizures.  There is a special form of this drug that can be put into a vein to stop status epilepticus, a seizure that does not stop by itself after a few minutes.

Topiramate blocks ion channels, and reduces the amount of sodium that enters neurons.  It also helps increase the action of freeze messengers.  It works best for partial seizures, but it may work for generalized seizures too.

Tiagabine prevents the freeze messenger GABA from being gathered up as quickly at the synapse (reduces re-uptake), which allows it to stay around longer and freeze neurons for a longer time.  It is good for partial or secondarily generalized seizures.

Levetiracetam is a brand new drug and scientists do not know how it works.  They are hopeful that it will work for people that aren't helped by other drugs.  It works for partial and generalized seizures.  It is now being studied in children.

Valproic Acid is a drug that is useful for many kinds of seizures.  It works well for absence seizures, partial seizures, generalized seizures, and myoclonic seizures.  It blocks a certain kind of calcium ion channel.

Vigabatrin is not available in the United States because it can destroy peripheral vision (the ability to see out of the "corner" of your eye) in some people.  It works by grabbing the enzyme that breaks down the freeze messenger GABA and not letting it go.  This increases the GABA levels in the brain.  This medicine works very well for some seizure disorders that don't respond to any other medicine.

Zonisamide may be an alternative to vigabatrin.  It blocks a certain type of ion channel that allows calcium into neurons.  Calcium must get into neurons in order for them to be able to release their chemical messengers (neurotransmitters).
 

Special Diet

The Ketogenic Diet can help stop seizures in some children who are not helped by medicines.  It's a very high fat diet with barely any sugar.  You can't eat any candy, and you can't drink whenever you want either.  All the foods have to be carefully weighed and measured, and you don't get much food to eat.  A typical meal is a cup of heavy cream, a sausage, and if you're lucky one strawberry!  Another possible dinner is 2 tablespoons full of pasta with a quarter cup of melted cheese and a few green beans.  This diet has to be started in the hospital, and you need to take a lot of vitamins and minerals because the diet is not balanced.  A nutritionist or registered dietician works with the family to design the food plan.  It takes a lot of self control to be on the ketogenic diet but some kids find that the seizure control is worth it.  About a third of children on the ketogenic diet have no more seizures, and about 40% have less seizures than they did before the diet.  For the other children, the diet does not work at all.  Scientists used to think that they diet worked because of ketones, special chemicals the body releases when it is starving, but now they are not sure how it works.

Implantable Devices Neurocybernetic Prosthesis® (vagus nerve stimulator) is a small machine like a pacemaker.  It gives tiny, painless electrical shocks to the vagus nerve, the largest nerve that comes out from the brain.  These shocks can be increased by the doctor or the person with epilepsy by holding a magnet over the device.  The use of the NCP in children with epilepsy is being studied by doctors.  It works for adults with partial seizures.  It also works well for atonic (drop) seizures. images courtesy of Cyberonics Inc.

Surgery

People who have tried medicine after medicine and the ketogenic diet with no seizure control may benefit from surgery.  There are many different types of surgery.  Surgery only works when a small area of damaged brain like a tumor, or a scar, or a tangle of abnormal blood vessels is causing the seizures.  Surgery works best for partial seizures where the part of the brain the seizures are coming from is small or not too important and can be taken out.  Sometimes the surgery works perfectly and the person never has another seizure, sometimes it makes the seizures worse because it makes new damage and sometimes it doesn't affect the seizures at all.
        Brain surgery can be done with either a scalpel (knife) or with radiation.  The gamma knife is a new way to do surgery with radiation.  The radiation dose is very low, and goes into the brain from different directions and meets at the part of the brain the doctors need to destroy.  This way the healthy brain does not get hurt from the radiation.  The gamma knife is still experimental for epilepsy surgery, but it has been used a lot to cure brain tumors.