Click here to view next page of this article

New Treatments for Epilepsy and Seizures

Epilepsy is defined as two or more recurrent seizures. By the time you reach 80 4%, four out of one hundred, would have had epilepsy; two or more seizures. By the time of 20 the population is 1%. Now by the time you reach 80, as I said, 4% would have had epilepsy.

Etiology: two-thirds of the time we don’t know what causes epilepsy, one-third of the time you know what is causing epilepsy. We’ll come back to this. Seizures: Two-thirds, 60-70%, are partial. More like 30% are generalized. Causes of epilepsy: each one of these; brain tumor, infection, head injury.

I’m back to head injury. With any penetrating head injury there is a very high risk of epilepsy. If you take 100 people with penetrating head injury, about half of them will have epilepsy. If you have prolonged unconsciousness - I’m talking about a day or two or a week in coma - incidence of epilepsy shoots up. If you have depressed skull fracture, very significant risk of epilepsy.

I’m not going to talk about brain tumors. I’m not going to talk about stroke. You can have ischemic stroke with seizures, you can have hemorrhagic stroke with seizures.

What is Sandifer’s syndrome? Infants. Esophageal reflux after feeding, like a choking, in the first few months of life. It mimics seizures. The child stiffens, stiffens up a little bit. That’s Sandifer’s syndrome. If you do serial EEG’s in epilepsy, three or four EEG’s, 90% would be positive.

Important differential diagnosis, pseudo-seizure. Acute confusion, especially with a previous history of seizure disorder. Remember non-convulsive status epilepticus. You need to do an EEG. Subtle status is a new entity. A typical example: a patient with epilepsy comes to the ER, having had two tonic-clonic seizures. Have another one in the ER.

Seizures in pregnancy: seizures increase in approximately one-third to about 50%. Occasionally it improves, a lot of times it doesn’t change from the pre-pregnancy seizure rate. What happens? Patients don’t take the pills, compliance is poor, so the drug level drops so they have more seizures. They are under stress, they worry about the fetus, they have more seizures.

Malformation, minor. All of these things you can have. These are all minor. What are the chances? The figures are as high as 20% of pregnant epileptics having children with some kind of minor malformation. Now what about major malformation, which you all need to worry about? In normal population it is about 2-3% non-epileptic.

Birth control pill: failure rate when you take anticonvulsants. This is actually the latest figure. It may sound little too high for you but that’s what the experts say. The birth control failure may be as high as 6%. The worst culprits are big time enzyme inducers; phenobarbital, phenytoin.

All right, let’s talk about this for a moment. I’m glad you pointed this out. I kind of overlooked it. Now baseline risk, if you have a child with epilepsy - we are talking about offspring, brother and sister of this child - if the parent has epilepsy the sibling risk is about 3-5%. Generalized epilepsy with the parent is bad, partial seizure in a parent still increases the risk above this 1% baseline. Baseline is just normal control risk.

Now I’m going to move to seizure drugs. Now I’m going to make some general comments with some specific examples. Bioavailability of a drug, the symbol used is F. Now this stands for the fraction of the drug reaching the blood stream. So if you administer 100 mg of phenytoin intravenously, 100 mg reaches the blood stream. So the bioavailability then is 100%. So any drug you administer IV has a bioavailability of 100%. For most seizure drugs, when you administer them by mouth, the bioavailability is better than 90%. Meaning that more than 90% of the total milligram dose gets into the blood stream, first pass. Some exceptions; carbamazepine, the bioavailability is about 75-80%. Gabapentin, which is vigabatrin.

If you use Infatabs phenytoin compared to the salt, which is the Dilantin capsule, Infatabs has higher bioavailability than the salt of phenytoin, which is in the capsule. So if somebody is on 200 mg of phenytoin capsules you change them to Infatabs 200 mg, a little more of the phenytoin is going to be absorbed, so they may become toxic. Is that a common problem? No. But all the clinical pharmacists talk about this all the time. This may show up on the exam. So Infatabs has higher bioavailability. If you store the medicine in high humidity, especially phenytoin.

Depakote is a good example, the valproic acid does not get into the blood. But once it reaches the duodenum the coating breaks down - because it’s a pH-related coating - as long as it’s acidic pH the coating stays. So in the duodenum and jejunum the coating goes, the Depakote gets into the blood. So it takes about three, four, five hours.

Now I talked about gabapentin absorption non-linearity. Increase the dose, the transporter doesn’t do its job. So the level actually drops. So there is a non-linearity in absorption. Here’s the non-linearity for Depakote because of protein binding. Dilantin is non-linear because of hepatic enzyme saturation. This you’ve got to memorize. There is no easy way. Dilantin gets excreted by ara-hydroxylation. Carbamazepine is a simple oxidation to epoxide.

Okay, let’s talk about interactions, and we talked about this. When phenytoin and valproic acid are highly protein bound, about 80-90% are protein bound. So if you add aspirin, aspirin displaces some Dilantin so the free percentage increases and you get toxic symptoms. If you use phenytoin and Depakote together you have a potential of Dilantin toxicity.

Neurontin; water soluble, renal, no interaction. Lamotrigine; the indications are getting larger. It’s approved for partial seizures, but there is evidence that it may work for generalized seizures too. If you use lamotrigine and valproic acid together you run a good risk of skin rash, including Stevens-Johnson syndrome. This is why you titrate very slowly, you titrate either drug.