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Chapter 2

More Is Better?

Medication toxicity.
Epilepsy, EEGs, generic substitution, infrequent grand mal seizures, labels (disease).
Dilantin, new anticonvulsants.
(Harry: patient), (Andrew: student); (boat analogy)

The shrill squeal sounded like a 130-decibel alarm going off.
Buppopbuppopbuppop! Everyone in the library heard this sharp, repetitive sound caused by the spasm of the muscles inside Harry's larynx--laryngeal stridor. This heralded to all around that he was having a grand mal seizure--a generalized tonic clonic episode of epilepsy. They saw Harry, lying there, unconscious, not knowing the trauma he was causing to the group that had accumulated around him. There he was, on the floor, shaking and flailing, but no longer making a sound. At first, he had a phase of utter stiffness--a tonic phase--lasting about 30 seconds. This was followed by an even more frightening minute of rhythmic, synchronous shaking of all four limbs--the clonic phase.

A little puddle accumulated. He had been incontinent of urine--another ignominy for this poor, unconscious, usually perfect gentleman. Gradually, his eyes opened, just briefly, and he got up on his knees for a few seconds, just long enough to throw up. Then he lay back down and went to sleep. He had no alert bracelet with seizure disorder written on it, so people could not have known that he was epileptic. This would have saved him a significant amount of distress.

Already one of the kind spectators had gone to phone for an ambulance, and another quickly came forward to help. Others assisted in carrying him, lying on his side, across the hall to an office where there was a couch. Fortunately, nobody tried to force an airway into his mouth so he could breathe. It was not necessary and could only have broken his teeth.

Harry, in fact, did not commonly have grand mal seizures. This was, by history, only the tenth in his lifetime. This time there was a clear but strange precipitator. As part of his higher Master's degree studies, he was in the University library working with a photocopy machine and the light seemed to be defective. He remembered it flashing, but that's all he remembered.

What had happened to Harry was the trigger of the so--called "photic stimulation" of the copier machine, in this instance, possibly three cycles per second. This synchronized with his brain and produced a buildup of a sharp series of discharges that ultimately led to a grand mal seizure.

Harry had also presented with a disorder of his muscle tone, but his was not plastic, like Priscilla's and Jocelyn's. * Harry's tone during the seizure was rigid and stiff; he had an entirely different condition, epilepsy.

Poor Harry woke up an hour later, after his deep sleep following on the grand mal seizure. For a moment he wondered what had happened. His wife was there to comfort him.

She whispered in an empathic voice.

You had a seizure, Harry.

But even before she spoke, he knew the answer. He was able to recognize the typical confusion features, with that awful headache and that sense of nausea.
Not again! It's not fair. I had pushed up my medication, and I thought that would have prevented it!

Harry was taking the anticonvulsant--medication to prevent seizures--Dilantin (phenytoin). He was taking it alone for his sometime, but infrequent, generalized tonic clonic seizures. Every so often, maybe monthly, he would have what he regarded as minor attacks, with little blankouts. These events had severely compromised him: They made it impossible for him to drive, and he felt a little ashamed to interact socially.

At that moment, I came into the room.
Doctor, you know, it's not fair. Two weeks ago, I felt as if maybe I was going to have a seizure, so I pushed up my dose of Dilantin, and what happens? This is the third seizure I've had in two weeks! And this time I ended up in the hospital, because it happened in the library, where people saw me and were amazed at my shaking! How can I tell them that I don't need to go to the hospital; it costs a fortune and all I was having was a regular seizure and they've just got to accept that? But of course, I can't communicate at all during these episodes.
It's always difficult. Have you contemplated getting a little bracelet, which may help?
Yeah, that's a good idea, Doctor.

Let's see if we can find out what may have been a cause for these seizures.
Well, I can't explain it, Doctor, because, after all, I pushed up my dose of Dilantin.
Yes, you pushed up the Dilantin. I suspect we already have a good solid reason for your having had that seizure.

What's that?
Your Dilantin level--your phenytoin level--was in the toxic range. It was 26. It should have been between 10 and 20.
Toxic? But all I was doing was trying to give my system more of my cure. Surely that's good? Surely that would prevent the seizures? Surely more is better?
No, in fact, we must be careful that we don't overdo it, that we don't give you too much anticonvulsant medication--antiseizure drugs.

Does that explain why I was feeling so funny?
In what way do you mean?
Well, you know, I found that I couldn't really walk straight, that I was unsteady on my feet, and at times, particularly in the morning, I would have double vision. Also, I felt nauseous quite a bit over these past couple of weeks.
These may all have been signs of Dilantin toxicity.

That's strange, Doctor, because I only pushed up the dose by 50 mg. I was taking 300 mg per day and I only went up to 350 mg. Surely that wouldn't be enough to make me toxic?
Strangely enough, there are certain medications that actually produce significant toxic reactions by small increments of doses. The liver had to break down the Dilantin, but couldn't.
Why's that?
The Dilantin is lipid--soluble, meaning fat--soluble. This means it dissolves not in water, but in alcohol like liquids. This is a characteristic of many psychiatric and neurological drugs as they need to pass into the brain through a barrier that only allows fat--soluble substances to pass. These brain drugs usually need to become more able to dissolve in water before they can be excreted through the kidneys in the urine.

So does the liver do this?

Impressed by Harry's awareness, I explained further.

You're right, Harry. The liver does this job through substances called enzymes. These liver enzymes break down the Dilantin, but at a certain point, reach a limit and cannot handle any more. We call this different kind of metabolism "zero order metabolism" and more correctly, it reflects non--breakdown. Suddenly, a small incremental increase in dose will produce an enormous increase in the blood level and toxicity at the level of the brain.

Are you saying that the additional 50 mg I took became transformed into a quantity of more than 50 mg?
Yes. Let me give you a perspective. With almost any drug, if you increase the dose of some medications, the body level is going to be higher, in general. With occasional drugs, unusual adaptations occur, where certain medications, like one called Tegretol, even speed up their own metabolism, but only to a certain new plateau. Sometimes, higher levels are linked with a decrease in absorption, as with iron tablets. However, with a drug like the Dilantin you have been taking, the liver, at a certain point, says "I can't handle beyond this dose." Consequently, the drug level rapidly escalates. This may originally have been 17 or 18; then with that small daily increase of 50 mg, the blood level suddenly rises to 28, because the liver cannot handle the difference.

Harry seemed interested.

Can you give me another analogy?
Yes, I can. The chemical factory of the liver is busy breaking down the substance and saying, "Give me more, I can handle it." It has ten workers--the enzymes--busy breaking down the Dilantin. The workers toil through 8--hour days spending all their time handling the Dilantin that's coming in, say 300 mg. You then up the dose to 350 mg, but those workers--the enzymes--only work eight hours a day; after that they punch out their time clocks and go home and never work overtime. So, if 350 mg starts coming in every day instead of 300 mg, the Dilantin is not down to zero after each work day, but down to 50 mg. The amount builds up every day, so that three days later, suddenly there may be up to 150 mg of extra Dilantin which, instead of being broken down, lies around unprocessed. Eventually, the workmen work a little overtime so the extra amounts don't greatly increase.

The interchange sparked a question in the mind of Andrew, always a keen--minded medical student.

But how does this extra Dilantin have any effect, let alone a bad effect, if it's not being broken down by the workers? Wouldn't it just lie there, inert?
No, Andrew. You're missing the point. The workers are in the liver. The Dilantin is still passing into the brain and in excess quantities. That's why it's causing toxicity.

Harry was clearly concerned.

So Dilantin is not so good?
It's good, provided we know what we're doing. Dilantin was one of our earliest anticonvulsants, and it still is a useful medication. But, at these high levels, it messes up your mind. So this is why it's important to modify the status quo.

Does this liver overload happen with other drugs?
Yes, it can, but seldom at a therapeutic dose. Dilantin is one of the few brain drugs with this tiny range between high therapeutic level and toxicity.

Well, Doctor, you tell me my side--effects are due to the Dilantin, and I believe you. But my last physician told me that my side--effects were all psychological.

What side--effects?
My wife told him about how irritable I had become and I told him about my thinking which was just lousy. I could not concentrate and I would do things twice because I had forgotten that I have already done them. I would play a poor game of chess, even though I was a champion. I couldn't focus for long, and worst of all, my kids told me I had changed as a father and not for the better.

And these were all regarded as psychological?
Yes, Doctor. My specialist told me he was not interested in all that psychological stuff. He told me to pull myself up, turn over a new leaf and stop being a hypochondriac.

I took a deep breath. I felt I was letting Harry know a well--kept secret.

You need to understand that when some doctors cannot find what's wrong, they may unconsciously feel intimidated and they attribute the symptoms to the patient's psyche. In other words, if they cannot find what's wrong, then it has to be in your head; it has to be purely psychological. To me the label "psychological" must be linked with several positive diagnostic features: It's not simply the negation of "not physical".
Thank you Doctor for saying so!

My attitude is that this psychological label can stress people out and ironically make many symptoms worse------psychologically! Then this justifies the doctor's diagnosis which has become a self--fulfilling prophecy.
I'm glad to hear this, Doctor.
All I say is, "Okay, we cannot find this, but that doesn't mean that there's nothing there. It means only that we cannot diagnose the cause at this time. For the time being, we have to live with this unknown and if necessary, treat the condition symptomatically. With persistence, we usually have some clues about how to treat it."

Harry wanted to learn more.

(The chapter continues...)

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