Vancouver Meeting, April 1, 2006
Dr. Ross A Kennedy, Guest Speaker
Dr. Ross Kennedy opened the meeting by developing the agenda for the meeting as he went through his list asking the members to vote by a show of hands in what they were interested in.
Under the heading "Topics" he had the following:
- How does BOTOX® work?
- The history of BEB and BOTOX®
- Meige Syndrome
- Injection Sites: the why and wherefore
- Photophobia/Glare/Ageing of and Dry eyes
- Treatment Failures
In creating the category "Words" Dr. Kennedy went on to say that medicine, even though it may not know the cause of the symptoms they still tend to, as he says, "put a word on it". When the medical community does this, he continues, "People assume because there's a word on it that people know what it is. When we talk about these words or labels, apraxia is one of those and dystonia is another, and, it is helpful nowadays because people do not take Greek and Latin in school anymore like they used to, it sounds even mystical".
In the "Words" category, Dr. Kennedy lumped the following:
- Cranial Dystonia
- Apraxia
The last category he termed "Side Effects" and under that he placed:
- double vision, and
- general weakness of the eye.
Dr. Kennedy then began his talk with the category "Words". Words, in general, give us a way to make sense of the way we put things together. If you were to take a needle and connect it to a device, a device that translates what goes on in the muscle, in order to hear or see the activity in muscle, and, you put a needle into the muscle, unless you're dead, there will be something there. Even when you're asleep there is activity in the muscle. Therefore, on your recorder you would get little spikes of information because the muscle would fire off at a different rate. When you went to move that muscle the activity rate would pick up. You would see different spikes; you would hear a sound depending on how that recording device is made. So, if a muscle is at rest and you put a needle into it, there is 'tone' in the muscle even at rest. It is not the same type of tone that people in the fitness world talk about: you are in tone, or, you are buffed or whatever, but rather a technical term for the electrical activity that is in the muscle itself. Okay, so the muscles are always alive, even when you are asleep: there is always activity in them.
Now, there is a Greek word that tells us something is not right. That is the Greek word "dys". You are dysfunctional or dyslexic or whatever. When you connect the word "dys", something is not working, with the word that describes the activity in the muscle; you come up with a word called dystonia. Now, when the scientific community knows something, they can actually describe how something works. When we do not know what's happening we label it. It is like a picture: we are taking a picture of it. And, the way that medicine works is that you get the descriptions of diseases, and, eventually, we work on the cause. If you know the cause it is a better way to describe it. The trouble with these dystonias is that you are looking at a description, which means we do not really know what is happening but we know there is some sort of trouble with the 'resting tone' in the muscle.
There are many different types of dystonia. There is a big one that everyone has heard of called Parkinson's disease. I am not implying that Parkinson's disease and blepharospasm are at all the same thing. But when the neurologist people sort things into categories, they throw all of them onto one side, and they will say these are the disorders of 'resting tone' in the muscle: as opposed to, let us say a disorder of voluntary movement. When a person has a stroke, they have a real problem with voluntary movement but the 'tone' in the muscle should be normal. Now, you can have babies born with overall low 'tone': hypotonic babies. They usually have generalized neurological disorders. Hence, there are all sorts of disorders of 'tone'. When they say that blepharospasm is a dystonia, they are not really helping you. Therefore, when someone says you have a facial dystonia, all they're saying is that your problem is in your face and, it is something to do with the tone. All of a sudden you will start to lose confidence in the medical profession because they do not really know very much. By no means am I putting us down. We are trying to make sense of things but it doesn't really help until you to get to the root of it.
How would you study dystonic diseases like Parkinson's? Some might say it is really a macabre way of studying things. We get hold of people who die and we look at their brains and we look at them with microscopes and, in recent years, we have looked at them biochemically. In people with Parkinson's disease we can actually find local areas of the brain that do not work very well. No one has ever found any area of the brain that is dysfunctional with people who have blepharospasm. No cortical disorder has been identified, and, that would be an area of research, to try to find out where in the brain this disease sort of lives, works or whatever: but there is nothing yet.
Let us follow this lead. If you could discover an area where a chemical is not working, you could try to change the chemical balance and make things work better. Therefore, in Parkinson's disease, a drug like Eldopa or Sinemet, works by altering the chemicals, which they found in that area of the brain not to be working. So, they take the brain of people who had Parkinson's and deduce that the area of the brain that is not working has a lot of dopamine in it, and, if we can raise the dopamine level then a lot of people with Parkinson's will get better with those types of drugs. However, it does not cure them because we do not really understand why the brain gets that way in the first place. But we are not even close with blepharospasm. If you look at what happened with that dystonic disease (Parkinson's), perhaps one day the same might happen here. That is one area for future exploration.
Someone mentioned that they had "cranial dystonia" which could be called upper body dystonia. The question which often leaps to mind is will my dystonia that occurs here going to creep all over me? If it starts here, does it go elsewhere? Basically, no. Sometimes people call what we have, benign essential blepharospasm, a focal dystonia: focal meaning something that is in one area. There is another word for you, 'focal'. There are other focal dystonia and some of them are not so 'focal'. Some of them are in the face and it creeps down to the neck, and, that is where the word Meige Syndrome comes down. It is very arbitrary. What happened, say a hundred plus years ago, a fellow named Meige looked at a bunch of patients and said, well you know they have a twitch in the eyes and they have a twitch in the face, and, he gets his name on it and, he lives forever.
But it doesn't really mean that anyone knows anything about it. I guess there must have been a Dr. Parkinson at one point, but it doesn't tell you anything about the dopamine pathways or the areas of substantia nigra that are dysfunctioning. Perhaps that is a good way to look at it because it really tells us that we do not know anything about it. But there do seem to be focal dystonia as opposed to a general hypotonia, or in Parkinson's, a hypertonia. People with Parkinson's disease have this rigidity in their muscles. These people can voluntarily move but it is not right; there is a problem with the tone. However, we know very little about benign essential blepharospasm.
Well, how do you get blepharospasm? I have seen people who originally got a mosquito bite, it was followed by encephalitis, which did something to their brain, and the end result was blepharospasm. Most of the time there is no indication of a cause. Most of the time it just happens to you, and, when I started seeing patients with blepharospasm in 1985, twenty years ago, blepharospasm didn't exist. You could find it in textbooks, but then there was no treatment for it. No one had the disease; no one identified it. And now here, on a Saturday morning, there are a lot of people with it. There is going to be hundreds of patients in our practice that have BEB but, it is like many things, once you start to identify these cases you can do something for it. People, like the Foundation and the various support groups, will make a difference through their efforts. These all will influence what happens in the course of future research into the actual cause. Personally, I do not see that yet.
So, those are the different words, dystonia, focal dystonia, benign essential blepharospasm, benign means it probably doesn't progress: it is benign as opposed to evil. Some one remarked it will not kill you and Dr. Kennedy retorted not unless you're driving and your eyes are closed. A definition of essential is we need it. Who, of you, needs this problem? Perhaps we should term this as benign 'unessential' blepharospasm. Blepharospasm comes from the Greek word 'blepharo' meaning eyelid. Spasm is self-explanatory. So, you get this long name and it implies that we know things, which in reality we do not. All those words are descriptive terms for what is going on with your problem. There is no hint of actually knowing what is the cause.
An English word, practical, has as its root the Greek word 'praxis', meaning doing something. Hence, the word practice comes from one of the various conjugations of 'praxis'. So, when you practice, you are doing something. 'A' means not. So, 'apraxia' means not being able to do something. Consequently, when someone says I have 'apraxic' thinking, it means you can't think. You would not use that word with 'thinking' because it refers to something physical. The word 'apraxia' is commonly used in neurology to describe a disorder. Apraxia is a neurogenic impairment involving planning, executing and sequencing motor movements.
With blepharospasm, in the early days, namely the '80s, we were putting needles into the muscles, just like we talked about previously, to look at the tone. If you put a needle into the orbicularis muscle that surrounds your eye, you would find spikes everywhere. It would just create static and you would hear that static all the time. If you were to go deeper, you would find a muscle in the mid upper lid that opens the eye called the levator. A lot of the time you'll fight to hold your eyelids open. You will voluntarily order your eyelids to open and you will be fighting this muscle (orbicularis) that is in spasm to close the eyelid. But there is a gap in some people. If you look at people with blepharospasm, you are much more likely to see a droopy eyelid and you would conclude that the eye is finally closed. But even at rest you're orbicularis muscle around the eye is closing and the levator is trying to open it and oftimes you are going to stretch the levator: one muscle working against the other, will cause it to stretch.
Therefore, if you look at the incidence of ptosis, which is a droopy eyelid in people with blepharospasm, it is much higher. What we discovered is that some people stretch that levator muscle and, even after the spasm stops; it took a long time to just get that lid open. This has a lot of significance for some people. You can poison, or, whatever nice word you want to use; your orbicularis with the botox, yet some people still cannot open their lids. This is something to do with the 'toning'. We see, for example, that in Parkinson's disease it is hard for them to get going. Once they are moving they are okay.
However, it is that first starting-up step that they cannot get over and get going. So, if you have an apraxic lid opening, often the terms are used very sloppily, you do not know that you have an apraxia of lid opening until you have totally wiped out your orbicularis: which brings us to our treatment failure. If you have not wiped out your orbicularis properly, do not tell me that you have an apraxic lid opening. But in some people you do get this even though you have calmed down the orbicularis, and, the lid still does not open easily. You can have all sorts of things like droopy skin on the lid, which makes things even more difficult for you. We will talk about the surgery as we go on.
Those are the different words that are used. Therefore, if someone tells you that you have a lid apraxia or facial dystonia, they are really talking about the same thing that everyone else around this room has. However, one little thing is interesting: the interaction between the muscle that holds the eyelid open and the one that closes it. Everyone knows what the orbicularis muscle is and that it is a critical muscle to us. How about the levator? Okay, when we are in an area of medicine where we are still just describing things, anatomy is really helpful to us.
Around your eye, the first barrier you would encounter, after you take off the skin, is a bunch of facial muscles. And they run in certain characteristic patterns: around the eye, the muscle is called the orbicularis. The area in the skull that holds the eye is called the orbic and some call it the orbicularis orb, and, because it is around the eye, it is the orbicularis oculi. There is an orbicularis oris around your mouth: a ring muscle. If you have a ring muscle that contracts over time like a purse string, you're going to create pull and, that is the origin of 'crows feet'. Your skin is leather and basically over time that orbicularis will crease the skin.
If you take off your orbicularis muscle, in the middle up top, is a muscle of much interest to eye doctors called the levator. That muscle is underneath the orbicularis and in the middle of the upper lid (see next Figure). For most Caucasian and many Orientals, part of the levator muscle branches through the skin and creates the fold of your upper lid. Just to give you some perspective, some Orientals do not have it and the upper lid is very flat; but that is the muscle we are talking about.
The levator muscle becomes important when we talk about side effects, for example, the how and why of dry eyes. That is your basic anatomical setup. Now of course you go over here and you get the frowning muscles and that is what makes a lot of doctors a lot of money that is where BOTOX® has sort of migrated to with the levator-fold and the crow’s feet and other spots there. We will come back to that anatomy at some point in this discussion.
Meige Syndrome is really a catch bag of symptoms. The textbook of medicine has a totally different definition than the eye books because it's not really a definite word. Sometimes this syndrome will reference the neck but it is not torticollis, which simply means a twisted neck. If you have involvement with the platys muscle, which is where that little line stands up in your neck, along with abnormal movements in the rest of the face, you call that Meige Syndrome. Dr. Meige originally described the neck as being involved too. There is going to be an overlap between people who just have the eye muscles involved. Why you would just have the orbicularis involved, I don't know. It does not make sense really.
One topic that I would like to talk about is hemifacial spasm and benign essential blepharospasm. People with hemifacial spasm have half their face twitch. Benign essential blepharospasm has to originate back in your brain, which sends out information to your muscles, because it involves both sides more or less equally. Hemifacial spasm is the involvement of one of the peripheral nerve routes, which carries information out. Therefore, you get a twitch as well. Both conditions look very similar. Some people have unequal blepharospasm and, finally, the muscle itself can writhe around. We treat people with all these different things exactly the same and that shows the non-specific nature of BOTOX®.
This would be a good time to talk about sites because we have already, as part of our words theme, delved into anatomy. In case you are interested, we (medical community) are revealing our secrets about how this is all very simple. Botulinum toxin, originally, was invented not at all for this disorder. A friend of mine, Alan Scott, in San Francisco, invented botulinum toxin A. He was a paediatric eye doctor like I was originally. In the mid to late 70's he was looking for a drug, which would correct kids who had crooked eyes: strabismus. That was his primary interest, and, he looked at many different drugs. He looked at local anaesthetics, which would work for an hour or two. For example, if your eye is turned in, he would inject the inside muscle and the injection would relax the muscle out but it would soon go back again. Scott wanted a drug that would work for a longer period of time. He injected absolute alcohol into eye muscles and destroyed eye muscles. That works but the eye still goes out. He wanted something that was sort of between an hour and two and not permanent. Scott had an acquaintance that worked for the Chemical and Biological Warfare Branch of the United States Government, and, that fellow suggested botulinum-A exotoxins. This bacteria elaborates five different toxins, one of which, the A toxin, dilates easily. Scott worked with that and found that it was very characteristic in weakened muscles. Clinically, some of the people who get botulism poising from a variety of means, developed permanent changes to their eye muscle balance.
Although BOTOX® works for this audience, you inject it today, nothing happens, it peaks in five to seven days, it lasts three or four months, and, then it goes away. Some people, however, end up with permanent changes in their eye muscle balance. The eye muscles are very special unlike your orbicularis muscle. If you weaken an eye muscle, an inside one for a period of time, the outside muscle will pull the eye out and you'll stretch the inside muscle resulting in a physical change in that muscle. According to how the eye muscles work, the effect can be permanent, and, that was what he was looking for. Initially there was no money for the drug. Alan wanted a drug, which would correct crooked eyes and it was not all that good. It only worked in sixty percent or so of the time. So, he arranged that eighteen of his Fellows, people who trained with him over the years, to inject the drug, which was under the Food and Drug Administration Act in the United States. There is a provision for what is called 'orphan drugs', which don't require the same type of money and intensive studies that other drugs require, and, all you only had to prove was that the drug was safe. Everyone knew that BOTOX® was safe including the government who had the drug for years for warfare purposes. The government knew what they had; yet he needed people to inject.
From 1984 to about 1994 we injected people. Dr. Stephen Kraft was one of his Fellows. I was one and Dr. Jean Carruthers, who was my associate for many years, was also one of the Fellows. So we injected people with BOTOX®. We did kids with crooked eyes (strabismus) because that was part of the protocol, but we needed volume. Scott had seen a few patients that had this twitching disorder called blepharospasm and asked if we could get a few patients that way. Well it turned out, of course, that there were masses of patients with BEB and, that is where the drug came from. In about 1995 it was hijacked and Allergan bought the drug to develop for cosmetic purposes and stuff like that. As a side effect of injecting for cosmetic purposes, we discovered it was good for migraines, trigeminal neuralgia, cerebral palsy, and constricted muscles: the list goes on. This, then you might say was the origin of BOTOX®.
Basically, pure and simple, the only thing botulinum toxin does is relax the muscle. When you come to treating a patient with blepharospasm, the question is how can we relax the muscle without causing trouble. If you look at the package-insert for BOTOX®, there are fifteen lines of fine print of side effects. There are no side effects to botox. It is all the right effect but somehow it has gone wrong. Therefore, let us talk about the orbicularis muscle around the eye that seems to be jamming your eyelid closed. Well, what if we just put botox through the whole thing? When you inject botox it spreads about 3 or 4 mm in and around the injection spot. You inject the toxin in a specific spot; it is a liquid and although we do use a small amount it still manages to defuse into the muscle a bit. It does not get absorbed into your body, so you do not develop antibodies. People after 1996 do not develop antibodies. It is like dropping a little bomb on the spot: it just knocks it out. Therefore, if I take enough BOTOX® and inject it into a muscle, I can knock it out. It works. BOTOX® does what it's supposed to do one hundred percent of the time, and, we will talk about treatment failures in a bit.
The question of "antibodies" is somewhat controversial. There are not a lot of people doing research into botox. Early on Alan did his work with monkeys and, again, you can immunize yourself if you inject it. He immunized himself: injecting it into himself intravenously. That is dedication. It is one thing to do things to patients, and, it is another to do it to one's self. So, Scott immunized himself. Bacteria-wise, clostridium botulinum and clostridium tetani, which is tetanus, are both neurotoxins. Tetanus, no one ever sees it anymore because we immunize everyone that gets it. Neurotoxin means dealing with the nervous system. You can immunize yourself against tetanus and you can immunize yourself against botulinum. There is no question that you can immunize yourself. I have some patients in my practice who have had BOTOX® now for 20 years or more. It is a long time.
Now, what is going on here? There were some people that developed antibodies to BOTOX®. When you make BOTOX®, you buy the stuff from the Federal Government of the United States. It comes in a vial and you plug it into the machine, and with it we used to use human serology, which is a blood by-product, just as a protein, mix it together and freeze dry it: that was it. From what I understand, some people, before 1996, developed antibodies to the other components of the molecules. In a bottle of BOTOX® you have 100 units of this. There are fifteen nanogram, I forget the exact number, that is, fifteen followed by nine zeros grams (fifteen billionth of a gram): it's that small. Most of the remaining material was something else just to 'bind' the material together. And it was from that 'binding' material that the antibodies came from prior to 1996. But you can, in theory, get antibodies to the botulinum molecule itself. However, from what I was told most recently there were no cases that they truly documented of a true allergy or true immunity to BOTOX®. Now allergy is different from immunity. You can develop immunity. No one as far as we know has an allergic reaction to the BOTOX® itself.
Dr. Kennedy was informed from some one in the audience that there is a know case of a patient being allergic to botulinum toxin Type A. They are hoping to use botulinum toxin Type B instead. Dr. Kennedy suggested that there might be a question as to whether it is the toxin itself, or, the carrier or filler. Just like people can be allergic to the preservatives used in medicine; like when you get your pill. The person who raised the question in the first place confirmed his suggestion. It was the food dye, the other components, which make up the BOTOX®. It is very, very rare. If you are unfortunate to be in this category then the botulinum toxin Type-B (MYOBLOC®,) is a potential option to the allergy. There is always an exception to the rule, however; in general no one is allergic to botulinum toxin Type-A.
Dr. Kennedy continued to explain about botox injection sites in order to knock out those muscles. If you inject the middle of the upper lid, you will drop the upper lid for three months for sure. That happens on occasion. It is not uncommon for ophthalmologists to send him patients whose eyelid they want to close for three months and they do not want to tape it shut. We will just shoot it with botox and close the lid for three months. Otherwise, they would have to glue it together with crazy glue, which they do sometimes to keep it closed. There are different ways of closing an eyelid to let it heal.
So, you have your botox and your needle, where are you going to put it? In the mid 1980s we started off with five units of botox, and, about as many random sites surrounding they eye. The brow gets involved as well. With each successive patient we do more and more. Therefore, when the papers were published, back in the early years, you came out with a scheme and the word empirical was used which meant we experimented with people. Trial and error sounds bad, so the word I prefer is customization. Incidentally, by experimenting with various sites they discovered on how to get rid of wrinkles.
No mention has been made of how much BOTOX® was given in these sites. We will talk about that later but for now we will start on the complications. You are trying to break this ring of muscle up (orbicularis) and there are other recruiting muscles in the brow and, you say well this is great, let us add more and more and more. As in many things in life, you start adding more and more and what happens is that you start to run into trouble. Well, let us talk about the troubles and we will sort of go over to the side effects at the same time. We talked about doing the orbicularis muscle and how unhappy people are with that. Their spasm is taken care of but they still cannot open their eyes for a couple of months. But still depending on which study you read, one in 50 people, or, one in 20 people will have some effect with it, and, that effect is not always consistent. Some people always are plagued with the inability to open their eyes: there must be something about their anatomy and how it works. Still, some people go along merrily with exactly the same pattern, and, one time they will get it and it is very embarrassing: so we cut the dose down. They will eventually go back to the original dosage and the problem does not recur. We do not know why this occurs. Originally, the syringes were made for immunizing people and we mixed it up in one cc of fluid and that was the concentration we used and the amount we used was 5 units. Now what's a unit?
If you measure true BOTOX®, in a sample, it is not equal to its effect. You cannot tell how effective the bottle of toxin is by its weight because, at the microscopic level, some of that stuff is inactive. In the lab in San Francisco, where it was invented, there was a lady who was in charge of the mice. And she would get a new batch that we had mixed up and she'd take a syringe and she'd inject a bunch of mice and, the dose at which half the mice died was 5 units of concentration. A unit of botox is not measured in milligrams but rather it is a biological calibration. It is very tricky to work with these toxins because the amounts are so small. Trying to put this into some type of scale, let us say you have one to the tenth of minus nine (0.000,000,001) and twenty-two percent of that sample is inactive, you can imagine how difficult it is to work with on a consistent basis: therefore, they calibrate biologically.
We are using units and you will find that five is sort of a round number. A lot of injections are given with 5 units. You mix it up in one test tube, 100 units in 1 cc of saline solution. They will set up half of 1 cc; you can see that on your syringe. It is a very tiny amount. Of course, the bigger the volume you use the more it diffuses the toxin. So, over time, we empirically arrived at what amount (five units) we put into what site. You can do the basic sites, four around the eyes, some in the brow, missing the upper lid and maybe some out in the face. The muscle that closes your eye is not just a big flabby ring with muscle. It is very complicated. When you blink the outer part of your eyelid closes, first like a zipper, and it squeezes the tear-fill over towards the pump that pumps the tears out of your eye. If you go and put too much botox in and around the location of the pump you interfere with its operation. That is one problem: interference. As you age your tear production drops and this is where the blepharospasm is helping you. Your eyes are closed half the time; you do not need as many tears. In the tears there is water-resistant oil. One drop of tear smeared overtop of the eye can be very good. If you have ten drops of tears but they are not moving anywhere they are of no use to you.
With time your tear production drops and your blepharospasm has been helping you because your eye is closed half the time. You are also, if you're blinking excessively, smearing whatever tears you have over the eye as well and, if one interferes with the pump action of the lower lid, all of a sudden you've got a dry eye. If your eyes were dry you would be very light sensitive. All of these things factor into the equation, and, that was the original theory behind why people had photophobia. In one of the early papers the dosage of these specific sites was dropped to two and a half and it was discussed about not doing the lower lid next time. The trouble is, if one does not do the lower lid, how much of that contributes to the orbicularis spasm? When one injects botulinum toxin in there, it is not to paralyse the muscle, like one does with the closed eye: it is not meant to knock its action down to the level where it tips the balance in your face and you cannot open the lid. So, you can see why these doses are very individual. As well, some people have bigger muscles around the eye than others and some are more active. Men require, in general, twice the dosage women do.
This brings us to the topic of treatment failures. It could be you have an immune reaction or a resistance. A true drug resistance would be rare. The biggest reason for a treatment failure would be dose related. And why would that be? Some patients are at 100, 125 units and it may become an economic issue. Once you get out of one bottle and into two bottles, the insurance companies start looking at you. It can be a physician, early on, who is not used to using it, although BOTOX® is much wider spread than it used to be. Sometimes physicians will look at the original papers and do not want to go beyond 25-27 units an eye. Whereas, the more experienced physicians will have one half of their patients above that. As a result, a certain percentage of the patients will fail. We have already talked about the apraxia of lid opening and, if we go and purposely poison your muscle while you have an apraxic lid opening you are not going to be that pleased with the outcome.
Also, there are local factors. As you get older, the aging eye again, your skin gets looser. If you have a lot of loose skin on your lid, just the weight of that along with a stretched levator muscle coupled with a little bit less toxin than maybe one ought to use, and, your lid does not open much. There are lots of little things that can go on in there. We will mention a side surgical treatment, not talking specifically about surgery targeted for botulinum toxin, but a lot of our patients have had lid lifts or blepharoplasty. And it helps them. A blepharoplasty, you just pinch the skin where it is required but usually you take a little bit of the orbicularis muscle with it.
You surgically remove some of the muscles that spasm your lid closed and you are taking some of the weight off of it and, if you think of all the things that can influence that, you check the balance in your favour. Despite the benefits, if you do have the surgery, you take some skin off the lid and tighten that lid with the result that it does not close as well then you can have horrendous problems with dry eyes. Therefore, it is not so simple, in the individual cases, to say why a patient's BOTOX® treatment is not doing what it is supposed to do.
Previously I said that BOTOX® has no side effects and I stand by that, but if a person has dry eyes after a botox injection that is called a side effect, and, in reality, it sounds like a rash with penicillin. It is not like a kidney failure from Motrin; nor is it like liver failure from Tylenol. It is not a side effect in that sense. It is the right effect; it is just not working locally. There are lots of different reasons why it might not work for you. But you are not interested in all that information you want to go back to a normal life. Yet all the different equations are in there balancing things out so it becomes the issue of trial and error or customization. You have to work with the people that are injecting you. The way life works; no one cares about your problem as much as you do. The doctors, on the other hand, are getting paid for what they do and they do care but, it doesn't matter as much to us as it does to you. You should get a copy, we do not do it that often, of where we inject. You keep your own notes and pretty soon you can tell us where to inject. It is not rocket science. You can understand that the only thing we really do is put the needle in another spot. It is not like we have any magic because we do not. If you arm yourselves with that information you can really help the professionals, as long as you tell them nicely.
Earlier on in the research, we were looking for ways to say how we can document the effects of BOTOX®. What we did is ask the patient to keep a diary in order to gauge when next to give the treatment and calculate how long the treatment lasted. We did not know. People would come in and we would have a little spring that went in their eyelids to measure the force of the spasm and we videotaped the procedure. We reviewed the videotape afterwards and counted the number of blinks per minute and recorded the grams-force of the blink. It was not too long into this procedure that Alan Scott asked what does it matter. The patient comes back when the patient comes back. They say when they want the injection. In most cases the people came back at three to four months. Before Heather and Katherine came and worked for me, we got into a little bit of a funny situation where people would just book regular appointments. Everyone was three or four months because when they'd leave the office they'd book right away or they would not get in. But when we left it open, we did find some natural variations; some people go four, five or six months while others are much shorter. Some people are just six weeks, which is odd. And you wonder is it really a recurrence or are they really afraid to go without it, or, whatever?
Let us go back to the question of double vision. Take off the orbicularis and take off the levator and now you're down to the eyeball per se. There are six muscles that affect the eye: one that pulls the eye right in, another right out, one up, one down and two minor ones that tilt. There are threads from the levator muscle, which attach to the muscle that pulls the eye up; that is why when you look up, the eye moves up and the lid goes along with it automatically. Therefore, if you are injected near the levator you are always going to droop the lid. If someone asked me to do a crooked eye, that is, one that is turning in, I can do that easy enough. If an eye is high and I inject the upper muscle of the eye, it is one hundred percent certain that you'll drop the lid down because the BOTOX® hits the muscles in the same area.
The way the anatomy works in your orbic, the inside muscle goes straight back, the outside muscle curves right around the eye and internally. So the outside plate is a long way away from the muscle whereas the inside site is quite close to the medial rectus muscle. So, if you inject near the upper lid you can droop and you can get double vision vertically. If you are too close to the medial rectus muscle the drift will cause some horizontal double vision. If I am injecting the medial rectus muscle, one in twenty people will get a droopy lid. If I inject the lateral rectus muscle, it is more like one in a hundred. Depending on which muscle you're trying to hit, the side effect is the other muscle. If you are trying to hit the orbicularis or levator, the side effect of double vision is part of that. I have had the same effect with the lower lid too where they have experienced a vertical double vision: even in small doses. That is why the lower lid is a much less popular hunting ground than the upper lid and the other ones. Therefore, we can list double vision as a side effect but it depends where you inject the toxin. It is not very common with blepharospasm. I have had one such case.
On the other hand, I have had one or two patients complain of trouble with focusing after a BOTOX® injection. That sort of thing is not supposed to happen but it obviously could because they complained about it. The muscle that controls your focusing is a different type of muscle than the muscle normally injected. The focusing muscle is the so-called smooth muscle or versus striated muscles and the botox is not supposed to affect that type of muscle. Obviously it does something and, as to why, we do not know the whole story. On the other hand, light sensitivity is a side effect and the theory is that you disrupt the tear tone and you get the light sensitivity. I am not convinced that is the whole story. It is the classic explanation. Maybe it is something to do with just the dystonia itself because if you flash a light at a newborn baby it will blink. So it may have something to do with that whole circuit, there has to be something else besides the tear film theory.
At this point Dr. Kennedy was asked if the injection done into the lid was either above or below the eyebrow. His answer was both. It depends on what muscles you're trying to get to. If you take a cross section through the skin of your lid, the skin is right on the surface. The layer underneath that is your orbicularis. There is something called a levator aponeurosis, which is a layer of tissue; there is fat; then there is the levator and finally there is eye muscle. Around the facial muscles in the skin, all you have to do is inject subcutaneously. If you were to speak to Heather, she would tell you that, when they teach you how to perform a subcutaneous injection at a specific site, you must raise a blip. There is a natural space between the two layers because they are not really stuck together and, if you're doing surgery, you can easily peel off the skin. There is sort of a natural plane: a surgical plane between the skin and the deep muscles. Therefore, when you put a botox needle in and your see a little blip come up you know you've got the right space and the result is a very safe injection.
When you're going for an eye muscle you have to know where you are. And that is why with these eye muscle injections we connect it to a little machine that amplifies electronic signal. I observed in one of those cosmetic day surgeries, in Los Angeles, one of the dermatologists using an electro myogram to hit to this layer below the skin. Obviously it was sloppy and totally unnecessary. I mean anyone can inject underneath the skin, you just raise a little blip. Where the injection goes is dependant on your muscle, everyone's face is different. The lid is the popular place to go and the brow is good. A patient related a personal experience of having an injection hit the elevator or levator muscle that lifts the lips and the nose. The result was that she was "crooked" for three months.
Dr. Kennedy answered by stating that he always tells his patients the good news and the bad news about botox: it always wears off. The good news is when you have a side effect that is really bad it will only last until the botox wears off. Another question asked if bruising was ever a normal side effect. Should one have bruising or black eyes as a result of being injected? Dr. Kennedy responded that it does happen. A doctor must pay attention to the medical history of the patient in case there is a history of bleeding in the family. Also, there are lots of little blood vessels around certain parts of your eye and they can be touched. It is unfortunate. It could be the needle or it could be some people are rougher than others. It could be bad luck. It should not happen. It could be as a result of body fat. If you are bruising a lot that could be clotting factors and stuff like that. That is unfortunate.
As a follow-up question Dr. Kennedy was asked if the size of the needle had an impact. Is there a specific size of needle that should be used? His response was that he would never tell you what someone else should do. In his practice they use a 30 or 31. Different brands are certainly better than others. Heather shops around for brands and tries them on herself and other people in the office. In some institutions, like the hospitals, the smallest needle they service is a 25. This question is an issue with some people. Quite frankly the big drive for this comes from the cosmetic side. People, who are paying big money for cosmetic injections, do not expect a bruise. They want a nice slick application.
There is the question of the 'stinging'. For years what was done with the original BOTOX® was to ensure that it was non-bacteriostatic. In other words, there had to be no preservative in the saline we mixed up. That was absolutely anathema. Alan thought that maybe one of the chemicals they used as a preservative would prevent the bacteria from multiplying thus knocking out the toxin. Back then there was a fear of this toxin being so fragile. As it turned out the toxin is really quite a strong toxin. But the package insert might say non-bacteriostatic still because they never change the package insert once it is gone through the FDA, which is now ten years ago. What surprised Dr. Kennedy, two or three years ago, was when the Allergan representative gave his office the brown-topped bottles, that it made a miraculous difference in the comfort of the injection: it just did not sting like it used to. Does it work as well? Well in practice it works just as well. People do not come back sooner, they are quite happy with it. Dr. Kennedy surmised that there are these soft little factors; needle size, brand, and sharpness of needle.
You have all seen the BOTOX® bottle. You mix it up with a big needle, usually you put the cc in and then, if you have the rubber stopper on, you put the little 30/31 gauge needle through the rubber stopper. Every time you pass the needle through you dull it. And the duller the needle is, the lower the advantage. Now, if you use a needle with a hub, you'll notice these come separate in syringes, and you put that together. Every time you drop into that needle you're wasting twenty-five dollars of the BOTOX®: there is that much wastage in the space in the syringe. The smaller insulin needle, 31 gauge, has no dead space. The needle is sharper but it is tiny and you can't possibly get that through the rubber stopper. You have to pop off the rubber stopper. So there are all these little tiny things might make a difference to a physician. And physicians are fairly conservative; they do not like changing things because it currently works so why change it. But there are many little tiny things, which can help and, they make a difference to you.
Another patient stated that they had their eyelid frozen prior to the injections and it works very well for her. "Your eyes stay frozen after" she continued, "and you go and shop and you see everything and it is really marvelous for that, it keeps your eyes open at least for an hour after the procedure… it works very well for me".
There was a time in the mid-nineties when, although the BOTOX® was made in the United States, they could not get insurance. Alan could not get insurance for it, so all of a sudden no one in the United States could get injections. As a result we had mass flights coming up to our office in Vancouver. Dr. Kraft was in Toronto and, since he was in hospital practice, he was limited in what he could do. We had senators and congressman literally flying in to get their botox injections. Some, from Los Angeles, would ask for a general anaesthetic. My standard reply was in Canada we do things a little bit differently. So that was one thing. Other people came in and asked for the ice packs. You can get a cosmetic BOTOX® injection with ice pack and freezing, so that is another way of doing it. The topical cream, either Emla or Lidocaine or Solarcaine can do it too. You simply put the cream on an hour beforehand. Now, how much do you need and do you really need general anaesthetic? From personal experience I get much more punch from the new dilution agent and a smaller needle than I get from the topical Solarcaine and the Emla. Most people accept the fact that there is some pain involved and they put up with the short-lived discomfort. I am not telling you that it is wrong but just asking is it really necessary.
Dr Kennedy was asked to comment on the ability to transport the toxin. He went on to say that there were things, which were done way back when BOTOX® started, that are on the label: the so-called on label and/or official uses of it. Of course, doctors and people experiment with what to do. As a result there is what is legal and official and there is no danger of being sued if you do that. There are things that are commonly done which are pressing the limit but, if it is common practice, then that is okay. Most drugs never get licensed for children. It is not because they are bad for children but no one would ever do the experiment on the child. Therefore, it is used in adult practice for a long time and, as the physicians get used to it they begin to give it to older children and then younger children. Cataract surgery, for example, you did not do implants in children or anyone under eighteen years of age. Now they will do implants in children as young as one year old.
BOTOX® comes as a freeze-dried product. It appears as a white scum on the bottom of the bottle. You mix different types of saline into it. Officially, one would probably still have to use non-bacteriostatic saline, but in common practice we know that is not true. We used to get the stuff shipped up from Albuquerque, New Mexico, and packed in dry ice and we would pick it up at the airport. One time it arrived on the weekend and they did not call us until Monday. The shipment sat at the airport over the weekend and the dry ice was all gone. We thought that we had lost thousands of dollars worth but upon checking we found that it was okay. On another occasion someone actually put some inside an eye and it was not a problem. Not all facts about BOTOX® are made known to the public.
The labeling on the package has changed. It used to be that you would have to store it below zero. Now, they state you can store it at just fridge temperature. In theory, the fact that it is frozen or freeze-dried, nothing should have to be done. However, it is best to follow the directions on the package. Personally, I think that the dry ice doesn't seem to be necessary. Transporting it around in a box without refrigeration for a period of time is probably safe, but I do not know that. I do not want any of you to press the limit. We store it in the fridge in the office. Once you mix it up, the manufacturer says you must throw that out after four hours. The concern here is both effectiveness and sterility, depending on who is mixing it, and who is administering it. We know for sure that it does deteriorate over time. Different people have unfrozen it and re-frozen it. It is hard to know because no one has experimented in this area: no one has actually done an official trial on it. It seems to have some effectiveness after we do all of this but we know it is probably not good. It is definitely not recommended that you save your own bottle for four months simply because its effectiveness drops off, and, when you inject it, you have no idea what you put in there.
Dr. Kennedy was asked what he meant by "mixed up". BOTOX® comes freeze-dried in a bottle. And when you get to the doctor's office, he will mix in saline with it. And that is the one that he was talking about when he mentioned 'stinging' earlier on. The different dilutants that go into it often cause the stinging. Once it is mixed up it is a totally different chemical. It starts to degrade. You definitely do not want the mixture to separate out again. You could probably keep the mixture in the fridge for a while. There are a lot of drugs we mix up, like penicillin and steroids that we keep in the fridge for a little while. Keeping it for a long time in the refrigerator is probably not a good idea because when you mix something up, even sterilely, there is always some contamination. So, you will get a slight increase in risk of contamination as time goes by. The company says you must use it within four hours; after that you throw it out. The effectiveness is dropping over time but probably not a lot.
Anecdotally, people have shown that they have mixed up a solution, and, despite the fact that it was out of the fridge for a week it is mistakenly used to inject a patient who seems to get an effect. No physician would do that on purpose but I'm glad they have published a paper that states it is probably still effective after a short while. The one or two days that it is in the fridge mixed up, is standard practice; three or four days is probably not a bad idea. However, several months are not a good idea. Essentially it comes down to the whole idea of how you run your practice. If British Columbia's PharmaCare covers you, you can pick your day within limits: you can come in with your bottle and we will mix it up for you. If you are paying for it, then a bottle of BOTOX® runs anywhere, retail, from $365 to $385 Canadian, something in that area. The price will be different in the various provinces. The American price is about $400 U.S. The Japanese price is $700 US dollars a bottle. Different countries will negotiate the price with the pharmaceutical companies in that country. The actual cost of production, for a drug, is all up front. You spend your millions and millions of dollars up front and, the actual cost of making the drug is fairly tiny.
The up-front costs are research, development, the clinical trial and marketing. After so many years, whenever the patent expires, and the generic pharmaceuticals, your Apotech, Pharmanova, and so on, get to manufacture the drug the cost to you comes down. We sell mostly whatever is needed for the patient. If someone has PharmaCare coverage, you bring your bottle and that is great. If you do not, then we'll buy it and we'll mix the bottle. We tend to lump patients together; for example, Heather will work on certain days and I'll work on certain days and we try to gather all the botox patients together on those days. But if you are paying for yourself then we'll sell you part of the bottle. The per-unit cost charged to the patient is based on the mixing, the number of syringes used and the wastage obtained from partial bottles and various other factors. Different doctors may calculate their per-unit cost differently and charge on other cost factors. However, if you are covered by the provincial medicare programme you are fortunate.
Dr. Kennedy was asked if doctors use a patient’s prescription for somebody else if there is some left over. Would physicians be allowed to do that? Another patient from the audience stated that because they are over 65 and they are getting it for free they ask that younger people follow them so that they get the benefit of the remaining bottle. Dr. Kennedy confirmed that very often that is what happens. The other thing that happens is based on timing. His office staff used to have, and this is going back a period of time, a buddy list where, in a bottle of a hundred units, they would pair up two or three patients. As the volume of patients grew this was no longer easy to do, also, in our province the PharmaCare coverage has changed quite a lot. One used to have to be over 65 for everything to be covered; now you have a deductible and a lot of things are covered.
Another patient wanted to know why ophthalmologists do not know about our problem or disease. Why do we have to go through several of them before we are correctly diagnosed? She then asked if it was due to a lack of information, because if that were the case, the patient would be glad to go back and explain what she now knows.
Dr. Kennedy felt that it would be a very good idea if it were done in the right way. No physician can know everything. If the truth were known, prior to 1984, blepharospasm did not exist. It was a non-existent disease. It had been rarely described and Meige put his name on it but, other than that, no one knew what it was. In the late 80s and early 90s we had patients come in and say I've had this condition for 20 years, and, each injection would become a huge ego boosting experience because the patient would really appreciate what you had done. People are no longer going 20 odd years before they know what they have. I have patients that have had BEB for two or three years. The patients are younger because people are recognizing it sooner. Harrison's, which is a 2000 page medical textbook that has all the diseases in it, has about four lines on blepharospasm. So, the chances of a new medical student actually knowing anything about the disease are slim. Exposure to the disease is the major way of finding out about it.
But you can do it. You can do it right. You can say listen, over time, these have been my symptoms and the treatment is doing this for me. I thought, for the next person you saw with this disease, this information might be helpful to you. And the person who would be most receptive is the lady at the desk: the nurse. The nurse will say okay I have seen this before. I am not faulting the doctor; physicians may react the way they react and that will depend on their personality. But you will help everybody by doing that. And that is how education occurs right? Groups like this one will help drive up the awareness: it is politics right. The Heart & Stroke Foundation and the Cancer Society are all great things because they have driven up the awareness. And people complain and say well the AIDS budget is this and the actual problem in the population is this. This disease has this but no one pays any attention. My disease is focal dystonia and it gets no attention; yet 4 % of the population has it. And that is politics and that is the way life works. And so you're raising the political awareness by doing that and you're going to help probably five people be diagnosed earlier by doing that.
A patient wondered why blepharospasm was a disease rather than a condition. She always thought that a disease was something you caught. Dr. Kennedy’s response was that it is a labeling issue more than anything else.
Another patient commented that it was odd but her Vetenarian knew what she had and he said that animals get blepharospasm. Treatment depends on finding the underlying infection that causes it and, when they do find it, they get 100% results out of animals.
Dr. Kennedy used this as a segue into his discussion on other treatments for blepharospasm. You can poison the brain and stop the brain from sending out these impulses. So if you put the patient to sleep with a general anaesthetic, the blepharospasm disappears. So, there is a treatment for blepharospasm but that is stupid because one cannot function. Therefore, the issue is not whether you can treat a problem but whether you can treat the problem so that the patient functions properly. You can get sedatives, Valium, for example, early on, it can stop the blepharospasm to an extent but the patient is asleep. Not good, so let's move down the list. What about Tegretol, one of the anti-seizure drugs? Well, if you can give a high enough dosage, it will calm down the twitch and put the patient into a coma. Artane, one of the early anti-virals will slow down blepharospasm. If things are not working with botox I send my patients off to Dr. Joseph Tsui. He loves these types of things, and he will try the drug and then report back. There are certain types of drugs that were classically tried to poison the central system and calm it down but they do not work very well.
You can attack the nerve branch. When I was in residency I saw people rip out the nerve endings to the eye and that would work for two years and fifty percent were back and the spasm was worse. So if you cut the nerve completely, you droop the face so that is no good either. Therefore, botox, which disrupted the flow between the nerve and the muscle, is helpful because it is short, and, you know it has very few side effects. That is why it is used; not that other things do not work. Now a fellow in Utah, Dr. Richard Anderson, we talked about taking the excess skin off the upper lid. If you also take the underlying orbicularis muscle, you will decrease the twitch: it is not a magical solution. The trouble with that type of surgery is taking out the right amount. In my opinion it is not science but rather an art. If you put in a lot of botox and totally paralyse the face you'll stop it, but imagine the side effects you'd have. We talked about the side effects you get from even having a little bit too much. So if some fellow goes and rips out all that muscle, it is permanent, it is gone, you can't get it back. Dr. Anderson has built a whole career around doing that type of surgery. I have sent probably three or four patients over the years to him to have the surgery done and they are delighted.
Dr. Kennedy was asked if there was a chance that the muscle regenerate and his reply was no because once the fibre is gone it is gone. He did mention that other muscle fibres could hypertrophy or grow. Dr. Kennedy went on to say that Dr. David Jordan, in Ottawa, trained under Dr. Anderson and he performs the same procedure. At this point Dr. Kennedy was informed of Dr. Yasser Kahn and his success in treating members of the Toronto Support Group. Dr. Kennedy was also made aware that this procedure, performed by both Doctors Jordan and Kahn, was covered under the Ontario provincial medicare (OHIP). Any one who enquires about physicians that perform this procedure, known as a myectomy, both names are given. It was also made known that both doctors ensure that botulinum toxin has completely failed before recommending the patient undergoes a myectomy. With this exchange of information, the presentation was ended.
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