BEBCRF Support Group Meeting – Toronto, September 30, 2012
Harmeet S. Gill, MD, FACS, FRCSC
I want to first thank you as members of the Foundation, for providing us with a research grant that allowed us to finish a study that looked at the long-term effects of botulinum toxic. We presented the study, it won an award, and, it was published in the Canadian Journal of Neurological Science.
People from around the world, on occasion, will e-mail and tell us that they have referenced our paper in their recent publications; so, I do believe that this paper has really been helpful. As a Healthcare Professional I would like to thank you for your contribution.
In terms of other projects, one of the big things is to improve the awareness of this condition, and, I know it is one of the society's mandates as well. Also we did publish a paper in the Canadian Family Physicians Journal, whose ongoing theme is to help General Practitioners to identify different conditions such as keratoconjunctivitis, facial myokimia and blepharospasm.
In the past two years I was at the University of California, San Francisco, doing some oculoplastics and I had the opportunity to work with world-class surgeons and preceptors who treat a lot of patients. As you know there are different types of therapies but at the end of the day, injections of botulinum toxin, and for those patients who are not responding, surgery, in the form of a partial myectomy, are the most reliable.
Now the reason why I wanted to present this paper was because a few of the surgeons that I was working with tried a drug called Ritalin. Ritalin is a drug that you may or may not be aware of. We give it to children who have Attention-Deficit Hyperactivity Disorder (ADHD) but I thought it would be valuable to talk about this pilot project for two reasons.
First of all, it introduces the idea that there is still alternative pharmacological therapy that people are investigating. Secondly, because I think as patients, it is valuable for you to understand some of the anatomy and some of the biochemistry and neuro-physiology related to this condition.
Having said that, I have myself have never prescribed methylphenidate, which is Ritalin's generic name. So, I am not saying you have to go out and convince your family doctor to use this but, it is important to keep in mind that, if you are not a surgical candidate and the toxin is not sufficient, it may be something just to think about.
Alternative therapy in the past fifty years has consisted of anti-psychotics, anti-anxiety drugs, stimulants, sedatives, anti-conclusive and many more. All the literature shows that they only provide partial relief.
Now this pilot study was done by Price KM, and colleagues and it is called "Can methylphenidate objectively provide relief in patients with uncontrolled blepharospasm?" Not only did they look at subjective measures, where you ask a patient if he feels better but, also at objective measurement of muscle contractions using surface electromyography to measure surface muscle contractions. Now that posture when you are talking about the circular muscle that surrounds the eye, the orbicularis oculi, causes eye lid closure and that is what we are really talking about here.
Now we know the condition affects women more than men. It usually presents later in life. During the fifth and sixth decade is when it is usually diagnosed. We know that the delay for that diagnosis is typically five years or more and this delay in diagnosis generally makes it more severe. Secondary causes, spastic activity of the eye lids, like dry eyes and ocular surface disease are important to think about particularly with people who manage a lot with dry eyes. Not all of them have blepharospasm.
The reason why blepharospasm occurs is because the actual reflex is not working the way it should. Now the spectrum of the disease is from frequent blinking all the way to functional blindness, which is where patients cannot open their eyes. You cannot function on a daily basis until it is treated. The best way to think about this condition is as a really hyper, excitable blink reflex and the blink reflex is vulnerable to some kind of trigger. All people have their own individual trigger in the environment such as light, being exposed to wind, and dryness of the eyes. That trigger causes a blink reflex to begin in a very aggressive way.
In the blink reflex there are two nerves that are involved. The trigeminal nerve, called cranial nerve 5 (CN5), innervates your forehead and your face. Facial sensations are picked up by one of its many branches dispersed throughout the face and one branch goes specifically to the cornea on the surface of the eye.
So, if you are chopping onions or you are exposed to some stimulus, the way your eye protects itself is via a reflex. CN5 senses the potential danger and a second cranial nerve, cranial nerve 7 (CN7), initiates the reflex movement. CN7 is also called the facial nerve because it is connected to all the muscles of the face. Whether we are raising our eyebrows, keeping our eyes shut or smiling, all of these actions are the result of the facial nerve. All we have here is a normal reflex where CN5 is giving a signal to CN7 and you are closing your eyes very quickly. That is what a normal reflex does.
Now what controls the reflex is various centres in the brain. It is not just one specific centre but rather a circuit. It is sort of like an electrical circuit. It is complex and, not totally understood. We are working on it and gaining more knowledge about it as time goes on. We know that the basal ganglia is involved and that the basal ganglia is crucial to the coordination of the whole body. Patients that do have Parkinson's and other disorders, or, that have tumors have demonstrated that the basal ganglia is very important for coordination: but it is not just there. The brainstem, midbrain and cerebellum are all centres making up this malfunctioning circuit.
In blepharospasm why is the blink reflex more excitable? The neurotransmitter called dopamine seems to be at the centre and it ties in a lot of different concepts. First of all, studies have shown that dopamine concentrations in these centres are decreased. There are low levels of dopamine within patients with blepharospasm and this is partly what is making the blink reflex so vulnerable or excitable to the environmental triggers of light or dryness. Our normal aging process further exacerbates the problem because of the progressive loss of dopamine in the substantia nigra, and, for blepharospasm patients this normal decrease makes the blink reflex even more excitable.
Ritalin or Methylphenidate is not a new drug. It was made in 1948 by Novartis. It became popular not so long ago in the 1990's because the Attention-Deficit Hyperactivity Disorder (ADHD) was not accepted as a real illness until recently. The recognition of the disease as a clinical entity is when methylphenidate became more and more popular. Ritalin is a psycho-stimulant drug. It was approved by the USA Federal Drug Administration (FDA) for ADHD. It is also prescribed for postural orthostatic tachycardia syndrome and narcolepsy. Its off-label uses are for lethargy, depression and obesity.
Now the question is why a stimulating drug would be helpful for a disease that is already hyperactive. Just thinking about this question helps one to understand what is going on with blepharospasm.
Evidence supports that hyperactivity is because the regulatory control of your blink reflex is actually an inhibitory type of a mechanism. This means that one would normally be "blinking", for example, all the time unless something in the brain was inhibiting that facial nerve. The lack of inhibition to the blink reflex is a good way to understand why your blink reflex is so hyperactive - you do not have the "off switch" which is dopamine. This is an over simplification, but this is why researchers are thinking "why you would not just increase dopamine".
It is not simply about dopamine, there are other neurotransmitters that methylphenidate effects. The thing with any drug is that, if you are going to have an effect, you are also going to have side effects because it is not that precise. It is going to hit all these different pathways. Norepinephrine, for example, releases adrenaline and you are going to feel jittery. To a lesser extent, serotonin, which will affect your sleep pattern to the point of insomnia as well as glutamate. All of these are involved in the inhibition of these pathways. Dopamine is the "off switch" to hyperactivities.
How does the drug Ritalin work? Its mechanism of action is that whenever we have these neurotransmitters floating around, our brain tries to maintain a concentration by balancing the production. The word that they use is "uptake" to indicate that the levels are being brought back down. So, what the drug Ritalin does is it blocks the uptake of the dopamine and this increases its concentration. Hence, the production factor is working along but the uptake, the disposal part of it, is stopped by this methylphenidate.
It also stops the uptake of norepinephrine so there will be more adrenaline in your system. That is the flight or fight type of activity. We also know that this suppression of the uptake of norepinephrine increases the amount of dopamine in the system. However, this increase of norepinephrine gives you some side effects.
The question "Why just not increase the dopamine?" comes to mind. With Parkinson's it is not a related disorder. It is different in that it is more of a degenerative disease and they do treat patients with L-Dopa. The problem with high levels of dopamine is that there is a disease that we all know about called schizophrenia. So if you look at adolescents who are very high in dopamine, they become psychotic. You cannot have high levels of dopamine. It has to be within a range of normal activity. Too high and too low gets you in a lot of trouble. So psychosis is something to think about with these drugs but, it is not very common with the dosages that are clinically usable.
Ritalin has a very long list of side effects and some have already been mentioned. Abdominal pain, for example. When you are in a fight or flight response you are not going to be eating. Your stomach is not going to be getting ready to have food but rather you have this abdominal pain and loss of appetite. You can have angina because your heart is pumping so fast. You can have a change in pulse. Your blood pressure can change. You can be dizzy and have headaches and a dry mouth.
There are contraindications. Patients who are already taking antidepressants that are already manipulating neurotransmitters in the brain will not want extra drugs on board because they there are interactions with these drugs. It is also potential for liver toxicity and this is not unique to this drug. Many drugs are either metabolized by your liver or by your kidney. This is a contraindication for lots of drugs.
What was the rational for the study? Why even use this drug. We talked about anatomy and the neuro-chemistry. There were some anecdotal reports, which means that someone just tried it. They tried it on a patient and it worked and they published it. So, there were case reports or anecdotal reports that showed methylphenidate was effective. In addition, a lot of physicians tried this with Parkinson's disease. There are a good deal of case control studies that also found that it was affective. The authors of this study feel that both botulinum toxin and eye-lid myectomy are the "gold-standard" but neither target the problem at the brain level: the neurologic blink circuit level.
Patients, that were not candidates for surgery or did not want surgery and were not being affected by the botulinum toxin alone, were asked if they wanted to participate in this study. This is not a randomized comparative study but is one where patients were asked if they wanted to try this drug and those who said yes were enrolled. They have seven patients.
Now, those patients saw their family practitioner and made sure they were eligible to try this drug and they were all fine with that. Seven patients with BEB who were already being treated with botulinum toxin and long-acting Ritalin were recruited. They received the Ritalin after their symptoms had returned. In other words, after your six to eight week mark, when you are ready for your next botulinum toxin injection. They told the patient that they were not going to get the botulinum toxin injection but rather the Ritalin. Patients were video monitored and underwent surface electromyography (EMG) to look at what the muscles were actually doing.
They did this before the patient received the treatment and two hours after the Ritalin administration. So, after two hours is the onset of action for this drug and a long acting dose form was used but, in terms of the purposes of this study, they looked at that precise point of time two hours after taking the medication.
In addition to the video monitoring and the electromyography patients were asked how do you feel before and after the treatment using a previously validated disability scale. The result is that the mean voltage of the EMG was lower in 13 of 14 pairs of eyes (7 patients) after administering the Ritalin.
For the right eye the voltage decreased by fifty percent which is quite significant within just a two hour mark. The left eye was less than thirty-one percent and the functional disabilities as well were significantly lower after taking the medication.
Again it is a very small study. The authors did suggest that they have enough from the study that we should study a randomized control trial and, my understanding is that these people are working on that. It takes time, and, a randomized control trial is the highest form of evidence where you take half of the test group and you give them a drug and the other half gets a placebo. Then you look at the results and no one knows who got what and, at the end of it, you find a significant difference it means that the drug actually works. An even higher quality study would be to "cross over", that is where the half of the patients who didn't get the drug get it, and, the first half who originally go the drug now get the placebo. That is the highest quality of randomized control trials.
And that is sort of something that we will look at in the future. The purpose of this presentation is not to go out and get Ritalin, for it does have side effects, but it is to think of these concepts and to understand your condition a little bit better. It is a normal blink reflex and dopamine seems to be at the heart of it.