ILLINOIS NEUROFIBROMATOSIS, INC. – FALL SYMPOSIUM

Hamburger University, Oak Brook, Illinois

October 22, 2005

Workshop presented by Dr. Derald Brackmann

Good morning. It’s a great pleasure to be here. I’m from Illinois actually. And so, when Kim called and said would I come, I accepted wholeheartedly. I like to come to Illinois in the fall. I was drafted during the Vietnam era and was sent to California, and by that time I had already been married several years and had a baby, and we loved the California lifestyle and weather. And so, we stayed and have never come back, at least to live. I do get nostalgic, though, in the fall. I tell people that I miss Illinois in the spring and fall. Last year it was October 28th and April 15th! The falls can be very short, as you well know. But I do miss Illinois in the fall.

But I really miss the people. You know, the Midwestern people are just the heart of America. So, I do miss that part of it. I still have family here, so it’s always a pleasure to come back and visit.

I asked Kim this morning, “Aren’t we getting things out of line a little bit? Nf-1 comes before NF-2.” And she said well, it didn’t make any difference. So I guess it doesn’t. But when I was in medical school at the University of Illinois here in Chicago. We thought it was the same disease. It was thought to be neurofibromatosis and then there was a central form NF, which has now become known as NF-2, and a peripheral form, which was at that time called the peripheral form of NF. And so, not until more recently when the genes were discovered was the difference defined. It’s really not very much connected in term of genetically or really in manifestations. But nevertheless, the marriage occurred early on and has maintained itself. And many things are similar in terms of problems that occur. So, I think it’s fitting that NF-1 and NF-2 stay together, rather than becoming completely divorced.

What I am going to talk about this morning is just a little bit of an overview of NF-2. I’m actually looking forward to the NF-1 talk. I know very little about NF-1, so I’m really looking forward to learning more about that. And then this afternoon we’ll get into more of the specifics of treatment, surgery, and so on. But this morning I’d like to give you just a little bit of an overview of NF-2. NF-1 is a lot more common than NF-2. I think NF-1 is what, one in every three or four thousand, as I recall, where as NF-2 is one in every 40,000 live births. It doesn’t respect race, religion, ethnicity. It occurs equally in all groups. The age of diagnosis Kim already mentioned, about age 22 is the average time of diagnosis. We hope to change that a lot by doing early screening and perhaps now with genetic testing. But currently the tumors don’t manifest themselves even though they are present. The tendency to develop them is present from birth, but it isn’t until about age 22 when the average diagnosis is made.

Family history—and I think this is the same for NF-1, but I’m not sure. I’ll be anxious to learn. Only 50 percent of people with NF-2 have a family history. Like NF-1, I believe it is a dominant gene. In other words, there are no such things as carriers. You know, the –maybe I ought to go back a little bit and talk a little bit about genes and what they are and who they are.

By the way, there’s an excellent little summary of the genetics of NF-1 and NF-2 particularly in your handout, which is very good. I read that while I was waiting. Actually it’s excellent. But genes control the way cells in the body act. They determine every characteristic of the human and how the cells act. Now in the case of NF-2, what occurs when you have a –either a mutation when it develops spontaneously or if it’s inherited, the gene that you inherit from your parent with NF-2, has an absence of a gene on the long arm of chromosome 22, which acts as a tumor suppressor gene.

You know, all cell growth in the body is regulated by genetic factors. In fact, probably cancer and all tumor growth is due to an absence of a suppression of what keeps those cells from growing out of control. So, in NF-2 you have an absence of a suppressor gene on chromosome 22, which then allows schwann cells to grow. So, you either spontaneously mutate that, which means that in half of the cases there is no family history, and this occurs as a freak of nature. And in the other half, if it’s inherited, then, you know, for—if you have one parent who has NF-2, remember each parent contributes one set of genes for the offspring, for the infant. And so, if half of them—and this is a dominant gene. So each person with NF-2, you have two copies of the gene. Only one of them has the NF-2 deletion. And so, when you have, say, four children, each of those children would have a possibility, a 50/50 chance of having that same deletion. So, you would have a 50/50 chance for all of the offspring to have NF-2.

Now I’ve had families where there are three offspring and all of them have it. I’ve had families where all three children did not have it. So, it’s like flipping a coin each time. And if you flip a coin only two or three or four times, it may come all come up heads or it may all come up tails. If you flip a thousand times, theoretically it should be 500 each. But for each pregnancy or each child, if you have NF-2, you would have a 50/50 chance of having that particular offspring have the gene and developing the symptoms of NF-2.

One question that’s often asked of me is how do you know – you know- NF2—and again, I’m sure NF-1, too, has a great deal of difference in the way it manifests itself among different individuals. That’s called the phenotype, the way it develops in individuals. I have patients who first develop bilateral acoustic tumors in their 70s, judging, obviously a very mild form or manifestation of NF2. The most severe case I have ever seen was a three-year-old child who had a tumor on every cranial nerve in her head at the age of three.

And then you have everything in between. You have some people who have only bilateral acoustic tumors, other people who have multiple spinal tumors. So it manifests itself very differently in different individuals. It tends to be along the same pattern in offspring as it is in the parents, tends to be. There are some exceptions to that, but that would be a generalization. When people have a spontaneous mutation, , in other words, no family history, then we have no idea what they’re going to have because they’re sort of , they’ve done it on their own and they are setting their own precedent. They’re setting their own course. We don’t have a way of knowing what their likely clinical course is going to be.

Now you’ll read in there that the gene for NF-2 and NF-1 too, have now been discovered. So it is this deletion of a tumor suppressor gene on chromosome 22 which is the defect which results in the clinical manifestation of NF-2. That has been or can be identified in about two-thirds of patients. And the question now arises about genetic testing and so on. It is easier to detect the gene in tissue. So, if you have had surgery where tissue has been taken, it’s easier to detect the gene in that tumor tissue than it is in the blood. So, if you are interested in pursuing genetic testing, and there’s pros and cons to that which you should discuss with a geneticist, a genetic counselor. if you are interested in doing that, it’s easier to detect the gene in tissue than it is in blood. But even then it is not a hundred percent affective.

So, people say, well if it can’t be assured if I have it, why should I do it at all, which is a good point. And some people choose not to do the genetic testing. But if it can be identified in the tumor, which occurs in about two-thirds of the patients, then it is fairly successful in detecting it in the offspring. And this may have implications of doing very early testing so that you can detect the tumors early because we feel that if the tumors can be detected early, they may be removed with the possibility of hearing preservation, which occurs—hearing loss virtually always occurs as tumors become larger. So it may have implications for early detection.

But on the other hand, it’s not one hundred percent. So, still we recommend doing MRIs at a very early age. Age six is usually when we start doing MRIs in children to detect the tumor. One new thing, I’ve not had a patient do this yet, but it is apparently possible, and there’s a whole bunch of ethnic and moral issues related to this, but if you know the gene, if the gene has been identified in a parent, you can do in vitro fertilization of embryos and detect the gene in the embryo. And this has great implication, of course, in—prior to implantation of the embryo so that theoretically you should be able to select only embryos that do not have NF-2 for implantation, rather than taking that 50/50 chance that an offspring might have NF-2. Theoretically you should be able to select an embryo that does not have the NF-2 gene deletion. And so, you could be assured that that offspring would not have NF-2.

Like I said, that raises a whole bunch of ethical, moral issues and so on. But that is something that I think we’ll be seeing developing in the future. So it’s a whole new—the whole field of molecular medicine is new and exciting. It’s going to have great implication not only for these diseases but for cancer and many other diseases. You know, there’s a great tendency for certain types of cancer to develop. And you can do genetic testing on offspring of people who have cancer to see if they’re going to develop it and so on. So, it’s a whole new, brand new, just exploding field that’s going to be very exciting in the future.

So let’s see. I’ve covered the family history, the genetic study, the NF-2 gene on chromosome 22. Now MRI is still the way to detect acoustic tumors. You know, by definition, if you have two acoustic tumors, you have NF-2. Now I’m going to show a slide in a minute that shows that you have NF-2 with other criteria. But if you have bilateral tumors, you have NF-2. I’m going to show you a series of MRIs here. And all of these people presented to us with normal hearing. This was a child, actually, you can see—let’s see, where’s my pointer. Anyway here is the acoustic tumor here, and here is the acoustic --I can’t see that. Can you see that?

Audience Member: No.

Dr. Brackmann: Well there it is right there. Here’s the acoustic tumor here and here’s the acoustic tumor here. The rest of them you’re going to be able to see. This was a screening in a six-year-old, a patient with NF-2. And the only time we’re successful in detecting these small tumors is when we screen asymptomatic patients. One of the characteristics of the tumors in NF-2 is that they become very large before they produce symptoms, unfortunately.

Much more common is the unilateral acoustic tumor. You know, the tumor that occurs in one ear. And usually they will produce symptoms when they’re much smaller. But in NF-2 the tumors are often very large before they produce any symptoms.

For instance, this patient also had normal hearing. She was dizzy is what precipitated doing the MRI. This patient also had normal hearing. And you see here, I don’t think I need to use a pointer to show you those tumors. These are bilateral acoustic tumors that are—the brainstem is squished between them. You wonder how someone like this can walk and talk, but they do and actually have normal hearing. So, we recommend—and this is a similar patient, normal hearing with huge bilateral acoustic neuromas.

So when you have a history of NF-2, we recommend very early screening. And I’m going to talk more about why and the surgery we do and so on this afternoon. But hearing preservation, when the tumors are detected when they’re small, is possible in about 75 percent of cases; whereas, if you wait and the tumors become large, invariably patients will lose hearing. So NF-2 by definition, if you have bilateral acoustic neuromas and you have NF-2, or if you have a first degree relative, meaning mother, father, brother, sister, has one acoustic tumor and then any with the following things, you also fulfill the criteria for having NF-2.

I mentioned a little bit—there’s a large NF-2 study. Kim mentioned earlier the army grant. The army grant supports NF-2 research. It’s like 25 or 26 million dollars a year. A part of that is what is called a natural history study of NF-2 to study what is the average course of a patient that’s diagnosed with NF-2. And there are several sites around the country, the House Ear Institute of one of those sites, and at the time this slide was made there were 540 patients in that study.

The first symptom, as you see here, most commonly is hearing loss. The numbness that occurs is when the trigeminal nerve, which is the nerve that supplies sensation to the face, is affected. That occurs fairly commonly. Ringing in the ear may be the only symptom. And some of these are discovered without any symptoms even though the tumors are big. That’s one of the treacherous things about NF-2 is that these tumors can grow to very large size while producing very few symptoms so that by the time they’re diagnosed, already the die is cast in terms of the hearing.

Men and women fare equally in this disease. In addition to acoustic tumors or schwannomas—I keep saying acoustic tumor, which is a misnomer. These really begin on the balance nerve. They’re really vestibular tumors. And the other nerve that is in close proximity to the acoustic nerve is the facial nerve. The facial nerve is oftentimes involved with these tumors along with the hearing and balance nerves. In addition to these tumors on both balance nerves, meningiomas, which are benign tumors that arise on the covering of the brain, nerves on the fifth cranial nerve which supplies sensation to the face and nerves that affect speech and swallowing, the lower cranial nerves are frequently affected, so that patients with severe form of Neurofibromatosis Type 2 have not only bilateral acoustic neuromas, which often result in hearing loss, deafness and sometimes facial nerve involvement along with that, but they frequently have numbness of the face, which produces a problem with the trigeminal nerve. It supplies sensation to the cornea. When you don’t feel the cornea, you’re subject to having problems with the eye and also problems with speech and swallowing. And, in fact, that is one of the more serious things that occur in the course of NF-2 is problems with speech and swallowing, swallowing particularly. Patients have difficulty maintaining their nutrition in the severe forms of NF-2 as these lower cranial nerve tumors, the tumors on the nerve that goes to the vocal cord and the pharynx are involved. So typically patients with NF-2, all of them have some problems or issues with hearing. And in the severe forms they have these other issues with multiple other tumors, meningiomas and schwannomas.

The other thing that occurs in patients with NF-2, you see on your left is the acoustic tumors, but on the right there—and I don’t know, I’m going to try to give this one more try. Yeah, I can’t see it. I hope the White Sox do better than this.

Audience Member: Dr. Brackmann, here’s one that might work, do you want to try it?

Dr. Brackmann: Well, thank you very much.

Audience Member: It’s a give-away.

Dr. Brackmann: A give-away. Leading Light for Life. We’ll see how this one does.

Hey, how about that? Small but mighty, huh?

Well, here is another problem that occurs in patients with NF-2. This is a tumor more that occurs from the ependymal lining of the spinal cord. So, patients with NF-2 in the severe form have not only tumors within their head, but they have multiple spinal tumors and also tumors on the peripheral nerves, on the nerve roots. So in the severe form patients with NF-2 may also have paraplegia and difficulty walking, gail and so on.

So it can be a devastating disease. And there’s all different manifestations. As I’ve said I’ve seen patients that are in their—that you know, live to old age and maintain hearing with a slow-growing tumor in their second ear all the way to the very severe manifestations that may occur in early childhood. So I’ve already mentioned most of this.

Every patient that is diagnosed with NF-2 at the time of diagnosis should have an MRI of the complete spine. Now, spinal tumors generally are not treated. In fact, no tumor in NF-2 is sort of treated expectantly except for the acoustic tumors, where we think if you can remove those early, you may preserve the hearing. But you don’t go with the idea I’m going to cure this patient of NF-2. It’s impossible. And the cure would be worse than the disease in many cases.

So in the case of multiple cranial nerve tumors, as well as spinal tumors, you sort of treat them as they present themselves and become symptomatic. So when patients have pain or if they begin to develop paralysis, then those spinal tumors are treated. The philosophy that I like to think of is that you want to produce the longest possible, best quality life for a patient. You don’t go in saying, “I’m gonna cure you,” because that’s impossible, not with surgery or not with medical treatment. You want to maintain the best quality life for as long as you possibly can. And that includes auditory rehabilitation.

I just had a quick glance at the new booklet that came out, which is a marvelous little booklet. They talked about that people with NF-2 should start auditory rehabilitation, sign language or lip reading and so on, which is a part of it.

Family screening, if you have NF-2 you should have your children screened. We recommend beginning at age 6 because the earlier the vestibular schwannomas are treated, the better the outcomes are. We recommend that every patient with NF undergo genetic counseling. Geneticists are much better at looking at all the subtleties and innuendoes of genetic counseling than I as a clinician. I am a surgeon. I am not a researcher, a primary researcher, I’m not a geneticist. You know, I can tell people that, yes, half of your kids are going to have NF-2, but that’s not good enough. They need to be given much more information than that. And as I mentioned, the testing now is an exciting whole new area in terms of deciding if you’re going to have children and so on.

These are the treatment options that we use. And then I’m going to stop after this slide just to give you an overview, which is the title of this talk, and then we’re going to talk about specifics of it this afternoon as it applies to each individual case.

Sometimes we don’t do anything in NF-2 until at least you get the idea of what the manifestation is going to be. Sometimes the treatment of some of these tumors is worse than the tumor itself. So, observing them is a very good option in many cases. If we see a patient who has tumors that are too big, which is about two and a half centimeters, if they’re too big to have a realistic expectation of hearing preservation, probably better to leave them alone and watch them because they may go many years, sometimes these tumors grow very slowly, and they may go many years maintaining their hearing; whereas, if you remove the tumor, they’re going to lose their hearing at the time of their tumor removal.

One other option that we sometimes use--you know, these are all benign tumors. I didn’t mention that before. These are not cancers. They do not change the cancer. So, these are all benign. All of the tumors in NF-2 are benign. So, one thing that we have done in some cases, about 60 or 70 cases now, is when hearing is beginning to deteriorate, we remove the bone from around the inner ear canal to allow the tumor to expand away from the hearing nerve. And some patients have had hearing maintained for many years following doing that. When the tumors are very small we are able to remove them and preserve the hearing about 75 percent of the time. Sometimes partial tumor removal is advocated. It is usually not successful. When we have done that, usually the hearing is lost and you still have the tumor.

Finally, non-hearing preservation; when tumors are large, they become life-threatening, like the ones that I showed you. These huge tumors, they do become life-threatening. They produce what is called hydrocephalus. They block off the flow of spinal fluid and patients get what’s commonly called water on the brain, and that can be a fatal event. So, they have to be removed regardless of the hearing, and when we remove the tumor, and hearing is lost, that’s when we do the auditory brainstem implant.

And patients do not by any means have normal hearing, but they do receive very useful auditory sensations from that which allows them to better lip-read and to hear environmental sounds. And we are hoping it is going to be a lot better. There’s a new generation of devices where electrodes are going to go into the cochlear nucleus as well as on the surface of it. And so, we’re hopeful that that’s going to produce better hearing a little bit down the road.

Radiation is controversial in NF-2. There are some people who administer radiation who no longer do it in NF-2. In our experience it does not work as well in NF-2 as it does in non NF-2 tumors. There’s always a concern about producing a further genetic mutation in a tumor which is already resulting from genetic mutation. So it’s somewhat controversial, the role of radiation in NF-2..

Okay, I think I am right on time. Now we are going to have some questions:

Audience member: You mentioned that there were several sites for the natural history study. What are some of the other sites other than House Ear Institute?

Dr. Brackmann: Boston, Mia MacCollin. She has been the foremost researcher in NF-2. She retired and her work is going to go on at Mass Eye and Ear. I can’t remember his name right now. A very nice young man has taken that over. I believe—that’s the only two that I actually know of in the States. There are some around the world.

Audience Member: I won’t be at the session this afternoon, so I wanted to ask now; we have had some—I’m from Michigan and run a support group there. We have had some doctors in Michigan recommend putting an ABI in when the first tumor comes out—we had identical twins with bilateral acoustics, and the doctors wanted to, even though there was still very good hearing and small tumors on the other side, wanted to start with an ABI immediately when the first one came out. Is that recommended?

Dr. Brackmann: Yes, we do re commend that for a couple of reasons. Number 1 is there is about an 8 percent failure rate in the ABI. In other words, in 8 percent of patients they receive no auditory percepts. So, if you do one on the first site and it fails, then you have another opportunity on the second side. So you sort of get two chances.

The other thing, it gives patients an opportunity to use the device while they still have hearing. Now typically they don’t use it because there’s nothing that you get from an ABI which is comparable to your good hearing; your normal hearing. But we have patients who, while their hearing sort of is going down, they sort of cross over. You know, they say “I’ll start using the ABI a little bit more,” so that they’re not suddenly deaf and then they’re starting the ABI. They’re using the ABI while they are sort of transitioning from hearing to not hearing. And it has made them—you know, we have some patients who still have hearing despite having life-threatening, monstrous tumors. And boy, that’s a hard decision. When do you sacrifice your hearing for your life, literally?

That sounds dramatic, but it really in some cases turns out to be that. And when do you sort of say well, I’m going to give up my hearing now so that I can avoid the risk to the brain and the facial nerve and so on? And it’s a little easier, people have at least some sound from an ABI. It’s a little bit easier for them to make that decision to say, well, I am not going to be totally deaf. I am going to have some hearing, and it makes it easier than saying, well, I’m going to go from hearing to absolutely deaf. So we do recommend doing that on the first tumor side for those three reasons.

Audience member: Okay, my own thinking was perhaps if you could wait several years, wouldn’t the technology be better? You know, people have more experience implanting them, etc.

Dr. Brackmann: Okay, well true. But there’s nothing says you can’t do a second one. We have now about 190 ABIs. And we now have, you know, with the new technology we can upgrade it, if there is new technology that’s going to be better. So I think it gives them a second chance. So we do recommend that.

Okay, thank you very much.