Jaishri Blakeley, MD, Associate Professor of Neurology, Oncology and Neurosurgery at Johns Hopkins University in Baltimore, Maryland, talks about a new treatment to restore the hearing for some people with NF2 associated hearing loss.
Interview conducted by Ivanhoe Broadcast News in March 2016.
Neurofibromatosis, what is it and what does it impact?
Dr. Blakeley: Neurofibromatosis actually covers three separate syndromes: Neurofibromatosis Type I, Neurofibromatosis Type II and Schwannomatosis. Neurofibromatosis Type II (NF2) is one of the more rare of the three syndromes. It affects about one in twenty five thousand people in the world. There are no cultural or gender preferences so everybody is equally at risk. Of the people that have NF2, 50% inherited the gene from a parent who also has NF2 and 50% have what is called a de novo mutation such that they are the first person in their family to have NF2.
What is it essentially, what does it impact?
Dr. Blakeley: The mutation results in a protein called Merlin not being made correctly. Merlin is a protein that regulates how cells communicate and how cells regulate their growth patterns. In the absence of Merlin there is excessive growth of certain cell types, the most common cell to be affected is something called the schwann cell and main job of the schwann cell is to insulate peripheral nerves. The way our body is organized is we have a central nervous system, that’s the brain and spinal cord, and we have a peripheral nervous system. All of the nerves that leave the brain and spinal cord are peripheral. In order for them to cover the distance they have to cover, say from your brain stem to your fingertip, they are myelinated, which means that they are encased in a sheath that makes the signal travel quickly, just like electrical wires are encased so that they can travel quickly. The cell that does that ensheathment is called the Schwann cell. In NF2 the Schwann cell is missing functional Merlin protein that’s supposed to regulate growth. The Schwann cell therefore grows too much and creates a number of tumors called Schwannomas.
Where are those tumors located? Is it primarily throughout the nervous system?
Dr. Blakeley: They can be anywhere there’s a Schwann cell so that’s any part of the peripheral nervous system. They have a predilection for a nerve called the eighth cranial nerve or the vestibular nerve and that’s the nerve that goes from the brainstem to the ear. It’s responsible for hearing and responsible for a portion of balance. However, they can be on any other cranial nerves as well; these are the nerves that control vision, facial function, swallowing, and control of regulation of our gut and they can be on any of the peripheral nerves from the spine and anywhere else in the arms and legs.
What is a patient experiencing when they have this condition?
Dr. Blakeley: A little bit depends on how old a person is when they present. People who present very early in life are more often going to present with a distant neurologic finding like a foot drop (weakness in one foot), or hand weakness or possibly a focal problem like vision loss. People who present in the typical time frame where we meet patients, in their late teens to their early thirties, , will present with hearing loss because of the very high frequency of having both of the vestibular nerves affected.
How difficult is it to get a diagnosis, is this something that most primary care physicians wouldn’t be looking for when you have hearing loss?
Dr. Blakeley: That’s a great question. Often times people do go through several permutations of doctors before they get their diagnosis. With the advent of the use of MRI very frequently the diagnosis is made much more quickly because there are some pathognomonic findings. Seeing a tumor on both the vestibular nerves is one of the main criteria for diagnosing NF2.There are other criteria like having multiple Schwannomas and Meningiomas or having multiple Schwannomas, Meningioma and Ependymoma, which are other types of tumors. These are all benign tumors. They are not cancer, but they can cause a great deal of damage and the collection of all those tumors together makes the diagnosis of NF2. Once there’s an MRI it’s relatively straight forward to make the diagnosis but getting people to MRI can take a long time. Particularly if there’s hearing loss on one side as the only presentation.
What is the current treatment?
Dr. Blakeley: The standard of care is very individualized and starts with vigilant observation to evaluate for change in function. Function being hearing, vision, balance, motor function of the arms and legs. If there is a change in function, the first consideration is for surgery. Surgery is for sure the standard of care. The trouble with surgery is it’s very difficult to remove the tumor without damaging the nerve. In most cases when there’s a surgery there’s a loss of function of some type. The most common surgery that happens in NF2 is removal of the Vestibular Schwannoma, the tumor that’s on the eighth cranial nerve, but with most of those surgeries people lose hearing on that side and often also lose facial nerve function, which controls our ability to smile or close our eye which is very important for expressing and communicating but also important for protecting our vision because our eyelid closure is what keeps our eye healthy, and important for speech and communication and swallowing. The facial nerve sits right in front of the eighth cranial nerve (where the vestibular schwannoma is) so it’s a close neighbor and one of the complications of surgery for these tumors is that people will have facial nerve palsy. Although surgery is the standard of care and is used when it’s indicated, it very often results in deficits.
Talk to me a little bit about the study, about other options that researchers are looking for.
Dr. Blakeley: Specifically because of the limitations of surgery that I just mentioned, as providers we became very frustrated that what we could offer patients is “you can either wait for the tumor to take your function or we can take your function for you”. We started to look for other options. We do understand a lot about how Merlin functions from the study of signal transduction pathways which means how cells talk to one another and what chemical signals they send to regulate their behavior. We started studying drugs that targeted specific targets in that transduction pathway. Also what we recognized was that Vestibular Schwannomas, the ones that are on the eighth cranial nerve in particular take up a lot of contrast. When someone has an MRI we often give contrast in the vein so we can see any abnormal areas in the brain and Vestibular Schwannomas take up a great deal of contrast. That implies that they have a lot of blood vessels. Bevacizumab is a drug that targets a protein called vascular endothelial growth factor and that is a growth factor specifically responsible for blood vessels and it’s the major growth factor that tumors use to make new blood vessels. The logic was if these tumors are lighting up bright with contrast they probably have a lot of blood vessels and maybe they have more than what they need and if we can stop the creation of blood vessels and even prune back some of the blood vessels we could get some improvement in tumor size and hopefully in function.
Tell me what this medication is used for currently.
Dr. Blakeley: It’s approved for cancer; it was designed as a cancer therapeutic because all cancers and many benign tumors like Vestibular Schwannomas require their own blood supply. They are growing larger than nature intended them to and so they have to make more blood vessels. It’s approved for colon cancer, some forms of lung cancer, and glioblastoma, but in the cancer setting it doesn’t work for very long because the cancerous tumor learns how to get around it. The other place this drug is used is for wet macular degeneration and it’s the same idea, to prune back blood vessels. In that case it’s given in the eye directly in tiny quantities. It is unique to test this drug for a benign tumor that’s part of a syndrome where there can be hundreds of tumors throughout the body.
Talk to me a little bit about your findings. What have you seen as patients have been using this.
Dr. Blakeley: Because we had a lot of experience with using Bevacizumab in the cancer setting, we understood that one of the things that we would expect to see is the blood vessels prune back which could make tumors smaller. If this happened, we would expect to see particular findings on MRI that are markers of blood vessel activity. We did in fact see those results so that was confirming a hypothesis that is potentially working on the blood vessels. We did see the blood vessels size diminish on imaging and we saw the tumors get smaller in just about fifty percent of people. But what’s most exciting and what we did that was a bit unique in this study is although that’s wonderful and exciting to see a biologic impact of a drug through the MRI, just because something gets smaller on an MRI doesn’t mean a person feels better. What we really wanted to ask is: could we make someone’s hearing get better? For that we designed the study so that the primary requirement to get on the study was that you had to be losing hearing and the primary end point; what we said will be successful; was if we restored hearing. To do that we worked with our colleagues in audiology who do the hearing tests and we used a specific thing called the word recognition score using a hundred word test. In this test you have head phones on they read one hundred monosyllabic words (cat, ball, car…) and you have to repeat them back. It’s as simple as the percentage correct that you can read back; that you can hear and say back again. What we found is that thirty six percent of all our participants who were by definition losing hearing when they entered the study gained back hearing on this test. Importantly, I mentioned before that in the setting of cancer this Bevacizumab does work but it works for only a short period of time and the cancer learns a way around it. In our study we were able to show that for of all those thirty six percent of patients who had hearing benefit from the drug, they held onto that benefit for 3 months in all cases and up to 6 months in some cases after they had stopped the drug… Why this is so exciting is we improved function in the form of hearing and we showed that we don’t need to be dosing the drug as high or as frequently as is needed in cancer. Even when we use lower doses less often we can maintain the benefit for patients much longer.
What are the implications for a study like this?
Dr. Blakeley: There are wonderful implications because before we had this drug when people were losing hearing because of their tumors they had a number of very bad options. They could have surgery and lose hearing immediately and potentially have an implant placed that helps provide some level of hearing which can be very beneficial for some patients but it’s not universally beneficial, or we had the option of letting the tumor simply progress and people losing hearing and adapt to that new reality. One of the major problems with NF2 is that the hearing loss happens later in life. We are all aware of how vibrant and full the non-hearing community is. There are wonderful secondary schools, universities and communities for people who do not have traditional hearing. However, if you lose hearing when you’re twenty five or thirty your life has been built around living in a hearing world. Losing hearing at that age can be very traumatic and very isolating. This drug provides us one additional tool that helps us at least preserve hearing, in the best case scenario for several years, and that is a major benefit to what we had available before. The other thing that we learned from this study is that we probably don’t have to give doses as high for people who respond to this drug as we would otherwise which means we can reduce both the cost to the patient and their healthcare system and maintain the drug longer without side effects. That’s all wonderful. However, this is not a perfect drug; we did see side effects and only thirty six percent of people had this long-term benefit. We obviously want to find a treatment that benefits100% of people afflicted with NF2. What it teaches us is that we can modify the natural history of these tumors, and in a situation that that was considered hopeless before, it has opened a window of opportunity that shows that this drug will work for some tumors beautifully. Now we have to look for other options for the tumors that didn’t respond to this drug or for the people who have too many side effects to stay on the drug.
I want to ask you a little bit about Heather’s case. How significant was the hearing loss when she came to you?
Dr. Blakeley: She did have quite significant hearing loss, and when people come to us the first thing we ask them is: how does this affect your life? It’s one thing to have a hearing test and you’re told the pure tone averages (which are the beeps) or the word recognition score is low but if you ask people how are you doing in life they may say I’m doing fine with that or they may say I’m really struggling with that. What is interesting is when we first met Heather what she shared with is that she was struggling in social situations and so on a one on one with her husband or with close friends, she was doing okay. But in any other situation she was very limited, this is what is very isolating is you can’t go to dinner with people or participate in group discussions at school or work because you can’t localize and interpret the sound. What changes in the hearing loss particular with Vestibular Schwannomas and NF2, is not necessarily the amplitude of sound, how loud it is, we can fix that with hearing aids and so forth, but rather it’s a loss of clarity. Things come in all muffled and we just can’t fix that with hearing aid technology.
How is she doing now?
Dr. Blakeley: She’s doing wonderfully now. Heather is one of our superstars on the study and I want to make a point about that. When Heather signed up for the study and when our other patients signed up for the study we had an idea that it might work but we really didn’t know. I think it’s crucial to recognize how important the people we take care of are in developing new therapies – they are truly our partners in this exercise. We can design the study, we can write the grants, we can the funding to do the study but if we don’t have brave people who say, sign me up let’s see what happens, we really can’t advance science at all. Heather definitely had a hearing response, has maintained this hearing response for going on five years. What I can say is that based on the hearing tests Heather had before enrolling on the study five years ago, she would have been deaf by now, that’s how the tumor would have progressed. We certainly can find solutions to adapt to being deaf, but it is a different world when you’re deaf late in life than if you had hearing.
Is there maintenance for Heather, does she still take the drug?
Dr. Blakeley: She’s still on Bevacizumab, she’s getting Bevacizumab maintenance dosing is honestly at this moment the dose and frequency are tailored to her specific hearing response and side effects because long-term Bevacizumab will cause high blood pressure, change in ovarian function and it can cause increased protein in urine which is a marker of kidney damage. When we see those things we modify the dose to minimize those complications. At the same time we want to keep the affect and for each person there’s a different perfect balance of minimizing the side effects and keeping the affect for each person. Heather is currently on maintenance and all of our long-term patients are on maintenance which is a lower dose than where we started but have to play with that dose to balance the side effect versus the benefit always with the goal of getting to the lowest effective dose.
You mentioned a hearing test is that still part of the monitoring that you do?
Dr. Blakeley: Yes.
That’s not something that you do here?
Dr. Blakeley: No, that is done by audiologists. They have a hearing testing center, there’s a booth and headphones and it’s a secured room so that there’s not background noise.
Is there anything I didn’t ask that would be important for people to know?
Dr. Blakeley: I think that what we’re struggling with is where do we go from here. This is not the best drug for all people with NF2. It is not the best drug for all people with Vestibular Schwannoma, this drug does have serious risks associated with it and I wouldn’t be too liberal in my use of this drug. For the right person it is the most wonderful almost miraculous opportunity but it should not be used for all people. It can cause severe damage and it is just unlikely to help a certain group of people.
END OF INTERVIEW
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