Neurofibromatosis Type 2: Current Diagnosis & Treatment

Podcast Transcript

Intro: Neuro Pathways, a Cleveland Clinic podcast, exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: Physicians involved in the care of patients with neurofibromatosis type 2, are frequently faced with challenging decisions when determining the best steps in the management of their NF2 related tumors. Their decisions often revolve between observation, medical treatments and surgical interventions. A methodologic and cautious management of NF2 patients can minimize complications and maximize their quality of life.

In today's episode of Neuro Pathways, we are discussing the care of patients with neurofibromatosis type 2. We hope to share the recent treatment advances that will greatly improve your decision-making for your patients. I'm your host, Glen Stevens neurologist, neuro-oncologist in Cleveland clinic's Neurological Institute. I'm very pleased to have Dr. Neha Patel join me for today's conversation. Dr. Patel is a pediatric neuro-oncologist who recently joined the Cleveland Clinic. She has interest and expertise in neurofibromatosis, and we'll share her insights on how to improve the journey for patients with NF2. Neha, welcome to Neuro Pathways.

Neha Patel, MD: Thank you for having me Glen.

Glen Stevens, DO, PhD: So Neha, I'll just start by asking you how'd you get interested in NF as a subset of your pediatric patient population?

Neha Patel, MD: It actually really started out through my journey during my fellowship training, where I started seeing patients with NF1 and a neuro oncologist during my fellowship training was a pediatric neurologist. So she saw many, many patients with NF1 and NF2 and that's when I started getting interested in taking care of these patients. And it was during my fellowship is where I also did some basic science research in neurofibromatosis mice model and that's some history.

Glen Stevens, DO, PhD: Excellent. Well, we're glad to have you looking after these patients. So let's start broad. Tell us a little bit about NF2, what it is, important aspects about it, how patients' present to the population is.

Neha Patel, MD: So, neurofibromatosis type 2 is a rare genetic disorder. It is caused due to either the normal mutation in NF2 gene or transmission of one abnormal NF2 allele from a parent. Mutation in the NF2 gene leads to decrease or absence of merlin, which is a tumor suppressor protein. Consequently, these patients do develop non-malignant tumors called schwannomas in the nerves. These patients also develop other central nervous system tumors such as meningiomas and ependymomas. Although schwannomas can involve any cranial, peripheral, or spinal nerves, almost all patients develop schwannomas in the bilateral vestibulocochlear nerves. The important part about taking care of children with NF2 is these patients can have variable clinical phenotype, as well as they can have manifestations at different ages. So most severe form of neurofibromatosis type 2 can become evident at younger age, but less severe becomes more apparent in adulthood.

Glen Stevens, DO, PhD: So NF1 patients is always a little more obvious to the parent, if they're seeing café au lait spots and bumps and those types of things. The NF2 doesn't have that so much. And as a pediatric oncologist, I'm sure it's difficult to tell a parent that their child is going to have to have some type of new imaging study under anesthesia. How do we diagnose it in children?

Neha Patel, MD: So many times in children, when we suspect the child has NF2, there may be other features that they may present to it. So for example, if you have a family history of NF2, it is much more easier to diagnose that child with NF2, because we would do either genetic testing or imaging. However, if there is no family history of NF2 there are some certain clinical features that brings to medical attention that eventually leads to NF2 diagnosis.

So let me give you an example. So we had a patient who has been followed in Cleveland clinic since he was a baby. Now he's a young adult, but at six months of age, he had developed some tumor in his retinal fibers, which at the time was called as hamartoma. Eventually, by three or four years of age, he developed tumors on the surface of the skin. Initially it was suspected that maybe he has a neurofibroma, so we did a biopsy and the biopsy actually showed this to be as schwannoma. And that's when it eventually led to an MRI scan and by four years or five years of age, he had vestibular schwannomas in both the vestibular nerves. And so we've been following this patient, now that he's a young adult, we've been following this patient with MR-imaging and hearing tests and other appropriate screening.

Glen Stevens, DO, PhD: So for screening, what do we need to do with these patients? What tests do we need to run as a screen?

Neha Patel, MD: So there are a multitude of tests that we run in these patients. First and foremost hearing test is very, very important in these patients. We do hearing test every six months. When they're young, we don't expect that they will exhibit any hearing loss. So it's okay to do on a yearly basis, but as they grew older, it's important to do it more frequently. So six months is typically the time period where we advise ours patients and other physicians to do hearing tests. And usually if they're younger, we can do it a baseline green STEM potential studies, but otherwise audiogram is pretty sufficient in detecting the early hearing loss. We also recommend MRI scan of the head, which should be done annually at minimum and MRI of the entire spine, which can be done every three years. When they're younger, we typically try to do it every three or five years. As they get older, we may have to do it more frequently depending on the symptoms. So those are really the main screening tests that these patients need to undergo.

Glen Stevens, DO, PhD: And besides the distributor schwannomas that you mentioned, what other tumors do you often see in these patients?

Neha Patel, MD: So the schwannomas not only involved in vestibulocochlear nerves, but they do involve the other cranial nerves, spinal nerves, and peripheral nerves. So certainly screening MRI will detect those schwannomas. But other tumors that are common in these patients, besides schwannomas, are ependymomas and meningiomas.

Glen Stevens, DO, PhD: And if you see a child that has a NF2, you do a scan, they have bilateral vestibular schwannomas, and the parents asked, do we need to go to medical genetics? What do you say to them?

Neha Patel, MD: I actually do encourage all our patients with NF2 to see a medical genetics, not only for establishing a diagnosis from clinical criteria, but also we would like germline mutation. Recently, there has been many studies showing some correlation with the severity of NF2 and certain gene mutations. So I think it's very important to have that for germline mutations established in these patients.

Glen Stevens, DO, PhD: So I bring my child to you and they have NF2. And I ask you, what's the likelihood that at some point my child will be deaf. What's the incidence of that?

Neha Patel, MD: The incidence is very high. I would say nearly a hundred percent for these patients. It's matter of time. Our goal is obviously to preserve hearing as long as we can, but the natural history for our patients with NF2, is that all the patients develop hearing loss.

Glen Stevens, DO, PhD: How do I decide when it's time to do something with the vestibular schwannoma?

Neha Patel, MD: So it's very important for these patients undergo screening, MRI scans and audiogram. About five years ago when we did the screening MRI, and when they started losing hearing or had tumor growth, we had nothing to offer, but now we have many things to offer. So there are many molecular targeted treatments that are currently already been established in these patients. And some clinical trials are ongoing.

Glen Stevens, DO, PhD: And I know you're a medical oncologist. Can you talk just briefly about surgical resection of the tumors? They're benign tumors, so from a treatment standpoint, you could cure the tumor by doing surgery. How do you decide whether or not to have the child undergo surgery?

Neha Patel, MD: It really depends on the extent of the tumor size and how it is pressing or compressing other vital structures around in the adjacent areas, such as brainstem and other cranial nerves. So if I do find that the tumor is growing significantly, that it is causing facial nerve palsy or brainstem compression, then I would encourage for those patients to go for surgery. However, if the patients have tumor growth, but do not have any compressive symptoms, I would consider other molecular targeted treatments first to shrink those tumors.

Glen Stevens, DO, PhD: Why don't you talk about that little bit more in terms of molecular drugs that you could use?

Neha Patel, MD: So we know that patients who have NF2 mutation do have mutation in the merlin protein, which is a tumor suppressor protein, which actually causes activation. Because you have mutation in the merlin protein, you will have upregulation of two parallel downstream pathways, which is the PI3/AKT/mTOR pathway and the Raf/MEK/ERK pathways.

And now we have many molecular targeted agents inhibiting these pathways and to decrease some of the tumor formation. So one of the initial child’s that was studied was using Bevacizumab and the data has been published. And these are significant response, not only in improvement in the hearing, so functional response, but also tumor shrinkage. So that is the first line treatment that we offer to our patients.

But since then, there have been many subsequent clinical trials and some of them have failed, though they had appropriate targets to hit, and some of them has shown some initial signs of response. Few of them are currently open and so, there are two agents that are currently open as clinical trials, Brigatinib and Crizotinib, but we have had some trials that have failed, like Lapatanib and Selumetinib. So it's very important to enroll these patients in clinical trials and study them very systematically.

Glen Stevens, DO, PhD: And I'll just mention to the group that if you go to the website clinicaltrials.gov, you can usually put in your tumor type and it will let you know the clinical trials that are ongoing in the country for various types of tumors. Do you have any other resources, Neha, than that you use? Neha Patel, MD: The resource I use specifically for patients for neurofibromatosis type 2 is children's tumor foundation website.

Glen Stevens, DO, PhD: Talk about radiation therapy a little bit. So obviously we have multiple different modalities that we can use. What about using radiation on these tumors?

Neha Patel, MD: So certainly, these tumors are at a very difficult location. So certainly radiation therapy has been explored extensively in these situations. So one of the ones that is most commonly used is Gamma Knife®. It's important that not all centers are proficient in using Gamma Knife®. So it's important which centers we send these patients to. But Gamma Knife® has shown to decrease the tumor growth and also preserve hearing.

Glen Stevens, DO, PhD: Is there an age at which you wouldn't treat with radiation therapy? Maybe there's not, but what's the typical age you try to not treat below?

Neha Patel, MD: I don't think that there's any certain age group under which we wouldn't treat. However, it's important to avoid radiation as long as we can. Specifically now that we have other molecular targeted treatments. If we can try to use those instead of radiation therapy, that will be my first line.

Glen Stevens, DO, PhD: If you treat somebody with bevacizumab, are you going to treat them for a defined period of time, or you would just keep going as long as they're getting response and benefits.

Neha Patel, MD: When I have used bevacizumab in patients, it really depends on the response that the patients are having from bevacizumab. So if they are continuing to have functional, as well as tumor response, I would continue on the bevacizumab. Initially we started with the higher dose, but then we may have to drop down the dose to keep it at a set level. But many times these patients do develop side effects of bevacizumab, mostly related to high blood pressures and proteinuria. And that may prevent us from continuing this drug for a long time.

Glen Stevens, DO, PhD: So it sounds like we really need a multidisciplinary team to look after these patients, since there's so many different modalities involved. Who do you work with to manage these patients? What's your team?

Neha Patel, MD: I absolutely agree by caring for these patients is very important to take a multi-disciplinary approach and involve the key medical and skilled surgical specialist for comprehensive management. Really, when it comes to medical care, a neuro-oncologist, a neurologist and an audiologist are very important in their care. But from the surgical perspective, it's very important that we have skilled surgeons who are involved in these patients' care and these neurosurgeons and maybe one skull-based surgeon, and also want to make sure that they can have different surgeons, surgical skills are important and having different surgeons for different surgical skills come together.

Glen Stevens, DO, PhD: Neha, tell me what you're currently doing to try to improve the care of NF2 patients at the Cleveland Clinic. I understand that there's an interest in rejuvenating an NF2 Clinic. Is that correct?

Neha Patel, MD: That is correct. So I joined Cleveland Clinic last year. My first goal is to start a consolidating care for a neurofibromatosis type 2 patients by really developing a comprehensive, multidisciplinary NF2 Clinic. But I have recruited many important key players in their care. So for example, we have our skull-based neurosurgeon, Dr. Pablo Recinos. We also have Dr. Erika Woodson, who is the Medical Director for cochlear implantation, who also participates in this clinic. And myself would be the represent for pediatric.

Glen Stevens, DO, PhD: So Neha, are there any particular patients that you've worked with that would demonstrate the utility of managing patients in a multidisciplinary approach?

Neha Patel, MD: I would love to talk about that. So I really joined Cleveland clinic last year, and it had become very evident that both our medical physicians and surgeons at Cleveland Clinic value the importance of collaboration to optimize patient outcomes and their quality of life. Let me give an example of a patient where this is clearly evident. We have a young woman with neurofibromatosis type 2, who's new to our practice. By the time she presented to us, she had already had multiple extensive meningiomas in the brain and spine and bilateral vestibular schwannomas. She had complete deafness in both ears. She had undergone an excision of the vestibular schwannoma on one side and several skull-based meningiomas. She had developed facial nerve, meningeal nerve and hypoglossal nerve dysfunction on the side that the tumor was removed. She also had multiple spinal schwannomas and many physical disabilities related to the schwannomas.

During her care with us, we found that the vestibular schwannoma and the surrounding meningioma now on the opposite side were also growing and the extent of the growth was causing brainstem compression. So we asked neurosurgeon to evaluate her and Dr. Pablo Recinos, who is an excellent skull-based neurosurgeon. He orchestrated the surgical removal of this vestibular schwannoma. He and his team recruited and coordinated the surgery with Dr. Erika Woodson, who, as you know, is a Section Head for Otology-Neurotology and Medical Director of Hearing Implant Program in Cleveland Clinic. And also Dr. Recinos's consultant, Dr. Patrick Byrne, who specializes in complex reconstructive surgery of the face, head and neck. So what Dr. Recinos and the surgical team did is very carefully remove the vestibular schwannoma, and also then Dr. Patrick Byrne did some facial nerve grafting for re-innovation on the other side, where she had to facial nerve palsy. And this patient, despite the complex surgery, patient recovered within 48 hours and was able to go home.

Glen Stevens, DO, PhD: Well, that's a great story. And it really sounds like these patients really need to be looked after in a multidisciplinary approach with all the options and the difficulty involved.

Neha Patel, MD: I agree. Really the positive outcome for these patients really is dependent on how we all, medical specialists and surgeons, come together and discuss each case very comprehensively and carefully.

Glen Stevens, DO, PhD: So, before we sound off, any closing comments for our audience members who may have challenges in the treatment of NF2 patients?

Neha Patel, MD: I think one of the most important aspect in caring for patients with NF2 is really doing a very systematic, comprehensive, and multidisciplinary care. And what these patients are looking for, is how much you care for them and, and how we can bring cutting edge treatments to them. The natural history for NF2 is going to change very soon as science is moving forward, as we have developed more and more in-vitro and mice models, and we are learning how molecular targeted therapies are improving their hearing, as well as decreasing the sizes of the tumor. I do believe that the outcome of these patients are going to change over time.

Glen Stevens, DO, PhD: Neha, thank you very much for joining me today. It's always exciting to learn how treatment options are evolving for our patients. And we really look forward to watching the development of the NF2 Clinic. Thank you.

Neha Patel, MD: Thank you, Glen, for having me. I'm very excited.

Outro: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, ClevelandClinic.org/neuropodcast or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our consult QD website. That's consultqd.clevelandclinic.org/neuro or follow us on Twitter @CleClinicMD, all one word and thank you for listening.