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00:00:20] Dr. Anna Sophie Hoffmann: So, hello, I'm actually starting now, and I'm Dr. Anna- Sophie Hoffmann from Hamburg, Germany, and I am a senior attending at the hospital in the EMT department. Today, I will talk about the otolaryngological manifestations of the MPS, and I will present you some case studies in the end. To start with, notes for everybody online here, please do not take any screenshots. Please do not reproduce any of the slides, content, or images without the express written permission of me, and it will be about 25 minutes presentations, and after that, you have the possibilities of answer questions. Please submit your questions in the question panel in the chat panel, so in the end, I can answer all of them, and they're supposed, of course, to be submitted via text and not verbally. All right, conflicts of interest, I have research funding from BioMarin Pharmaceuticals for one of my research studies, and nothing else. To give you an overview of the next 25 minutes, of course, I start with the overview of the ENT manifestations in kids with MPS, then the therapy options, and in the end, I will present you three case studies. So what is MPS? Everybody of you knows it's a progressive multisystemic disorder, and it encompasses a group of rare leucosomal storage disorders that are associated with the accumulation of glucosaminoglycans in organs and tissues, and this accumulation can lead to the progressive development of a variety of clinical manifestations, and today, I will talk about the three important manifestations, the ear, the nose, and the throat, and the respiratory problems, as well as the problems with the ear, nose, and throat are very common in the patients with MPS and are often among the first symptoms to appear. The kids come to see an ENT doctor because they have ear infusion, a middle ear infusion, and then the progress starts in diagnosing MPS. So first, I will start with the ear, and more the outer ear, the alterations, and the middle ear. So what kind of problems do you see in MPS? Often, those kids have narrowing of the external auditory canals, which leads to chronic otitis externa. So here on the left side, you can see just a regular eardrum with no infusion. It's just totally fine, no infection of the outer external ear, and here in the middle, you can see it's very swollen. It's a little red, and on this side, you can see there is a chronic otitis externa, and often, you also have fluid, and it's infected, and it's not really easy to treat it because sometimes it's very aggressive, and it takes a long time to treat it. So then, you have the kids with the ear infusion, the middle ear infusion, then with chronic inflammation of the middle ear. Here, I show you one of the pictures. When you have a chronic inflammation of the middle ear, which stays there for a longer time, and all the time, if fluid comes out, then it becomes a hole in the eardrum or a perforation in the eardrum becomes bigger and bigger and stays there for a long time, which is also not very good because it predicts often infections of the middle ear. Then, in some of those children, you see the deformation of the ossicles, especially the stapes, and very rarely, you see thickened mucosa and granulation in the middle ear. Then, what kind of therapeutic options do you have for those? For the outer ear infections, externally infection, you can use local antibiotics, but for the ear infusion, you need to have. usually very soon after your diagnosis ventilation tubes. Why? Because here on this slide you can see most of the kids have big adenoids and those are blocking the eustachian tube, which is here. And when on this picture you can already see, I choose a picture where you have already an infection and here you see the mucosa is very swollen and because of that there is not really a possibility of a good ventilation in the middle ear and that's when the effusion starts to build. And when you have here in the middle ear the effusion, those kids have conductive hearing loss, meaning that you can't really get a good hearing from the outer ear into the inner ear because here is lots of fluid. And what you can do for that, you make a little mirroring to me, meaning you cut the eardrum and then you place a tube in it. There are different styles of tubes. Here you can see a Titan tube, which we use all the time in the beginning and with the kids because first those are very easy, they fall out after six months and then you usually don't have any problems with the eardrum. When you continue to have problems, you usually use a T- tube, which is made out of plas silicon and those stay in longer, but you have to take them out depending on how old the kids are under anesthesia because it hurts a little bit and sometimes when they're in there very long, they leave a little hole and this hole doesn't close by itself and it has to be closed. So when you optimize the ventilation of the middle ear, this is very important. This does not automatically normalize the hearing ability. Often those kids make a little jump in their hearing process, meaning suddenly they're speaking better, they're hearing better, but this often is not really helping with their actual hearing ability because they don't have only conductive fingers, they also have sensorineural hearing loss. So the clinicians, especially the ENT doctors should not delay considering hearing aids for the MPS children. It's very important and it's something I want to also give the pediatricians in the audience that you really look for that. It's important to use the hearing aids as early as possible. So the inner ear and MPS children the hearing loss seems to increase with age and you have a high variability. We don't really know the etiology has been discussed, but it's still unclear. Is it an infiltration of the cochlear duct, the stria vascularis or also the cochlear nerve afferents? We don't really know that, why? So the management of hearing loss to conclude this and to keep it in your mind is close observation. As soon as you see any infusion, send it to an ENT doctor and then with the management is as follows, it will be surgical. And we at the university hospital in Hamburg, we usually see those children in the pediatric department that my colleagues see them there every year and they have a yearly follow- up, but of course they are supposed to see in between their local ENT doctor to have a look if the ventilation tubes still in or if they are blocked or if they have already been fallen out. And then the second point in my presentation is the nose. Often those children also have nasal obstruction where does it come from? Here I gave you a CT scan of a coronal CT scan and you can see in this patient, he has a hyperplasia of the inferior turbinate, sorry, of the inferior turbinate, which also makes often the problems that they are, that the breathing through the nose is very hard for them. Then those patients have recurrent nose infections and sinus infections. Here on the second CT scan I showed you, one was the sinus infection of the left maxillary and those kids seem to have often those problems with the infections. And of course the adenoids, when they are very big, they block also the flow through the nose and it's also kind of obstructed because of that. And what can you do against that? To do the treatment options in this case, of course, the adenoids have to be removed. And with the nasal obstruction, there are different possibilities. Either you can use the cautery, or we use radiation frequency ablation, which also small as the mucosa. So, and then when you go to the next point, the throat or the mouth, here, one of our patients, I show you, it's, here's actually the typical signs. Here, you see the sickened lips, the gingival hyperplasia with gaped teeth, and then they have the mycoglossia, those are the bigger tongue. And on the one of the next pictures, I show you the tonsillar hypertrophy, which is also one of the problems, because they can't really open the mouth how they should open it, just because of this huge tongue. And which comes to the next point, it's not very easy to intubate those children. And that's also always one of the points. I really, really recommend doing surgeries on MPS children in a university, or like in a specialized hospital, where everything is well known, and the possible risks are also known by the anesthesiologists, and they know how to handle them. Respiratory manifestations, I show you one of the tables from Mühlebach et al., and here you see the key respiratory manifestations in the different MPS types. Here you can see one and two, they have upper, lower, and restrictive lung problems. In three, they are all minimal. In four, the upper and the lower are also not that high. And in six and seven, they're again more manifested. So often those children have sleep apnea, significant upper airway obstruction, the hypertrophy of the adenoids and the tonsils, and the sickening of the mucosa. tongue, the hypopharynx, and the larynx. So this is very important, not only because of the sleep apnea, but also in regard of having anesthesia in the future for those children. So I'm finished now with the ENT problems, and the ENT manifestations, and now I choose three children I've seen in our outpatient center. And the first one is a six- year- old boy. The history is he has MPS type 1. His initial diagnosis was made in December 2015. He had a bone marrow transplantation in July 2016, so half a year later. And he has a hypoplasia of his dense axis. He has a cervical spinal stenosis. He has a global development delay, and he was hospitalized because of a pneumonia in February 2015, and a herniatomy on both sides also in 2015. And here you can see the ENT visits he had. And first he came in, also it was sometime in, I think, June 2015, and he had middle ear infusion on both sides, and he was only a year old by then, so we decided, okay, we put ventilation tubes in on both sides. A year later, they fall out, and we did the same procedure again. And he had adenotomy and ventilation tubes, and on the audiogram here, where I show on my arrow, you can see the hearing is actually very bad on this case. We also did OIAs and Bera, which also showed he has not only conductive hearing loss, he also has a little sensorineural hearing loss. Not that bad, but still enough to, supply him with hearing aids. So in 2017, the ventilation tubes, they were not in anymore, and we decided to put in T- tubes. And here in the tympanogram, you can see it was all the time very flat again after they have fallen out, and this is the reason, or that's the reason he had to have again ventilation tubes. tubes. In 2018, you can already see his hearing and the testing has improved, and he is only at 40 decibels anymore, and the rest, usually normal hearing is between 20 and 30, usually in children, and the rest, they optimized with hearing aids in this case. But this was not the end of his ENT problems. He showed 2018 a cholesteatoma on the right side. He had tympanoplasty in 2018. It was atichotomy without reconstruction. So we didn't reconstruct the ossicles. And because usually when you have a big cholesteatoma, you first take out the cholesteatoma and then you reconstruct after six months or after one year. So in one year later, he had the revision tympanoplasty and again, also the atichotomy and a mastoidectomy. And it was still not reconstructed, his hearing. So that's also the reason why his hearing is again, pretty low on this audiogram because there is not really a possibility from the eardrum to get into the inner ear because the ossicles have not been reconstructed. So in 2020, he showed again a recurrent cholesteatoma and it was very small, but he had revision tympanoplasty and he got a port. What is that? That are a type 3a. That's a partial ossicular replacement prosthesis. Everything from the ossicles which was destroyed by the cholesteatoma was taken away and just part of the ossicles were replaced by prosthesis. And after that, now he is with 60 decibel, he has 70% of hearing. So that's actually okay and with the hearing aids, we get him probably to 80, 90% of hearing. Here you have a picture of him right after the surgery I took where he has still the bandaid on his ear and he was very, it's a very happy little boy. And hopefully he will be fine with the last surgery now. The second case report is the nine year old boy. His history is he has an MPS type 3c and has mitral and aortic regurgitation grade one, tricuspid regurgitation grade three. And his initial diagnosis was in January 2014 when he was three years. He has also a developmental delay. And in his case, he had also middle ear infusion, ventilation tubes and adenotomy in 2013. We found a sensorineural hearing loss. As you can see here in the bearer, he has a threshold about 50 decibels. So we optimized his hearing with hearing aids. But he kept on having problems with breathing and with his ears. So he had tonsillotomy. This means we smaller the tonsils. They will not be taken out like in total, just part of it. And we did again an adenotomy and put in T- tubes in November 2017. And the last visit, which was just a few weeks ago, he had no infusion on the right side. There was no T- tube in there anymore, but still no infusion. And on the left side, the T- tube is still in situ. And the last case report is a 10- year- old girl. And I think in this case, you can see also that you don't have to have a sensorineural hearing loss, but still conductive hearing loss can make you a lot of problems over a few years in the beginning. So she has the MPS type 1. Her initial diagnosis was in December 2011. She has mitral valve failure grade two, aortic valve failure grade one, also a dense axis dysplasia. She has allogenic bone marrow transplantation in March 2012. And she has spinal canal stenosis, hip dysplasia, X- lags, and carpal tunnel syndrome. Her first ENT visit showed she had also middle ear infusion, snoring, possible obstructive sleep apnea syndrome and she had ventilation tubes and adenotomy in February 2012,. The same thing with added tonsillotomy about a year later, and then again the whole thing again one year later in 2014,, and then again and again, as you can see. So it's a very often visit to the ENT and all the time the same problems with the adenoids. They are growing again and they make the problems with the infusion in the ears. So the last one was in 2018, and since then she doesn't have any problems anymore. The T- tubes are still in and that's the reason why it's not perfectly overlapping the curve, but you can see her inner ear is working perfectly and there is just a little conduction here from 10 decibels, so that is also quite acceptable and she can hear pretty well. This was the one just in. That one was in 2018, and here one which is from this year, from July 2020, and here you can see it hasn't really changed and the inner ear is still very good in this curve. So I'm at the end from those case reports and I will just give you one little introduction to one of the things I'm trying to do a little research in our department together with the pediatric and Nicole Muchol, which is the head of the department at our pediatric clinic, and the aim of our we want to find out the smell and taste disorders in children with MPS and the aim of the study was to investigate or is to investigate- I'm still on it- and the sense of smell as well as possible influences of the causal therapies. So is it: are the kids smelling well or is there any difference with kids who had ERT or who haven't had ERT? And we're trying to find this out. Which patients are included? You have to be at least six years and of course you have to be able to somehow tell me what kind of smell you can smell. So if you have a very bad developmental delay- sometimes it's not even with 10 or 15 years possible- they will be examined. Usually we only- I try only- to examine at the moment those who are treated with ERT, because that's the easiest way to get them, because they are often in the pediatric day clinic and you can catch them and during their getting ERT I can test them for smelling and tasting. But we don't have that many children who are able to get into the study who haven't had ERT. And then we have a questionnaire on the detected ENT, infections, therapies and previous surgeries. They are given to the patients and the parents and to be answered. And we, what are we doing? We do the olfactometry with this 12 sniffing sticks and gustometry, and therefore we're using flavors of the following four basic qualities: sweet, sour, salty and bitter. And that is actually the end of my presentation. I thank you very much for listening and I'm now getting into the chat channel to be able to answer questions. So the first question which came from the audience I will read for you, is: what setting is most appropriate for treating MPS, patients with ENT problems- general hospital settings or specialized centers? And, as I told you, in my opinion it is extremely important to filter those patients with MPS and of course they can see their local ENT for follow- up. But for surgery and also for diagnosing often and for helping with indications, I think a hospital which is specialized for MPS is important. So in our case we have patients from definitely the whole north and also from some of them are coming even from the south of Germany just to see our pediatric department and then they were referred to us and often they have the surgery at our hospital. There is a question also, what is the most appropriate age for tonsillectomy in MPS patients? So we usually do not do that often tonsillectomies, we usually do tonsillotomies first because tonsillectomy, there has to be a strict reason why you take them out. So for tonsillotomy, we usually, you can start with one year or with two years. Often first it helps to take out the adenoids, but if you can already see that the tonsils are touching, I would definitely recommend doing a tonsillotomy for better airway and for everything, also for speech and for swallowing and all of that. So there's the next question, do you recommend use of Leukotriene Antagoniste for runny nose in MPS? I don't do it, I usually try... to optimize that, but I, or me for myself, I don't do Leukotriene Antagoniste. Most of the time they don't really have the runny nose, it's more of the stuffy nose and I tell the parents to kind of clean it and use a nasal rinse to get it better. But when the inferior turbinate is very hyperplastic, very big, it's very hard sometimes to get better, like less obstruction. One more question, would you recommend total tonsillectomy at the first time? To repeat that, no, I definitely don't recommend... tonsillectomy I recommend tonsillotomy and no tonsillectomy so partial tonsillectomy. so next question is after tonsillotomy how often do you find the tons have returned to their previous size do you then do another tonsillotomy. Yes so this is the same thing with the adenoids that we often see that they have re- adenoids. so again they have been grown again and the same is with the tonsils they have been growing in between and we have to do re tonsilotomy, a tonsilotomy again, the same with the adenoids. the next question is: are there distinctive ENT signs between the different MPS types. and this is not very easy for me to answer as I have shown this one tablet you can see some of them have milder signs and some of them have stronger signs. and one of the things I haven't really explained because we haven't really found it out is, does the ERT help with the infections, yes or no? In some patients, yes, because of the ERT they have less infections, but it doesn't help with, for example, future sensorineural hearing loss, in my mind. I'm not sure about the transplantation, if this is done very early, if this helps or not, I'm not into this research and I'm not the perfect specialist on answering that question, but as I read in one of the papers, is that there is a possibility of helping the progress of hearing loss in bone marrow transplanting. Okay, then there are no further questions from the audience and I thank you for listening and I would like to end the webinar right now. Bye- bye.