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[00:00:08] Prof. Ingeborg Kraegeloh-Mann: Hello everybody. My name is Ingeborg Krägeloh-Mann, and I come from Tübingen, or I am actually in Tübingen, and I'm very happy to talk to you about the referral and clinical management of metachromatic leukodystrophy. It is really a pity that I can't see you. Maybe at another time we'll see one another at hopefully a meeting which won't be online anymore. You have heard in the last two sessions about this disease already, but before starting I have to tell you again about the regulations. Please don't take screenshots, that's the most important one. And if you want to reproduce things, please address me. You can have information from our papers without any problems. Please address me and you'll get them. And I think there are other things you know about it. At the end you'll be able to put questions in a written form. Today's objectives are to review different disease trajectories, also with respect to different needs, and then at the end especially to explore possible misdiagnosis. And again, the clinical management will be part of what we are talking about. And you have been confronted with that already during the last two sessions. And it is such an important thing and it's the overriding topic of the whole series. The early signs of MLD, how to spot them, and what to do to really find out a child with a disease. And to summarize what you have learned already, MLD is a very rare disorder. It is an autosomal recessive disorder with mutations in the ARSA gene which are responsible for enzyme deficiency which leads to lysosomal accumulation of sulfatides and that leads to demyelination which is seen in the MRI as this, sorry that was too quick, as this leukodystrophy and it causes severe neurological dysfunction. And I'll present you this little lady in a minute. And you also have been informed about that traditionally MLD is sort of happening in different forms. They're early to middle and late. The late juvenile starts before the age of two and a half and it is mainly characterized at the beginning by cross-motor problems which are due to spasticity and motor weakness and cognitive decline then follows. There is juvenile, the juvenile form is usually considered as a disease having cognitive and cross-motor symptoms starting at around the same time. And then in adulthood the later the onset is cognitive and behavioural problems are at the beginning and that is really a challenge for diagnosis and neurological signs come only late. MLD is characterized also not just by central, by brain involvement but also by nerve involvement so the nerve conduction velocity is reduced and a characteristic sign of MLD is the elevation of protein in the CSF. And I'll tell you about that a little later because it so important for the differential diagnosis. And now, the point of why it is important to think of MLD although it is a rare disorder because there are several treatment options evolving and you'll hear about it next week from Francesca Fumagalli from Milano. She'll talk about gene therapy, stem cell transplantation and enzyme replacement. In all these situations treatment has to start probably quite early to have any success so this highlights the need to really think of MLD and try to get the diagnosis early done so that children can be referred to treatment. So our main topic of today is the different disease trajectories and I'll start with a classical situation. You've heard about it already last time from Dr Simon Jones but I'll tell you again I think you can't see as many typical cases as possible. This is the little lady I've shown you before, the image, the photo. She was born after an uneventful pregnancy and also birth conditions were absolutely normal and her first development was absolutely normal. She was sitting without support at the age of seven months. She crawled at the age of eight months and she walked with assistance at the age of ten months. And you have to take into consideration that the percentiles for these milestones, she was in the 75th percentile or in the 50th percentile. So she was really a rather normally developing child in the middle of what is considered normal. And I'll take this up in the next slide, and to start with, to show you that her development was normal. But then, since the end of 10 months, there was some stagnation in her cross-motor development. And only at the age of 18 months, she started to walk alone, but was unstable. And when you take into consideration that percentiles, she used to be before, namely, the 50s and the 75, would have been 12 or 13 months, respectively. So she was really much later than for what she had shown at the beginning. And people and parents were anxious and consulted pediatricians but,hey were reassured that development may be quite variable, and so the child is still within the reference norm, so they shouldn't worry. Because otherwise, the child was very cognitively, very interested, and started to talk, and was interested in exchange. And only then, more than a year after the beginning of stagnation, the diagnosis was then finally done, because parents changed the – went to a hospital, and asthma deficiency was recognized. And shortly after, this terrible decline, which is so characteristic for MLDs, started. That can start with an infection, with fever, so that can, so to speak, trigger the decline. And in fact, one month later, she had swallowing difficulties, and lost her independent walking, and already five months later, she could no longer sit with support, and her speech was severely dysarthric. And I'll show you a little bit of her situation at that age. We have the permission of the parents for that. So you see, she is – she is in – she rapidly answers to when she is talked to. You see her outstretched legs, a sign of spasticity, and she is really not having any more truncal control, but some head control. She tries to bring her arms forward, but this is difficult for her. And when she is taken up, now she is asked to put – to lift her head, which is still possible. And she is really interested in when one talks to her, and she wants to grasp – she grasps at that time. Now she is more interested in the camera than in the toy, which is also quite normal. And only two months later, she could no longer grasp. She did not speak any more, and then she lost also head control, and lost her interest in the environment completely. And in that stage, she survived, severely disabled, until death at the age of eight years. And I'll show you this terrible – this devastating state at the very end. The mother tries to make her look at the toys, which she was interested in before, but she doesn't react any more. She is really in a near vegetative state. So when you look at these disease trajectories, you can identify that the child first is really completely normal, and that is extremely important. MLD has a totally normal development to start with, and then children fall out of this normal trajectory and have a stagnation period before they go into a severe and rapid regression and decline. And then they may stabilize on a very low level for years, which is a very terrible situation, or it is a very frustrating situation for the parents, not for the child any more. And it is important to know this three-phasic course, because you have to recognize the disease already during the stagnation period, and hopefully not much later, which is usually not the case. And that is why we all want to try to raise your attention for children falling out of their normal disease – of their normal developmental trajectory. I would like to take up her history to tell you a little bit about needs and management. We did a quality of life study in families with children having been diagnosed with MLD and it turned out that the two most stressing periods during the disease of their children were: first, when diagnosis was not yet known, because parents are aware that there is something going on wrongly, that the child is not as it has been, and that is the first very important message, and all of you who are pediatricians know that you should be attentive to worries of parents and should really be responsive to that. And then, once the diagnosis was done- and they were usually very grateful for a very open and honest discussion about the perspective of the child, because then they could adapt to this perspective and could still try to make the child enjoy as much of his life which was still before the child- and the second most terrible period for the parents, what they reported as most distressing, was this end stage, which can last quite a long time, where the child is in a near to vegetative state. So this is where parents need most of your support, also maybe of a psychologist, and what is also extremely helpful in such situations is to learn to know other families with children with MLD, because families can help one another quite effectively in this situation. The child needs quite some support at its difficult stages of the disease, especially at the beginning, when there is this gross motor decline. The children are often frustrated because they can't do anything what they used to be able to do with respect to gross motor function, but they are still, cognitively and with respect to language, quite attentive and interested. So you need to talk to, you need to support, to introduce support for this decalage between the two developmental domains and help parents and children so that they can still be cognitively active, although the motor development is not so brilliant anymore. Specificity which evolves may need medication- and this is what you usually take- including botulinum toxin, maybe even sometimes necessary, though there are no other rules than what you are used to deal with in specificity movement disorders, with one exception: children with leukodystrophies, such as metachromatic leukodystrophy, but also Kruppel disease. They respond quite well on vigabatrin, so you could also- this is used for epilepsy- you could use this for the spastic movement disorder when they suffer from these spasms due to the specificity. I have told you that the children then lose their swallowing capacity. So you have to start quite early to talk to parents about gastrostomy. That is extremely helpful then and of course when they can't sit anymore they need specific tools. But this is not something which is specific for MLD. This is just which has to be regulated according to the disease stage they are in, the functional possibilities they have or the dysfunctions they have. We have introduced to describe in a more standardised way this disease trajectory of MLD and so you can really show the time course from walking un-aided but unstable at the beginning, then walking with aids and walking impossible. So with these different scores- and you can visualise that, and I'll show you another child with a juvenile form which you have the different time scale here, much longer of course, and you see that the child started to be a bit abnormal with walking. It stumbled to a degree, the walking pattern was abnormal, but it stayed like that for nearly three years because a decline started, walking was lost and the decline was as rapid as in the earlier, in the late infantile form. I think you have been, you have learned about that already from Simon Jones last time. And again, the child stabilises on a low level here with some head control in this third phase. And in fact, when you look at a higher number of MLD children, this is something which is very typical. First in what I would like to show you in this graph, the late infantile disease trajectory is extremely homogeneous. Children go down rather rapidly and they reach the stage where they have no gross motor function anymore before the age of 40 months, all of them, at least all of them who we have studied. There is the juvenile form is much more variable, but the, I'm sorry, my screen responds too quickly. When you look at level two, where walking is lost, and level five where you only have head control, this happens within a very short time frame. All of the juvenile children, once they lose independent walking, they decline very rapidly, as rapidly as in the late infantile form. But I would like to draw your attention to the fact some patients are not represented because they had only cognitive decline for years. And that is, please keep that in mind. Language as a proxy for cognition is also something which is extremely rapidly declining in late infantile MLD, and it can decline quite rapidly in some patients with juvenile, but it's much more variable here. And what I would like to show you again is these clinical forms which we have just discussed at the beginning, where you have the late infantile, juvenile and adult form first with motor, cognitive and motor and cognitive. And we have asked ourselves the question, does really age at onset determine disease progression and what is the role of type of onset at disease, the role of type of symptoms at disease onset? And I'll show you here. We looked at the children starting as in the as late infantile MLD. And indeed, most have motor signs that is the lilacs in motor cross motor signs at the beginning and some very few had also motor and cognitive. And then when you look at early infantile, most had either... or motor and cognitive signs at the beginning. And only after the age of six and a half, in fact, some patients also started with only cognitive signs that is the blue colour here and which is true also for the adult situation. And what you And And what you can see in this graph also is that numbers are much higher in the late infantile so this is the typical MLD form and then adult and late juvenile MLD cases are rarer. And what I would like to show you here is when you look at this disease trajectories from time to onset, this is showing the different disease forms from time at onset to MLD, that is when they level two, when they lose walking or then at the right when they use when they only have had control. And you can see here that those who had cross motor symptoms at the beginning, either alone or with cognitive symptoms were much quicker than those, the blue ones from the last slide. The blue ones, only cognitive signs, they were much slower. So the type of symptoms determines progression. Disease progression is much slower when first symptoms are only cognitive. But that is only seen in late juvenile and adult forms. And I'll show you here, this is a bit confusing, maybe seem to you confusing. These are on the left the traditional forms, late infantile, early juvenile, late juvenile and adult. And you see that the early forms are quicker than the later forms.
[00:20:38] Prof. Ingeborg Kraegeloh-Mann: But when you then differentiate between only cognitive and cross motor plus minus cognitive, you see that this is really making a big difference, not just for motor in the upper row, but also for swallowing or for language function in the lower row. And you have heard about leukodystrophy signs in MLD. And that is what I want to show you before going to the final chapter, the early signs you have to be attentive to. Earlier signs are the white matter changes and the changes in corpus callosum. Atrophy and cerebellar white matter anomalies are later changes. And also for MRI, we have developed a scoring which shows you here in the graph that the juvenile form when it's at onset here, at onset, these children already have symptoms on the MRI. So when you are suspicious of a child having a juvenile form, you can rely that the MRI is already showing white matter changes. Whereas in the infantile form at the very beginning, you may have MR which is considered normal. And I want to show you such an MR which has been considered normal because the white matter changes are still quite variable at that age. But the neuroradiologist was not aware that early signs in the corpus callosum can be an indicator for MLD. So to then finalize my talk, I would like to address with you the possible misdiagnosis and pitfalls. And the first, and I try really to show you that developmental trajectories are important. A child which is presented to you with a gross motor development being slow, but which has been quicker before, this is something you really have to take out and look at it in more detail. Or a child which is addressed to you because of school difficulties and behavioral disabilities, but they are new and the child was beforehand not at all showing these signs. You have to check that in more detail. So you have to make a difference between a child which has always shown these signs and the child which is really falling out of its trajectories and going into stagnation. And the next point is I have shown you that at the beginning that the CSF protein is high and that the peripheral nervous system may be involved at the beginning as only sign. This can be misdiagnosed as Guillain- Barre syndrome. And even contrast enhancement of nerve roots can occur in both conditions. So you should check the ather enzyme in a child which shows little or no improvement on intravenous immunoglobulin in the diagnosis of Guillain- Barre syndrome, especially when the weakness was subacute. And then when you thought of MLD, but you got a normal enzyme result, check for sulfatides in urine because it may be activator deficiency and you have this topic has been addressed in the last two sessions already. And as I showed to you, MRI may be considered normal at the very beginning in the late infantile child, not in the later onset. And if this is so, please, you could consider asking an expert and I have shown you this corpus callosum signs which really have to be, you have to look at it specifically. And there may even be, when there has been contrast given, there may be an enhancement of nerve roots which has been overlooked. This is a child which we looked together with the Amsterdam group and who had a normal MRI with respect to local distribute changes, but there was an enhancement of nerve roots. And this is quite new and it is a paper which is hopefully coming out soon between the Amsterdam group. Shanice Beerepoot is the first author and our group. There are about 20, about 1% to 22% of patients with late infantile MLD who have a squint even before they have any gross motor symptoms. It can occur weeks before the onset of gross motor symptoms. In around 80% it started before the children had gross motor symptoms. So in a child which is presented to you with a squint, please also think of looking at ARSA deficiency. And don't forget, and I would like to repeat it for the 10th time I think, stagnation after normal initial development is something you really have to worry about and you really have also to think of MLD. And that was the last and I would like to thank you for your attention and I just put the names of our group and also of the Amsterdam group but before because it's quite late already I think we should start now with the questions that is probably more interesting to you. So the first question is what should I do when I think of MLD in a child and want to have it checked? And as I said already, please do first the enzyme measurement because this is not very expensive and it is quite quick. Nowadays we have not so rarely the situation that the first test is genetics because people are very quickly thinking of doing a screening so when your geneticists are offering whole exome sequencing very easily you could also, especially when you think it could be MLD but it could also be something else, you then could also go into whole exome sequencing. But from a pediatric neurologist point of view I think you should really think of looking at the enzyme.
[00:27:33] Prof. Ingeborg Kraegeloh-Mann: So next, when a child does not yet have symptoms, can MLD be diagnosed and is there a biomarker to predict the form and the cause of the disease? Yes, it can be very reliably diagnosed again with enzyme deficiency and genetics. And both can be biomarkers for the progression. Enzyme results are very low in the rapid forms and higher in the slower forms. And for genetics there are some, but in around 20 to 25 percent you can predict the cause with your genotype but genotype very often does not precisely predict you the cause. And of course when you have a sibling with MLD then you can be quite sure that if there is a sibling with late infantile MLD your child will have also a late infantile cause and not a later cause. But onset can vary for quite some months, even a year in late infantile and in juvenile it can vary between months and years even. But when you have a cognitive first MLD trajectory so it will be cognitive also in your sibling. Is epilepsy a feature in MLD? It is a very late feature and not very complicated. So this is not something which gives much worry to the parents. So I wonder, we sometimes see hypotonia in the late stage rather than spasticity. Do you see this and why? Yes, that is true because it may be that during the decline the spasticity is predominant but then the weakness takes over because the neuropathy is getting more important and then which is a relief for the child in fact because spasticity alone gives often very severe discomfort, spasms and that is why I talked about vigabatrin in that case. So it is the neuropathy. Do we have any more questions? Yes, that is. Can convulsions be present in MLD? It is a later sign. Some children never have epileptic seizures and they are usually not very complicated, not very difficult to control. I am looking whether there are still no more questions. So I think we are just at the end of our session. I do thank you for your attention again and if you have anything specific to ask about our, if you want to have some results in more detail or papers, please address me and I would like to motivate you to go into the next session because then it will be all about treatment. Thank you very much.