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IAGSA—Discussion meeting with parents— 29 May 2001
doi: 10.1053/ejpn.2002.0580 available online at http://www.idealibrary.com on European Journal of Paediatric Neurology 2002; 6(Suppl A): A77±A86
DISCUSSION MEETING
IAGSA ± Discussion meeting with parents ± 29 May 2001
Introduction The essential part of the discussion held on 29 May 2001 at ``Fondazione Mondino'' between the parents who were present, some of them accompanied by their own doctor, and the Chairmen of the previous day's meetings, follows here. It was really an interesting and stimulating session in which several problems that worry the parents were clearly pointed out. At the end of the meeting, they were satisfied because the opportunity to discuss their problems was very helpful in order to assuage their many doubts but also to encourage them to carry on with their difficult daily routine. This discussion was also useful for us, as doctors, because if we understand better the problems and difficulties facing these families every day, we can promise them as well as technical aid, a sharing and genuine human presence at their suffering.
Discussion meeting Lanzi I think Mr Oriano deserves to be the first to ask a question. Oriano First, I would like to thank all of the Contributors for their dedication and, especially, for being so kind as to accept the invitation from our association. It is very important for us to meet them because in them we place the greatest hope and expectations for the future of our children. Certainly, our children live in the present and not in the future. We are well aware that the timing of medicine and research is very different from the stringent needs of our children. However, at the 1090±3798/02/06/A0077+10 $35.00
same time, we do hope that your work and your commitment may soon lead to concrete results and may give us an opportunity to get out of the tunnel where we are at present. I don't refer to us as parents, but especially to our children, in terms of hope for them. We have many questions and we hope you will be patient enough to answer them all. Unfortunately, Aicardi-GoutieÁres syndrome is still a disease that is poorly known internationally. Consequently, there are still cases where not only is the first child born affected by Aicardi-GoutieÁres syndrome, but the second child is also affected. Still today this disease is incorrectly diagnosed at first and is seen as a possible consequence of a viral infection. In order to prevent these cases, I am asking whether an international protocol may be recommended in order to allow for a prompt diagnosis whenever such an unfortunate event occurs. I repeat, these wrong diagnoses still occur and there are families today who have an affected child aged perhaps 4 or 5 years, but also have a second affected child; perhaps only 2 years old, born in the year 2000, but nonetheless affected by Aicardi-GoutiereÁs syndrome. I think that an international protocol would help. Please consider that, in the United States ± perhaps the most technologically advanced country in the world ± AicardiGoutieÁres syndrome is practically unknown. They know the Indian Cree syndrome but not AicardiGoutieÁres syndrome ± or know it only partially. What do you think about the drafting of an international protocol? Aicardi It is true that the syndrome is not yet widely known, despite all the efforts that have been made to make it better known. I think it is true that there are still misdiagnoses and especially the confusion with infectious disorders which we actually made & 2002 European Paediatric Neurology Society
A78 with our first family and which is easily understandable. It is obviously not a common disease and it raises the problem of all rare diseases. In France, for instance, the information from the Registry of Rare Diseases is sent out to physicians by INSERM (Institut National de la Sante et de la Recherche MeÂdicale) categorized by the organ under investigation. On an international level, I cannot see what we can do. We can try to publish in journals which are widely known and we have done this (FrancËoise GoutieÁres and myself) quite recently. This is the one thing we can do which is likely to improve the recognition of this syndrome. Barth I think it would not be very practical to propagate knowledge about the Aicardi-GoutieÁres syndrome for the large paediatric or neurological population because each message decays. Whenever you get to the broad public with such a message, it will be in their minds for a few months, a year, then again it fades away. But there is another option and it is that in general, paediatricians and neurologists should be critical about the diagnoses they make and not refrain from going back on their first diagnosis and consulting colleagues when they still have doubts. In my country it is not unusual, in Aicardi-GoutieÁres syndrome, for the first diagnosis to be wrong and then usually this turns out to be wrong for several criteria. For instance, there may be fever and there may be cells in the cerebrospinal fluid so the paediatrician may think there is an infection but when that infection lingers on for months and months, he or she may have second thoughts about the kind of infection ± or whether it is not an infection at all but something else ± and then consult a paediatric neurologist. Most paediatric neurologists in my country are aware of Aicardi-GoutieÁres syndrome even though some have never seen it. So my main hope is that by having second thoughts, the proper diagnosis will eventually be made within the time necessary to allow the parents to have a good genetic counselling and to prevent a second birth with the same diagnosis. I completely concur with Professor Aicardi that this is a very difficult message to propagate ± but in general this is how a disastrous consequence of medical ignorance may be prevented. Question You have told us that, at present, researchers are heading towards considering interferon-alpha as one of the factors causing the greatest disorders
Discussion meeting with parents connected to this syndrome. However, we still do not know whether interferon-alpha is the primary cause or whether, upstream of its increased level, something else has occurred. Do you already have a hypothesis in terms of research and of possible results? What direction do you intend to follow? Aicardi I think that all physicians who deal with this syndrome are perfectly aware that interferon is not the be-all and the end-all; clearly there is something behind the situation. Interferon at the moment is the convenient marker for the condition in terms of diagnosis. Whether it is a cause for the disease, not necessarily the only one, or whether it is only another manifestation of the syndrome remains to be firmly established. I would like to pass this question to the physicians who are more competent than I am in this field. Kuijpers I fully agree with Professor Aicardi. I think that interferon-alpha, at the moment, cannot be judged as the cause of the disease. It is something that goes hand in hand with other factors. But the levels of interferon-alpha drop in time, whereas there is no change in the clinical progression of the disease. So, I think that scientists and physicians and also parents should not be completely focused only on interferon-alpha. There is probably another underlying factor and as long as we do not fully understand what the pathogenesis of this particular clinical disease is, then it is very hard to tackle. There are several points that should be sorted out in the near future and that is simply a matter of time. First we need to find a kind of pathogenic mechanism ± what is this disease caused by? Second we need to see whether we can find the gene. These two aims will probably lead to an understanding of the disease but I think it is too early to speculate on this. Lebon Interferon is not the only marker in this disease, but I think that it has deleterious effects on the central nervous system. This was shown by the experiment of Campbell, but it was also shown by Gresser 20 years ago in the model of congenital infection with a virus (choriomeningitis virus) infection in the mouse. When he treated the infected mice with antibody against interferon-alpha the mice were better than the controls. I am sure that interferonalpha plays a role in the development of some
Discussion meeting with parents symptoms of the disease. It is another problem to explain why interferon is produced, but this is not an ``ideÂe fixeÂe'' for me, and I think that a mutation of one gene could constitutively produce interferon-alpha without the presence of virus. Question I am a parent with two children with AicardiGoutieÁres syndrome. I would like to know why some families have two children and some families have only one child affected with this condition. Aicardi This is a problem of probability. The probability for parents who are carriers of the gene for this condition have a one in four chance, as was explained by Dr Crow, of having an affected child and a three in four chance of not having an affected child. This obviously does not mean that when you have an affected child you are then going to have three normal children. It is like throwing dice, you can get the same number several times, despite the fact that you have one chance in six of throwing the same number. That is the way we explain the probablility. It is not a very good explanation, but it is the one which is true. Question We understand the one in four chance of having an affected child again, but as families we are aware that ± and you know more families than we do ± if you count up the number of normal children and the number of affected children, it seems to be skewed, to be higher than one in four. Why does it look that way? Crow I wonder if the explanation for this observation comes from our earlier discussion about the possibility for misdiagnosis of the disease, so only when you have had a recurrence of what you thought was a sporadic condition or an undiagnosed congenital infection or an undefined congenital infection would you consider in some cases the diagnosis of Aicardi-GoutieÁres syndrome. Perhaps it is simply a bias because of an underrecognition of the diagnosis. I have no doubt that this is a genetic disease and that there is a one in four chance of recurrence in each and every pregnancy. I think that if you took enough families with the correct diagnosis in all, it would be a one in four chance. That also means that both parents
A79 can be carriers and never have a child with AicardiGoutieÁres syndrome, so there are couples presumably who never have a child with AicardiGoutieÁres syndrome because there is also a three in four chance that you will not have a child who is affected. But I wonder if your observation is simply due to the fact that it may be not diagnosed unless you have a second case. Question One priority for families ± and perhaps not so much for doctors ± is that we need to know how to manage our children day by day. Can you give us your ideas on feeding, on positioning in wheelchairs, possible surgery, what the future is, and the daily management that would help us take better care of our children. I have many subject areas I would like to ask about. First I will ask about feeding. All these children have problems with feeding difficulties. Some are tube fed and become normal in size, but there are many who eat just small amounts orally and are very small. Should these children be in the normal height±weight range, or is typical that they are small? Do you recommend tube feeding for the best nutrition and the best health of these children? In some countries it is recommended but not in others. Aicardi In the first place, there is no universal rule, because the cases are not the same. Some children do eat reasonably well, and do not need any special method of feeding ± but some, especially the earlyonset cases, certainly do, because feeding problems are really quite often in the forefront of the clinical picture. In these cases obviously all the available techniques should be used, including tube feeding. In severe cases where it is essential to maintain the infant in a reasonable state of nutrition but it is impossible to do this with natural feeding ± then this can often be done by tube feeding. There is no reason for systematically rejecting tube feeding. I have seen patients who really improved considerably when the tube was inserted, not only from the obvious nutritional point of view, but also in terms of their general well-being and comfort. Question Earlier, reference was made to the alteration of the white matter. We would like to know whether white matter is the same as myelin. We have heard
A80 that, for multiple sclerosis, there are some treatments aimed at strengthening myelin that seem to be beneficial to the patients. Would such an approach also benefit Aicardi-GoutieÁres syndrome children? Aicardi I am not very aware of the treatment of multiple sclerosis because I work exclusively with children in whom multiple sclerosis is not a common disorder. No, myelin is not the same as white matter. Myelin is just one of the major constituents of white matter, but not the only one. There are many other proteins and lipids and other substances which are also constituents of the white matter. I would be happy for someone else on the panel to comment on multiple sclerosis. Kuijpers The pathogenic mechanism behind multiple sclerosis is to a very large extent unknown. It is caused by the influx of inflammatory cells, white cells, Tcells to be exact, and these cause the inflammatory lesions. What they exactly recognize there is still a puzzle. We have some clues, but they may be different from patient to patient. Nonetheless, if you take away these cells, so you delay their influx, and if you can dampen that inflammation, then the white matter is spared more than myelin production is boosted. So you just take away or you prevent inflammation. And that is why substances now widely used in multiple sclerosis seem to work. One substance used in multiple sclerosis is interferon-beta for instance; there are also other medical approaches that affect more or less the same type of cell, but in a different way, although all are meant to prevent the inflammation. Question I come from Vancouver, Canada and have a 3year-old daughter with Aicardi-GoutieÁres syndrome. First, thank you for your work; second, my daughter received her diagnosis from a geneticist and the paediatric neurologist was not aware of Aicardi-GoutieÁres syndrome. My daughter has bilateral basal ganglia calcifications, she has also had two positive results of leukocytes in the cerebrospinal fluid over a 4-month period. The interferon tests were not easily available and the Canadian doctors did not really want to push to have this done. So, my first question is: can this diagnosis be made based on those two symptoms? Should we at this point still have the interferon
Discussion meeting with parents tests done? Is there an approximate age where the interferon level drops so low that perhaps having the tests may show nothing? My second question is my trying to understand correctly the presentations. Did I understand correctly that this disease can be static, that there were some children where this happens, that in fact the calcifications do not increase after the first to second years of life? Aicardi I think the best person to answer your first question is Professor Lebon. Lebon Yes, at 3 or 4 years interferon could strongly decrease, as you saw yesterday in the diagrams. Barth There are few places in the world where the interferon-alpha test can be done reliably. We, in Amsterdam, used to send it to Professor Lebon. But until a few years ago we did not do that either; we used to make a preparation of the cells in the cerebrospinal fluid to examine under electron microscopy. By doing that, you can see peculiar inclusions that are specific for interferon-alpha. So, even if you do not have easy access to the determination of interferon-alpha such as Professor Lebon has in his laboratory, there is an alternative route which is quite reliable and may be available in your local medical centre. Lebon I am sure that in Canada there are teams which can dose interferon. Such teams working on interferon are present in Montreal; I can give you their address. Aicardi With regard to your second question about the late appearance of calcifications, this is certainly possible. I have seen it in at least in one patient. Calcification still appears early in life, not I would say after the first year of life or the first year and a half. I have another comment on this which causes us some concern. A computerized tomography (CT) scan is excellent for exposing the calcifications, but nowadays CT scanning is replaced more and more by magnetic resonance imaging (MRI) and MRI is
Discussion meeting with parents highly preferable to CT in all regards, except one: calcifications. So what seems to be a diagnostic hazard is that when a doctor is trying to make a diagnosis in a child with white matter disease and increased cells he may miss the calcifications unless he makes that jump in his mind. That of course is not basically your concern, but it should be ours. Crow I think we don't know the minimum diagnostic criteria for this disorder. If your child has a normal cerebrospinal fluid interferon-alpha level, it will not take away from the significant possibility that this is an Aicardi-GoutieÁres syndrome. So I think in a sense you have to make a decision about whether you want to put your daughter through that test, because a normal level would not make it less likely; a positive result would confirm the diagnosis, but I don't think there is a should or a shouldn't; I think you decide. The other thing is that there are some cases that are static, children who do not regress, who do not get worse. I think Professor Lanzi's contribution suggested that children sometimes improve. Question Would you recommend immunizing these children with routine vaccines that are usually planned in the first years of a child's life? What did you do with the patients that you personally follow? Aicardi I certainly immunize my patients; I think they are particularly susceptible or may be particularly susceptible to infections. It does not help for these children to catch measles or the sort of infectious diseases that can be prevented by immunization. I do not think there is any definite contraindication to immunization in these patients, even though the small number of cases makes that statement perhaps a little too absolute, but my feeling is that certainly these patients should be immunized like the rest of the children. Lebon I agree with Professor Aicardi about the probability of no side-effects with vaccination; but what is the efficacy of vaccination in these children? Because they produce interferon which is anti-viral and when one injects the measles, or mumps or rubella vaccine, one injects live viruses, viruses which normally replicate in the child. The question is:
A81 have you tested immunity in children after vaccination against measles, mumps, to know if the immunization is present? Probably few children have been vaccinated, I think it might be important to study if the vaccinations were without any effect. Aicardi The answer is no we have not. Question In your paper you said that you have identified the locus 3p21. But we know that based on the results of DNA testing for many of us this locus was not recognized in all cases, in fact not in almost half of the cases. How do you intend to proceed for those children in whom the locus has not been recognized? How will you continue your research? Crow One of the grants we have applied for is to perform a genome search by the same technique we used the first time, using only samples that we know are not linked to chromosome 3p21. So whereas previously we had 13 families available to us with enough DNA to use ± because you need quite a lot of DNA for that kind of search throughout all the chromosomes ± now, because of the results of our study and because of this organization, there is more DNA available, and because of the collaboration within the group I belong to ± there are many more samples. The idea is to use those families that do not link to chromosome 3p21. So, one of the grants has been to an organization called The Marshfield in America. It is very good because it is a free genotyping service. They will do for free what we have spent a year doing and they will probably do it in 2 months and probably better. So, I will be very pleased if they accept our proposal. As an American sponsor is needed, Ian Campbell sent a letter of collaboration for the grant. This is specifically to try and identify a second locus in families who are definitely not linked to the first. Previously I said that there are some families who may be linked to chromosome 3p31; of course they may also be linked to the other locus or the other loci. But I think that this is a sensible way to proceed, to use families who are definitely not linked to try and identify a second locus, and then we can look at all the individual families. The second approach ± and I mentioned it in my paper ± is that if you identify the first gene, you may be able to quickly leap-frog to the next gene at
A82 another place, because if you understand gene function ± sometimes you can jump very quickly, sometimes not.
Discussion meeting with parents displaced? So, is botulinum effective and does it have any side-effects? Could it be dangerous? Aicardi
Question In talking with other families, we have noticed that the regression in this disease is not slow, it is episodic. When a stressful time comes, then the child may rapidly regress and then stabilize. And then another stress comes and the pattern is repeated ± do you agree? For example, the stressful tests we have noticed are if the child is dehydrated, or overheated, or if the child loses calories for 2 or 3 days because they are sick, they may regress. And a very noticeable stress is sedation ± for example for an MRI ± or anaesthesia for surgery. Very often our children, when they wake, are not the same while going through these stressful periods. Have you noticed that? Should we try to manage our children's lives so that there is little stress? And should they no longer have MRIs because this requires sedation ± and should surgery be limited because they require anaesthesia? Aicardi Yes, there are definitely periods of aggravation following episodes of infection or even episodes of fever without detectable infection, especially acute nutritional problems following any sort of stress ± as you say. Let's put it that way, as it is very broad. Clearly there is a relationship between the general health of the child and the evolution of the disease. I think that the aggravation is mostly temporary, but this perhaps needs further analysis. What you said regarding the magnetic resonance I think is important, because this usually requires at least sedation and very often general anaesthesia, which is not desirable in these children. I would certainly add that in many cases I cannot really see the necessity of repeating the MRI investigation at least in the close range period once you have a clear-cut image that is sufficient for the diagnosis. Certainly you can wait for years before repeating it because it doesn't add very much, as far as I can tell. Question We have a question regarding the treatment of hypertonia, i.e. when children suffer from attacks and become rigid. Would you recommend the use of botulinum? Another question: does it make any sense to cut the muscles before the hip is
I think that botulinum toxin is not generally indicated in these patients, because the spasticity they have is diffuse and it is difficult to use the botulinum toxin in very diffused contractures. On the other hand, in the case of a specific problem around a particular joint, then the indication of botulinum toxin is possible, and this could apply to the adductors, and apply to other muscles as well. But that is a temporary effect and it has to be included in a general plan of treatment. Botulinum toxin is not a miracle drug, it can be used in certain definite circumstances, for specific purposes, but it should not be thought of as the complete answer or even an answer to the problem of these children. Regarding the second question, this is also a specific problem. In general, I do not think that it is a good idea to operate on these children. However, if there is an immediate emergency threat on the hip, this possibility can be considered. Question I would like to comment on botulinum and doctors. My younger son had botulinum shots. The third time he went to severe seizures; his brain was swollen like encephalitis; he had very severe reactions, lost his eye-sight, couldn't move any more and it took many months for him to get back to normal, and he has permanent vision loss. I believe Professor Lebon said that one other child with this syndrome had a similar reaction to botulinum toxin, so I would be very concerned about other families trying this treatment. I don't want this reaction to happen to the other children if this may be something related to the syndrome. As for releasing adductors and other muscles, if it can be done under a local anaesthetic, I think that would be better. My sons have had a local anaesthetic rather than a general anaesthetic. I recommend this if it is at all possible. Aicardi I am not aware of any sort of accidents like the one that you observed. There is now a large experience with botulinum toxin, not specifically in this syndrome, but in the general population, and there are known complications, especially when related to large doses or excessively large doses which can produce weakness and lasting weakness ± not indefinitely lasting, but for some time. I
Discussion meeting with parents have never heard of convulsions precipitated by botulinum toxin. I certainly believe that botulinum toxin, like any drug or any surgical intervention, has to be included in a general plan of treatment of the child. It may be quite useful to reduce a specific contracture at one joint, but certainly not as a basic sort of therapy. That is certainly not an aim. It has very specific aims if any indications exist; these are for specific problems and temporary problems, especially in the case of these children, who have a number of other problems and who certainly do not tolerate general anaesthesia very well. If any medical process has to be done, clearly it would be better to do it, if possible, under local anaesthesia.
Question I have a question for both Professor Barth and Dr Kuijpers. Earlier you discussed a new pilot treatment. We think we have understood the idea underlying this treatment. At present, we know that interferon-alpha is not the main cause, but we know that it is responsible for some damage to these children. For this reason, we attempt to limit such damage. However, also based on our personal experience, we have seen that, usually, interferonalpha tends to decrease in these children while they grow older. Do you think that this kind of therapy may also help those children whose interferon has already dropped below 2 or is dropping ± perhaps it is now around 5, 4, 6 ± and is now very close to a normal level?
Barth I think that you have understood the message well. The message is that it is possible to lower the interferon-alpha by the use of a certain drug. You also understood that interferon-alpha is contributory to the damage, but we don't know if it is really the origin of the problem. So we have the idea that it might help some patients with a high level of interferon-alpha to bring the level down, but nothing has been proved about possible results. So we have to rethink what we have found before we can take the next steps that may be a reward to early cases. I think the IAGSA would be an excellent platform to discuss such an approach before we go to the next step and maybe go for a proposal. This is very preliminary, but we are interested and I'm sure we will come back to it.
A83 Question My 5-year old boy is affected, but I have another 8year child who is unaffected. First of all, I would like to thank you; second, we come from Rome and we would like to acknowledge that Dr Bertini has helped us very much with this syndrome. Just before we went to see him, he had already diagnosed Aicardi-GoutieÁres syndrome in a little girl. Our diagnosis is not confirmed yet, but it is supposed to be Aicardi-GoutieÁres syndrome. We were very well assisted and I would like to acknowledge this, because I know how painful it is when you realize that you are confronted with a rare disease. My child is very nervous and, at times, he is also very stiff. Can these muscle contractions be painful for him? I would also like to add that my child underwent adductor surgery and has considerably improved after that. Before surgery, he could no longer open his legs, whereas now he can keep them apart and he has also become less nervous. I have another question: do you have any idea about the life expectancy of these children? How long do they live? This is something I really would like to know. Aicardi Regarding the second question, we don't have any systematic follow-up study, but we certainly know that there is a high mortality, especially in the first years of life in the severe cases with early onset. In the milder cases of late onset we have certainly seen patients ± at least two patients ± who are now 17±18 and are doing reasonably well. So I cannot give a complete answer, but certainly there is a possibility for at least some of these patients to live for a reasonable period of time as far as I can tell. About the pain in muscles: muscles are not usually very painful; the hips may be, on the other hand. It is certainly uncomfortable to have a marked abduction of the thighs and makes life more complicated as well in terms of care. As I have already mentioned, there are specific indications for a specific surgery with a specific purpose. That is the best answer that I can give. Barth This does not apply just to your case, but I think it is worth a general comment for the parents with Aicardi-GoutieÁres syndrome children: the rehabilitation doctors or their orthopaedic surgeons may come to think of the problem of those children as a kind of spasticity similar to cerebral palsy. In some
A84 cases, there is, in addition to spasticity, what we call `dystonia'. In these children there may be very painful spasms and I think it is very important for parents to know that and, when they have a suspicion of it, to specifically remind the rehabilitation doctor and the orthopaedic surgeon of the situation.
Question Since Aicardi-GoutieÁres syndrome seems to have some features of an autoimmune disease, have you ever considered the possibility of performing bone marrow or stem cell transplantation? This is a question from parents and not from experts, but we would like to know your answer.
Discussion meeting with parents Question I would like to thank the Association for what they are doing for these children who are really suffering. My 4-year-old son is affected; the diagnosis was made by Dr Bertini when the child was 4 or 4 months old. He is suffering quite a lot and it is not easy to manage him, because he presents with a very intense dystonia. It is even more difficult to manage his disease when he is sleeping. When he is relaxed and sleeps, he suffers from sudden apnoeas, so that he must be given oxygen. Is there a method you can recommend to manage his breathing. Consider that, sometimes, when his apnoeas are very severe, we have to rush to the emergency ward for oxygen and other aids. Thank you. Barth
Kuijpers That is a very good question, but a good answer is only possible if you know a little more about the mechanism and we just started thinking about a therapy. We did it with a kind of bolus infusion with methylprednisolone to limit the side-effects of that steroid treatment. What we did see on one hand is a very steep drop in interferon-alpha ± that would be great if this was the cause of the disease. On the other hand, the cells that we characterized were never seen before. Also, if we look at what the treatment did to the number or the phenotypes ± how these cells looked ± that had not changed at all. Now the question we have to answer first is: are these the cells that we should direct therapy at? Your question: should we give bone marrow transplantation or stem cell transplantation? ± is very difficult to answer because those types of therapy are in a way very cruel and should be limited to those patients who have no other alternative. It is too early to say that this is the same in Aicardi-GoutieÁres syndrome. So I would say: try to have a little more patience before jumping to choose the most cruel therapy available. If this disease is revealed to be driven by something like a cell type which is not a leukocyte, and not a white cell type, driven for instance by a brain-derived cell, one can insert bone marrow from a perfectly matched donor or a healthy sibling, but end up with a similar kind of mechanism. This brain-derived cell will cause the same autoimmune or immune attack, even if it is due to a new bone marrow. In that case, the disease will be exactly the same and the child has gone through a terrible period of ± in effect ± false therapy.
The problem that you describe is not specific for Aicardi-GoutieÁres syndrome, but it has to be analysed before it can be treated. In neurologically handicapped children, there are two reasons for apnoea ± I am excluding the third, which is seizures as I assume that in this case these are not seizures. Either these are `obstructive' apnoea, which means that when the child is lying on his back he may become obstructed because his tongue falls back or because his palate does not lift enough. For this, the treatment should be directed at removing or at least relieving the obstruction. The other possibility is that the apnoea is caused by an abnormal steering mechanism of the brainstem (`primary' apnoea). In most cases, it is `obstructive' although I do not know your son's details. In our situation the child is usually analysed before advice and treatment can be given. This is not a complete answer but indicates the analysis needed to relieve the problem. Question I come from Rome and I have a 5-year-old daughter. Going back to the 25% chance to have an affected child, I have noticed that there are families where the first child is healthy and the second is affected, and I have seen several cases where there are two brothers or two sisters, both affected. Do you know of any families where the first child is affected and the second is healthy? Crow The answer is `yes'. If you take a coin, heads and tails, you toss it once, it can come down heads once; you toss it again, it can come down heads again,
Discussion meeting with parents but it doesn't mean to say there is no tails on one side. It is chance or probability as Professor Aicardi said. If you have had one child affected and the diagnosis is made, there is no way of saying that your next child will not be affected, so for some couples this is a strong enough reason not to have another child. Perhaps this is the reason why you have not met such families. I am convinced that this is a genetic disease. It is an important observation, especially when we consider that the disease may be due to an undefined infection. As I mentioned in my presentation, there are families where two affected children are separated by the birth of an unaffected child, over a long period of time, and this is very much against the possibility of an unidentifiable infection that disappears and reappears. This is important evidence. I would like to make the point here that I have come across many of the samples from people in the audience and their children. These samples have been collected through their physicians and doctors and taken with their permission. I have a number of consent forms and if families wish to be involved in the research or to continue to allow us to use their samples and those of their children, then please sign these consent forms to allow the research. Question My orthopaedic surgeon has recognized that my children are not very spastic, but they are rigid and he says the difference is that in spasticity the muscles are more uneven in their strength and there are more spasms. With rigidity ± the muscles are more even and stiff. Have you recognized in other children that they have rigidity more than they have spasticity and is there any different way to control this rigidity; for example would the medication baclofen help that? And is there any specific treatment for dystonia as well? Barth First of all, in Aicardi-GoutieÁres syndrome you may have pure spasticity, you may have spasticity combined with dystonia and you rarely have only dystonia ± I am not aware of cases with only dystonia. The hazards of both are of course dislocation of the joints and pain. Dystonia especially may cause pain. You ask whether there is a specific treatment for dystonia. Well, there are drugs that are specially designed to treat dystonia, but it is an empirical treatment and it rarely completely relieves dystonia.
A85 Question Going back to the treatment of rigidity ± we said that botulinum may carry some risks and I am rather worried. Is there any alternative treatment to botulinum, should my daughter need it? I have a second question regarding child feeding. With regard to tube feeding, can we give special liquid food to our children, also orally, as is usually done with terminally ill patients, for instance? Does this make any sense? When a child improves through better feeding, is this more connected to the quantity of food he receives through the tube or to the quality of that food? Could we also use some similar food orally?
Barth For your first question: there may have been a little misunderstanding about the botulinum toxin, because as is given, it is applied very locally to the place where the nerve enters the muscle. By doing that, you paralyse the muscle for 3±6 months. The importance of this treatment is that you do not actually damage the muscle or tendon or nerve, you only remove its action for a certain time. The implication is that you can apply it to several muscles at the same time and see whether it works and, if it works, it can help in the decision for instance to cut the tendon. So, in a way, the application of botulinum toxin and surgery are complementary and usually there should be a good co-operation between the rehabilitation specialist and the orthopaedic surgeon. They should combine their efforts, ideally, to allow a good choice of what to do. And there are other kinds of treatments for spasticity and dystonia, but they are not available in all the centres, so I think that it is perhaps not practical to debate very much about them. But botulinum toxin and tendon surgery are always available. When children cannot be fed in the usual way and have to be tube-fed for a prolonged time, there usually comes a moment that you have to consider a percutaneous gastrostomy, which means that you make a small hole in the abdomen to feed the child. That relieves many problems, including problems of aspiration, problems rising from the tube being too long in place, etc. In our experience, we apply percutaneous gastrostomy more and more for children with prolonged severe feeding problems necessitating tube feeding for a very long time. We have the experience that most of the families are very relieved by this appliance.
A86
Discussion meeting with parents
Lanzi
Lebon
I think that we can close this meeting with the experts. They have answered many questions and I think you may be satisfied. I would like Professor Lebon and Professor Barth to join the other doctors to discuss future research plans.
I would like to express my deep appreciation for all of you, parents, and for the Association that you have created. We are very encouraged to continue our work on this extremely rare and mysterious disease. Many thanks to all of you.
DISCUSSION MEETING
IAGSA ± Discussion meeting with parents ± 29 May 2001
Introduction The essential part of the discussion held on 29 May 2001 at ``Fondazione Mondino'' between the parents who were present, some of them accompanied by their own doctor, and the Chairmen of the previous day's meetings, follows here. It was really an interesting and stimulating session in which several problems that worry the parents were clearly pointed out. At the end of the meeting, they were satisfied because the opportunity to discuss their problems was very helpful in order to assuage their many doubts but also to encourage them to carry on with their difficult daily routine. This discussion was also useful for us, as doctors, because if we understand better the problems and difficulties facing these families every day, we can promise them as well as technical aid, a sharing and genuine human presence at their suffering.
Discussion meeting Lanzi I think Mr Oriano deserves to be the first to ask a question. Oriano First, I would like to thank all of the Contributors for their dedication and, especially, for being so kind as to accept the invitation from our association. It is very important for us to meet them because in them we place the greatest hope and expectations for the future of our children. Certainly, our children live in the present and not in the future. We are well aware that the timing of medicine and research is very different from the stringent needs of our children. However, at the 1090±3798/02/06/A0077+10 $35.00
same time, we do hope that your work and your commitment may soon lead to concrete results and may give us an opportunity to get out of the tunnel where we are at present. I don't refer to us as parents, but especially to our children, in terms of hope for them. We have many questions and we hope you will be patient enough to answer them all. Unfortunately, Aicardi-GoutieÁres syndrome is still a disease that is poorly known internationally. Consequently, there are still cases where not only is the first child born affected by Aicardi-GoutieÁres syndrome, but the second child is also affected. Still today this disease is incorrectly diagnosed at first and is seen as a possible consequence of a viral infection. In order to prevent these cases, I am asking whether an international protocol may be recommended in order to allow for a prompt diagnosis whenever such an unfortunate event occurs. I repeat, these wrong diagnoses still occur and there are families today who have an affected child aged perhaps 4 or 5 years, but also have a second affected child; perhaps only 2 years old, born in the year 2000, but nonetheless affected by Aicardi-GoutiereÁs syndrome. I think that an international protocol would help. Please consider that, in the United States ± perhaps the most technologically advanced country in the world ± AicardiGoutieÁres syndrome is practically unknown. They know the Indian Cree syndrome but not AicardiGoutieÁres syndrome ± or know it only partially. What do you think about the drafting of an international protocol? Aicardi It is true that the syndrome is not yet widely known, despite all the efforts that have been made to make it better known. I think it is true that there are still misdiagnoses and especially the confusion with infectious disorders which we actually made & 2002 European Paediatric Neurology Society
A78 with our first family and which is easily understandable. It is obviously not a common disease and it raises the problem of all rare diseases. In France, for instance, the information from the Registry of Rare Diseases is sent out to physicians by INSERM (Institut National de la Sante et de la Recherche MeÂdicale) categorized by the organ under investigation. On an international level, I cannot see what we can do. We can try to publish in journals which are widely known and we have done this (FrancËoise GoutieÁres and myself) quite recently. This is the one thing we can do which is likely to improve the recognition of this syndrome. Barth I think it would not be very practical to propagate knowledge about the Aicardi-GoutieÁres syndrome for the large paediatric or neurological population because each message decays. Whenever you get to the broad public with such a message, it will be in their minds for a few months, a year, then again it fades away. But there is another option and it is that in general, paediatricians and neurologists should be critical about the diagnoses they make and not refrain from going back on their first diagnosis and consulting colleagues when they still have doubts. In my country it is not unusual, in Aicardi-GoutieÁres syndrome, for the first diagnosis to be wrong and then usually this turns out to be wrong for several criteria. For instance, there may be fever and there may be cells in the cerebrospinal fluid so the paediatrician may think there is an infection but when that infection lingers on for months and months, he or she may have second thoughts about the kind of infection ± or whether it is not an infection at all but something else ± and then consult a paediatric neurologist. Most paediatric neurologists in my country are aware of Aicardi-GoutieÁres syndrome even though some have never seen it. So my main hope is that by having second thoughts, the proper diagnosis will eventually be made within the time necessary to allow the parents to have a good genetic counselling and to prevent a second birth with the same diagnosis. I completely concur with Professor Aicardi that this is a very difficult message to propagate ± but in general this is how a disastrous consequence of medical ignorance may be prevented. Question You have told us that, at present, researchers are heading towards considering interferon-alpha as one of the factors causing the greatest disorders
Discussion meeting with parents connected to this syndrome. However, we still do not know whether interferon-alpha is the primary cause or whether, upstream of its increased level, something else has occurred. Do you already have a hypothesis in terms of research and of possible results? What direction do you intend to follow? Aicardi I think that all physicians who deal with this syndrome are perfectly aware that interferon is not the be-all and the end-all; clearly there is something behind the situation. Interferon at the moment is the convenient marker for the condition in terms of diagnosis. Whether it is a cause for the disease, not necessarily the only one, or whether it is only another manifestation of the syndrome remains to be firmly established. I would like to pass this question to the physicians who are more competent than I am in this field. Kuijpers I fully agree with Professor Aicardi. I think that interferon-alpha, at the moment, cannot be judged as the cause of the disease. It is something that goes hand in hand with other factors. But the levels of interferon-alpha drop in time, whereas there is no change in the clinical progression of the disease. So, I think that scientists and physicians and also parents should not be completely focused only on interferon-alpha. There is probably another underlying factor and as long as we do not fully understand what the pathogenesis of this particular clinical disease is, then it is very hard to tackle. There are several points that should be sorted out in the near future and that is simply a matter of time. First we need to find a kind of pathogenic mechanism ± what is this disease caused by? Second we need to see whether we can find the gene. These two aims will probably lead to an understanding of the disease but I think it is too early to speculate on this. Lebon Interferon is not the only marker in this disease, but I think that it has deleterious effects on the central nervous system. This was shown by the experiment of Campbell, but it was also shown by Gresser 20 years ago in the model of congenital infection with a virus (choriomeningitis virus) infection in the mouse. When he treated the infected mice with antibody against interferon-alpha the mice were better than the controls. I am sure that interferonalpha plays a role in the development of some
Discussion meeting with parents symptoms of the disease. It is another problem to explain why interferon is produced, but this is not an ``ideÂe fixeÂe'' for me, and I think that a mutation of one gene could constitutively produce interferon-alpha without the presence of virus. Question I am a parent with two children with AicardiGoutieÁres syndrome. I would like to know why some families have two children and some families have only one child affected with this condition. Aicardi This is a problem of probability. The probability for parents who are carriers of the gene for this condition have a one in four chance, as was explained by Dr Crow, of having an affected child and a three in four chance of not having an affected child. This obviously does not mean that when you have an affected child you are then going to have three normal children. It is like throwing dice, you can get the same number several times, despite the fact that you have one chance in six of throwing the same number. That is the way we explain the probablility. It is not a very good explanation, but it is the one which is true. Question We understand the one in four chance of having an affected child again, but as families we are aware that ± and you know more families than we do ± if you count up the number of normal children and the number of affected children, it seems to be skewed, to be higher than one in four. Why does it look that way? Crow I wonder if the explanation for this observation comes from our earlier discussion about the possibility for misdiagnosis of the disease, so only when you have had a recurrence of what you thought was a sporadic condition or an undiagnosed congenital infection or an undefined congenital infection would you consider in some cases the diagnosis of Aicardi-GoutieÁres syndrome. Perhaps it is simply a bias because of an underrecognition of the diagnosis. I have no doubt that this is a genetic disease and that there is a one in four chance of recurrence in each and every pregnancy. I think that if you took enough families with the correct diagnosis in all, it would be a one in four chance. That also means that both parents
A79 can be carriers and never have a child with AicardiGoutieÁres syndrome, so there are couples presumably who never have a child with AicardiGoutieÁres syndrome because there is also a three in four chance that you will not have a child who is affected. But I wonder if your observation is simply due to the fact that it may be not diagnosed unless you have a second case. Question One priority for families ± and perhaps not so much for doctors ± is that we need to know how to manage our children day by day. Can you give us your ideas on feeding, on positioning in wheelchairs, possible surgery, what the future is, and the daily management that would help us take better care of our children. I have many subject areas I would like to ask about. First I will ask about feeding. All these children have problems with feeding difficulties. Some are tube fed and become normal in size, but there are many who eat just small amounts orally and are very small. Should these children be in the normal height±weight range, or is typical that they are small? Do you recommend tube feeding for the best nutrition and the best health of these children? In some countries it is recommended but not in others. Aicardi In the first place, there is no universal rule, because the cases are not the same. Some children do eat reasonably well, and do not need any special method of feeding ± but some, especially the earlyonset cases, certainly do, because feeding problems are really quite often in the forefront of the clinical picture. In these cases obviously all the available techniques should be used, including tube feeding. In severe cases where it is essential to maintain the infant in a reasonable state of nutrition but it is impossible to do this with natural feeding ± then this can often be done by tube feeding. There is no reason for systematically rejecting tube feeding. I have seen patients who really improved considerably when the tube was inserted, not only from the obvious nutritional point of view, but also in terms of their general well-being and comfort. Question Earlier, reference was made to the alteration of the white matter. We would like to know whether white matter is the same as myelin. We have heard
A80 that, for multiple sclerosis, there are some treatments aimed at strengthening myelin that seem to be beneficial to the patients. Would such an approach also benefit Aicardi-GoutieÁres syndrome children? Aicardi I am not very aware of the treatment of multiple sclerosis because I work exclusively with children in whom multiple sclerosis is not a common disorder. No, myelin is not the same as white matter. Myelin is just one of the major constituents of white matter, but not the only one. There are many other proteins and lipids and other substances which are also constituents of the white matter. I would be happy for someone else on the panel to comment on multiple sclerosis. Kuijpers The pathogenic mechanism behind multiple sclerosis is to a very large extent unknown. It is caused by the influx of inflammatory cells, white cells, Tcells to be exact, and these cause the inflammatory lesions. What they exactly recognize there is still a puzzle. We have some clues, but they may be different from patient to patient. Nonetheless, if you take away these cells, so you delay their influx, and if you can dampen that inflammation, then the white matter is spared more than myelin production is boosted. So you just take away or you prevent inflammation. And that is why substances now widely used in multiple sclerosis seem to work. One substance used in multiple sclerosis is interferon-beta for instance; there are also other medical approaches that affect more or less the same type of cell, but in a different way, although all are meant to prevent the inflammation. Question I come from Vancouver, Canada and have a 3year-old daughter with Aicardi-GoutieÁres syndrome. First, thank you for your work; second, my daughter received her diagnosis from a geneticist and the paediatric neurologist was not aware of Aicardi-GoutieÁres syndrome. My daughter has bilateral basal ganglia calcifications, she has also had two positive results of leukocytes in the cerebrospinal fluid over a 4-month period. The interferon tests were not easily available and the Canadian doctors did not really want to push to have this done. So, my first question is: can this diagnosis be made based on those two symptoms? Should we at this point still have the interferon
Discussion meeting with parents tests done? Is there an approximate age where the interferon level drops so low that perhaps having the tests may show nothing? My second question is my trying to understand correctly the presentations. Did I understand correctly that this disease can be static, that there were some children where this happens, that in fact the calcifications do not increase after the first to second years of life? Aicardi I think the best person to answer your first question is Professor Lebon. Lebon Yes, at 3 or 4 years interferon could strongly decrease, as you saw yesterday in the diagrams. Barth There are few places in the world where the interferon-alpha test can be done reliably. We, in Amsterdam, used to send it to Professor Lebon. But until a few years ago we did not do that either; we used to make a preparation of the cells in the cerebrospinal fluid to examine under electron microscopy. By doing that, you can see peculiar inclusions that are specific for interferon-alpha. So, even if you do not have easy access to the determination of interferon-alpha such as Professor Lebon has in his laboratory, there is an alternative route which is quite reliable and may be available in your local medical centre. Lebon I am sure that in Canada there are teams which can dose interferon. Such teams working on interferon are present in Montreal; I can give you their address. Aicardi With regard to your second question about the late appearance of calcifications, this is certainly possible. I have seen it in at least in one patient. Calcification still appears early in life, not I would say after the first year of life or the first year and a half. I have another comment on this which causes us some concern. A computerized tomography (CT) scan is excellent for exposing the calcifications, but nowadays CT scanning is replaced more and more by magnetic resonance imaging (MRI) and MRI is
Discussion meeting with parents highly preferable to CT in all regards, except one: calcifications. So what seems to be a diagnostic hazard is that when a doctor is trying to make a diagnosis in a child with white matter disease and increased cells he may miss the calcifications unless he makes that jump in his mind. That of course is not basically your concern, but it should be ours. Crow I think we don't know the minimum diagnostic criteria for this disorder. If your child has a normal cerebrospinal fluid interferon-alpha level, it will not take away from the significant possibility that this is an Aicardi-GoutieÁres syndrome. So I think in a sense you have to make a decision about whether you want to put your daughter through that test, because a normal level would not make it less likely; a positive result would confirm the diagnosis, but I don't think there is a should or a shouldn't; I think you decide. The other thing is that there are some cases that are static, children who do not regress, who do not get worse. I think Professor Lanzi's contribution suggested that children sometimes improve. Question Would you recommend immunizing these children with routine vaccines that are usually planned in the first years of a child's life? What did you do with the patients that you personally follow? Aicardi I certainly immunize my patients; I think they are particularly susceptible or may be particularly susceptible to infections. It does not help for these children to catch measles or the sort of infectious diseases that can be prevented by immunization. I do not think there is any definite contraindication to immunization in these patients, even though the small number of cases makes that statement perhaps a little too absolute, but my feeling is that certainly these patients should be immunized like the rest of the children. Lebon I agree with Professor Aicardi about the probability of no side-effects with vaccination; but what is the efficacy of vaccination in these children? Because they produce interferon which is anti-viral and when one injects the measles, or mumps or rubella vaccine, one injects live viruses, viruses which normally replicate in the child. The question is:
A81 have you tested immunity in children after vaccination against measles, mumps, to know if the immunization is present? Probably few children have been vaccinated, I think it might be important to study if the vaccinations were without any effect. Aicardi The answer is no we have not. Question In your paper you said that you have identified the locus 3p21. But we know that based on the results of DNA testing for many of us this locus was not recognized in all cases, in fact not in almost half of the cases. How do you intend to proceed for those children in whom the locus has not been recognized? How will you continue your research? Crow One of the grants we have applied for is to perform a genome search by the same technique we used the first time, using only samples that we know are not linked to chromosome 3p21. So whereas previously we had 13 families available to us with enough DNA to use ± because you need quite a lot of DNA for that kind of search throughout all the chromosomes ± now, because of the results of our study and because of this organization, there is more DNA available, and because of the collaboration within the group I belong to ± there are many more samples. The idea is to use those families that do not link to chromosome 3p21. So, one of the grants has been to an organization called The Marshfield in America. It is very good because it is a free genotyping service. They will do for free what we have spent a year doing and they will probably do it in 2 months and probably better. So, I will be very pleased if they accept our proposal. As an American sponsor is needed, Ian Campbell sent a letter of collaboration for the grant. This is specifically to try and identify a second locus in families who are definitely not linked to the first. Previously I said that there are some families who may be linked to chromosome 3p31; of course they may also be linked to the other locus or the other loci. But I think that this is a sensible way to proceed, to use families who are definitely not linked to try and identify a second locus, and then we can look at all the individual families. The second approach ± and I mentioned it in my paper ± is that if you identify the first gene, you may be able to quickly leap-frog to the next gene at
A82 another place, because if you understand gene function ± sometimes you can jump very quickly, sometimes not.
Discussion meeting with parents displaced? So, is botulinum effective and does it have any side-effects? Could it be dangerous? Aicardi
Question In talking with other families, we have noticed that the regression in this disease is not slow, it is episodic. When a stressful time comes, then the child may rapidly regress and then stabilize. And then another stress comes and the pattern is repeated ± do you agree? For example, the stressful tests we have noticed are if the child is dehydrated, or overheated, or if the child loses calories for 2 or 3 days because they are sick, they may regress. And a very noticeable stress is sedation ± for example for an MRI ± or anaesthesia for surgery. Very often our children, when they wake, are not the same while going through these stressful periods. Have you noticed that? Should we try to manage our children's lives so that there is little stress? And should they no longer have MRIs because this requires sedation ± and should surgery be limited because they require anaesthesia? Aicardi Yes, there are definitely periods of aggravation following episodes of infection or even episodes of fever without detectable infection, especially acute nutritional problems following any sort of stress ± as you say. Let's put it that way, as it is very broad. Clearly there is a relationship between the general health of the child and the evolution of the disease. I think that the aggravation is mostly temporary, but this perhaps needs further analysis. What you said regarding the magnetic resonance I think is important, because this usually requires at least sedation and very often general anaesthesia, which is not desirable in these children. I would certainly add that in many cases I cannot really see the necessity of repeating the MRI investigation at least in the close range period once you have a clear-cut image that is sufficient for the diagnosis. Certainly you can wait for years before repeating it because it doesn't add very much, as far as I can tell. Question We have a question regarding the treatment of hypertonia, i.e. when children suffer from attacks and become rigid. Would you recommend the use of botulinum? Another question: does it make any sense to cut the muscles before the hip is
I think that botulinum toxin is not generally indicated in these patients, because the spasticity they have is diffuse and it is difficult to use the botulinum toxin in very diffused contractures. On the other hand, in the case of a specific problem around a particular joint, then the indication of botulinum toxin is possible, and this could apply to the adductors, and apply to other muscles as well. But that is a temporary effect and it has to be included in a general plan of treatment. Botulinum toxin is not a miracle drug, it can be used in certain definite circumstances, for specific purposes, but it should not be thought of as the complete answer or even an answer to the problem of these children. Regarding the second question, this is also a specific problem. In general, I do not think that it is a good idea to operate on these children. However, if there is an immediate emergency threat on the hip, this possibility can be considered. Question I would like to comment on botulinum and doctors. My younger son had botulinum shots. The third time he went to severe seizures; his brain was swollen like encephalitis; he had very severe reactions, lost his eye-sight, couldn't move any more and it took many months for him to get back to normal, and he has permanent vision loss. I believe Professor Lebon said that one other child with this syndrome had a similar reaction to botulinum toxin, so I would be very concerned about other families trying this treatment. I don't want this reaction to happen to the other children if this may be something related to the syndrome. As for releasing adductors and other muscles, if it can be done under a local anaesthetic, I think that would be better. My sons have had a local anaesthetic rather than a general anaesthetic. I recommend this if it is at all possible. Aicardi I am not aware of any sort of accidents like the one that you observed. There is now a large experience with botulinum toxin, not specifically in this syndrome, but in the general population, and there are known complications, especially when related to large doses or excessively large doses which can produce weakness and lasting weakness ± not indefinitely lasting, but for some time. I
Discussion meeting with parents have never heard of convulsions precipitated by botulinum toxin. I certainly believe that botulinum toxin, like any drug or any surgical intervention, has to be included in a general plan of treatment of the child. It may be quite useful to reduce a specific contracture at one joint, but certainly not as a basic sort of therapy. That is certainly not an aim. It has very specific aims if any indications exist; these are for specific problems and temporary problems, especially in the case of these children, who have a number of other problems and who certainly do not tolerate general anaesthesia very well. If any medical process has to be done, clearly it would be better to do it, if possible, under local anaesthesia.
Question I have a question for both Professor Barth and Dr Kuijpers. Earlier you discussed a new pilot treatment. We think we have understood the idea underlying this treatment. At present, we know that interferon-alpha is not the main cause, but we know that it is responsible for some damage to these children. For this reason, we attempt to limit such damage. However, also based on our personal experience, we have seen that, usually, interferonalpha tends to decrease in these children while they grow older. Do you think that this kind of therapy may also help those children whose interferon has already dropped below 2 or is dropping ± perhaps it is now around 5, 4, 6 ± and is now very close to a normal level?
Barth I think that you have understood the message well. The message is that it is possible to lower the interferon-alpha by the use of a certain drug. You also understood that interferon-alpha is contributory to the damage, but we don't know if it is really the origin of the problem. So we have the idea that it might help some patients with a high level of interferon-alpha to bring the level down, but nothing has been proved about possible results. So we have to rethink what we have found before we can take the next steps that may be a reward to early cases. I think the IAGSA would be an excellent platform to discuss such an approach before we go to the next step and maybe go for a proposal. This is very preliminary, but we are interested and I'm sure we will come back to it.
A83 Question My 5-year old boy is affected, but I have another 8year child who is unaffected. First of all, I would like to thank you; second, we come from Rome and we would like to acknowledge that Dr Bertini has helped us very much with this syndrome. Just before we went to see him, he had already diagnosed Aicardi-GoutieÁres syndrome in a little girl. Our diagnosis is not confirmed yet, but it is supposed to be Aicardi-GoutieÁres syndrome. We were very well assisted and I would like to acknowledge this, because I know how painful it is when you realize that you are confronted with a rare disease. My child is very nervous and, at times, he is also very stiff. Can these muscle contractions be painful for him? I would also like to add that my child underwent adductor surgery and has considerably improved after that. Before surgery, he could no longer open his legs, whereas now he can keep them apart and he has also become less nervous. I have another question: do you have any idea about the life expectancy of these children? How long do they live? This is something I really would like to know. Aicardi Regarding the second question, we don't have any systematic follow-up study, but we certainly know that there is a high mortality, especially in the first years of life in the severe cases with early onset. In the milder cases of late onset we have certainly seen patients ± at least two patients ± who are now 17±18 and are doing reasonably well. So I cannot give a complete answer, but certainly there is a possibility for at least some of these patients to live for a reasonable period of time as far as I can tell. About the pain in muscles: muscles are not usually very painful; the hips may be, on the other hand. It is certainly uncomfortable to have a marked abduction of the thighs and makes life more complicated as well in terms of care. As I have already mentioned, there are specific indications for a specific surgery with a specific purpose. That is the best answer that I can give. Barth This does not apply just to your case, but I think it is worth a general comment for the parents with Aicardi-GoutieÁres syndrome children: the rehabilitation doctors or their orthopaedic surgeons may come to think of the problem of those children as a kind of spasticity similar to cerebral palsy. In some
A84 cases, there is, in addition to spasticity, what we call `dystonia'. In these children there may be very painful spasms and I think it is very important for parents to know that and, when they have a suspicion of it, to specifically remind the rehabilitation doctor and the orthopaedic surgeon of the situation.
Question Since Aicardi-GoutieÁres syndrome seems to have some features of an autoimmune disease, have you ever considered the possibility of performing bone marrow or stem cell transplantation? This is a question from parents and not from experts, but we would like to know your answer.
Discussion meeting with parents Question I would like to thank the Association for what they are doing for these children who are really suffering. My 4-year-old son is affected; the diagnosis was made by Dr Bertini when the child was 4 or 4 months old. He is suffering quite a lot and it is not easy to manage him, because he presents with a very intense dystonia. It is even more difficult to manage his disease when he is sleeping. When he is relaxed and sleeps, he suffers from sudden apnoeas, so that he must be given oxygen. Is there a method you can recommend to manage his breathing. Consider that, sometimes, when his apnoeas are very severe, we have to rush to the emergency ward for oxygen and other aids. Thank you. Barth
Kuijpers That is a very good question, but a good answer is only possible if you know a little more about the mechanism and we just started thinking about a therapy. We did it with a kind of bolus infusion with methylprednisolone to limit the side-effects of that steroid treatment. What we did see on one hand is a very steep drop in interferon-alpha ± that would be great if this was the cause of the disease. On the other hand, the cells that we characterized were never seen before. Also, if we look at what the treatment did to the number or the phenotypes ± how these cells looked ± that had not changed at all. Now the question we have to answer first is: are these the cells that we should direct therapy at? Your question: should we give bone marrow transplantation or stem cell transplantation? ± is very difficult to answer because those types of therapy are in a way very cruel and should be limited to those patients who have no other alternative. It is too early to say that this is the same in Aicardi-GoutieÁres syndrome. So I would say: try to have a little more patience before jumping to choose the most cruel therapy available. If this disease is revealed to be driven by something like a cell type which is not a leukocyte, and not a white cell type, driven for instance by a brain-derived cell, one can insert bone marrow from a perfectly matched donor or a healthy sibling, but end up with a similar kind of mechanism. This brain-derived cell will cause the same autoimmune or immune attack, even if it is due to a new bone marrow. In that case, the disease will be exactly the same and the child has gone through a terrible period of ± in effect ± false therapy.
The problem that you describe is not specific for Aicardi-GoutieÁres syndrome, but it has to be analysed before it can be treated. In neurologically handicapped children, there are two reasons for apnoea ± I am excluding the third, which is seizures as I assume that in this case these are not seizures. Either these are `obstructive' apnoea, which means that when the child is lying on his back he may become obstructed because his tongue falls back or because his palate does not lift enough. For this, the treatment should be directed at removing or at least relieving the obstruction. The other possibility is that the apnoea is caused by an abnormal steering mechanism of the brainstem (`primary' apnoea). In most cases, it is `obstructive' although I do not know your son's details. In our situation the child is usually analysed before advice and treatment can be given. This is not a complete answer but indicates the analysis needed to relieve the problem. Question I come from Rome and I have a 5-year-old daughter. Going back to the 25% chance to have an affected child, I have noticed that there are families where the first child is healthy and the second is affected, and I have seen several cases where there are two brothers or two sisters, both affected. Do you know of any families where the first child is affected and the second is healthy? Crow The answer is `yes'. If you take a coin, heads and tails, you toss it once, it can come down heads once; you toss it again, it can come down heads again,
Discussion meeting with parents but it doesn't mean to say there is no tails on one side. It is chance or probability as Professor Aicardi said. If you have had one child affected and the diagnosis is made, there is no way of saying that your next child will not be affected, so for some couples this is a strong enough reason not to have another child. Perhaps this is the reason why you have not met such families. I am convinced that this is a genetic disease. It is an important observation, especially when we consider that the disease may be due to an undefined infection. As I mentioned in my presentation, there are families where two affected children are separated by the birth of an unaffected child, over a long period of time, and this is very much against the possibility of an unidentifiable infection that disappears and reappears. This is important evidence. I would like to make the point here that I have come across many of the samples from people in the audience and their children. These samples have been collected through their physicians and doctors and taken with their permission. I have a number of consent forms and if families wish to be involved in the research or to continue to allow us to use their samples and those of their children, then please sign these consent forms to allow the research. Question My orthopaedic surgeon has recognized that my children are not very spastic, but they are rigid and he says the difference is that in spasticity the muscles are more uneven in their strength and there are more spasms. With rigidity ± the muscles are more even and stiff. Have you recognized in other children that they have rigidity more than they have spasticity and is there any different way to control this rigidity; for example would the medication baclofen help that? And is there any specific treatment for dystonia as well? Barth First of all, in Aicardi-GoutieÁres syndrome you may have pure spasticity, you may have spasticity combined with dystonia and you rarely have only dystonia ± I am not aware of cases with only dystonia. The hazards of both are of course dislocation of the joints and pain. Dystonia especially may cause pain. You ask whether there is a specific treatment for dystonia. Well, there are drugs that are specially designed to treat dystonia, but it is an empirical treatment and it rarely completely relieves dystonia.
A85 Question Going back to the treatment of rigidity ± we said that botulinum may carry some risks and I am rather worried. Is there any alternative treatment to botulinum, should my daughter need it? I have a second question regarding child feeding. With regard to tube feeding, can we give special liquid food to our children, also orally, as is usually done with terminally ill patients, for instance? Does this make any sense? When a child improves through better feeding, is this more connected to the quantity of food he receives through the tube or to the quality of that food? Could we also use some similar food orally?
Barth For your first question: there may have been a little misunderstanding about the botulinum toxin, because as is given, it is applied very locally to the place where the nerve enters the muscle. By doing that, you paralyse the muscle for 3±6 months. The importance of this treatment is that you do not actually damage the muscle or tendon or nerve, you only remove its action for a certain time. The implication is that you can apply it to several muscles at the same time and see whether it works and, if it works, it can help in the decision for instance to cut the tendon. So, in a way, the application of botulinum toxin and surgery are complementary and usually there should be a good co-operation between the rehabilitation specialist and the orthopaedic surgeon. They should combine their efforts, ideally, to allow a good choice of what to do. And there are other kinds of treatments for spasticity and dystonia, but they are not available in all the centres, so I think that it is perhaps not practical to debate very much about them. But botulinum toxin and tendon surgery are always available. When children cannot be fed in the usual way and have to be tube-fed for a prolonged time, there usually comes a moment that you have to consider a percutaneous gastrostomy, which means that you make a small hole in the abdomen to feed the child. That relieves many problems, including problems of aspiration, problems rising from the tube being too long in place, etc. In our experience, we apply percutaneous gastrostomy more and more for children with prolonged severe feeding problems necessitating tube feeding for a very long time. We have the experience that most of the families are very relieved by this appliance.
A86
Discussion meeting with parents
Lanzi
Lebon
I think that we can close this meeting with the experts. They have answered many questions and I think you may be satisfied. I would like Professor Lebon and Professor Barth to join the other doctors to discuss future research plans.
I would like to express my deep appreciation for all of you, parents, and for the Association that you have created. We are very encouraged to continue our work on this extremely rare and mysterious disease. Many thanks to all of you.