This is exactly the sort of case in which there may be reasonable disagreement about what would be best for a child. However, there is an additional complication that might arise in a future case of treatment disagreement relating to SMA. There are two new experimental treatments for SMA, whose benefits are still unclear, but which might offer significant benefit.
Important new evidence about both of these treatments was published in the second half of Nusinersen is a novel drug that is designed to increase the amounts of survival motor neuron protein. It works via a backup gene for SMN1. Children who have more copies of the back-up gene have less severe forms of SMA. Nusinersen works on this backup gene to increase the amount of protein made.
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It is given by repeated injections into the spinal fluid. Several pilot studies of Nusinersen had suggested that this treatment could lead to improvement in muscle strength in infants with SMA 1, and potentially improve survival. The first randomised trial of Nusinersen, published in the New England Journal of Medicine in November , studied the treatment in infants, half of whom received the new drug.
None of the infants in the control group achieved any of these milestones. The risk of infants either dying, or needing to receive permanent breathing support was halved in the treated infants. This involves a single injection of a modified virus. In mice with a form of SMA, the gene therapy had been shown to allow nerve cells and other tissues to produce the Survival Motor Neuron protein. At a higher dose, the gene therapy increased mice survival from only 15 days to more than days.
Twelve infants received a higher dose; 9 of these infants were able to sit by the end of the study, 2 were able to walk. By the end of the study, none of the 15 treated infants had died, or required permanent mechanical ventilation at an age of 20 months. While the published studies of both of these new drugs look extremely promising, neither is a cure for SMA. There are also considerable uncertainties and downsides. For both drugs, scientific studies at the time of writing have reported follow-up only for the first year or two of life.
It is not clear whether the apparent improvement will be sustained, or whether treatment will unmask problems in other tissues and organs. There are some very significant practical limitations to nusinersen — it needs to be given via regular injections into the spinal fluid — potentially life-long.
It is also extremely expensive. It has not yet been approved for clinical use by regulatory authorities. Whether there could be long-term serious side effects of the gene therapy is unknown.
Hypothetical case of Infant ‘S’
For example, it excludes some of the most severely affected infants. S is born in late He is a long-awaited first child to his parents, Stefan and Janeczka, who are academics who migrated to the UK from Poland several years ago. Routine ultrasounds during pregnancy were normal, however, there are problems apparent immediately after S is born. S makes only a weak cry, he is floppy and appears to have poor breathing effort. He is admitted to the neonatal intensive care unit, where doctors initially suspect that he may have birth asphyxia.
He is put on a ventilator within the first hours of birth because of respiratory failure. However, further tests raise the possibility that S has an underlying disorder of his muscles or nerves. Brain scans and brain electrical tracings are normal. He has further assessment by specialist neurology and genetics teams. Molecular genetic testing reveals that S has a deletion of the SMN1 gene, confirming a diagnosis of severe neonatal onset type 1A Spinal Muscular Atrophy. He has a single copy of the backup gene SMN2. The medical teams explain that S has the most severe neonatal form of SMA.
There is no available cure and all affected infants with this condition die in infancy. The doctors mention that while an experimental treatment is sometimes helpful in other forms of the condition it is not an option for S. Stefan and Janeczka find this news difficult to accept. They do some reading on the internet and find descriptions of long-term survival in some children with type 1a SMA. They have also read the recent papers describing the effect of scAAV-9 and nusinersen. They refuse to allow the doctors to withdraw treatment.
They argue that S should be allowed a trial of at least one of these drugs preferably both. If the doctors in England will not allow this, they wish to take him overseas to receive the treatment. In this case, there has been a policy assessment that relates to one of the experimental treatments that Stefan and Janeczka are seeking for their son. The NHS commissioning policy for Nusinersen, published in August , allows the drug to be given as part of the Expanded Access Program supplied by the drug company for infants with type 1 spinal muscular atrophy.
However, that policy specifically excludes infants with the more severe type 1A genetic subtype affecting S. The next option would be whether there is a relevant clinical trial that S could enrol in. If so, that might allow access to one or both of the experimental therapies. However, this may well not be possible. Most of the clinical trials to date have restricted eligibility to infants with 2 copies of the SMN2 gene.
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In Chapter 5 , we argued that it is ethically flawed to exclude patients from trials with the most severe forms of disease and who will certainly die without treatment. If the policy excludes treatment for S, and there are no trials, that might seem to be the end of the question. However, while the national policy about nusinersen assessment is highly relevant, the question is whether existing evidence can be applied to a specific infant, whose condition and outlook may be different from those who were studied in trials.
Moreover, there is a further question not addressed by the policy , whether this treatment could be available if privately funded. This is exactly the type of situation where the process model that we described for reviewing treatment would be valuable. As described in the previous chapter, this is an independent body ie distinct from a hospital ethics committee , which would have representation from expert health professionals as well as incorporating ethicists and lay representatives.
Its aim would be to provide an impartial, fair, non-court based process for arbitrating disagreement about specialised medical treatment. After receiving the referral, the panel asks the clinical team to explore the feasibility of providing the desired treatment as a time-limited trial. If there is a way to commence treatment while the review process is being undertaken that might conceivably provide useful information about how well it is tolerated, as well as any early signs of effectiveness. There is some urgency to commence treatment, given that SMA is a degenerative disorder, and some of the available evidence suggests that earlier treatment is more likely to be effective.
By contrast, scAAV-9 is unlikely to be available outside a trial since it is not yet approved for clinical use. S has a first injection of nusinersen the day prior to the CTRP meeting. As in the case of Charlie Gard, there are two linked questions: should intensive care for S be continued, and should he be provided with experimental treatment?
The CTRP decides to address those questions separately. The panel also asks to hear directly from any health professionals who would support providing treatment for S, and about their reasons for reaching a different conclusion. Finally, they hear from Stefan and Janeczka about their views on further intensive care and experimental treatment for S.
As discussed in chapter 7 , the important question is whether this is disagreement is reasonable or unreasonable. We also indicated more substantive criteria for reasonable disagreement: are those supporting treatment able to provide clear reasons in favour of their view? Do the views appear to be sensitive to changes in evidence? Are they based on reasons that are acceptable within the legal and ethical framework for decisions about children in the UK?
They describe their grave concern for his quality of life, and worry that he is suffering, despite being unable to show outward signs of distress. They further note that nusinersen relies on using the back-up gene SMN2, and S has only a single copy of this gene. They feel that continuing intensive care to try this treatment would likely do more harm than good.
On the other side, the CTRP hears from a US paediatric rehabilitation specialist with considerable experience in the care of children with SMA, including children with the severe type 1A form that afflicts S. The specialist explains that children with this condition are often able to be managed with non-invasive face-mask breathing support at home, and can survive into adulthood. Those children and their families, he argues, report having happy and fulfilling lives, despite their challenges. The specialist is not able to attend the panel meeting because of pressing clinical commitments.
However, a UK paediatrician who has trained with the US specialist has reviewed S in person, and gives evidence. Stefan and Janeczka, meanwhile, make the case that they want to give S the chance of this treatment. They do not wish to keep him alive on life support at all costs.
They hope that he might be able to transition to non-invasive breathing support as described by the US expert. If he shows no sign of improvement, they would not wish S to have long-term mechanical ventilation and would seek to withdraw life support. What would the CTRP decide in this case?
They make James do all the cleaning and never let him away from the house to meet other children or make friends.
But James's luck starts to change when he meets a mysterious old man who hands him a magical gift that will change his life - and introduce James to some of the most unusual friends a young boy could ever have Lavender is Matilda Wormwood 's best friend. Described as "gutsy and adventurous," she is just as enthralled by Hortensia 's Trunchbull horror stories as Matilda, and later on she devises her own way to cause that terrible headmistress of theirs a few troubles.
It involves a glass of water and a slippery creature When we first meet him at the beginning of The Minpins , Little Billy is bored. His mother has stopped him going out to play and most especially going to visit The Forest of Sin.
But Little Billy is a resourceful boy and he sneaks out when his mother's not watching, ignoring her warnings about The Spittler and those terrible Vermicious Knids. There is no Spittler but in the forest, Little Billy does indeed come across some ferocious beasts. He also meets The Minpins - tiny human-like creatures who live in the trees - and that resourcefulness comes in very handy when he needs to get home, past the dreaded Gruncher So clever is Matilda that by the age of four, she has read all the children's books in her local library.
By the time she begins school aged five she has graduated to Charles Dickens and Rudyard Kipling. What's more, she can multiply large numbers with no trouble and can compose and recite limericks with barely a breath. Her schoolteacher Miss Honey thinks she's a genius. Unfortunately, her parents aren't so impressed. Mr and Mrs Wormwood completely fail to appreciate her incredible abilities - but luckily for Matilda, this also means they never fail to fall for her tricks Because as well as being very clever, Matilda is no stranger to a spot of mischief.