A recent randomised clinical trial published in Developmental Medicine & Child Neurology assessed whether injections of botulinumtoxin-A in calf muscles benefit children with cerebral palsy.
“We hypothesised that injections with botulinumtoxin-A in the calf muscles would make walking easier, caused by improved ankle joint functioning following spasticity reduction,” the authors wrote.
In the trial, one botulinumtoxin-A treatment was not superior to placebo in making walking easier (measured as a reduction in energy cost or improved walking capacity); however, there was some evidence of a delayed improvement in energy cost. Moreover, there was some evidence of a decrease in calf pain intensity. No serious adverse events related to botulinumtoxin-A treatment were recorded.
The world’s largest study of cerebral palsy (CP) genetics has discovered genetic defects are most likely responsible for more than a quarter of cases in Chinese children, rather than a lack of oxygen at birth as previously thought.
The study, published in Nature Medicine, used modern genomic sequencing and found mutations were significantly higher in CP cases with birth asphyxia, indicating a lack of oxygen could be secondary to the underlying genetic defect. The results are consistent with smaller studies globally.
More than 1500 Chinese children with CP were involved in this collaborative effort between the University of Adelaide and Fudan University Shanghai, Zhengzhou University, Zhengzhou and associates.
The Australian team was led by obstetrician and University of Adelaide’s Emeritus Professor Alastair MacLennan AO and human geneticist, Professor Jozef Gecz.
“24.5 percent of Chinese children in the study had rare genetic variations linked to cerebral palsy. This revelation mirrors our earlier findings in our Australian cerebral palsy cohort, where up to one third of cases have genetic causes,” said Professor Gecz, who is the University of Adelaide’s Head of Neurogenetics at the Adelaide Medical School and the Robinson Research Institute.
“Our research shows at least some babies who experience birth asphyxia and are diagnosed with CP may have improper brain development as a result of the underlying genetic variants rather than a lack of oxygen.
“Crucially, clinically actionable treatments were found in 8.5 percent of cases with a genetic cause. It is exciting to see how genetic pathways to cerebral palsy inform tailored treatments for these individuals.”
Cerebral palsy affects movement and posture and is the most common motor disability in children. The disorder is diagnosed in up to 2 per 1000 children globally and is sometimes in association with epilepsy, autism and intellectual difficulties. Symptoms often emerge during infancy and early childhood and can range from mild to severe.
The research team identified 81 genes with causation mutations in the children with CP. These genes are known to play important roles in neural and embryonic development and may affect the molecular pathways responsible for respiration.
Oxygen deprivation frequently claimed in medical litigation
“A lack of oxygen at birth is often claimed to be the cause of CP in medical litigation following a diagnosis and this has led to the presumption that the condition is preventable with better obstetrics or midwifery. This is simply not the case,” said Professor MacLennan, who has spent the past 30 years advocating that there is little scientific evidence to support the myth that cerebral palsy is due to trauma or lack of oxygen at birth.
Professor MacLennan said frequent litigation has been associated with a high increase in “defensive” caesarean delivery and high insurance premiums for obstetricians.
“These results highlight the need for early genetic testing in children with cerebral palsy, especially those with risk factors like birth asphyxia, to ensure they receive the right medical care and treatment.
“All children with cerebral palsy merit modern genetic screening as early and customised interventions really can make a difference and improve their long-term outcomes,” he said.
Ongoing genetic research is also investigating other types of contributing genetic variation to the cause of CP and, as a result, the researchers expect that the overall genetic diagnosis rate is likely to increase.
Ten percent of babies born before 32 weeks will develop cerebral palsy resulting from infections that damage white matter, nerve fibres deep in the brain. While it’s known that the white matter loss will lead to neurological deficits, there is currently no treatment to avoid this.
Now, researchers at Duke Health have conducted experiments using neonatal mice and identified a fatty molecule in breast milk that triggers a process in which stem cells in the brain produce cells that create new white matter, reversing the injury.
The study appears in the journal Cell Stem Cell. Corresponding author Eric Benner, MD, PhD, said that further study in a clinical trial is needed, but the finding is promising.
“Developing therapies for children – especially such medically fragile children – is very difficult to do because there are justifiably strict safety concerns,” Benner said. “The fact that this molecule is already found in something that is safe for premature babies – breast milk – is extremely encouraging.
“It’s been known that fats in breast milk benefit a child’s brain development, but there are many types of fats in breast milk,” Benner said. “This work has identified a lipid molecule in breast milk that promotes white matter development. Now, we can begin to develop a therapy that isolates and delivers this lipid in a way that is safe for the unique challenges of these infants.”
Benner is a neonatologist at Duke University and one of the co-founders of Tellus Therapeutics, a Duke spinout company developed with the help of the Duke University Office for Translation & Commercialization to bring this therapy from the bench into the neonatal intensive care unit.
The fatty molecule identified in the study will be administered intravenously to patients in an upcoming clinical trial. This is significant because many of the infants who are part of this vulnerable population also have gastrointestinal issues and cannot safely be given milk or medication by mouth.
The lipid molecule enters the brain and binds with stem cells there, encouraging the stem cells to become or produce a type of cell called oligodendrocytes.
The oligodendrocytes are like a hub that allow for the production of white matter in the central nervous system. This newly produced white matter in pre-term infants prevents the neurological damage that would otherwise impact the child’s ability to move – the hallmarks of cerebral palsy.
“The timing of brain injury is extremely difficult to predict, thus a treatment that could be safely given to all preterm babies at risk would be revolutionary,” said Agnes Chao, MD, a former fellow in the Division of Neonatology and first author of the paper.
“As a neonatologist, I’m so excited that I may be able to offer a treatment to families with babies that are affected by preterm brain injury who would otherwise have no other options,” Chao said.
Premature birth is the main cause of brain injury and cerebral palsy in babies. Evidence shows that babies can be protected from brain injury by giving magnesium sulfate to women who are at risk of premature birth, reducing the risk of cerebral palsy by a third. From a societal and lifetime perspective, the health gains and cost savings associated with the preventative treatment generated a net monetary benefit of £866 per preterm baby, according to an evaluation published in Archives of Disease in Childhood.
The prevention of cerebral palsy in pre-term labour (PReCePT) programme was developed in 2014 and aimed to support all maternity units in England to increase the use of magnesium sulfate in premature births. It was then piloted in five NHS trusts in the West of England, and this pilot was evaluated by the NIHR Applied Research Collaboration West (NIHR ARC West). It has since been rolled out across England via the AHSN Network as a national programme.
The evaluation of the national programme, also led by NIHR ARC West, found that PReCePT was both effective and cost-effective. The researchers looked at data from the UK National Neonatal Research Database for the year before and year after PReCePT was implemented in maternity units in England.
While use of magnesium sulfate had been increasing before, the study showed that PReCePT was able to accelerate uptake. It increased by 6.3 percentage points on average across all maternity units in England during the first year, over and above the increase that would be expected over time as the practice spread organically. After also adjusting for variations in when maternity units started the programme, the increase in use of magnesium sulfate was 9.5 percentage points. By May 2020, on average 86.4% of eligible mothers were receiving magnesium sulfate.
The researchers also estimated that the programme’s first year could be associated with a lifetime saving to society of £3 million. This accounts for the costs of the programme, administering the treatment and of cerebral palsy to society over a lifetime, and the associated health gains of avoiding cases. This is across all the extra babies the programme helped get access to the treatment during the first year.
In the five pilot sites, the improved use of magnesium sulfate has been sustained over the years since PReCePT was implemented. As the programme costs were mostly in the first year of implementation, longer-term national analysis may show that PReCePT is even more cost-effective over a longer period.
John Macleod, NIHR ARC West Director, Professor in Clinical Epidemiology and Primary Care at the University of Bristol and principal investigator of the evaluation, said: “Our in-depth analysis has been able to demonstrate that the PReCePT programme is both effective and cost-effective. The programme has increased uptake of magnesium sulfate, which we know is a cost-effective medicine to prevent cerebral palsy, much more quickly than we could have otherwise expected.
Professor Lucy Chappell, Chief Executive Officer of the National Institute for Health and Care Research, said: “This important study shows the impact of taking a promising intervention that had been shown to work in a research setting and scaling it up across the country. Giving magnesium sulfate to prevent cerebral palsy in premature babies is a simple, inexpensive intervention that can make such a difference to families and the health service. We look forward to seeing ongoing use of magnesium sulfate across our maternity units so that these benefits continue.”
