The lives of people with epilepsy and their relatives are usually severely disrupted when it starts. Epilepsy among very young children can be difficult to treat and can leave lifelong scars related to health, well-being and education. A new study of young children with epilepsy shows that a cause can be found for two thirds of them. This knowledge is important in helping doctors to give parents reliable guidance about their child’s disease and potential consequences, to find the right treatment and to give hope for the future.
Violent seizures in which the body stiffens followed by spasms throughout the body: most people recognize this as an epileptic seizure. However, the types of seizures differ enormously, although they often involve behaviour change and influence consciousness. Children with epilepsy differ as much as children in general do. New research is increasingly helping to pinpoint the cause of the disorder in the electrical circuitry in the brain that leads to the potentially disabling epileptic seizures affecting about 0.4–1.0% of children.
“The proportion of epilepsy cases with a known cause remained unchanged for decades. In general, the cause was discovered in only one third of the cases across all ages. Although this proportion has been higher for young children, it has often been said that the only thing these children have in common is that they have epilepsy. The known causes are heterogeneous, and a significant proportion have remained undiagnosed. In our new study, we found physical and/or genetic causes for two thirds of young children. This means that we can treat epilepsy better and guide the parents, which eases the situation and creates hope,” explains a main author, Tommy Stödberg, Senior Consultant in Child Neurology, Karolinska University Hospital, Stockholm, Sweden.
Causes vary considerably
The new study examined children’s medical records from 2001 to 2006 through the Stockholm Incidence Registry of Epilepsy. The study cohort was defined as all children living in the study areas who had their first unprovoked epileptic seizure leading to medical attention before 2 years of age, and their medical records up to age 7 years were reviewed so that the study cohort only included children who met the epilepsy criteria.
“We found 116 children who had epileptic seizures before 2 years of age. Of these, a specific epilepsy syndrome could be diagnosed for slightly more than half the children based on the existing International League Against Epilepsy classification of seizure types,” says Tommy Stödberg.
The current description of an epilepsy syndrome refers to a cluster of functions that tend to be related. For example, these include seizure types, associated symptoms such as cognitive or motor impairments, the brain’s electrical activity patterns measured through electroencephalography (EEG) and images of the brain from magnetic resonance imaging (MRI). In the new study, the researchers also threw themselves into explaining the actual causes of epilepsy for all the children. Frontline genetic diagnosis was offered to children for whom routine investigations had not revealed the cause of epilepsy.
“The causes of epilepsy differ as much as the symptoms. Epilepsy may result from infection and changes in the immune system, which can be difficult to measure, from stroke or perinatal asphyxia, and from congenital brain malformations and metabolic disorders. Some malformations and most metabolic disorders in themselves have a genetic cause, but by genetic epilepsy we usually refer to cases without structural or metabolic abnormalities “between” the gene and the epilepsy. In this study we managed to find structural changes in the brain as the cause in about one third of the cohort and genetic epilepsy in about one fifth,” explains Tommy Stödberg.
The study revealed the huge added value of genetically investigating the protein-coding part of the genome (whole-exome sequencing) or whole-genome sequencing.
“In cases in which we suspected a genetic cause but so far had no evidence, the parents were offered an examination, and this enabled us to explain the cause of the epilepsy for another 16 children of 26 examined” says Tommy Stödberg.
Aiming for 100%
The new study confirms that epilepsy syndromes can be diagnosed and the causes revealed in most early-onset cases. The study also shows that genome sequencing can help to provide a molecular diagnosis for many children and therefore, according to the researchers, should increasingly be included when young children with epilepsy are examined in the future.
“Finding a cause and performing genetic diagnosis are extremely important, especially in severe epilepsy syndromes, which almost always affect children’s cognitive development. Genetic diagnosis is essential to genetic counselling, prenatal diagnosis and precision therapy since drugs for epilepsy work very differently depending on the nature of the syndrome,” explains Tommy Stödberg.
Tommy Stödberg especially emphasizes future interdisciplinary collaboration between clinicians, biochemists, geneticists and mathematicians as key to this new knowledge, which will develop even better tools to reveal new causes of epilepsy.
“Developments in knowledge about which brain defects and which metabolic diseases can lead to epilepsy demonstrate that we are on the right track towards the aim of eventually being able to explain almost all epilepsy cases. Right now we have a list of important genetic defects that is constantly being updated as we receive data from more and more genetic studies,” says Tommy Stödberg.
In addition to ensuring appropriate physical and pharmaceutical treatment for the children with epilepsy, mitigating the mental effects of epilepsy is at least as important for both the children and their parents. In a follow-up study to the one just published, the researchers followed up the children in the study to the age of 7 years.
“Many of these children can have almost normal development and a normal life. That is why ensuring that both the children and their parents remain hopeful is extremely important. We hope that our new results can contribute to this, so that doctors can provide the right treatment and tell people that there is a way forward and reason to keep struggling, even when it is difficult,” concludes Tommy Stödberg.