BY SUSAN FITZGERALD
Doctors often must tell parents of children with early-life epilepsy that they don't know why their child has seizures, but a new study suggests that they would have more answers if genetic testing was routinely done as part of the diagnostic workup.
The study, which tracked more than 700 infants and young children with epilepsy, found that 40 percent of those who underwent genetic testing for epilepsy had one of the genetic variants known to be associated with the disease.
In a July 31 online report in JAMA Pediatrics, the authors concluded that genetic testing, particularly gene sequencing, should be incorporated into the initial evaluation of young children with epilepsy so that an optimal treatment plan can be devised. Often genetic testing for epilepsy is not conducted until doctors exhaust traditional means of evaluation, such as neuroimaging and metabolic testing, the study authors said.
"Genetic testing can end the diagnostic odyssey and that is a huge thing," said lead author Anne T. Berg, PhD, research professor of pediatrics at Ann & Robert H. Lurie Children's Hospital of Chicago and the Northwestern University Feinberg School of Medicine. She said the sooner a precise diagnosis can be made, the sooner a child can be started on the most appropriate therapy, which can help protect against seizures during a critical time of development and perhaps save on medical expenses.
The study involved a prospective review of medical charts and diagnostic evaluations (neuroimaging, metabolic, genetic) for 775 children under age 3 who were seen between 2012 and 2015 for newly diagnosed epilepsy at 17 US pediatric epilepsy centers. Ninety-five of the children had an acquired brain injury and were excluded from the analysis.
Of the remaining 680 children, 327 (48 percent) underwent genetic testing, whether karyotyping, microarrays, epilepsy panels, whole exome sequencing, mitochondrial function gene panels and other targeted genetic investigations. Genetic testing identified pathogenic variants in 40 percent of the children who were tested.
"Aside from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9/11, 82 percent), metabolic diseases (11/14, 79 percent) and brain malformations (20/61, 33 percent)," the researchers reported. Genetic testing yielded a specific diagnosis in 25 percent of children for whom the cause of epilepsy would have been otherwise impossible to pinpoint.
The researchers found that in children with initially unexplained etiology, the diagnostic yield was substantially less for chromosome microarray, which is currently more commonly used, than it was for sequencing methods, including epilepsy panels and whole exome sequencing.
They noted that like magnetic resonance imaging, genetic tests "have substantial diagnostic yields regardless of clinical features, certainly higher than the many metabolic tests that are frequently ordered."
They concluded that "genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluations of early-presenting ELE [early-life epilepsies] and not just reserved for those with severe presentations and poor outcomes."
The researchers acknowledged that genetic testing technology continues to evolve. The meanings of many of the genetic variants associated with epilepsy are not fully understood.
"Previously, most ELEs were relegated to the undifferentiated category pf symptomatic (sometimes 'secondary' or 'catastrophic) generalized epilepsy with a few electroclinical syndromes (for example, West syndrome or infantile spasms) specifically recognized. Causes in half or more remain unknown."
The study noted that while neuroimaging is standard in the evaluation of ELE, genetic testing has never been recommended for the initial diagnostic work-up.
"This is despite a growing literature directed at gene discovery for ELE, which has utilized individual techniques such as whole exome sequencing, chromosome microarray, epilepsy panels, and single-gene testing in selected patients," the paper said.
The researchers also noted limitations of their study. It was not a population-based study and involved only children evaluated at hospital-based epilepsy centers. It is not known whether the same trends for genetic testing would emerge for children at community practices.
Another downside is that genetic testing can cost thousands of dollars, and even with genetic testing, the cause of a child's seizures may not be found.
Still, Dr. Berg said genetic testing could result "in a huge cost savings" if it allows for better tailoring of treatment and keeps kids out of the hospital.
"We are just on the cusp of precision medicine in epilepsy, being able to select therapies that target the underlying physiology rather than just suppressing the symptoms," Dr. Berg said. She said precision medicine begins with a precise diagnosis, and she said she hoped the paper's findings would influence insurance coverage policies.
Look for expanded coverage of the study, including expert commentary, in an upcoming issue of Neurology Today.