BY THOMAS R. COLLINS
NEW ORLEANS—The estimated incidence of epilepsy is one case for every 395 live births, with etiology identified about half the time through imaging and genetic testing, according the findings of a large population-based study in Scotland presented here at the American Epilepsy Society annual meeting.
For the prospective study, all pediatricians and pediatric neurologists in the West of Scotland — with a population of three million and 31,000 births a year — were asked to refer all children younger than 3 years old presenting with epilepsy to the national genetic epilepsy service for genetic testing. The researchers also reviewed the clinical case notes of the 1,318 children who had undergone electroencephalography before their fourth birthday from 2014 through 2017.
Children were included if they had experienced a second afebrile seizure before their third birthday and within the three-year study period. Of the 228 included, 205 underwent neuroimaging, 124 cytogenetic testing, and 210 molecular genetic testing.
Researchers found that 116, or 51 percent, had an etiology identified — 32 percent had genetic causes, 24 percent structural, and 4 percent metabolic; about 10 percent were placed in more than one of these etiology groups.
Among the 28 percent of patients with global developmental delay (GDD) and who were drug-resistant, an etiology was found 75 percent of the time: 33 of the 54 etiologies were genetic and the others structural. Among the 21 percent with GDD who were not drug-resistant, an etiology was found in 5 percent of cases: 19 of the 33 had structural causes.
The researchers conducted whole genome sequencing (WGS) on patients with drug-resistant epilepsy and GDD in whom MRI or gene panel testing had not identified an etiological diagnosis. WGS uncovered genetic and etiological diagnoses in in 29 percent and 79 percent of these patients, respectively.
The findings could help clinicians trying to decide whether to perform genetic testing in their patients younger than age 3, said Joseph D. Symonds, MBChB, a clinical research fellow in pediatric epilepsy genetics at the Royal Hospital for Sick Children, who presented the findings.
"If the children are under the age of 3, it's a pretty good justification for more testing with at least the panel that includes the most commonly indicated genes," he said. In findings that were not presented with this set of data — about 80 percent of the genetic diagnoses were made using seven of the most common genes, so even a smaller, less expensive panel might be worthwhile, Dr. Symonds noted.
He said that he and his colleagues are planning to expand their study to include all of Scotland.
Daniel B. Lowenstein, MD, professor of neurology at the University of California, San Francisco, said the study may be the first of this type covering such a large population.
"These results strike me as extremely important," he said. "I believe this may be the first study to ever capture the incidence/prevalence of epilepsy in this age group and this large of a regional population. As such, it provides new insights into the population characteristics of epilepsy in infancy and early childhood."
Dr. Lowenstein noted, though, that the study covered a very homogeneous population, and future studies will need to demonstrate how applicable these findings are to other populations.
"What is particularly notable is that the emergence of genetic testing along with the remarkable improvements in brain imaging have brought us to the point where it is possible to define the etiologic basis of epilepsy in more than 50 percent of patients, with an even higher percentage — 75 percent — in patients with GDD," Dr. Lowenstein said.
"Recent studies focusing on genetics have shown that genetic causes can be identified in at least 50 percent of patients with epileptic encephalopathies, but these findings were based in large part on referrals of patients to specialized epilepsy centers. That is why this study constitutes a very important contribution to our understanding of early-onset epilepsy."
The current study was supported by charitable grants from Epilepsy Research UK and Glasgow Children's Hospital Charity. Drs. Symonds and Lowenstein reported no disclosures.
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AES Abstract 1.402: Symonds JD, Elliott KS, Knight JC, et al. Comprehensive phenotyping and genotyping in a Scottish population-based cohort of children presenting with epilepsy <3 years.