Treatment of both clinical and electrographic seizures in neonates did not lead to better 2-year survival or neurodevelopment results compared to treating only clinically detected seizures, a randomized trial showed.
The odds of death or severe disability were not significantly different between the electrographic seizure group – in which seizures detected by electroencephalography (EEG) were treated in addition to clinical seizures – compared to the clinical seizure group, in which only clinically detected seizures were treated (OR 1.83, 95% CI 0.96-3.49, P= 0.14), reported Rod Hunt, PhD, of Monash University in Australia, and the co-authors of JAMA network open.
Contrary to what the researchers had assumed, the clinical seizure group had better cognitive scores at 2 years.
“This is the largest study to date exploring whether or not we should treat all electrographic seizures in newborns, and the result is not unexpectedly conclusive,” Hunt said. MedPage today.
“We have to be careful in treating all seizures with the anticonvulsant drugs currently in use, as we may not be improving outcomes for these vulnerable infants,” he said.
Neonatal seizures indicate the presence of acute brain damage such as hypoxic-ischemic encephalopathy (EHI) or stroke, congenital brain malformations or genetic epileptic syndromes, observed Martin Offringa, MD, PhD, and Brian Kalish, MD, both from The Hospital for Sick Children in Toronto, in an accompanying editorial.
“Given concerns about the risk that ongoing seizures lead to increased seizure activity and may cause additional brain damage, neonatal seizures are often treated aggressively with anticonvulsant drugs,” Offringa and Kalish wrote.
“Most neonatal seizures are subclinical, that is, epileptogenic EEG discharges occur without any time-related motor or autonomic clinical symptoms, and, moreover, the diagnosis of clinical seizures in neonates is very unreliable, ”they added. “As a result, neuromonitoring with amplitude integrated EEG (aEEG) or continuous EEG (cEEG) has become the standard of care among tertiary neonatal intensive care units. [neonatal intensive care units]. “
The trial evaluated full-term or short-term (at least 35 weeks’ gestation) neonates with encephalopathy who were less than 48 hours old. They were recruited from 2012 to 2016 in tertiary NICUs and randomized into two groups.
The researchers aimed to enroll 300 newborns in each group. However, recruitment ended prematurely with 212 newborns due to slow progress and loss of balance when a paper was published suggesting that treatment for all electrographic seizures was beneficial.
Over 2 years, 20 infants from each group were lost to follow-up or had incomplete data, leaving 86 in the electrographic seizure group and 86 in the clinical seizure group for the primary analysis. Both groups underwent aEEG, but the electrographic seizures in the clinical group were not disclosed to the attending physician.
In both arms of the study, clinically apparent seizures were treated. In the electrographic group, seizures detected by EEG meeting diagnostic criteria were treated if they lasted more than 2 minutes or occurred more than twice in 24 hours.
The primary endpoint was death or severe disability at 2 years. Severe disability was defined as scores in any domain of development more than 2 standard deviations below the Australian mean on the Bayley Scales for Infant and Toddler Development, Third Edition (BSID-III), or the presence of cerebral palsy, blindness or deafness.
Of the 212 newborns, the mean gestational age was 39.2 weeks and 58% were male. Most newborns (72%) had moderate to severe EHI and 84% had electrographic seizures. In the electrographic group, 86% of newborns were treated with anticonvulsants, as did 69% in the clinical group.
A total of 38 infants (44%) in the electrographic group and 27 (31%) in the clinical group achieved the primary outcome. Ten newborns in the electrographic group and four in the clinical group died before evaluation at 2 years.
At 2 years, cognitive domain scores on BSID-III were worse in the electrographic group (mean scores 97.4) than in the clinical group (mean scores 103.8; mean difference -6.5, 95% CI -1.2 to -11.8, P= 0.01). Secondary outcomes, including time taken to suck food, seizure load, and brain injury scores on MRI, were similar between groups.
With the early closing of recruitment, the trial lacked the necessary power for its primary and secondary outcomes, the researchers acknowledged. “Further analysis is underway to question the direct impact of our commonly used anticonvulsants,” Hunt said. “Urgent research is needed to find more effective anticonvulsants that are also neuroprotective.”
This study was funded by the National Board of Health and Medical Research (NHMRC) of Australia. Two researchers were supported by career development grants from the Medical Research Future Fund.
Hunt had no disclosure. The co-authors reported relationships with the NHMRC and Chiesi Farmaceutici.
The editorial writers had no disclosure.