Simple blood tests could one day track disease activity in children with LGS
Researchers link frequent seizures to higher levels of nerve-damage biomarkers
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New data show a link between frequent seizures and markers of nerve damage in children with Lennox-Gastaut syndrome. (Image from iStock)
Children with Lennox-Gastaut syndrome (LGS) show significantly higher blood levels of proteins linked to nerve injury and cell death than healthy children, a small study in India suggests.
Researchers discovered that these biomarker changes directly track with a heavier seizure burden, raising the possibility that simple blood tests could one day help doctors monitor disease activity or track how well a patient responds to treatments.
The study, “mRNA profiling of caspase-3 and neurofilament light chain in Lennox-Gastaut Syndrome,” was published in Epilepsy Research.
The daily impact of childhood LGS
LGS is a rare and severe form of epilepsy that can arise from a range of causes, including genetic mutations and brain injury. It usually begins in early childhood and is marked by multiple seizure types that are often difficult to control with antiseizure medication. Children with the condition may also experience developmental delays, cognitive impairment, and behavioral problems.
Because repeated seizures sharply increase the brain’s energy demands, researchers suspect they disrupt normal brain function and trigger apoptosis, which is a process of programmed cell death that leads to nerve cell injury.
Two biomarkers may help provide clues about these processes. One is neurofilament light chain, or NfL, a structural protein found in nerve fibers that is released when they are damaged and is increasingly studied as a marker of nerve injury. The other is caspase-3, a protein that plays a central role in apoptosis and has been linked to tissue injury in neurological diseases.
Although both biomarkers have been studied in epilepsy and other neurological disorders, studies examining blood levels of NfL and caspase-3 in people with LGS are lacking.
To address this gap, a team of researchers in India conducted a study involving 23 children with LGS enrolled at a tertiary care teaching hospital between February 2023 and January 2024. A total of 14 healthy children matched by age and sex were included for comparison.
The researchers collected clinical histories, assessed disease severity, and performed brain MRIs and electroencephalography (EEG), which records the brain’s electrical activity. They then analyzed blood samples to determine how NfL and caspase-3 protein levels correlated with seizure burden and brain abnormalities.
Participants had a median age of 6 years, and 69.6% were boys. Most (73.9%) developed LGS following perinatal hypoxic-ischemic encephalopathy, which is a brain injury caused by a lack of oxygen around birth, while the cause was unknown in the remaining children.
Seizures had started very early in life, at a median age of 5 months, and the children showed substantial developmental impairment. Overall disease severity was also high, with a median Clinical Global Impression-Severity score of six, indicating severe illness.
Despite treatment with multiple antiseizure medications, a median of three per child, seizures remained frequent.
All participants experienced drop attacks or atonic seizures, which involve a sudden loss of muscle tone and can cause falls or collapse. Other common seizure types included:
- tonic seizures, which is marked by body stiffening
- focal seizures, which begin in one area of the brain
- myoclonic seizures, which involve sudden muscle jerks
- atypical absence seizures, which can cause staring and reduced awareness
In the month before blood collection, the children experienced a median of 371 seizures, most commonly drop attacks.
How seizure frequency links to cell damage
When researchers analyzed the blood samples, they found that children with LGS had significantly higher expression of both biomarkers than healthy peers. Median NfL expression was about six times higher than in healthy kids, while caspase-3 expression was roughly three times higher.
These changes also tracked with seizure burden in the month before blood collection. Higher NfL levels were linked to greater burden of focal seizures and higher caspase-3 levels. Meanwhile, higher caspase-3 levels were associated with greater overall seizure burden as well as higher numbers of atypical absence and myoclonic seizures.
Most children in the study showed MRI abnormalities (91.3%) and typical LGS patterns on their EEGs (60.9%). However, neither these test results nor overall disease severity scores were significantly associated with NfL or caspase-3 levels. The researchers suggested that because severe disease features and scan abnormalities were already common among the participants, it was difficult to distinguish subtle differences in the biomarker data.
“The higher expression of NfL and caspase-3 in LGS, and their association with seizure burden, suggests seizure-induced [nerve] injury and apoptosis,” the researchers wrote. They noted that future studies are needed to determine whether these blood markers can effectively monitor disease activity and, potentially, evaluate treatment responses.
