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Accumulated seizure burden predicts neurodevelopmental outcome at 36 months of age in patients with tuberous
S Katie Z Ihnen1,2, Samuel Alperin3,4, Jamie K Capal5
1Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Insights
In tuberous sclerosis complex (TSC), accumulated seizure burden, not seizure onset age, best predicts neurodevelopmental outcomes by 36 months. Aggressive seizure management in early childhood is crucial for optimizing cognitive function in TSC patients.
Area of Science:
- Neuroscience
- Developmental Pediatrics
- Genetics
Background:
- Tuberous sclerosis complex (TSC) frequently involves epilepsy and intellectual disability.
- Early childhood seizures and neurodevelopmental deficits are correlated in TSC, but the specific impact of seizure timing and burden is unclear.
Purpose of the Study:
- To investigate the distinct effects of age at seizure onset and accumulated seizure burden on neurodevelopmental outcomes in infants and young children with TSC.
- To identify predictive biomarkers for neurodevelopmental trajectories in TSC.
Main Methods:
- Analysis of seizure diaries, serial neurodevelopmental testing, and brain MRI in 129 TSC patients (0-36 months).
- Machine learning applied to identify and track neurodevelopmental subgroups at 12 and 36 months.
- Logistic regression used to assess candidate biomarkers (seizure onset age, seizure burden, tuber volume, sex, prior test scores) for predicting 36-month neurodevelopmental outcomes.
Main Results:
- Two neurodevelopmental subgroups (higher and lower scoring) identified at 36 months, with 75% stability at 12 months.
- Accumulated seizure burden showed the largest univariable effect on subgroup, followed by earlier test scores and tuber volume.
- A multivariable model combining accumulated seizure burden and earlier test scores accurately predicted 36-month neurodevelopmental group (82% accuracy, AUC .86).
Conclusions:
- Accumulated seizure burden is a more significant predictor of 36-month neurodevelopmental outcomes in young TSC patients than age at seizure onset.
- These findings highlight the critical importance of aggressive seizure management in the first three years of life for TSC patients to improve both seizure control and cognitive function.
Objective:
Epilepsy and intellectual disability are common in tuberous sclerosis complex (TSC). Although early life seizures and intellectual disability are known to be correlated in TSC, the differential effects of age at seizure onset and accumulated seizure burden on development remain unclear.
Methods:
Daily seizure diaries, serial neurodevelopmental testing, and brain magnetic resonance imaging were analyzed for 129 TSC patients followed from 0 to 36 months. We used machine learning to identify subgroups of patients based on neurodevelopmental test scores at 36 months of age and assessed the stability of those subgroups at 12 months. We tested the ability of candidate biomarkers to predict 36-month neurodevelopmental subgroup using univariable and multivariable logistic regression. Candidate biomarkers included age at seizure onset, accumulated seizure burden, tuber volume, sex, and earlier neurodevelopmental test scores.
Results:
Patients clustered into two neurodevelopmental subgroups at 36 months of age, higher and lower scoring. Subgroup was mostly (75%) the same at 12 months. Significant univariable effects on subgroup were seen only for accumulated seizure burden (largest effect), earlier test scores, and tuber volume. Neither age at seizure onset nor sex significantly distinguished 36-month subgroups, although for girls but not boys there was a significant effect of age at seizure onset. In the multivariable model, accumulated seizure burden and earlier test scores together predicted 36-month neurodevelopmental group with 82% accuracy and an area under the curve of .86.
Significance:
These results untangle the contributions of age at seizure onset and accumulated seizure burden to neurodevelopmental outcomes in young children with TSC. Accumulated seizure burden, rather than the age at seizure onset, most accurately predicts neurodevelopmental outcome at 36 months of age. These results emphasize the need to manage seizures aggressively during the first 3 years of life for patients with TSC, not only to promote seizure control but to optimize cognitive function.
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