Abstract
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.
Joshi C. Developmental Outcome at 36 Months in Tuberous Sclerosis: Are There any Modifiable Predictors? Epilepsy Currents. 2025;0(0). doi:10.1177/15357597251351453 (commentary on the above)
Main Take-Home Message
What has been uncovered:
1.
DQ at 12 months is likely to stay stable up to 36 months of age since 74% of patients segregated into the same subgroup at 12 months as at 36 months.
2.
On univariable analysis, persistently lower scores on DQ at 36 months are associated with larger tuber volume, earlier age at seizure onset, higher accumulated seizure burden, and lower 12-month DQ.
3.
Although the lower scoring subgroup had mean age at seizure onset nearly 2 months earlier than the higher scoring subgroup; this variable did not achieve statistical significance in the multivariable logistic regression model.
4.
On multivariable analysis, the accumulated seizure burden with focal seizures is more important than presence or absence of epileptic spasms and earlier age of onset such that the number of seizure (focal) days per week per patient was clearly higher in the lower scoring subgroup compared to the higher scoring subgroup.
5.
Ninety percent of those in the favorable group experienced seizure reduction following surgery (90% vs. 69%; p = not significant). As a corollary, patients exposed to higher numbers of antiseizure medications segregated into the lower scoring group.
6.
There was a higher proportion of TSC1 compared to TSC2 pathogenic variants in the higher scoring group (p = not significant).
7.
The combination of accumulated seizure burden and 12-month DQ was more powerful (82% accuracy) than either variable alone in predicting 36-month DQ.
What remains to be seen:
1.
Authors did not analyze EEG variables and burden of subclinical seizures or interictal abnormalities on ultimate development.
2.
A biological effect of sex was found on post hoc analysis such that girls in the lower scoring subgroup are likely to have earlier onset of seizures. This finding needs replication in larger studies.
Conclusion
All in all, the most critical variables identified in the study include focal seizure days and DQ at 12 months as actionable variables for the managing clinician.
The sequential analysis of data from these TOSCA and TACERN registries evoked memories of reading newer editions of a reference book with updated information with each new edition. We eagerly await further analysis of ictal and interictal EEG abnormalities and whether they affect ultimate development.
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