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. 2021 Oct:123:1-9.
doi: 10.1016/j.pediatrneurol.2021.06.012. Epub 2021 Jul 6.

Epilepsy Is Heterogeneous in Early-Life Tuberous Sclerosis Complex

S Katie Z Ihnen  1 , Jamie K Capal  2 , Paul S Horn  3 , Molly Griffith  3 , Mustafa Sahin  4 , E Martina Bebin  5 , Joyce Y Wu  6 , Hope Northrup  7 , Darcy A Krueger  3 ; TACERN study group
Affiliations

Epilepsy Is Heterogeneous in Early-Life Tuberous Sclerosis Complex

S Katie Z Ihnen et al. Pediatr Neurol. 2021 Oct.

Abstract

Background: Epilepsy in tuberous sclerosis complex (TSC) typically presents with early onset, multiple seizure types, and intractability. However, variability is observed among individuals. Here, detailed individual data on seizure characteristics collected prospectively during early life were used to define epilepsy profiles in this population.

Methods: Children aged zero to 36 months were followed longitudinally. Caregivers kept daily seizure diaries, including onset and daily counts for each seizure type. Patients with >70% seizure diary completion and >365 diary days were included. Developmental outcomes at 36 months were compared between subgroups.

Results: Epilepsy was seen in 124 of 156 (79%) participants. Seizure onset occurred from zero to 29.5 months; 93% had onset before age 12 months. Focal seizures and epileptic spasms were most common. Number of seizures (for median 897 days) ranged from 1 to 9128. Hierarchical clustering based on six metrics of seizure burden (age of onset, total seizures, ratio of seizure days to nonseizure days, seizures per seizure day, and worst seven- and 30-day stretches) revealed two distinct groups with broadly favorable and unfavorable epilepsy profiles. Subpopulations within each group showed clinically meaningful differences in seizure burden. Groups with higher seizure burden had worse developmental outcomes at 36 months.

Conclusions: Although epilepsy is highly prevalent in TSC, not all young children with TSC have the same epilepsy profile. At least two phenotypic subpopulations are discernible based on seizure burden. Early and aggressive treatments for epilepsy in TSC may be best leveraged by targeting specific subgroups based on phenotype severity.

Keywords: Epilepsy in infancy; Epilepsy phenotype; Epileptic spasms; Focal seizures; Seizure burden; Seizure diary; Tubers.

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Conflict of interest statement

Disclosures of conflicts of interest:

Dr. Bebin reports grants from Greenwich Biosciences, other from REGENXBIO, other from Neurelis, other from MEDSCAPE, outside the submitted work. Dr. Capal reports grants from Roche, outside the submitted work. Dr. Krueger reports grants from National Institutes of Health (NINDS), during the conduct of the study; personal fees from Novartis Pharmaceuticals, personal fees from Greenwich Bioscience, grants from Marinus Pharmaceuticals, personal fees from Nobelpharma America, personal fees from REGENXBIO, grants and non-financial support from Tuberous Sclerosis Complex Alliance, outside the submitted work. Dr. Northrup has no conflicts of interest related to the submitted work. Dr. Sahin reports grant support from Novartis, Roche, Biogen, Astellas, Aeovian, Bridgebio, Aucta and Quadrant Biosciences. He has served on Scientific Advisory Boards for Novartis, Roche, Celgene, Regenxbio, Alkermes and Takeda. Dr. Wu reports grants and other from Greenwich Biosciences, other from Novartis, outside the submitted work. The remaining authors have nothing to disclose.

Figures

Figure 1:
Figure 1:
CONSORT-like flow diagram depicting patient selection
Figure 2:
Figure 2:. Heat map of individual seizure burden over time measured by the number of seizure days each week.
Patients are organized along the y-axis according to hierarchical cluster membership. Each square across the x-axis represents one week of study enrollment starting at birth through study completion (0–36 months). Each row represents one individual patient (n=88) who reported at least one seizure during the reporting period. Squares are color coded according to the number of seizure days (0–7) for each week that each patient was enrolled and data was complete. Blank squares indicate missing data or time outside of (before or after) the reporting period.
Figure 3:
Figure 3:. Characteristics of TSC subgroups according to seizure burden.
(A) Dendrogram depicting the hierarchical clustering solution for seizure burden in early TSC. Each of 88 participants is represented by a single tick on the x-axis. Dissimilarity distance is shown on the y-axis, with high and low thresholds applied to identify separable subpopulations; thresholds are depicted as dotted lines. (B) Median values for each seizure burden metric for each of the five sub-groups, by group. (C) Patterns for each seizure burden metric for each of the five sub-groups, by individual. Each is color-coded and organized according to cluster membership, starting with cluster A on the left and then showing clusters B, C, D and E. (D) Summary of seizure burden characteristics for each of the five sub-groups.
Figure 4:
Figure 4:. Differences in seizure types among TSC subgroups separated by seizure burden.
Proportion of patients reporting focal seizures only, epileptic spasms only, or both focal seizures and epileptic spasms is shown for each of the five sub-groups, by group.
Figure 5:
Figure 5:. Differences in developmental outcome among TSC subgroups separated by seizure burden.
Box and whisker plots depicting the median developmental quotient (DQ), by group, at 36 months of age. Solid brackets indicate a significant pairwise group difference at p<0.05; dotted brackets indicate a significant pairwise group difference at p<0.005.
See this image and copyright information in PMC

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