Rationale:
Tuberous sclerosis complex (TSC) is a genetic disorder in which ~90% of patients develop epilepsy. Knowledge about the natural history of TSC is limited by considerable inter-subject heterogeneity and little data on outcomes after childhood. Only two single-center studies reported on TSC mortality. We used the Tuberous Sclerosis Alliance Natural History Database, a consortium of 18 United States centers, to study mortality in TSC.
Method:
We retrospectively analyzed data from the TSC Natural History Database of 2,233 patients. Thirty-three patients died between March 1, 2008 and February 14, 2020. We reviewed available data to identify causes of death (COD). For suspected SUDEP cases, we categorized patients into definite, probable, and possible SUDEP, and determined risk factors present for each patient.
Results:
Among the 33 decedents, 16 (48.5%) were male and 17 (51.5%) were female. There was no data on COD or date of death for two patients. Of the remaining 31 patients, 13 (41.9%) were < 21 years old and 18 (58.1%) were >21 years old. The mean age of death was 29 years (median 28 years). Molecular testing results were available for 16 patients: mutation in TSC1 (2), TSC2 (11), and no TSC gene mutation (3). The COD was available for 26/31 cases: 12 had COD definitely related to TSC, 11 had COD possibly related to TSC, and three deaths were unrelated to TSC. The CODs included respiratory conditions in 6/26 (23.1%) patients (lymphangioleiomyomatosis in one), tumors in 3/26 (11.5%), suicide in 2/26 (7.7%), cardiopulmonary in 2/26 (7.7%), shunt malfunction (1), and drowning (1). Sudden unexpected death in epilepsy (SUDEP) occurred in 11/26 (35.5%) deaths: eight in children and three in adults. The mean age of death was 21 years (median 18 years). Seven of these cases were in males, and four in females. SUDEPs were classified as Definite (5), Probable (4), and Possible (2). The Possible SUDEPs were older (mean 57 years) than Definite (mean 14 years) or Probable (mean 11 years). Four SUDEP cases were sleeping when they died; two were supervised (one directly witnessed after seizure and the other via baby monitor), and two unsupervised. This information was unavailable for the remaining seven. All 11 SUDEP patients had a history of epilepsy; date of onset was known for five (mean 7 months). Ten SUDEP cases were being treated with a mean of three anti-seizure drugs (ASDs) at death; 7 had intractable epilepsy and 3 were controlled with ASDs.
Conclusion:
SUDEP was the leading cause of mortality in this TSC cohort and comprised a higher portion of all CODs compared to studies in other epilepsy populations. The high rate of treatment resistant epilepsy, multiple ASD therapies, comorbid intellectual and psychiatric disabilities may all contribute to the risk of SUDEP in TSC patients. Alternatively, these may reflect more severe TSC and epilepsy, which directly drive increased SUDEP risk. Given the frequency of SUDEP in TSC, these patients and their families should be counseled about the importance of ASD adherence and lifestyle factors and the potential role of nocturnal supervision or seizure detection devices.
Funding:
:No funding
FIGURES
Figure 1