Two recent papers looked at distinct sources of data to understand causes of premature death in people living with tuberous sclerosis complex (TSC). Both groups of researchers concluded that Sudden Unexpected Death in Epilepsy (SUDEP) contributes significantly to mortality in individuals with TSC and is among the leading causes of premature death in this population.
One paper1 published in 2021 analyzed data from 31 individuals who had died as of February 14, 2020, from among 2,233 individuals enrolled in the TSC Alliance’s Natural History Database at that time. A paper2 published in 2025 analyzed data from 13 studies (including the 2021 publication1) that reported a total of 411 deaths from 6,735 TSC individuals.
SUDEP accounts for a substantial percentage of deaths, with rates reported in various studies ranging from 22.2 to 34.6 percent of deaths in people with TSC being caused by SUDEP. In the TSC Natural History Database cohort, SUDEP was responsible for 42.3 percent of fatalities. This rate is considerably higher than those observed in the general epilepsy population, which typically ranges from 7-17 percent of deaths occurring due to SUDEP. The actual rate of SUDEP in TSC might be even higher than reported, as SUDEP cases may be under-reported on death certificates or categorized under less specific terms like “death attributable to epilepsy.” Males appear to comprise a majority of SUDEP cases in TSC, with one study reporting 63.6 percent of SUDEP cases were male.
Many SUDEP cases in TSC involve individuals treated with multiple anti-seizure medications (ASMs). A high percentage of SUDEP cases (seven out of ten in the TSC Natural History Database study) are associated with treatment-resistant epilepsy (TRE), meaning the person’s epilepsy was not controlled even after trying multiple ASMs or other treatments such as surgery. Individuals who die from SUDEP in TSC tend to be younger than those who die from other causes, whether the other causes were unrelated to TSC or related to TSC, such as lymphangioleiomyomatosis (LAM) and end-stage renal disease. In the TSC Natural History Database study, the average age of epilepsy onset was seven months in the SUDEP cases.
Intellectual and psychiatric disabilities, alongside the high rate of TRE and use of multiple ASMs, are factors that may contribute to SUDEP risk in TSC patients. However, it is also possible that intellectual and psychiatric disabilities are more common in severe TSC which correlates with more severe epilepsy rather than directly contributing to SUDEP.
In summary, SUDEP is a critical and often leading cause of death in individuals with tuberous sclerosis complex, occurring at higher rates than in the general epilepsy population. Factors such as male gender, treatment-resistant epilepsy, the use of multiple anti-seizure medications, and co-occurring intellectual and psychiatric disabilities are associated with an increased risk of SUDEP in this group.
Paper 1:
Lead author: Orrin Devinsky, MD, NYU Epilepsy Center, 223 E 34 St, New York, NY 10016, United States.
Paper 2:
Lead author: Robin Whitney, MD, Department of Pediatrics, McMaster Children’s Hospital, Hamilton, Ontario, Canada
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