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Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine.

ABSTRACT: Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that antagonise the mammalian isoform of the target of rapamycin complex 1 (mTORC1) - a key mediator of cell growth and metabolism. TSC is characterised by the development of benign tumours in multiple organs, together with neurological manifestations including epilepsy and TSC-associated neuropsychiatric disorders (TAND). Epilepsy occurs frequently and is associated with significant morbidity and mortality; however, the management is challenging due to the intractable nature of the seizures. Preventative epilepsy treatment is a key aim, especially as patients with epilepsy may be at a higher risk of developing severe cognitive and behavioural impairment. Vigabatrin given preventatively reduces the risk and severity of epilepsy although the benefits for TAND are inconclusive. These promising results could pave the way for evaluating other treatments in a preventative capacity, especially those that may address the underlying pathophysiology of TSC, including everolimus, cannabidiol and the ketogenic diet (KD). Everolimus is an mTOR inhibitor approved for the adjunctive treatment of refractory TSC-associated seizures that has demonstrated significant reductions in seizure frequency compared with placebo, improvements that were sustained after 2 years of treatment. Highly purified cannabidiol, recently approved in the US as Epidiolex® for TSC-associated seizures in patients ⩾1 years of age, and the KD, may also participate in the regulation of the mTOR pathway. This review focusses on the pivotal clinical evidence surrounding these potential targeted therapies that may form the foundation of precision medicine for TSC-associated epilepsy, as well as other current treatments including anti-seizure drugs, vagus nerve stimulation and surgery. New future therapies are also discussed, together with the potential for preventative treatment with targeted therapies. Due to advances in understanding the molecular genetics and pathophysiology, TSC represents a prototypic clinical syndrome for studying epileptogenesis and the impact of precision medicine.

SUBMITTER: Schubert-Bast S

PROVIDER: S-EPMC8290505 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective:To estimate health-related quality of life (HRQoL) in patients with tuberous sclerosis complex (TSC) and associated manifestations and to identify potential factors associated with HRQoL in this population of patients. Methods:We performed a retrospective chart review of adults with TSC who attended the outpatient clinic of the University Medical Center Utrecht in the Netherlands from 1990 to 2015 (N = 363; on average 33.6 years of follow-up). HRQoL data were assessed in 2012 using the Health Utility Index version 3 (HUI-3) questionnaire completed by patients or caregivers (N = 214 with HUI score and ?1 TSC manifestation, including renal angiomyolipomas [rAMLs], subependymal giant cell astrocytoma [SEGA], or epilepsy). Results:Of 214 patients in the study sample, 171 had TSC-associated epilepsy (with or without rAML/SEGA), 37 had TSC and rAML (without epilepsy or SEGA), and 6 had other combinations of manifestations. The median HUI score for the 214 patients with ?1 TSC manifestation was 0.51 (-0.371 to 1 scale, 1 = perfect health, 0 = death, <0 = worse than death). Among all components used to build the overall HUI score, the cognition component had the lowest score (mean = 0.47; 0-1 scale). Patients with TSC-epilepsy had significantly lower overall HUI than patients with TSC and rAML only (median HUI = 0.31 vs 0.95, P < .05), especially those who were in refractory state for prolonged periods of time (median HUI = -0.11 among patients with seizures during the entire duration of their follow-up time). In multivariate analyses, severe impairment of daily functioning was the strongest predictor of HRQoL decrement (adjusted HUI difference between patients with severe vs. no impairment = -0.55, P < .05). Significance:This study showed that TSC-related epilepsy is associated with lower HUI, especially for patients who have refractory seizures for prolonged periods of time. Early and effective interventions to control or reduce seizures and preserve patients' cognitive functions may help to improve patients' quality of life.

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Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine.

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