Orphanet Journal of Rare Diseases | Systematic Review of the Disease Burden in TSC-related Epilepsy

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This systematic review comprehensively assesses the impact of TSC-related epilepsy on patients' and caregivers' quality of life, healthcare resource utilization, and economic burden, highlighting the necessity of early diagnosis and effective treatment.

 

Literature Overview
This article, titled 'Burden of illness in tuberous sclerosis complex-associated epilepsy: a systematic literature review of epidemiology, health-related quality of life, costs and resource use', published in the Orphanet Journal of Rare Diseases, reviews and summarizes the disease burden of TSC-associated epilepsy on patients and caregivers, including epidemiology, quality of life, medical costs, and resource utilization.

Background Knowledge
Tuberous Sclerosis Complex (TSC) is a rare autosomal dominant genetic disorder caused by mutations in the TSC1 or TSC2 genes, leading to hamartoma formation in multiple organs, including the brain, kidneys, lungs, skin, and retina. TSC-associated epilepsy is one of the most common neurological manifestations, affecting over 60% of patients, with nearly half developing drug-resistant epilepsy. Seizures often begin early in infancy and are highly associated with cognitive impairment, autism spectrum disorder (ASD), and neuropsychiatric disorders. Current main treatments for TSC-related epilepsy include everolimus and cannabidiol, but therapeutic options are limited, and comprehensive assessments of the disease burden are lacking. This study focuses on the burden of TSC-related epilepsy through a systematic literature review, complementing the review by Zöllner et al. (2020), with a particular emphasis on the impact of epilepsy on quality of life, caregiver stress, and healthcare resource utilization.

 

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Research Methods and Experiments
The research team conducted a systematic literature review following the PRISMA guidelines, searching databases including Medline, EMBASE, Cochrane Library, and conference websites up to April 2023. Included studies addressed epidemiology, quality of life, economic evaluation, healthcare resource use, and impacts on work or education in TSC patients. Studies focusing on treatment efficacy and safety or non-neurological manifestations were excluded. Ultimately, 241 relevant articles were included, with 182 covering epidemiological data, 58 addressing quality of life, 93 focusing on costs and resource use, and 59 discussing treatment patterns.

Key Findings and Perspectives

• The global incidence of TSC ranges from 0.153 to 17.24 per 100,000 live births, with a prevalence of 0.6 to 12.7 per 100,000 population. Incidence is lower in Asian countries, whereas earlier studies reported higher values.
• The average prevalence of TSC-associated epilepsy in children is 79.8%, and in adults, it is 64.1%. Approximately 45.5% of mixed-age patients, 63.4% of adults, and 85.4% of children have drug-resistant epilepsy.
• TSC mutations in epilepsy patients are more commonly found in TSC2, and TSC2 mutation carriers tend to experience more severe seizures, earlier diagnosis, and a higher likelihood of intellectual disability.
• Cortical tubers are a significant risk factor for epilepsy (OR 5.1), and cardiac rhabdomyomas (OR 1.9) and cortical tubers (OR 3.4) are independent predictors of TSC-related epilepsy.
• Epilepsy significantly affects patients' quality of life, particularly in language, attention, social interaction, and learning. Caregiver burden and family stress also increase, especially with higher seizure frequency.
• In terms of medical costs, the annual direct healthcare cost for TSC patients with epilepsy is £14,335, significantly higher than £4,448 for those without epilepsy. Epilepsy also increases hospitalization rates and physician visits, impacting patients' and caregivers' careers and education.
• Early seizure onset, especially infantile spasms, is associated with increased risk of autism and cognitive impairment. Early interventions, such as sirolimus and vigabatrin, may reduce seizure occurrence and improve neurodevelopmental outcomes.
• Although epilepsy is a major manifestation of TSC, there remains a lack of long-term adult burden data and validated PRO instruments, with no formal statistical analysis conducted to date.

Research Implications and Future Directions
This study underscores the high burden of TSC-associated epilepsy, including reduced quality of life, increased healthcare costs, and greater caregiver stress. It supports early seizure recognition and effective management to alleviate disease burden and highlights the need for higher-quality epidemiological data and standardized assessment tools to guide future treatment strategies.

 

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Conclusion
This systematic review comprehensively analyzed the disease burden of TSC-associated epilepsy, covering its impact on epidemiology, quality of life, healthcare resource use, and treatment patterns. The study found that TSC-related epilepsy imposes significant psychological and financial burdens on patients and caregivers, especially in drug-resistant cases. While current therapies such as everolimus and cannabidiol exist, treatment options remain limited, and long-term adult data are lacking. Therefore, the study calls for deeper epidemiological investigations and the application of standardized patient-reported outcome measures to support future clinical management and therapeutic development. Early seizure intervention not only improves neurodevelopmental outcomes but also positively affects the overall disease burden. In summary, this study provides important references for clinicians and researchers regarding the burden of TSC-associated epilepsy, emphasizing the necessity of interdisciplinary collaboration and family support in disease management.

 

Alexandra Furber, Alison Martin, Andrea Bertuzzi, Sally Bowditch, and Jamshaed Siddiqui. Burden of illness in tuberous sclerosis complex-associated epilepsy: a systematic literature review of epidemiology, health-related quality of life, costs and resource use. Orphanet Journal of Rare Diseases.