Direct and indirect costs and cost-driving factors of Tuberous sclerosis complex in children, adolescents, and caregivers: a multicenter cohort study
Authors: Grau Janina , Zöllner Johann Philipp , Schubert-Bast Susanne , Kurlemann Gerhard , Hertzberg Christoph , Wiemer-Kruel Adelheid , Bast Thomas , Bertsche Astrid , Bettendorf Ulrich , Fiedler Barbara , Hahn Andreas , Hartmann Hans , Hornemann Frauke , Immisch Ilka , Jacobs Julia , Kieslich Matthias , Klein Karl Martin , Klotz Kerstin A. , Kluger Gerhard , Knuf Markus , Mayer Thomas , Marquard Klaus , Meyer Sascha , Muhle Hiltrud , Müller-Schlüter Karen , Noda Anna H. , Ruf Susanne , Sauter Matthias , Schlump Jan-Ulrich , Syrbe Steffen , Thiels Charlotte , Trollmann Regina , Wilken Bernd , Willems Laurent M. , Rosenow Felix , Strzelczyk Adam 
Published: June 2021

Abstract
Background
Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients.

Methods
A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany.

Results
The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7–21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088–5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027–1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221–3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193–586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs.

Conclusions
This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting.
Trial registration: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.