Direct and indirect costs and cost-driving factors in adults with tuberous sclerosis complex: a multicenter cohort study and a review of the literature.

BACKGROUND: Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC. METHODS: A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019). RESULTS: We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18-78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533-7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780-1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503-3840) among working-age individuals (< 67 years in Germany). Multiple regression analyses revealed mTOR inhibitor use and persistent seizures as independent cost-driving factors for total direct costs. Older age and disability were independent cost-driving factors for total indirect costs, whereas epilepsy, psychiatric disease, and disability were independent cost-driving factors for nursing care costs. CONCLUSIONS: This three-month study revealed substantial direct healthcare, indirect healthcare, and medication costs associated with TSC in Germany. This study highlights the spectrum of organ manifestations and their associated treatment needs in the German healthcare setting. TRIAL REGISTRATION: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045 .

Economic burden, work, and school productivity in individuals with tuberous sclerosis and their families.

AIMS: Tuberous sclerosis complex (TSC) is a multi-organ autosomal-dominant, genetic disorder with incomplete penetrance. The multiple manifestations of TSC and impacts to numerous organ systems represent significant disease, healthcare, and treatment burden. The economic and employment burden of the disease on individuals and their families is poorly understood. This study assessed the cost of illness and work and school productivity burden associated with TSC in a cross-sectional web-survey sample. MATERIALS AND METHODS: Eligible TSC individuals and caregivers were invited through the Tuberous Sclerosis Alliance advocacy group to complete a web-based survey about illness characteristics, treatment, disease burden, direct and indirect healthcare costs, work and school impairment. RESULTS: Data from 609 TSC adults or caregiver respondents with no cognitive impairments were analyzed. TSC adults (>18 years of age) had significantly higher direct out-of-pocket costs for ER visits, expenses for medical tests and procedures, alternative treatments, medications and lifetime cost of surgeries compared to TSC pediatric individuals. Both TSC adults and TSC caregivers reported work and school absenteeism and presenteeism; however, adults reported significantly higher absenteeism and presenteeism and overall activity impairment due to TSC, as might be expected, compared to TSC caregivers. TSC adults had significantly higher absenteeism and presenteeism rates compared to adults with moderate-to-severe plaque psoriasis and muscular sclerosis. CONCLUSIONS: TSC results in considerable direct out-of-pocket medical costs and impairment to work productivity, especially for adults. Future studies should include the comparator group and examine direct cost burden in the US using electronic medical records and insurance databases.

Understanding the health economic burden of patients with tuberous sclerosis complex (TSC) with epilepsy: a retrospective cohort study in the UK Clinical Practice Research Datalink (CPRD).

INTRODUCTION: Epilepsy is highly prevalent in tuberous sclerosis complex (TSC), a multi-system genetic disorder. The clinical and economic burden of this condition is expected to be substantial due to treatment challenges, debilitating co-morbidities and the relationship between TSC-related manifestations. This study estimated healthcare resource utilisation (HCRU) and costs for patients with TSC with epilepsy (TSC+E) in the UK. METHODS: Patients with TSC+E in the Clinical Practice Research Datalink (CPRD) linked to Hospital Episodes Statistics were identified from April 1997 to March 2012. Clinical data were extracted over the entire history, and costs were reported over the most recent 3-year period. HCRU was compared with a matched Comparator cohort, and the key cost drivers were identified by regression modelling. RESULTS: In total, 209 patients with TSC+E were identified, of which 40% recorded ≥2 other primary organ system manifestations and 42% had learning disability. Treatment with ≥2 concomitant antiepileptic drugs (AEDs) was prevalent (60%), potentially suggesting refractory epilepsy. Notwithstanding, many patients with TSC+E (12%) had no record of AED use in their entire history, which may indicate undertreatment for these patients.Brain surgery was recorded in 12% of patients. Routine electroencephalography and MRI were infrequently performed (30% of patients), yet general practitioner visits, hospitalisations and outpatient visits were more frequent in patients with TSC+E than the Comparator. This translated to threefold higher clinical costs (£14 335 vs £4448), which significantly increased with each additional primary manifestation (p<0.0001). CONCLUSIONS: Patients with TSC+E have increased HCRU compared with the general CPRD population, likely related to manifestations in several organ systems, substantial cognitive impairment and severe epilepsy, which is challenging to treat and may be intractable. Disease surveillance and testing appears to be inadequate with few treatments trialled.Multidisciplinary care in TSC clinics with specialist neurologist input may alleviate some of the morbidity of patients, but more innovative treatment and management options should be sought.

Outcome after temporal lobectomy in patients with medically-refractory mesial temporal epilepsy in Iran.

BACKGROUND: Epilepsy surgery has been proved to be feasible and cost-effective in developing countries. In the current paper, we discussed the outcome of patients with mesial temporal lobe epilepsy (MTLE) and medically-refractory seizures who had surgery at our center in Shiraz, Iran. METHODS: Patients aged 18 years and older with refractory MTLE and mesial temporal sclerosis operated at Namazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran from May 2009 through December 2011 were enrolled. Presurgical evaluation included clinical history, neurological examination, 2-hour video-EEG recording, and 1.5-T MRI. All patients were submitted to standard temporal lobectomy at the side determined by MRI and video-EEG. RESULTS: Twenty-two patients (12 women and 10 men) underwent surgery between May 2009 and December 2011. All patients were followed postoperatively for at least 12 months (mean=24.8±7.7 months; minimum=12 months; maximum=36 months). At the last follow-up visit, 18 patients (81.8%) had a good outcome (15 patients [68.2%] had Engel class 1 and three others had Engel class 2). The total cost of presurgical evaluation and epilepsy surgery at our center was less than $500. CONCLUSIONS: Resources are limited for the vast majority of medically-refractory patients with epilepsy who live in the developing countries. However, it is feasible to select good surgical candidates for anterior temporal lobectomy relying on the clinical history and examination, MRI and interictal EEG. Broader application of epilepsy surgery should be encouraged in countries with limited financial resources.

Healthcare utilization and costs in patients with tuberous sclerosiscomplex-related renal angiomyolipoma.

OBJECTIVE: To quantify healthcare utilization and costs in patients with tuberous sclerosis complex (TSC) and renal angiomyolipoma (AML) in a matched cohort of patients without TSC or AML. METHODS: Administrative data from the MarketScan Research Databases were used to select patients with TSC and renal AML during January 1, 2000-March 31, 2013 from the Commercial database and January 1, 2000-June 30, 2012 from the Medicaid database. Patients were required to have at least 30 days of follow-up from initiation into the study, and were followed until inpatient death, end of insurance coverage, or the end of study. Age, calendar year, and payer-matched controls that had no TSC and no AML were selected. All-cause annualized healthcare utilization and costs were calculated by service category. RESULTS: A total of 218 patients under 18 years and 377 patients 18 years and older with TSC-renal AML were selected from the Commercial database, and matched to 654 and 1,131 controls, respectively. Thirty-eight patients under 18 years and 110 patients 18 years or older with TSC-renal AML were selected from the Medicaid database, and matched to 54 and 212 controls, respectively. Within the Commercial cohort, and across both age groups, TSC-renal AML patients utilized more healthcare services than their matched controls. Within the Medicaid cohort, in both age groups, utilization was higher in TSC-renal AML patients vs control patients for inpatient admissions, emergency room visits, physician office visits, and hospital-based outpatient visits. Across age groups and in both the Commercial and Medicaid cohorts, the annual average total costs were significantly higher in TSC-renal AML patients compared to control patients (p < 0.05 for all). Healthcare costs ranged from $29,240-$48,499 for TSC-renal AML patients and from $2,082-$10,864 for control patients. CONCLUSIONS: Compared to controls, TSC-renal AML patients incurred substantially higher annual healthcare utilization and costs.

The economic burden of tuberous sclerosis complex in UK patients with renal manifestations: a retrospective cohort study in the clinical practice research datalink (CPRD).

BACKGROUND: Tuberous sclerosis complex (TSC) is a multi-system genetic disorder in which renal manifestations occur in ∼50% of children and 80% of adults. Since these often present alongside other manifestations, renal TSC is likely to incur significant costs. This study aims to quantify healthcare resource use (HCRU) and costs for renal TSC patients in the UK. METHODS: TSC patients in the Clinical Practice Research Datalink (CPRD) linked to Hospital Episodes Statistics were identified from January 1987-June 2013. Clinical data were extracted over the entire history and costs were reported over the most recent 3-year period. HCRU was compared with a matched comparator cohort. Incremental costs were reported and the key cost drivers by primary manifestation category were identified by regression modeling. RESULTS: A total of 79 renal TSC patients were identified with manifestations including chronic kidney disease stage 3-5 (with prevalence increasing with age) and renal angiomyolipoma. Renal TSC patients consistently reported greater HCRU than the comparator. Inpatient hospitalizations were more frequent for renal TSC patients (3.2 vs 1.6), but length of stay was comparable; however, 70.9% of renal TSC patients recorded no kidney-related procedures ever and averaged <1 test per year in the 3-year period. Average costs for renal TSC patients were nearly 3-fold greater than the comparator (£15,162 vs £5672). Costs increased with additional manifestation categories (£3600: only renal; £27,531: renal with ≥4 additional manifestation categories [25% of patients]). Additional nervous system and dermatology/psychiatric manifestations significantly (p < 0.028) affected costs. CONCLUSIONS: Renal TSC patients have greater HCRU than the general CPRD population, likely to result from progression of renal disease and additional manifestations; however, surveillance for disease progression appears to be deficient. Inadequate monitoring may contribute to a lack of co-ordinated care and increased healthcare-associated costs. Efforts should be made to follow the TSC guidelines to effectively monitor and treat patients.

The economic burden of tuberous sclerosis complex in the UK: A retrospective cohort study in the Clinical Practice Research Datalink.

BACKGROUND: Tuberous sclerosis complex (TSC) is a multi-system genetic disorder characterized by the development of diverse clinical manifestations. The complexity of this disease is likely to result in substantial challenges and costs in disease management throughout the patient's lifetime. This retrospective database study aims to quantify healthcare resources utilized by TSC patients. METHODS: TSC patients in the Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database were identified between January 1987 and June 2013. Analyses were conducted over the most recent 3-year period of data and stratified by pediatric (< 18) and adult patients. Prescriptions, procedures, diagnostic tests, and healthcare encounters were reported in comparison with a matched comparator cohort. Costs and key economic drivers by primary organ system manifestations were also examined. RESULTS: A total of 286 patients with TSC were identified and consistently reported 2-fold greater resource use than the matched presumably healthy controls. Despite this comparatively greater resource use, half of TSC patients did not record any procedures, and 20% of patients did not record any diagnostic tests; however, inpatient hospitalizations were greater for the TSC cohort (3.1 vs 1.3), but length of stay was comparable. TSC patients had costs totaling £12,681 per patient over the 3-year period, a figure 2.7-fold greater than the total costs in the comparator cohort (£4,777). Costs for patients with specific primary manifestations were even greater, with brain manifestations incurring £22,139 per affected patient. Kidney and nervous system manifestations were the main cost drivers. CONCLUSIONS: The economic burden of TSC and its impact on NHS healthcare resources is mostly attributable to the broad spectrum of manifestations that develop within multiple organ systems. TSC patients may benefit from co-ordinated care based on their requirement for high numbers of healthcare visits across specialties.

Tuberous Sclerosis Health Care Utilization Based on the National Inpatient Sample Database: A Review of 5655 Hospitalizations.

INTRODUCTION: Tuberous sclerosis complex (TSC) has an incidence of 1/6000 in the general population. Overall care may be complex and costly. We examine trends in health care utilization and outcomes of patients with TSC over the last decade. METHODS: The National Inpatient Sample (NIS) database for inpatient hospitalizations was searched for admission of patients with TSC. RESULTS: During 2000-2010, the NIS recorded 5655 patients with TSC. Most patients were admitted to teaching hospitals (71.7%). Over time, the percentage of craniotomies performed per year remained stable (P = 0.351). Relevant diagnoses included neuro-oncologic disease (5.4%), hydrocephalus (6.5%), and epilepsy (41.2%). Hydrocephalus significantly increased length of stay and hospital charges. A higher percentage of patients who underwent craniotomy had hydrocephalus (29.8% vs. 5.3%; P < 0.001), neuro-oncologic disease (43.5% vs. 3.4%; P < 0.001), other cranial diseases (4.2% vs. 1.2%; P < 0.001), and epilepsy (61.4% vs. 40.1%; P < 0.001). CONCLUSIONS: Our study identifies aspects of inpatient health care utilization, outcomes, and cost of a large number of patients with TSC. These aspects include related diagnoses and procedures that contribute to longer length of stay, increased hospital cost, and increased in-hospital mortality, which can inform strategies to reduce costs and improve care of patients with TSC.

Kidney involvement in tuberous sclerosis complex: the impact on healthcare resource use and costs.

OBJECTIVE: Tuberous sclerosis complex (TSC) is associated with non-malignant kidney lesions-angiomyolipomata-that may be associated with chronic kidney disease (CKD). This study investigated the relationship between renal angiomyolipomata and CKD in TSC, including the impact on healthcare resource utilization (HCRU) and costs. METHODS: This was a retrospective, longitudinal cohort study based on medical record data spanning January 1990-April 2012 for 369 TSC patients treated at a specialty center in the Netherlands. Cohorts were established based on CKD stage and angiomyolipoma size. Rates of HCRU (physician visits, monitoring, and interventions) were compared across cohorts using rate ratios. Healthcare costs were compared across cohorts using cost differences. Regression models were used to identify predictive factors for HCRU and healthcare costs. RESULTS: Sixteen per cent of patients reached CKD stage 3 or higher during follow-up. Patients at more advanced stages of CKD more frequently had either large or multiple small angiomyolipomata and higher HCRU rates and healthcare costs. In the multivariate analyses, male gender, CKD stage >1, angiomyolipoma size ≥3.5 cm, embolization, and the presence of moderate or severe lymphangioleiomyomatosis (LAM) were associated with greater HCRU (p ≤ 0.002 for all comparisons). Definite (vs suspected) TSC diagnosis, CKD stage 5 (vs CKD stage 1), angiomyolipoma size ≥3.5 cm, and moderate or severe LAM were associated with higher costs (p = 0.050 for TSC diagnosis, p ≤ 0.002 for other comparisons). Costs in CKD stage 5 were driven primarily by dialysis. CONCLUSIONS: A substantial proportion of patients with TSC developed moderate-to-severe CKD, which was associated with renal angiomyolipomata and increased HCRU and costs.

Direct medical costs for patients with tuberous sclerosis complex and surgical resection of subependymal giant cell astrocytoma: a US national cohort study.

OBJECTIVE: To estimate direct medical costs for patients with tuberous sclerosis complex (TSC) and surgical resection of subependymal giant-cell astrocytoma (SEGA). METHODS: This retrospective cohort study selected patients who had SEGA surgery and TSC claims between 2000-2011 from three large US nationwide claims databases. Selected patients were age 35 or less and had continuous health insurance in the year before and the year after their first SEGA surgery claim. The study examined the patients' demographic and clinical characteristics and estimated inpatient, outpatient, medication, and total medical costs paid by insurance companies for the pre-surgery year, post-surgery year, and other study periods, respectively. Repeated measures analysis and bootstrapping technique were used to assess the impact of the surgery on the direct medical costs. RESULTS: Select patients (n = 47) had a mean baseline age of 11.6 years and 66% were male. Many had seizures (91.0%), hydrocephalus (59.6%), vision disorders (38.3%), stroke and hemiparesis (36.2%), and shunt (34.0%) in the pre-surgery year. The mean direct medical costs were $8543 (inpatient: $3770; outpatient: $3473; medication: $1300) for the pre-surgery year, and $85,397 (inpatient: $71,562; outpatient: $11,497; medication: $2338) for the post-surgery year. With the exclusion of the costs during the surgery month, the inpatient, outpatient, medication, and total costs in the post-surgery year were 1.6-4.3 times as much as the costs in the pre-surgery year (inpatient: 4.3:1; outpatient: 2.5:1; medication: 1.6:1; total: 3.1:1, p < 0.05). Repeated measures analysis with bootstrapping confirmed a link between the surgery and increases in direct medical costs (p < 0.05). CONCLUSIONS: SEGA surgery had a substantial impact on direct medical costs. TSC patients with the surgery experienced significant post-surgery increases in their inpatient, outpatient, and medication costs. Additional research should be conducted to examine the surgery's cost-impact in a longer duration, or to compare the cost-effectiveness of the surgery vs other treatments.

The burden of subependymal giant cell astrocytomas associated with tuberous sclerosis complex: results of a patient and caregiver survey.

Tuberous sclerosis complex is a genetic disorder characterized by benign tumor growth including lesions in the ventricular system of the brain known as subependymal giant cell astrocytomas. This analysis focuses on the clinical presentation, management, and associated burden of subependymal giant cell astrocytomas in patients with tuberous sclerosis complex in the United States. An institutional review board-approved web-based survey of tuberous sclerosis complex patients and caregivers collected information, and descriptive analyses were conducted on age-based subgroups. A total of 116 tuberous sclerosis complex-subependymal giant cell astrocytoma patients or caregivers responded (17% of the total tuberous sclerosis complex sample). Mean and median patient ages were 25.5 and 23.5 years. Besides subependymal giant cell astrocytomas, patients also experienced skin lesions (72%), seizures (65%), and cognitive concerns (60%). Forty-five percent reported having brain surgery (22% for subependymal giant cell astrocytoma). In the past year, 42% of patients were admitted at least once to the hospital whereas 39% went to the emergency department. Results demonstrate that tuberous sclerosis complex-subependymal giant cell astrocytoma is associated with significant clinical burden, resource utilization, and decreased well-being.

Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review.

OBJECTIVES: Tuberous sclerosis complex (TSC) is a progressive genetic disorder characterized by pervasive benign tumor growth. We sought to assess the current understanding of burden of TSC-related neurological manifestations. METHODS: We systematically searched MEDLINE- and EMBASE-indexed, English-language literature (5/2000-5/2010) and non-indexed materials. RESULTS: In total, 119 articles were included, 115 on epidemiology and treatment. Recent prevalence estimates from Ireland and Taiwan report TSC in 1:14,000-25,000 individuals, below older estimates of 1:10,000. While neurological manifestations are common, treatment is largely unaddressed by guidelines and focuses on symptoms, with resection standard for subependymal giant cell astrocytomas (SEGAs) and common practice for refractory epilepsy. Antiepileptic drugs and mammalian target of rapamycin inhibitors safely, effectively minimize the need for surgery for severe epilepsy and SEGAs. CONCLUSION: Morbidity and treatment burden of prevalent neurological manifestations is significant, suggesting substantial economic and humanistic burden; however, these areas are poorly studied, indicating total disease burden is unknown. Future research should assess quality of life, caregiver burden, and costs.