Dravet syndrome: A systematic literature review of the illness burden.

We performed a systematic literature review and narrative synthesis according to a pre-registered protocol (Prospero: CRD42022376561) to identify the evidence associated with the burden of illness in Dravet syndrome (DS), a developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with neurocognitive and neurobehavioral impairment. We searched MEDLINE, Embase, and APA PsychInfo, Cochrane's database of systematic reviews, and Epistemonikos from inception to June 2022. Non-interventional studies reporting on epidemiology (incidence, prevalence, and mortality), patient and caregiver health-related quality of life (HRQoL), direct and indirect costs and healthcare resource utilization were eligible. Two reviewers independently carried out the screening. Pre-specified data were extracted and a narrative synthesis was conducted. Overall, 49 studies met the inclusion criteria. The incidence varied from 1:15 400-1:40 900, and the prevalence varied from 1.5 per 100 000 to 6.5 per 100 000. Mortality was reported in 3.7%-20.8% of DS patients, most commonly due to sudden unexpected death in epilepsy and status epilepticus. Patient HRQoL, assessed by caregivers, was lower than in non-DS epilepsy patients; mean scores (0 [worst] to 100/1 [best]) were 62.1 for the Kiddy KINDL/Kid-KINDL, 46.5-54.7 for the PedsQL and 0.42 for the EQ-5D-5L. Caregivers, especially mothers, were severely affected, with impacts on their time, energy, sleep, career, and finances, while siblings were also affected. Symptoms of depression were reported in 47%-70% of caregivers. Mean total direct costs were high across all studies, ranging from $11 048 to $77 914 per patient per year (PPPY), with inpatient admissions being a key cost driver across most studies. Mean costs related to lost productivity were only reported in three publications, ranging from approximately $19 000 to $20 000 PPPY ($17 596 for mothers vs $1564 for fathers). High seizure burden was associated with higher resource utilization, costs and poorer HRQoL. The burden of DS on patients, caregivers, the healthcare system, and society is profound, reflecting the severe nature of the syndrome. Future studies will be able to assess the impact that newly approved therapies have on reducing the burden of DS.

The burden of illness in Lennox-Gastaut syndrome: a systematic literature review.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with multiple seizure types starting in childhood, a typical slow spike-wave pattern on electroencephalogram, and cognitive dysfunction. METHODS: We performed a systematic literature review according to the PRISMA guidelines to identify, synthesize and appraise the burden of illness in LGS (including "probable" LGS). Studies were identified by searching MEDLINE, Embase and APA PsychInfo, Cochrane's database of systematic reviews, and Epistemonikos. The outcomes were epidemiology (incidence, prevalence or mortality), direct and indirect costs, healthcare resource utilization, and patient and caregiver health-related quality of life (HRQoL). RESULTS: The search identified 22 publications evaluating the epidemiology (n = 10), direct costs and resource (n = 10) and/or HRQoL (n = 5). No studies reporting on indirect costs were identified. With no specific ICD code for LGS in many regions, several studies had to rely upon indirect methods to identify their patient populations (e.g., algorithms to search insurance claims databases to identify "probable" LGS). There was heterogeneity between studies in how LGS was defined, the size of the populations, ages of the patients and length of the follow-up period. The prevalence varied from 4.2 to 60.8 per 100,000 people across studies for probable LGS and 2.9-28 per 100,000 for a confirmed/narrow definition of LGS. LGS was associated with high mortality rates compared to the general population and epilepsy population. Healthcare resource utilization and direct costs were substantial across all studies. Mean annual direct costs per person varied from $24,048 to $80,545 across studies, and home-based care and inpatient care were significant cost drivers. Studies showed that the HRQoL of patients and caregivers was adversely affected, although only a few studies were identified. In addition, studies suggested that seizure events were associated with higher costs and worse HRQoL. The risk of bias was low or moderate in most studies. CONCLUSIONS: LGS is associated with a significant burden of illness featuring resistant seizures associated with higher costs and worse HRQoL. More research is needed, especially in evaluating indirect costs and caregiver burden, where there is a notable lack of studies.

Trends in resource utilization and cost of illness in patients with active epilepsy in Germany from 2003 to 2020.

OBJECTIVE: This study was undertaken to calculate epilepsy-related direct, indirect, and total costs in adult patients with active epilepsy (ongoing unprovoked seizures) in Germany and to analyze cost components and dynamics compared to previous studies from 2003, 2008, and 2013. This analysis was part of the Epi2020 study. METHODS: Direct and indirect costs related to epilepsy were calculated with a multicenter survey using an established and validated questionnaire with a bottom-up design and human capital approach over a 3-month period in late 2020. Epilepsy-specific costs in the German health care sector from 2003, 2008, and 2013 were corrected for inflation to allow for a valid comparison. RESULTS: Data on the disease-specific costs for 253 patients in 2020 were analyzed. The mean total costs were calculated at €5551 (±€5805, median = €2611, range = €274-€21 667) per 3 months, comprising mean direct costs of €1861 (±€1905, median = €1276, range = €327-€13 158) and mean indirect costs of €3690 (±€5298, median = €0, range = €0-€11 925). The main direct cost components were hospitalization (42.4%), antiseizure medication (42.2%), and outpatient care (6.2%). Productivity losses due to early retirement (53.6%), part-time work or unemployment (30.8%), and seizure-related off-days (15.6%) were the main reasons for indirect costs. However, compared to 2013, there was no significant increase of direct costs (-10.0%), and indirect costs significantly increased (p < .028, +35.1%), resulting in a significant increase in total epilepsy-related costs (p < .047, +20.2%). Compared to the 2013 study population, a significant increase of cost of illness could be observed (p = .047). SIGNIFICANCE: The present study shows that disease-related costs in adult patients with active epilepsy increased from 2013 to 2020. As direct costs have remained constant, this increase is attributable to an increase in indirect costs. These findings highlight the impact of productivity loss caused by early retirement, unemployment, working time reduction, and seizure-related days off.

Costs and cost-driving factors of acute treatment of status epilepticus in children and adolescents: A cohort study from Germany.

OBJECTIVE: To provide data on inpatient costs and cost-driving factors in children and adolescents due to non-refractory (NSE), refractory (RSE), and super-refractory status epilepticus (SRSE). METHODS: All children and adolescents treated for status epilepticus (SE) between 2011 and 2018 at the Frankfurt University Hospital were analyzed for health care utilization. RESULTS: We evaluated 223 admissions in 174 patients (6.8 ± 5.1 years, median 5.5 years, range 0.1-17.5 years, 109 males [62.6%]) treated for SE. Mean costs of hospital treatment were €5,711 (median €2,330, range = €654-€102,414) per patient per admission, with a mean length of stay (LOS) of 9.2 days (median 5.0, range = 1-101), resulting in mean costs of €621 per SE treatment day. Course of SE had a significant impact on the mean costs, which were €3,386 in NSE (median €2,139, range €654-€38,236, €529 per treatment day; 37% of total inpatient costs due to SE), €7,409 in RSE (median €2,772, range €700-€38,236; €612 per treatment day, 38% of total inpatient costs due to SE) and €17,436 in SRSE (median €6,911, range €2,138-102,414; €842 per treatment day, 25% of total inpatient costs due to SE). Independent cost-driving factors were three or more treatment steps, acute-symptomatic etiology, and unfavorable modified Rankin Scale score at admission. Increased LOS was predicted by three or more treatment steps and unfavorable modified Rankin Scale score at admission. Overall mortality at discharge was 1.3% (three patients). CONCLUSIONS: Acute treatment of SE, and particularly RSE and SRSE, is associated with high hospital costs and prolonged LOS. Patients with disabilities are at risk for an unfavorable course of SE, resulting in prolonged LOS. In general, mortality associated with SE is low in children and adolescents, however three or more treatment steps are associated with high treatment costs.

Multicenter, cross-sectional study of the costs of illness and cost-driving factors in adult patients with epilepsy.

OBJECTIVE: This study was undertaken to quantify epilepsy-related costs of illness (COI) in Germany and identify cost-driving factors. METHODS: COI were calculated among adults with epilepsy of different etiologies and severities. Multiple regression analysis was applied to determine any epilepsy-related and sociodemographic factors that serve as cost-driving factors. RESULTS: In total, 486 patients were included, with a mean age of 40.5 ± 15.5 years (range = 18-83 years, 58.2% women). Mean 3-month COI were estimated at €4911, €2782, and €2598 for focal, genetic generalized, and unclassified epilepsy, respectively. The mean COI for patients with drug-refractory epilepsy (DRE; €7850) were higher than those for patients with non-DRE (€4720), patients with occasional seizures (€3596), or patients with seizures in remission for >1 year (€2409). Identified cost-driving factors for total COI included relevant disability (unstandardized regression coefficient b = €2218), poorer education (b = €2114), living alone (b = €2612), DRE (b = €1831), and frequent seizures (b = €2385). Younger age groups of 18-24 years (b = -€2945) and 25-34 years (b = -€1418) were found to have lower overall expenditures. A relevant disability (b = €441), DRE (b = €1253), frequent seizures (b = €735), and the need for specialized daycare (b = €749) were associated with higher direct COI, and poorer education (b = €1969), living alone (b = €2612), the presence of a relevant disability (b = €1809), DRE (b = €1831), and frequent seizures (b = €2385) were associated with higher indirect COI. SIGNIFICANCE: This analysis provides up-to-date COI data for use in further health economics analyses, highlighting the high economic impacts associated with disease severity, disability, and disease-related loss of productivity among adult patients with epilepsy. The identified cost drivers could be used as therapeutic and socioeconomic targets for future cost-containment strategies.

Epidemiology, healthcare resource use, and mortality in patients with probable Dravet syndrome: A population-based study on German health insurance data.

OBJECTIVE: Ten-year retrospective study to assess burden of illness in patients with probable Dravet syndrome (DS) identified from German healthcare data. METHODS: In the absence of an International Classification of Diseases code, patients with probable DS were identified using a selection algorithm considering diagnoses and drug prescriptions. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, annual hospitalization rate (AHR) and length of stay (LOS), medication use, and mortality. RESULTS: In the final study year, 64 patients with probable DS (mean [range] age: 33.2 [3-82] years; male: 48%) were identified. Prevalence: 4.7 per 100,000 people. During the study, 160 patients with probable DS were identified and followed up for 1,261 patient-years. Mean cost of healthcare was €11,048 per patient-year (PPY), mostly attributable to inpatient care (47%), medication (26%), and services and devices (19%). Annual healthcare costs were significantly greater for those with prescribed rescue medication (15% of patient-years) vs. without (€16,123 vs. €10,125 PPY, p < 0.001). Mean (standard deviation [SD]) AHR and LOS were 1.1 (1.7) and 17.5 (33.5) days PPY. AHR was significantly greater in patients with prescribed rescue medication vs. without (1.6 [2.0] vs. 1.0 [1.6] PPY, p < 0.001). Mean (SD) number of antiseizure medications prescribed was 2.6 (1.2) PPY and 5.0 (2.5) over the entire observable time for each patient. Mortality rate was significantly higher for probable DS vs. matched controls (11.88% [19 events] vs. 1.19% [172 events], p < 0.001). CONCLUSION: Probable DS is associated with substantial healthcare costs in Germany.

Seizures and epilepsy in patients with ischaemic stroke.

BACKGROUND: With the increased efficacy of stroke treatments, diagnosis and specific treatment needs of patients with post-stroke seizures (PSS) and post-stroke epilepsy have become increasingly important. PSS can complicate the diagnosis of a stroke and the treatment of stroke patients, and can worsen post-stroke morbidity. This narrative review considers current treatment guidelines, the specifics of antiseizure treatment in stroke patients as well as the state-of-the-art in clinical and imaging research of post-stroke epilepsy. Treatment of PSS needs to consider indications for antiseizure medication treatment as well as individual clinical and social factors. Furthermore, potential interactions between stroke and antiseizure treatments must be carefully considered. The relationship between acute recanalizing stroke therapy (intravenous thrombolysis and mechanical thrombectomy) and the emergence of PSS is currently the subject of an intensive discussion. In the subacute and chronic post-stroke phases, important specific interactions between necessary antiseizure and stroke treatments (anticoagulation, cardiac medication) need to be considered. Among all forms of prevention, primary prevention is currently the most intensively researched. This includes specifically the repurposing of drugs that were not originally developed for antiseizure properties, such as statins. PSS are presently the subject of extensive basic clinical research. Of specific interest are the role of post-stroke excitotoxicity and blood-brain barrier disruption for the emergence of PSS in the acute symptomatic as well as late (> 1 week after the stroke) periods. Current magnetic resonance imaging research focussing on glutamate excitotoxicity as well as diffusion-based estimation of blood-brain barrier integrity aim to elucidate the pathophysiology of seizures after stroke and the principles of epileptogenesis in structural epilepsy in general. These approaches may also reveal new imaging-based biomarkers for prediction of PSS and post-stroke epilepsy. CONCLUSION: PSS require the performance of individual risk assessments, accounting for the potential effectiveness and side effects of antiseizure therapy. The use of intravenous thrombolysis and mechanical thrombectomy is not associated with an increased risk of PSS. Advances in stroke imaging may reveal biomarkers for PSS.

Epidemiology, healthcare resource use, and mortality in patients with tuberous sclerosis complex: A population-based study on German health insurance data.

PURPOSE: 10-year retrospective study to assess burden of illness in individuals with tuberous sclerosis complex (TSC) identified from German healthcare data. METHODS: Patients with TSC were identified by International Classification of Diseases code Q85.1. Patients with epilepsy were identified by epilepsy diagnosis or antiseizure medication (ASM) prescription after TSC diagnosis. RESULTS: Using data from 2016 (final study year), 100 patients with TSC were identified (mean [range] age: 38 [1-86] years; male: 40%); prevalence: 7.9 per 100,000 (TSC), 2.2 per 100,000 (TSC with epilepsy). During the 10-year study period (2007-2016), 256 patients with TSC were identified and followed up for 1,784 patient-years (epilepsy: 36%, 616 patient-years). TSC manifestations/comorbidities (apart from epilepsy) were identified more frequently in patients with epilepsy than without. Mean annual healthcare costs for patients with TSC were €6,139 per patient-year (PPY), mostly attributable to medication (35%) and inpatient care (29%). Patients with epilepsy incurred costs more than double those without. Mean (standard deviation [SD]) annual hospitalisation rate (AHR) and length of stay (LOS) PPY: 0.5 (1.0) and 5.9 (18.6) days for TSC. AHR and LOS were greater in patients with epilepsy than without. Mean (SD) number of ASMs prescribed (TSC with epilepsy): 3.0 (2.3) over the entire observable time per patient. Mortality rates (vs. control): 5.08% (vs. 1.69%, p<0.001) for TSC, 7.53% (vs. 0.98%, p<0.001) for TSC with epilepsy, 3.68% (vs. 2.03%, p = 0.003) for TSC without epilepsy. CONCLUSION: Healthcare costs, resource utilisation, and mortality were greater in patients with TSC and epilepsy than those without epilepsy.

Direct and indirect costs and cost-driving factors of Tuberous sclerosis complex in children, adolescents, and caregivers: a multicenter cohort study.

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.

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 .

Epidemiology, healthcare resource use, and mortality in patients with probable Lennox-Gastaut syndrome: A population-based study on German health insurance data.

OBJECTIVE: This retrospective study examined patients with probable Lennox-Gastaut syndrome (LGS) identified from German healthcare data. METHODS: This 10-year study (2007-2016) assessed healthcare insurance claims information from the Vilua Healthcare research database. A selection algorithm considering diagnoses and drug prescriptions identified patients with probable LGS. To increase the sensitivity of the identification algorithm, two populations were defined: all patients with probable LGS (broadly defined) and only those with a documented epilepsy diagnosis before 6 years of age (narrowly defined). This specific criterion was used as LGS typically has a peak seizure onset between age 3 and 5 years. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, hospitalization rate and length of stay (LOS), medication use, and mortality. RESULTS: In the final year of the study, 545 patients with broadly defined probable LGS (mean [range] age: 31.4 [2-89] years; male: 53%) were identified. Using the narrowly defined probable LGS definition, the number of patients was reduced to 102 (mean [range] age: 7.4 [2-14] years; male: 52%). Prevalence of broadly defined and narrowly defined probable LGS was 39.2 and 6.5 per 100,000 people. During the 10-year study, 208 patients with narrowly defined probable LGS were identified and followed up for 1379 patient-years. The mean annual cost of healthcare was €22,787 per patient-year (PPY); greatest costs were attributable to inpatient care (33%), home nursing care (13%), and medication (10%). Mean annual healthcare costs were significantly greater for those with prescribed rescue medication (45% of patient-years) versus those without (€33,872 vs. €13,785 PPY, p < 0.001). Mean (standard deviation [SD]) annual hospitalization rate was 1.6 (2.0) PPY with mean (SD) annual LOS of 22.7 (46.0) days. Annual hospitalization rate was significantly greater in those who were prescribed rescue medication versus those who were not (2.2 [2.3] vs. 1.1 [1.6] PPY, p < 0.001). The mean (SD) number of different medications prescribed was 11.3 (7.3) PPY and 33.8 (17.0) over the entire observable time per patient (OET); antiepileptic drugs only accounted for 2.1 (1.1) of the medications prescribed PPY and 3.8 (2.0) OET. Over the 10-year study period, mortality in patients with narrowly defined probable LGS was significantly higher than the matched control population (six events [2.88%] vs. oneevent [0.01%], p < 0.001). CONCLUSION: Annual healthcare costs incurred by patients with probable LGS in Germany were substantial, and mostly attributable to inpatient care, home nursing care, and medication. Patients prescribed with rescue medication incurred significantly greater costs than those who were not. Patients with narrowly defined probable LGS had a higher mortality rate versus control populations.

[Inpatient treatment costs, cost-driving factors and potential reimbursement problems due to epileptic seizure-related injuries and fractures]. / Stationäre Versorgungskosten, kostenverursachende Faktoren und potenzielle Vergütungsprobleme bei Verletzungen und Frakturen im Rahmen epileptischer Anfälle.

BACKGROUND: The systematic analysis of disease-specific costs is becoming increasingly more relevant in an economically oriented healthcare system. Chronic diseases are of particular interest due to the long duration as well as frequent hospitalization and physician visits. Epilepsy is a frequent neurological disorder affecting all age groups with the clinical hallmark of paroxysmal epileptic seizures, which are often associated with injuries. OBJECTIVE: The aim of this work was to process the inpatient treatment costs due to seizure-related injuries and fractures. Moreover, relevant cost-causing factors were addressed. Using an alternative calculation of the costs of care, the question of potential reimbursement problems in the current German diagnosis-related groups (G-DRG) system was additionally assessed. METHODS: For this monocentric retrospective analysis the actual proceeds of 62 inpatients who were treated at the University Hospital Frankfurt between January 2010 and January 2018 for injuries and fractures due to epileptic seizures were used. The analysis of potential cost-causing factors was carried out with respect to relevant sociodemographic and clinical aspects. The alternative calculation of the costs of treatment was carried out using established health economic methods. RESULTS: The average DRG revenue was 7408€ (±8993€, median 5086€, range 563-44,519€), the average calculated costs were 9423€ (±11,113€, 5626€, range 587-49,830€). A length of stay ≥7 days (p = 0.014) was identified as a significant cost-driving factor. Due to the significant difference (p < 0.001) between revenue and calculated costs, an analysis was made according to factors for potential reimbursement problems, which remained significant for a length of stay of ≥7 days (p = 0.014) and for treatment in the intensive care unit (p = 0.019). CONCLUSION: The inpatient treatment costs for patients with injuries and fractures due to epileptic seizures are high and therefore relevant from a health economic perspective. In general, reimbursement according to the G­DRG appears to cover the actual costs, but there may be reimbursement problems for patients with a long period of hospitalization or a stay in an intensive care ward.

A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC).

OBJECTIVE: This review will summarize current knowledge on the burden of illness (BOI) in tuberous sclerosis complex (TSC), a multisystem genetic disorder manifesting with hamartomas throughout the body, including mainly the kidneys, brain, skin, eyes, heart, and lungs. METHODS: We performed a systematic analysis of the available literature on BOI in TSC according to the PRISMA guidelines. All studies irrespective of participant age that reported on individual and societal measures of disease burden (e.g. health care resource use, costs, quality of life) were included. RESULTS: We identified 33 studies reporting BOI in TSC patients. Most studies (21) reported health care resource use, while 14 studies reported quality of life and 10 studies mentioned costs associated with TSC. Only eight research papers reported caregiver BOI. Substantial BOI occurs from most manifestations of the disorder, particularly from pharmacoresistant epilepsy, neuropsychiatric, renal and skin manifestations. While less frequent, pulmonary complications also lead to a high individual BOI. The range for the mean annual direct costs varied widely between 424 and 98,008 International Dollar purchasing power parities (PPP-$). Brain surgery, end-stage renal disease with dialysis, and pulmonary complications all incur particularly high costs. There is a dearth of information regarding indirect costs in TSC. Mortality overall is increased compared to general population; and most TSC related deaths occur as a result of complications from seizures as well as renal complications. Long term studies report mortality between 4.8 and 8.3% for a follow-up of 8 to 17.4 years. CONCLUSIONS: TSC patients and their caregivers have a high burden of illness, and TSC patients incur high costs in health care systems. At the same time, the provision of inadequate treatment that does not adhere to published guidelines is common and centralized TSC care is received by no more than half of individuals who need it, especially adults. Further studies focusing on the cost effectiveness and BOI outcomes of coordinated TSC care as well as of new treatment options such as mTOR inhibitors are necessary.

A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.

OBJECTIVE: To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug-resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany. METHODS: Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days). RESULTS: Mean total direct costs were highest for DS patients (€4864 [median €3564] vs €3049 [median €1506] for DRE [excluding outliers], P = 0.01; and €1007 [median €311], P < 0.001 for SR). Total lost productivity over 3 months was highest among caregivers of pediatric DS (€4757, median €2841), compared with those of DRE (€1541, P < 0.001; median €0) and SR patients (€891, P < 0.001; median €0). The proportions of caregivers in employment were similar across groups (62% DS, 63% DRE, and 63% SR) but DS caregivers were more likely to experience changes to their working situation, such as quitting their job (40% DS vs 16% DRE and 9% SR, P < 0.001 in both comparisons). KINDL scores were significantly lower for DS patients (62 vs 74 and 72, P < 0.001 in both comparisons), and lower than for the average German population (77). Pediatric caregiver EQ-5D scores across all cohorts were comparable with population norms, but more DS caregivers experienced moderate to severe depressive symptoms (24% vs 11% and 5%). Mean Beck Depression Inventory (BDI-II) score was significantly higher in DS caregivers than either of the other groups (P < 0.001). SIGNIFICANCE: This first comparative study of Dravet syndrome to difficult-to-treat epilepsy and to epilepsy patients in seizure remission emphasizes the excess burden of DS in components of QoL and direct costs. The caregivers of DS patients have a greater impairment of their working lives (indirect costs) and increased depression symptoms.

General Trends in Prices and Prescription Patterns of Anticonvulsants in Germany between 2000 and 2017: Analysis of National and Cohort-Based Data.

OBJECTIVE: Our aim was to explore trends in price evolution and prescription volumes of anticonvulsants (AEDs, antiepileptic drugs) in Germany between 2000 and 2017. METHOD: This study used data from annual reports on mean prescription frequency and prices of defined daily doses (DDD) of AEDs in Germany to analyze nationwide trends. Interrupted time series (ITS) analysis was employed to test for significant effects of several statutory healthcare reforms in Germany on AED price evolution. These data were compared to cohort-based prescription patterns of four German cohort studies from 2003, 2008, 2013, and 2016 that included a total of 1368 patients with focal and generalized epilepsies. RESULTS: Analysis of national prescription data between 2000 and 2017 showed that mean prices per DDD of third-generation AEDs decreased by 65% and mean prices of second-generation AEDs decreased by 36%, whereas mean prices of first-generation AEDs increased by 133%. Simultaneously, mean prescription frequency of third- generation AEDs increased by 2494%, while there was a substantial decrease in the use of first- (- 55%) and second- (- 16%) generation AEDs. ITS analysis revealed that in particular the introduction of mandatory rebates on drugs in 2003 affected prices of frequently used newer AEDs. These findings are consistent with data from cohort studies of epilepsy patients showing a general decrease of prices for frequently used AEDs in monotherapy by 62% and in combination therapies by 68%. The analysis suggests that overall expenses for AEDs remained stable despite an increase in the prescription of "newer" and "non-enzyme-inducing" AEDs for epilepsy patients. CONCLUSION: Between 2000 and 2017, a distinct decline in AED prices can be observed that seems predominately caused by a governmentally obtained price decline of third- and second-generation drugs. These observations seem to be the result of a German statutory cost containment policy applied across all health-care sectors. The increasing use of third-generation AEDs to the disadvantage of "old" and "enzyme-inducing" AEDs reflects the preferences of physicians and patients with epilepsy and follows national treatment guidelines.

Burden and epidemiology of status epilepticus in infants, children, and adolescents: A population-based study on German health insurance data.

OBJECTIVE: Status epilepticus (SE) is an important medical emergency condition with particularly unfavorable outcome in refractory and superrefractory SE (SRSE). The economic impact of SE and especially of SRSE in the pediatric population remains unclear. We aimed to determine the burden of illness of SE in a pediatric patient population. METHODS: Insurance records for patients aged 0-18 years admitted between 2008 and 2015 were selected from a nationwide insurance research database utilizing International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes for SE (G41), epilepsy (G40), or febrile convulsions (R56). Patients were further classified based on admission to the intensive care unit and use of mechanical ventilation. RESULTS: The algorithm identified 11 693 seizure-related admissions and classified 4% as SE. Of these cases, 282 (60.4%) were classified by the algorithm as nonrefractory SE (NRSE), 125 (26.8%) as refractory SE (RSE), and 60 (12.8%) as SRSE. The crude SE incidence was 17.6/100 000, with NRSE being 11.4/100 000, RSE 3.9/100 000, and SRSE 2.3/100 000. SRSE incidence peaked in the 0- to 1-year-old age subgroup accounting for 48.3% of all pediatric SRSE admissions. The median length of stay (LOS) for all SE cases was 7 days, with median 44.5 days in SRSE, 5 days in NRSE, and 12 days in RSE. Mean admission costs for total SE were €15 880, with a mean expense for SRSE of €75 358, for NRSE of €4119, and for RSE of €13 864. The mean LOS for non-SE epilepsy admissions was 3 days, with mean costs of €2697 for epilepsy and €1614 for febrile convulsion admissions. There were no deaths in non-SE and NRSE admissions, whereas the overall mortality for SE was 3%, with 5.6% in RSE and 11.7% in SRSE. SIGNIFICANCE: Although cases classified as SE represented 4% of the seizure-associated admissions, they accounted for 22% of the overall costs. These costs were disproportionately represented by SRSE cases, which accounted for 62% of all SE-associated costs.

Burden-of-illness and cost-driving factors in Dravet syndrome patients and carers: A prospective, multicenter study from Germany.

INTRODUCTION: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany. METHODS: A validated 3-12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany. RESULTS: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months-33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis. CONCLUSIONS: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.

Counseling and social work for people with epilepsy in Germany: A cross-sectional multicenter study on demand, frequent content, patient satisfaction, and burden-of-disease.

BACKGROUND: The diagnosis of epilepsy is accompanied by relevant personal, interpersonal, and professional restrictions for patients and their caregivers. Specialized epilepsy counseling services (ECS) have been introduced to inform, advise, and support patients with disease-related problems. AIM AND SCOPE: The objective of this cross-sectional, multicenter study was to determine the demand, typical content, and outcomes of ECS in children, adolescents, and adults in two adjacent German regions of Hessen and Lower Franconia. All ECS sites in these regions participated in 2014 and 2015, offering a total population of 7.5 million inhabitants. RESULTS: A total number of 435 patients [323 adults (74.3%), 51.7% female, mean age: 40.3 ±â€¯14.7 years and 112 children/adolescents (25.7%), 52.7% female, mean age: 9.4 ±â€¯4.6 years] were enrolled at six ECS sites. The most common reasons for counseling were general information needs (n = 304; 69.9%), administrative help (n = 208; 47.8%), problems with education or work (n = 176; 40.5%), and recreational activities (n = 119; 27.3%). In addition, 6.2% reported epilepsy-related questions on family planning as a specific reason for desiring counseling. Recommendation by the treating physicians was the most frequent reason for receiving counseling through ECS (62.5%), and most patients preferred to receive a personal consultation (73.1%). Patient satisfaction as measured by the ZUF-8 client satisfaction score was high with a mean of 29.7 points (standard deviation: ±2.7 points, median: 29.9 points), and 83.9% of patients said they would recommend ECS. Disease-related job loss or change in school was avoided in 72% of 82 patients. Suggestions for improvement of ECS included an extension of service hours (58.6%) and a better availability of more sites located nearby (32.8%). CONCLUSION: Epilepsy counseling services are necessary, valued, and effective institutions for people with epilepsy complementing outpatient and inpatient care. To improve the care for people with epilepsy, access to and availability of ECS should be improved.

Trends in resource utilization and prescription of anticonvulsants for patients with active epilepsy in Germany from 2003 to 2013 - A ten-year overview.

This study evaluated trends in resource use and prescription patterns in patients with active epilepsy over a 10-year period at the same outpatient clinic of a German epilepsy center. We analyzed a cross-sectional patient sample of consecutive adults with active epilepsy over a 3-month period in 2013 and compared them with equally acquired data from the years 2003 and 2008. Using validated patient questionnaires, data on socioeconomic status, course of epilepsy, as well as direct and indirect costs were recorded. A total of 198 patients (mean age: 39.6±15.0years, 49.5% male) were enrolled and compared with our previous assessments in 2003 (n=101) and 2008 (n=151). In the 2013 cohort, 75.8% of the patients had focal epilepsy, and the majority were taking antiepileptic drugs (AEDs) (39.9% monotherapy, 59.1% polytherapy). We calculated epilepsy-specific costs of €3674 per three months per patient. Direct medical costs were mainly due to anticonvulsants (20.9% of total direct costs) and to hospitalization (20.8% of total direct costs). The proportion of enzyme-inducing anticonvulsants and 'old' AEDs decreased between 2003 and 2013. Indirect costs of €1795 in 2013 were mainly due to early retirement (55.0% of total indirect costs), unemployment (26.5%), and days off due to seizures (18.2%). In contrast to our previous findings from 2003 and 2008, our data show a stagnating cost increase with slightly reduced total costs and balanced direct and indirect costs in patients with active epilepsy. These findings are accompanied by an ongoing cost-neutral increase in the prescription of 'newer' and non-enzyme-inducing AEDs. However, the number and distribution of indirect cost components remained unchanged.

Costs, length of stay, and mortality of super-refractory status epilepticus: A population-based study from Germany.

OBJECTIVE: Super-refractory status epilepticus (SRSE) is a severe condition in which a patient in status epilepticus (SE) for ≥24 h does not respond to first-, second-, or third-line therapy. The economic impact of SRSE treatment remains unclear. A health insurance research database was used for a population-based estimation of SRSE-associated inpatient costs, length of stay, and mortality in Germany. METHODS: An algorithm using International Classification of Diseases, 10th Edition coding and treatment parameters identified and classified patients in a German statutory health insurance database covering admissions from 2008 to 2013 as having refractory SE (RSE) or SRSE. Admissions data in our study refer to these classifications. Associated patient data included costs, procedures, and demographics. RESULTS: The algorithm identified 2,585 (all type) SE admissions, classified as 1,655 nonrefractory SE (64%), 592 (22.9%) RSE, and 338 (13.1%) SRSE, producing database incidence rates of 15.0 in 100,000, 5.2 in 100,000, and 3.0 in 100,000 per year, respectively. Median cost per admission was €4,063 for nonrefractory SE, €4,581 (p < 0.001) for RSE, and €32,706 (p < 0.001) for SRSE. Median length of stay varied significantly between 8 days (mean = 13.6) in nonrefractory SE, 14 days in RSE, and up to 37 days in SRSE. Discharge mortality increased from 9.6% in nonrefractory SE to 15.0% (p < 0.001) in RSE and 39.9% (p < 0.001) in SRSE. SIGNIFICANCE: This study evaluated the hospital treatment costs associated with admissions classified by the algorithm as SRSE in Germany. SRSE represented 13% of all SE admissions, but resulted in 56% of all SE-related costs. The lack of approved treatments and limited number of evidence-based treatment guidelines highlight the need for further evaluations of the SRSE burden of illness and the potential for further optimization of treatments for SRSE.