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Background and purpose: Transient splenial oedema, also known as reversible splenial lesion syndrome (RESLES), is a rare magnetic resonance imaging (MRI) finding that presents as a round or ovoid focal oedema in the posterior corpus callosum, and is associated with a wide range of clinical conditions. The aetiology of RESLES is not fully clear. We aimed to investigate conflicting pathophysiological hypotheses by measuring local glucose metabolism in patients with RESLES.
Methods: We retrospectively analysed patients with RESLES after reductions in antiseizure medications during in-hospital video electroencephalography monitoring. We measured local glucose uptake using positron emission tomography/computed tomography and compared matched cohorts of patients with and without MRI evidence of RESLES using nonparametric tests.
Results: Local glucose metabolism in the splenium of seven patients with RESLES was not significantly different from the glucose metabolism of the seven patients in the matched cohort. This was true using both regular and normalized standardized glucose uptake value calculation methods (p = 0.902 and p = 0.535, respectively).
Conclusion: We found no evidence of local glucose hypometabolism in RESLES, which supports previous pathophysiological considerations that suggest that RESLES is an intercellular, intramyelinic oedema rather than a typical intracellular cytotoxic oedema, which is not reversible.
Hintergrund
In Anbetracht ihres bedeutenden Potenzials zur Verbesserung der medizinischen Versorgung wird Telemedizin weiterhin zu wenig genutzt. Trotz einiger erfolgreicher Pilotprojekte in den vergangenen Jahren ist insbesondere über die Hindernisse der Etablierung und Verstetigung von Telemedizin wenig bekannt. Diese Studie hatte das Ziel, die Einstellung niedergelassener Neurologen hinsichtlich der Nutzung von Telemedizin in der Epileptologie und resultierende Hinderungsgründe zu verstehen. Gleichzeitig werden mögliche Lösungsansätze präsentiert.
Methoden
Mithilfe eines individuell erstellten 14-Item-Fragebogens befragten wir prospektiv alle Neurologen, die zuvor die Teilnahme an einem transregionalen Telemedizinpilotprojekt im Bereich der Epileptologie abgelehnt oder keine Rückmeldung gegeben hatten, zu Gründen für und gegen den generellen Einsatz von bzw. die Teilnahme an Telemedizin.
Ergebnisse
Von 58 kontaktierten Neurologen antworteten 33 (57 %). Die häufigsten Gründe für die fehlende Nutzung der Telemedizin waren ein vermuteter Zeitmangel oder ein vermuteter zu großer organisatorischer Aufwand (49 %). Zudem wurden Bedenken bezüglich der technischen Ausstattung (30 %) und eine Präferenz für alternative Wege der intersektoralen Kommunikation (30 %) angegeben. Befürchtete Probleme in Bezug auf die Kostenerstattung für telemedizinische Leistungen waren für 27 % ein Hindernis. Neurologen in ländlichen Gebieten waren signifikant häufiger bereit, zunächst eine telemedizinische Konsultation anzufordern, bevor sie eine Überweisung ausstellen (p = 0,006).
Schlussfolgerungen
Die flächendeckende Etablierung von Telemedizinstrukturen ist immer noch durch Hindernisse erschwert, die meist im organisatorischen Bereich liegen. Die bestehenden Herausforderungen im Gesundheitswesen in ländlichen Gebieten sind eine besondere Chance für die Implementierung von Telemedizin. Die meisten Probleme der Telemedizin können gelöst werden, sollten aber bereits bei der Konzeptionierung von Projekten mitbedacht werden, um ihre Verstetigung zu erleichtern.
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.
A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC)
(2020)
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.
Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions: From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).
Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.
Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.
Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.
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.
Objective: This study was undertaken to evaluate the long-term efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. Methods: A multicenter, retrospective cohort study recruited all patients who initiated BRV between February and November 2016, with observation until February 2021. Results: Long-term data for 262 patients (mean age = 40 years, range = 5–81 years, 129 men) were analyzed, including 227 (87%) diagnosed with focal epilepsy, 19 (7%) with genetic generalized epilepsy, and 16 (6%) with other or unclassified epilepsy syndromes. Only 26 (10%) patients had never received levetiracetam (LEV), whereas 133 (50.8%) were switched from LEV. The length of BRV exposure ranged from 1 day to 5 years, with a median retention time of 1.6 years, resulting in a total BRV exposure time of 6829 months (569 years). The retention rate was 61.1% at 12 months, with a reported efficacy of 33.1% (79/239; 50% responder rate, 23 patients lost-to-follow-up), including 10.9% reported as seizure-free. The retention rate for the entire study period was 50.8%, and at last follow-up, 133 patients were receiving BRV at a mean dose of 222 ± 104 mg (median = 200, range = 25–400), including 52 (39.1%) who exceeded the recommended upper dose of 200 mg. Fewer concomitant antiseizure medications and switching from LEV to BRV correlated with better short-term responses, but no investigated parameters correlated with positive long-term outcomes. BRV was discontinued in 63 (24%) patients due to insufficient efficacy, in 29 (11%) for psychobehavioral adverse events, in 25 (10%) for other adverse events, and in 24 (9%) for other reasons. Significance: BRV showed a clinically useful 50% responder rate of 33% at 12 months and overall retention of >50%, despite 90% of included patients having previous LEV exposure. BRV was well tolerated; however, psychobehavioral adverse events occurred in one out of 10 patients. Although we identified short-term response and retention predictors, we could not identify significant predictors for long-term outcomes. Key Points Long-term postmarketing data for brivaracetam in 262 patients showed an overall retention rate of 50.8%; At 12 months, the 50% responder rate for brivaracetam was 33.1%, with 10.9% reporting seizure freedom; Previous treatment with levetiracetam (90%) did not impact brivaracetam retention or efficacy; Levetiracetam treatment failure should not preclude brivaracetam introduction; No long-term efficacy predictors could be identified.
Objective: This study was undertaken to evaluate the long-term efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. Methods: A multicenter, retrospective cohort study recruited all patients who initiated BRV between February and November 2016, with observation until February 2021. Results: Long-term data for 262 patients (mean age = 40 years, range = 5–81 years, 129 men) were analyzed, including 227 (87%) diagnosed with focal epilepsy, 19 (7%) with genetic generalized epilepsy, and 16 (6%) with other or unclassified epilepsy syndromes. Only 26 (10%) patients had never received levetiracetam (LEV), whereas 133 (50.8%) were switched from LEV. The length of BRV exposure ranged from 1 day to 5 years, with a median retention time of 1.6 years, resulting in a total BRV exposure time of 6829 months (569 years). The retention rate was 61.1% at 12 months, with a reported efficacy of 33.1% (79/239; 50% responder rate, 23 patients lost-to-follow-up), including 10.9% reported as seizure-free. The retention rate for the entire study period was 50.8%, and at last follow-up, 133 patients were receiving BRV at a mean dose of 222 ± 104 mg (median = 200, range = 25–400), including 52 (39.1%) who exceeded the recommended upper dose of 200 mg. Fewer concomitant antiseizure medications and switching from LEV to BRV correlated with better short-term responses, but no investigated parameters correlated with positive long-term outcomes. BRV was discontinued in 63 (24%) patients due to insufficient efficacy, in 29 (11%) for psychobehavioral adverse events, in 25 (10%) for other adverse events, and in 24 (9%) for other reasons. Significance: BRV showed a clinically useful 50% responder rate of 33% at 12 months and overall retention of >50%, despite 90% of included patients having previous LEV exposure. BRV was well tolerated; however, psychobehavioral adverse events occurred in one out of 10 patients. Although we identified short-term response and retention predictors, we could not identify significant predictors for long-term outcomes. Key Points Long-term postmarketing data for brivaracetam in 262 patients showed an overall retention rate of 50.8%; At 12 months, the 50% responder rate for brivaracetam was 33.1%, with 10.9% reporting seizure freedom; Previous treatment with levetiracetam (90%) did not impact brivaracetam retention or efficacy; Levetiracetam treatment failure should not preclude brivaracetam introduction; No long-term efficacy predictors could be identified.
Highlights
• German patients with LGS identified using most specific algorithm to date.
• Prevalence of probable LGS with epilepsy diagnosis before age 6 was 6.5 per 100,000.
• High healthcare costs of €22,787 PPY; mostly due to inpatient and home nursing care.
• Costs were greater in patients prescribed rescue medications.
• Over 10 years, LGS patients had significant mortality vs. controls (2.88 vs. 0.01%).
Abstract
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. one event [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.