Complex elbow fracture-dislocations- what factors are associated with a poor post-operative outcome?

PURPOSE: Despite standardized treatment algorithms, patients with complex elbow fracture-dislocation frequently suffer from poor post-operative elbow function leading to reduced quality of life. Up to now, there is no valuable data regarding risk factors that lead to poor post-operative outcome after surgical reconstruction of complex elbow fracture-dislocations. METHODS: From 06/2010 to 12/2020 134 patients (51.3 ± 15.1 years, 44% women) undergoing surgical treatment of complex elbow fracture-dislocations could be included in this study. Follow-up period was 4.4 years (SD 2.5). All patients were clinically evaluated for elbow movement, elbow stability and common elbow scores (MEPS, OES, DASH-Score). Potential risk factors for poor post-operative outcome were identified using bi- and multivariate analyses. RESULTS: Overall good post-operative outcome has been achieved, mean MEPS was 88.8 ± 17.6. Post-operative complications occurred in 31.3% of the cases, while 25.4% required surgical revision. Patients with transolecranon dislocation fractures showed the significantly worst functional outcomes (p = 0.01). In addition, it has been shown that a patient's age of more than 70 years (OR = 10, p = 0.003) and a BMI of more than 35 kg/m2 (OR = 7.6, p = 0.004) are independent risk factors for a poor post-operative outcome. In contrast, gender and time to surgery showed no significant influence on post-operative outcome. CONCLUSION: In most cases, good post-operative functional results can be achieved using standardized treatment protocols. However, complication and revision rates remain high. Patients older than 70 years of age or with a BMI over 35 kg/m2 are at risk for an inferior outcome and require close follow-up monitoring.

Patients' and physicians' awareness of clinical symptoms and disease severity in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare inherited disease with the potential to affect virtually every organ system. Clinical presentation is age- and partly sex-dependent and varies broadly with respect to disease manifestations including treatment-refractory epilepsy, intellectual disability and TSC-associated neuropsychiatric disorders, chronic kidney disease or progressive lung function decline. Given the complexity of this disease, multidisciplinary care in specialized TSC centres is recommended. We aimed to elucidate the state of knowledge of patients/caregivers and physicians on individual disease manifestations. We further examined whether the association to a TSC centre has an impact on the comprehensive consideration of potential disease manifestations. Therefore, a survey was performed in a cohort of German TSC patients and their physicians. Complete information was available for 94 patients with a median age of 18 years [range 1-55] and a sex distribution of 53.2% (male): 48.8% (female). Using almost identical questionnaires for patients/caregivers and their respective physician, there was a good correlation for disease assessments associated with relevant morbidity and mortality like epilepsy, renal angiomyolipoma, cardiac rhabdomyomas or intellectual disability. Correlation was moderate for several neuropsychiatric disorders and only poor for hypomelanotic macules, dental pits or retinal achromic patches. Estimation of overall disease severity using a numeric rating scale correlated highly significantly (Pearson correlation coefficient = 0.767; p < 0.001) between patients/caregivers and physicians. In general, physicians more likely quoted items as 'unknown' than patients (822 answers vs. 435 answers in the respective groups). Questionnaires completed by physicians who were associated with a specialized TSC centre declared a significantly lower proportion of items as unknown (mean 8.7% vs. 20.5%; p < 0.001). These findings indicate that patients treated by specialized TSC centres seem to obtain a more comprehensive surveillance. Furthermore, it shows that there were reasonable surveillance strategies in general and sufficient patient/caregiver interaction and education in the examined cohort. However, for the most prominent disease characteristics there was a good awareness within both the patients/caregivers and the physicians group.

[Terrible triad injuries]. / Terrible-Triad-Verletzungen.

The complex injury pattern of a posterior elbow dislocation with concomitant radial head and coronoid fractures is usually referred to as a terrible triad injury. Due to the concomitant compromise of several osteoligamentous structures of the elbow joint relevant for stability, these injuries pose a particularly major challenge to the treating trauma surgeons. For this reason, a careful preoperative analysis of all relevant injury components is mandatory in order to make an adequate treatment decision. In most cases, surgical treatment addressing all elements relevant for stability is necessary to achieve a stable and congruent elbow joint. Only this enables early functional follow-up treatment and minimizes the complication rate. Delayed or even insufficient treatment with persistent (sub)dislocation must be avoided at all costs, otherwise there is a high risk of serious posttraumatic functional disorders of the elbow with rapid progression of osteoarthritis.

Prospective clinical cohort study: low incidence of Barrett esophagus but high rate of reflux disease at 5-year follow-up after sleeve gastrectomy versus Roux-en-Y gastric bypass.

BACKGROUND: Gastroesophageal reflux disease seems more frequent after laparoscopic sleeve gastrectomy (LSG) than Roux-en-Y gastric bypass (LRYGB). Retrospective case series have raised concerns about a high incidence of Barrett esophagus (BE) after LSG. OBJECTIVE: This prospective clinical cohort study compared the incidence of BE ≥5 years after LSG and LRYGB. SETTING: St. Clara Hospital, Basel, and University Hospital, Zürich, Switzerland. METHODS: Patients were recruited from 2 bariatric centers where preoperative gastroscopy is standard practice and LRYGB is preferred for patients with preexisting gastroesophageal reflux disease. At follow-up ≥5 years after surgery, patients underwent gastroscopy with quadrantic biopsies from the squamocolumnar junction and metaplastic segment. Symptoms were assessed using validated questionnaires. Wireless pH measurement assessed esophageal acid exposure. RESULTS: A total of 169 patients were included, with a median 7.0 ± 1.5 years after surgery. In the LSG group (n = 83), 3 patients had endoscopically and histologically confirmed de novo BE; in the LRYGB group (n = 86), there were 2 patients with BE, 1 de novo and 1 preexisting (de novo BE, 3.6% versus 1.2%; P = .362). At follow-up, reflux symptoms were reported more frequently by the LSG group than by the LRYGB group (51.9% versus 10.5%). Similarly, moderate-to-severe reflux esophagitis (Los Angeles grade B-D) was more common (27.7% versus 5.8%) despite greater use of proton pump inhibitors (49.4% versus 19.7%), and pathologic acid exposure was more frequent in patients who underwent LSG than in patients who underwent LRYGB. CONCLUSIONS: After at least 5 years of follow-up, a higher incidence of reflux symptoms, reflux esophagitis, and pathologic esophageal acid exposure was found in patients who underwent LSG compared with patients who underwent LRYGB. However, the incidence of BE after LSG was low and not significantly different between the 2 groups.

Proximal ulna non-union: treatment concept and postoperative outcome.

PURPOSE: Non-union of the proximal ulna is a serious complication after surgical treatment of olecranon and complex elbow fractures, frequently leading to poor functional outcome. To date, there is a lack of data regarding optimal treatment strategies and functional outcome parameters after surgical revision. METHODS: From 02/2010 to 12/2018, 31 patients undergoing surgical treatment of proximal ulna non-union could be included. Follow-up period was seven years (SD 2.5 years). All patients were clinically assessed using a clinical assessment tool set and standard elbow scores (MEPS, OES, DASH score). All complications and unplanned revision surgeries were recorded and all radiographic material was analyzed. RESULTS: Initial non-union procedures were performed at an average of 6.6 months (SD 3 months) after the index procedures. Those included the use of autologous spongiosa graft in all patients and concomitant compression re-osteosynthesis in 28 patients. Radiological consolidation was achieved in all patients. Overall, patients achieved a good to fair functional outcome with Mayo elbow performance score measuring 78.5 (SD 9.1), DASH score 34.7 (SD 14.4), and Oxford elbow score 31.2 (SD 6.6) points. Initial malreduction/implant-malposition could be identified as a main reason for the occurrence of the non-union. Furthermore, inferior postoperative outcome was detected in patients > 60 years and BMI > 30 kg/m2. CONCLUSION: Using a standardized protocol, bony union and acceptable functional outcomes can be achieved in proximal ulna non-unions. However, surgeons should be aware of potential risk factors and proper initial fracture reduction as key to achieve sufficient bone healing.

Disentangling tumorigenesis-associated DNA methylation changes in colorectal tissues from those associated with ageing.

Physiological ageing and tumorigenesis are both associated with epigenomic alterations in human tissue cells, the most extensively investigated of which entails de novo cytosine methylation (i.e., hypermethylation) within the CpG dinucleotides of CpG islands. Genomic regions that become hypermethylated during tumorigenesis are generally believed to overlap regions that acquire methylation in normal tissues as an effect of ageing. To define the extension of this overlap, we analysed the DNA methylomes of 48 large-bowel tissue samples taken from women of different ages during screening colonoscopy: 18 paired samples of normal and lesional tissues from donors harbouring a precancerous lesion and 12 samples of normal mucosa from tumour-free donors. Each sample was subjected to targeted, genome-wide bisulphite sequencing of ~2.5% of the genome, including all CpG islands. In terms of both its magnitude and extension along the chromatin, tumour-associated DNA hypermethylation in these regions was much more conspicuous than that observed in the normal mucosal samples from older (vs. younger) tumour-free donors. 83% of the ageing-associated hypermethylated regions (n = 2501) coincided with hypermethylated regions observed in tumour samples. However, 86% of the regions displaying hypermethylation in precancerous lesions (n = 16,772) showed no methylation changes in the ageing normal mucosa. The tumour-specificity of this latter hypermethylation was validated using published sets of data on DNA methylation in normal and neoplastic colon tissues. This extensive set of genomic regions displaying tumour-specific hypermethylation represents a rich vein of putative biomarkers for the early, non-invasive detection of colorectal tumours in women of all ages.

Health-related quality of life in children and adolescents with tuberous sclerosis complex and their caregivers: A multicentre cohort study from Germany.

OBJECTIVE: This study aimed to measure health-related quality of life (HRQOL) in children and adolescents with tuberous sclerosis complex (TSC) and quality of life (QOL) and depressive symptoms among caregivers. METHODS: Adequate metrics were used to assess HRQOL in children and adolescents with TSC (4-18 years, KINDLR) as well as QOL (EQ-5D) and symptoms of depression (BDI-II) among caregivers. Predictors for reduced HRQOL and depressive symptoms were identified by variance analysis, ordinal regression, and bivariate correlation. RESULTS: The mean HRQOL score was 67.9 ± 12.7, and significantly lower values were associated with increasing age, attending special needs education, TSC-associated psychiatric symptoms, and drug-related adverse events. The mean QOL of caregivers was 85.4 ± 15.7, and caregiver's sex, TSC mutation locus, familial TSC clustering, special needs education, degree of disability, care dependency, presence of TSC-associated psychiatric symptoms, and TSC severity were significant predictors of lower QOL. Depressive symptoms were identified in 45.7% of caregivers, associated with female sex of the caregiver, familial TSC clustering, special needs education, and presence of TSC-associated psychiatric symptoms of the child. Multivariate regression analysis revealed adolescence and drug-related adverse events as significant predictors for lower HRQOL in TSC children, and TSC2 variants predicted lower QOL and depressive symptoms in caregivers. CONCLUSION: Compared with other chronic diseases, such as headache, diabetes or obesity, children with TSC have significantly lower HRQOL, which further decreases during adolescence. A decreased HRQOL of patients correlates with a lower QOL and increased symptoms of depression of their caregivers. These results may improve the comprehensive therapy and care of children and adolescents with TSC and their families and caregivers. TRIAL REGISTRATION: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.

Historical Patterns of Diagnosis, Treatments, and Outcome of Epilepsy Associated With Tuberous Sclerosis Complex: Results From TOSCA Registry.

Background: Epilepsy is the most common neurological manifestation in individuals with tuberous sclerosis complex (TSC). However, real-world evidence on diagnosis and treatment patterns is limited. Here, we present data from TuberOus Sclerosis registry to increase disease Awareness (TOSCA) on changes in patterns of epilepsy diagnosis, treatments, and outcomes over time, and detailed epilepsy characteristics from the epilepsy substudy. Methods: TuberOus Sclerosis registry to increase disease Awareness (TOSCA) was a multicentre, international disease registry, consisting of a main study that collected data on overall diagnostic characteristics and associated clinical features, and six substudies focusing on specific TSC manifestations. The epilepsy substudy investigated detailed epilepsy characteristics and their correlation to genotype and intelligence quotient (IQ). Results: Epilepsy was reported in 85% of participants, more commonly in younger individuals (67.8% in 1970s to 91.8% in last decade), while rate of treatments was similar across ages (>93% for both infantile spasms and focal seizures, except prior to 1960). Vigabatrin (VGB) was the most commonly used antiepileptic drugs (AEDs). Individuals with infantile spasms showed a higher treatment response over time with lower usage of steroids. Individuals with focal seizures reported similar rates of drug resistance (32.5-43.3%). Use of vagus nerve stimulation (VNS), ketogenic diet, and surgery remained low. Discussion: The epilepsy substudy included 162 individuals from nine countries. At epilepsy onset, most individuals with infantile spasms (73.2%) and focal seizures (74.5%) received monotherapies. Vigabatrin was first-line treatment in 45% of individuals with infantile spasms. Changes in initial AEDs were commonly reported due to inadequate efficacy. TSC1 mutations were associated with less severe epilepsy phenotypes and more individuals with normal IQ. In individuals with TSC diagnosis before seizure onset, electroencephalogram (EEG) was performed prior to seizures in only 12.5 and 25% of subsequent infantile spasms and focal seizures, respectively. Conclusions: Our study confirms the high prevalence of epilepsy in TSC individuals and less severe phenotypes with TSC1 mutations. Vigabatrin improved the outcome of infantile spasms and should be used as first-line treatment. There is, however, still a need for improving therapies in focal seizures. Electroencephalogram follow-up prior to seizure-onset should be promoted for all infants with TSC in order to facilitate preventive or early treatment.

Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients' Perspectives.

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.

Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA).

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients. METHODS: TuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2). RESULTS: Overall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years. TSC1 mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%). CONCLUSION: Rare manifestations were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.

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.

Quality of life and its predictors in adults with tuberous sclerosis complex (TSC): a multicentre cohort study from Germany.

BACKGROUND: Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC. METHODS: We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders. RESULTS: We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18-61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p < 0.001), active epilepsy (large effect, p < 0.001), and neuropsychiatric manifestations (medium effect, p = 0.003) were independently associated with worse HRQoL, explaining 65% of the variance (p < 0.001). The HRQoL among patients with active TSC-associated epilepsy was worse than that among patients with drug-refractory mesial temporal lobe epilepsy (p < 0.001), and the generic QoL among patients with more than three TSC organ manifestations was similar to those of patients with severe migraine and uncontrolled asthma. CONCLUSIONS: Active epilepsy, neuropsychiatric manifestations (such as anxiety and depression), and therapy-related adverse events are important independent predictors of worse quality of life among adults with TSC. Generic quality of life in TSC with several manifestations is similar to uncontrolled severe chronic diseases and significantly negatively correlates with TSC severity. TRIAL REGISTRATION: DRKS, DRKS00016045 . Registered 01 March 2019.

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 .

[Preparing for a pandemic]. / Vorbereitungen auf eine pandemische Welle.

On 16 March 2020 the government of Bavaria declared a state of emergency due to the coronavirus disease 2019 (COVID-19) pandemic. This confronted all clinics with completely new and difficult challenges. In accordance with the official requirements, pandemic officers were appointed at the Kempten Clinic and a clinical management team was established. It was important to keep a relevant proportion of employees off duty at all times, and thus to have a constant reserve available in the event of expected infection-related absences of physicians and nurses. These structural changes were complemented by staff briefings and the creation of a training program on the subject of COVID-19. Within a very short time, algorithms were designed and defined how to manage patients presenting in the hospital or in the emergency room. The surgical program was limited to operations that could not be postponed, such as extrauterine pregnancy or adnexal torsion, and oncological diagnoses without the possibility of primary systemic therapy. In the case of breast cancer, however, therapy was started in all cases in which primary systemic therapy (PST), whether cytotoxic or endocrinological, appeared possible and indicated. As of 1 April 2020, more than 50% of the usable beds in the Kempten Clinic were empty. The utilization of the intensive care unit had also been reduced so that higher numbers of patients requiring artificial respiration could have been cared for at any time.

Prescription patterns of antiseizure drugs in tuberous sclerosis complex (TSC)-associated epilepsy: a multicenter cohort study from Germany and review of the literature.

OBJECTIVE: Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC. METHODS: We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence. RESULTS: TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs. CONCLUSIONS: The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.

TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex.

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.

Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas.

Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study was to describe in detail the prevalence and outcome of renal angiomyolipomas in patients with TSC, enrolled into the TuberOus SClerosis registry to increase disease Awareness (TOSCA) from 170 sites across 31 countries worldwide. We also sought to evaluate the relationship of TSC-associated renal angiomyolipomas with age, gender and genotype. The potential risk factors for renal angiomyolipoma-related bleeding and chronic kidney disease (CKD) were studied in patients who participated in the TOSCA renal angiomyolipoma substudy. Of the 2,211 eligible patients, 1,062 (48%) reported a history of renal angiomyolipomas. The median age of TSC diagnosis for the all subjects (n = 2,211) was 1 year. The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years. Renal angiomyolipomas were significantly more prevalent in female patients (p < 0.0001). Rates of angiomyolipomas >3 cm (p = 0.0119), growing lesions (p = 0.0439), and interventions for angiomyolipomas (p = 0.0058) were also higher in females than males. Pre-emptive intervention for renal angiomyolipomas with embolisation, surgery, or mammalian target of rapamycin (mTOR) inhibitor may have abolished the gender difference in impaired renal function, hypertension, and other complications. The rate of interventions for angiomyolipomas was less common in children than in adults, but interventions were reported in all age groups. In the substudy of 76 patients the complication rate was too low to be useful in predicting risk for more severe CKD. In addition, in this substudy no patient had a renal hemorrhage after commencing on an mTOR inhibitor. Our findings confirmed that renal angiomyolipomas in subjects with TSC1 mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with TSC1 and TSC2 mutations needing intervention. The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary. We found that pre-emptive intervention was dramatically successful in altering the outcome compared to historical controls; with high pre-emptive intervention rates but low rates of bleeding and other complications. This validates the policy of surveillance and pre-emptive intervention recommended by clinical guidelines.

Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study.

Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population.

Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project.

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters.