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· 2018
Das große Standardwerk zur klinischen Neurologie liegt jetzt unter der Federführung des international renommierten Herausgeberteams und der Mitarbeit von über 150 FachexpertInnen als erweiterte und komplett überarbeitete Neuauflage vor. Die aktuellen Erkenntnisse zum Stand von Klinik, Verlauf und Therapie neurologischer Erkrankungen werden systematisch zusammengefasst und für die praktische Anwendung gewichtet - sowohl für häufige als auch für seltene Krankheitsbilder. Zudem profitiert die 8. Auflage von neuen Kapiteln zu funktionellen Bewegungsstörungen, dissoziativen Anfällen, spinaler Muskelatrophie sowie zu neurologischen Nebenwirkungen von Tumor-Therapien. Das Werk wurde konzeptionell und didaktisch weiterentwickelt, um den heutigen Anforderungen des modernen und zunehmend digital geprägten Klinikalltags gerecht zu werden. Die Bewertungen von Evidenzlevels und Empfehlungsstärken der relevanten Therapien sowie klinische Pfade veranschaulichen die Best Practice. Das etablierte Werk, welches die gesamte Neurologie abbildet, ist aus der alltäglichen Arbeit von FachärztInnen und AllgemeinmedizinerInnen in Klinik und Praxis sowie einer erfolgreichen Aus-, Fort- und Weiterbildung nicht mehr wegzudenken.
Angeborene Muskelerkrankungen gehören zu den „Orphan Diseases“, die von der Pädiatrie zunehmend in die Erwachsenenmedizin hinein reichen - darunter die spinale Muskelatrophie, Becker- und Duchenne-Muskeldystrophie, myasthene Syndrome, Morbus Pompe und andere. Die Entwicklung effektiver symptomatischer Maßnahmen und die Fortschritte in der Molekulargenetik haben in den letzten Jahren entscheidend zur Verbesserung der vitalen Prognose und der Lebensqualität der Patienten beigetragen. Neuropädiater und Neurologen sind bei der schwierigen Diagnose und Versorgung dieser Patienten auf sich allein gestellt, insbesondere außerhalb von Zentren für seltene Erkrankungen. Dieses Buch unterstützt Kinderneurologen, nicht spezialisierte Pädiater und Neurologen darin, sich zu diesen Krankheiten fortzubilden. Das Autorenteam aus Neuropädiatern und Neurologen präsentiert anhand von typischen Fallbeispielen einen in der Klinik anwendbaren Werkzeugkasten von der Familien-Anamnese zurschwierigen Differenzialdiagnose bis hin zur Versorgung. Dieser klinisch orientierte Leitfaden liefert einen interdisziplinären Beitrag zur Transition bei neuromuskulären Erkrankungen und gibt konkrete Antworten auf die Fragen: Wie stellen sich die unterschiedliche Manifestationen im Kindes- und im Erwachsenenalter dar? Wie verändert sich die Symptomatik im Verlauf der Krankheit? Was muss der Neurologe wissen, der einen jugendlichen Patienten vom Pädiater übernimmt? Wie sind Befunde richtig einzuordnen? Das erste Buch, das systematisch und interdisziplinär die Transition bei seltenen Erkrankungen anhand einer Krankheitsgruppe behandelt.
Die Flut neuer diagnostischer und therapeutischer Möglichkeiten macht es bei seltenen Erkrankungen schwer, den Überblick zu bewahren. Wann muss ich an eine neuromuskuläre Erkrankung denken? Was setze ich zur gezielten Diagnostik ein? Welche Differenzialdiagnosen muss ich bedenken? Welche Konsequenzen ergeben sich für den Patienten? Das praxisorientierte Buch, das aus der täglichen Arbeit der Autoren mit neuromuskulären Erkrankung entstanden ist, zeigt Lösungsstrategien auf und gibt Leitstrukturen an die Hand, um Kinder und Jugendliche mit neuromuskulären Erkrankungen sinnvoll betreuen zu können.
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· 2018
Abstract: Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle weakness and muscle atrophy. Nusinersen acts as a splicing modifier and has recently been approved for intrathecal treatment of SMA. Objective: Prior to approval, nusinersen was provided to patients with SMA type 1 in Germany within an Expanded Access Program (EAP). In contrast to previous clinical trials, children of different age groups and different stages of the disease were treated with nusinersen. Methods: We conducted a prospective, longitudinal data collection of patients treated with nusinersen within the EAP in seven neuromuscular centers in Germany. Standardized assessments including CHOP-INTEND and HINE-2 motor milestones were performed at baseline and 60 and 180 days after start of treatment. Results: Data from 61 SMA type 1 patients (mean age 21.08 months, range 1-93) were available for analysis. After six months of treatment, 47 children (77.0%) improved by ≥4 points in CHOP INTEND score. Mean change in CHOP INTEND score was 9.0±8.0 points. Nineteen patients (31.1%) improved by ≥2 points in HINE-2 motor milestones. Regression analysis revealed age at onset of treatment as major determinant of change in CHOP INTEND from baseline. Conclusion: When analyzing a broad spectrum of SMA type 1 patients, many children showed an improvement of motor function after six months of treatment with nusinersen, which is generally not expected within the natural course of the disease. Long-term observation and follow-up of patients with later onset types of SMA are crucial to understand the clinical impact of treatment with nusinersen
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· 2023
Abstract: Background Patients with myasthenia gravis (MG) are potentially prone for a severe COVID-19 course, but there are limited real-world data available on the risk associated with COVID-19 for patients with MG. Here, we investigate whether current immunosuppressive therapy (IST) influences the risk of SARS-CoV-2 infection and COVID-19 severity. Methods Data from the German myasthenia gravis registry were analyzed from May 2020 until June 2021 and included patient demographics, MG disease duration, comorbidities, current IST use, COVID-19 characteristics, and outcomes. Propensity score matching was employed to match MG patients with IST to those without, and multivariable binary logistic regression models were used to determine associations between IST with (1) symptomatic SARS-CoV-2 infection and (2) severe COVID-19 course, as measured by hospitalization or death. Results Of 1379 patients with MG, 95 (7%) patients (mean age 58 (standard deviation [SD] 18) presented with COVID-19, of which 76 (80%) received IST at time of infection. 32 patients (34%) were hospitalized due to COVID-19; a total of 11 patients (12%) died. IST was a risk factor for hospitalization or death in the group of COVID-19-affected MG patients (odds ratio [OR] 3.04, 95% confidence interval [CI] = 1.02-9.06, p = 0.046), but current IST was not associated with a higher risk for SARS-CoV-2 infection itself. Discussion In this national MG cohort study, current IST use was a risk factor for a severe disease course of COVID-19 but not for SARS-CoV-2 infection itself. These data support the consequent implementation of effective strategies to prevent COVID-19 in this high-risk group. Trial registration information German clinical trial registry (https://www.drks.de), DRKS00024099, first patient enrolled: February 4th, 2019
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· 2022
Abstract: Background The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the last 4 years but treatment responses differ remarkably between individuals and therapeutic decision-making remains challenging - underlining the persistent need for validated biomarkers. Methods We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and ELISA. Further, levels of peripheral neurofilament H and L were determined. Results Untargeted proteomic analysis of CSF samples of 3 SMA type 1 patients revealed the lysosomal protease Cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1=12, type 2=9, type 3=6, presymptomatically treated=4; age 0-16 years) revealed a significant decline of Cathepsin D levels in SMA patients ≥2 months at the start of treatment. While evident in all older age categories, this decline was only significant in the group of patients that showed a positive motor-response. Moreover, downregulation of Cathepsin D was evident in muscle biopsies of SMA patients. Conclusions We identified a decline of Cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of 'treatment responders' than in 'non-responders'. We believe that our results indicate a suitability of Cathepsin D levels as possible biomarker in SMA also in older patients - in combination with analysis of pNF-L in adolescents or alone in adult patients
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· 2020
Abstract: Introduction: Congenital myasthenic syndromes (CMS) refer to a heterogenic group of neuromuscular transmission disorders. CMS-subtypes are diverse regarding exercise intolerance and muscular weakness, varying from mild symptoms to life-limiting forms with neonatal onset. Long-term follow-up studies on disease progression and treatment-response in pediatric patients are rare. Patients and Methods: We analyzed retrospective clinical and medication data in a cohort of 32 CMS-patients including the application of a standardized, not yet validated test (CMS-ST) to examine muscular strength and endurance in 21 patients at the last follow-up. Findings obtained in our cohort were compared with long-term follow-up studies of (adult) CMS-cohorts from the literature by considering the underlying molecular mechanisms. Outcomes of CMS-ST were compared to results of normal clinical assessment. Results: Thirty-two pediatric patients with defects in eight different CMS-genes were followed by a median time of 12.8 years. Fifty-nine percentage of patients manifested with first symptoms as neonates, 35% as infants. While 53% of patients presented a reduced walking distance, 34% were wheelchair-bound. Even under adequate therapy with pyridostigmine (PS) and 3,4-diaminopyridine, CHAT-mutations led to the progression of muscular weakness partly in combination with persistent respiratory and bulbar symptoms. RAPSN, CHRND, and CHRNB1 patients with neonatal manifestation, early respiratory problems, and bulbar symptoms showed a good and maintained treatment response. CHAT and CHRNE patients required higher PS dosages, whereas RAPSN patients needed a lower mean dosage at the last follow-up. The benefits of short-term medication and long-term progression of symptoms were highly dependent on the specific genetic defect. CMS-ST was carried out in 17/21 patients, determined affected muscle groups including bulbar and ocular symptoms, some of which were not reported by the patients. Conclusions: Our findings and comparison with the literature- suggest a better treatment-response and less severe progression of symptoms present in patients suffering from mutations in CMS-genes directly associated with receptor deficiency, while patients with defects leading to synaptopathy and presynaptic defects tend to have worse outcomes. Assessment of affected muscular groups and clinical symptoms by CMS-ST may be a useful tool for optimal therapeutic management of the patients, especially for future clinical studies
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Die Fulle neuer diagnostischer und therapeutischer Moglichkeiten macht es bei seltenen Erkrankungen schwer, den Uberblick zu behalten. Wann muss ich an eine neuromuskulare Erkrankung denken? Was setze ich zur gezielten Diagnostik ein? Welche Differenzialdiagnosen muss ich bedenken? Welche Konsequenzen ergeben sich fur die Patienten? Dieses praxisorientierte Buch gibt Leitstrukturen und Losungsstrategien an die Hand, um Kinder und Jugendliche mit neuromuskularen Erkrankungen bestmoglich zu behandeln.