Search

This article presents long-term data on the efficacy of gene replacement therapy (GRT) for spinal muscular atrophy (SMA) using onasemnogene abeparvovec (OA). The study includes patients who were older, heavier, or more severely affected than those in previous clinical trials, as well as a large cohort of presymptomatic SMA patients identified through newborn screening. The results show that younger patients treated with OA had better motor function outcomes compared to those treated at a later age. The study provides valuable evidence for future treatment decisions, particularly for patients with limited trial data available. [Extracted from the article]

This article, published in the journal Neuropediatrics, discusses the clinical and imaging features of children with autoimmune encephalitis (AE) and glial fibrillary acidic protein (GFAP) antibodies. The study included 16 children who met the diagnostic criteria for possible AE and tested positive for GFAP antibodies in their serum and/or cerebrospinal fluid. The children presented with symptoms such as encephalopathy, headache, focal seizures, and ataxia. MRI imaging revealed abnormalities in 13 out of 16 children, including freckling lesions in the pons and nucleus caudate, signal abnormalities around the aqueduct, and myelin indicative of transverse myelitis. The study recommends including GFAP antibody testing in the work-up of children with suspected AE, particularly in cases involving brainstem involvement. [Extracted from the article]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH)., Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status., Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0-90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups., Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio., Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements)., Competing Interests: No author received financial support for the present manuscript. CW received honoraria for presentations and/or travel support from Novartis, Roche and Biogen and participated on advisory boards for Novartis, Roche and Biogen. JF received honoraria from Novartis for presentations. AB received honoraria for presentations from Roche and Pfizer and attend advisory boards for Roche and Pfizer. SI received honoraria for presentations and advisory board meetings from Novartis and Roche. OS received honoraria from Biogen, support for attending meetings from Novartis and participated on an advisory board for Novartis. GB received honoraria for advisory boards and/or presentations from Novartis, Roche and Biogen and support for attending meetings from Novartis. MvdH received grants from Deutsche Gesellschaft für Muskelkranke and Innovationsfond (INTEGRATE ATMP and KoCoN), honoraria from Pfizer, Biogen and PTC Therapeutics, and participated on advisory boards for Roche, Sarepta, Novartis, and Pfizer. RAH received consulting fees from Biogen and honoraria for presentations from Novartis, and participated on advisory boards by Novartis and Roche. KG participated on an industry symposium and an advisory board by Novartis. JK received funding for clinical research from Biogen, Novartis, Roche, ScholarRock and Biohaven, consulting fees from Biogen, Novartis and Roche, payment for educational activities from Biogen, Novartis and Roche and attended a data safety monitoring board for Biogen. AP received research funding form Roche, Novartis and Biogen. MFB received consulting fees for advisory boards from Roche, Novartis and Biogen and payment for presentations from Novartis and Biogen. GS received honoraria for a case report and participated on an advisory board for Novartis. US received honoraria for presentations from Biogen, Novartis and Roche and support for attending meetings from Roche and Novartis. BP received honoraria for a presentation from Biogen and participated on advisory boards for Novartis and Biogen. RT received honoraria for presentations from Desitin, PTC and Roche and participated on advisory boards for PTC, Roche and Santhera. VH attended an adivisory board for Biogen. MB received compensation for advisory boards and speakers honoraria from Novartis, Biogen and Roche and compensation for travel costs to meetings from Roche. AK is clinical lead of the Swiss Reg NMD, attended advisory board meetings of Novartis and received honorarium for a presentation by Novartis. AE received honoraria and payment for expert testimony from Biogen, Roche and Novartis, support for attending meetings from Biogen and Roche and participated on an advisory board for Biogen, Roche and Novartis. GMS participated on advisory boards from Biogen, Novartis and Roche and is member of the steering board for Swiss-Reg-NMD. SC received payment for a presentation. JJ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, IFT, Roche, PTC, Pfizer and Sarepta Therapeutics. AZ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, ITF, Roche, Pfizer and Sarepta Therapeutics. LLB, AH, EW, CK, OH, and SFG indicated no potential conflicts of interest to disclose., (© 2024 The Author(s).)

Background: The diagnostics of autism spectrum disorder is complex due to missing biological markers and numerous comorbidities. The aim was to assess the role of neuropediatric diagnostics and to develop a standard operating procedure for a targeted assessment., Method: All patients presenting to the neuropediatric outpatient clinic at Saarland University Hospital between April 2014 and December 2017 with ICD code F84 pervasive developmental disorders were included., Results: A total of 82 patients were included (male 78%, female 22%; mean age 5.9 ± 2.9 years, range 2-16 years). The most frequent examination was electroencephalography (EEG) (74/82; 90.2%) with pathological findings in 33.8% (25/74). Based on the history and/or EEG epilepsy was diagnosed in 19.5% (16/82). Magnetic resonance imaging (MRI) was performed in 49/82 (59.8%) patients, 22/49 (44.9%) showed at least 1 cerebral abnormality and definite pathologies could be detected in 63.6% (14/22). A metabolic diagnostic work-up was performed in 44/82 (53.7%) cases and in 5/44 (11.4%) it resulted in a diagnosis or suspicion of a metabolic disease. Genetic testing results were available in 29/82 (35.4%) children and 12/29 (41.4%) showed abnormal results. Delay in motor development was more frequently associated with comorbidities, EEG abnormalities, epilepsy and abnormalities in metabolic and genetic testing., Conclusion: Neuropediatric examination in cases of suspected autism should include a detailed history, a thorough neurological examination and an EEG. An MRI, comprehensive metabolic and genetic testing are only recommended if clinically indicated., (© 2023. The Author(s).)

Background and Objectives: Glial fibrillary acidic protein (GFAP) antibodies (abs) have been described primarily in adults with a spectrum of autoimmune-mediated diseases. In children, data on clinical and neuroradiologic features of children with autoimmune GFAP astrocytopathy are limited. The aim of this study was to describe the clinical and radiologic features in children with GFAP-ab-associated diseases., Methods: We retrospectively recruited children from 13 clinical centers between 2020 and 2023 who (1) tested positive for GFAP-ab in serum and/or CSF and (2) of whom a complete clinical and MRI data set was available., Results: We identified and included 15 children (5 girls, 10 boys). The median age at onset was 9.9 years (range: 2-16 years). All children presented with features of AE or meningitis, acute cerebellitis, or transverse myelitis. CSF pleocytosis was common (13/15, median 245 cells/μL), and 13 (87%) of 15 harbored GFAP-abs in their CSF, 8 (53%) of whom did not have detectable GFAP-abs in their serum. MRI was abnormal in 15 (100%) of 15 children: Specific patterns included confluent lesions in the pons or caudate nucleus (11/15; 73%), peri-aqueductal regions (13/15; 87%), and spinal cord (6/10; 60%). 12 children had a favorable outcome (mRS score of

Purpose: Spinal muscular atrophy (SMA) is a rare, autosomal-recessive disease characterized by progressive muscular atrophy and weakness resulting in substantial disability and short life expectancy. The objective of this cross-sectional study was to assess health-related quality of life (HRQoL) of adults with SMA in Germany in the era of disease-modifying therapy., Methods: Adults with SMA were recruited via the German national TREAT-NMD SMA patient registry. HRQoL was measured using the EQ-5D-5L, the Health Utilities Index Mark III (HUI), and the Short Form (36) Health Survey (SF-36). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III)., Results: A total of 82 adults with SMA (mean age: 42 years, 51% female) self-completed the study questionnaire. The mean EQ-5D-5L utility was estimated at 0.5135 (range across subgroups: 0.31-0.99), mean EQ-VAS at 69.71 (64.67-90.00), mean HUI-derived utility at 0.3171 ( - 0.02-0.96), mean SF-6D utility at 0.6308 (0.58-0.65), and mean SF-36 Physical Component Summary and Mental Health Component Summary scores at 33.78 (9.92-53.10) and 53.49 (21.02-72.25), respectively., Conclusions: We show that adults with SMA experience considerable impairment across a wide range of health dimensions, including mobility, dexterity, pain, and emotional well-being. However, our results exhibit non-trivial variability across clinical subgroups and HRQoL measures. These data contribute to our understanding of the subjective impact of living with a severely debilitating neuromuscular disease, such as SMA., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Importance: There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking., Objective: To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset., Design, Setting, and Participants: This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months., Exposure: Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system., Main Outcomes: The primary end point was the achievement of motor milestones., Results: A total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%)., Conclusions and Relevance: This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group., Trial Registration: German Clinical Trials Register: DRKS00012699.

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals., (© 2024. The Author(s).)

Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites., Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded., Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified., Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA., Funding: Financial support for the registry from Biogen, Novartis and Roche., Competing Interests: SB, ZU, MH, TK, KM, BI, JB, MTM, TB, BS, SF, CS, MTo, AG, MTue, MS, CR, PB, MFB, CK, KPS, SG, ST, JN, RS, MWeb, GW and OvV declare no conflicts of interest. RG has received personal fees from Biogen and Hoffmann-La Roche and served on advisory boards from Biogen, Hoffmann-La Roche, ITF Pharma, Zambon and research support from Biogen, outside of the submitted work. CDW has received personal fees from Biogen and Hoffmann–La Roche outside of the submitted work. AO has received speaker fees from Biogen outside of the submitted work. OSK received academic research support from the Hannover Medical School (MHH) and the German Neuromuscular Society “Deutsche Gesellschaft fuer Muskelkranke” (DGM e.V.), 2019–2021 (grant no. Sc 23/1); and received honoraria as a speaker and/or funding for travel expenses from the German Neuromuscular Society “Deutsche Gesellschaft fuer Muskelkranke (DGM e.V.), Biogen GmbH, Biermann Verlag GmbH, and MK + S—Medizin, Kommunikation & Service GmbH, outside the submitted work. SP has received speaker fees, non-financial support and research support from Biogen, Roche, AL-S Pharma, Amylyx, Cytokinetics, Ferrer, ITF-Pharma, Zambon, and Sanofi and served on advisory boards of Amylyx, Biogen, Roche, Zambon and ITF Pharma outside of the submitted work. MCW has served on advisory boards for Avexis, Biogen, Grünenthal, Novartis, Pfizer, PharNext, PTC Therapeutics, Roche, Santhera, Sarepta, Ultragenyx, Wave Sciences, received funding for Travel or Speaker Honoraria from Biogen, Novartis, PTC Therapeutics, Santhera, and worked as an ad-hoc consultant for Affinia, Audentes Therapeutics, Avexis, Biogen, BridgeBio, Edgewise, Fulcrum, Grünenthal, ML Bio, Novartis, Pfizer, PharNEXT, PTC Therapeutics, Roche. MWei has received advisory board and consultant honoraria from Biogen and Hoffmann-La Roche, and speaker honoraria and travel support for conference attendance from Biogen, outside of the submitted work. MW is a member of the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD). MF has received a speaker honorarium and non-financial support from Biogen outside the submitted work. HSL is receiving advisory fees from Biogen but has no financial or non-financial conflict of interest to declare related to the content of this manuscript. IC has received research grants and speaker fees from Biogen and Hoffmann-La Roche, outside of the submitted work. PL has received honoraria for advisory boards and consultancies from Stadapharm, Abbvie, Alexion, Bial, ITF Pharma, Desitin, Novartis, Woolsey Pharma outside the scope of this work. MD has received personal fees as speaker/consultant from Biogen and Roche, outside of the submitted work. Aha received research grants from Novartis Gene Therapies, and advisory board honoraria and speaker fees from Biogen, Roche, and Novartis. AR has received advisory board honoraria from Biogen outside of the submitted work. DZ received compensation from Biogen for participation on advisory boards, from Novartis for consultancy work, and travel compensation from Angelini Pharma outside of the submitted work. JCK has received personal fees from Biogen and Roche for advisory boards and development of educational material outside of this study. AHe has received personal fees and non-financial support from Biogen and Desitin for advisory board meetings outside the reported work. CK has received advisory board honoraria from Biogen, Roche and Ipsen Pharma, speaker honoraria from Biogen and unrestricted travel grants from Ipsen outside of the submitted work. SN has received financial support for consultancy and lecturing from Allergan, Hormosan, Lilly, Lundbeck, Novartis, Teva and Medscape, research support from Novartis, all outside of the submitted work. AM has received advisory board honoraria from Hormosan and Sanofi, outside of the submitted work. CN has received personal fees from Biogen and Hoffmann–La Roche outside of the submitted work. HCL received honoraria for speaking and advisory board engagements or academic research support Biogen. MG has received an advisory board honorarium from Hoffmann-La Roche and a speaker fee from Novartis outside of the submitted work. AP received compensation for advisory boards, training activities and research grants from Novartis and Biogen. JK received compensation for clinical research and/or consultancy activities from Biogen, Novartis, Roche and ScholarRock. GB has received research grants from PTC, advisory board honoraria and speaker fees from Biogen, Hoffmann-La Roche, Novartis, Pfizer, PTC and personal fees from Roche outside of the submitted work. PM has received honorary as an advisory board member from Biogen unrelated to this work. GMzH received compensation for serving on scientific advisory boards (Alexion, Roche, LFB) and speaker honoraria (Alexion). WL received advisory board honoraria and speaker fees from Biogen and Roche outside of the submitted work MFB has received honoraria from Biogen, Roche and Novartis as an advisory board member and for lectures from Novartis. US has received honoraria for counseling at advisory boards and invited talks for Biogen, Novartis and Roche. WMF has received compensation for scientific advisory boards for Biogen, Novartis, PTC, Sarepta, Sanofi-Aventis, Roche and Cytokinetics and received travel expenses and speaker fees from Biogen, Novartis, PTC, Roche, Sarepta and Sanofi-Aventis. HLo received support for research projects and clinical trials from Amplo Biotechnology, AMO Pharma, argenx, Biogen, Desitin, Fulcrum Therapeutics, Harmony Biosciences, KYE Pharmaceuticals, Milo Biotechnology, Novartis, Pfizer, PTC Therapeutics, Hoffman-La Roche Limited, Sanofi-Genzyme, Santhera, Sarepta, Satellos, Spark Therapeutics and Ultragenyx. HL is the Editor-in-chief for the Journal of Neuromuscular Diseases (IOS Press). CK has received compensation for lectures and advisory boards as well as research funds from Biogen, Roche and Novartis. ACL is a member of Advisory Boards of Roche Pharma AG, Biogen, Alector and Amylyx. He received compensation for talks from Biologix, the German Society of Neurology, Biogen, Springer Medicine, Amylyx and the company Streamed Up! GmbH. He is involved in trials which are sponsored by Amylyx, Ferrer International, Novartis Research and Development, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, the European Union, BMBF, Biogen and Orphazyme, Ionis Pharmaceuticals, QurAlis and Alector. TH has received research grants, advisory board honoraria and speaker fees from Biogen, Hoffmann-La Roche, Novartis and personal fees from Roche and Novartis outside of the submitted work., (© 2024 The Author(s).)

Background: Spinal muscular atrophy (SMA) is a rare, severely debilitating neuromuscular disease characterized by a wide spectrum of progressive muscular atrophy and weakness., Objectives: The objective of this pilot study was to estimate self-assessed health-related quality of life (HRQoL) of children with SMA., Methods: Children with SMA were recruited via the German national TREAT-NMD SMA patient registry and asked to self-complete the following rating-scales: KIDSCREEN-27, KINDL, the PedsQL 3.0 Neuromuscular Module (PedsQL 3.0 NMM), EQ-5D-5L, and the Health Utilities Index (HUI). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III)., Results: In total, 17 children with SMA (mean age: 9.88 years, SD: 4.33 years, range: 5-16 years; 59% female) participated in the study. Across examined strata, the mean KIDSCREEN-27 total score was estimated at between 48.24 and 83.81; the mean KINDL total score at between 60.42 and 76.73; the mean PedsQL 3.0 NMM total score at between 58.00 and 83.83; the mean EQ-5D-5L utility at between 0.31 and 0.99; and the mean HUI-derived utility at between -0.02 and 0.96., Conclusions: The results from this pilot study show that German children with SMA, despite significant physical disability, have surprisingly good HRQoL as assessed using KIDSCREEN-27. Yet, many reside in health states associated with low utility. The disease burden was generally higher among non-sitters compared with walkers, and SMA type I compared with type III, but more research is needed to further delineate this variability. Our preliminary findings contribute to the understanding of HRQoL in pediatric patients with SMA and should be helpful to inform the design of future studies of this patient population.

Background/objective: Neurofilament light chain (NfL) has been proposed as a biomarker reflecting disease severity and therapy response in children with spinal muscular atrophy type 1 and 2 (SMA1 and 2). The objective of this study was to examine how serum NfL changes after gene replacement therapy (GRT) with onasemnogene abeparvovec-xioi., Methods: We measured NfL in serum probes from 19 patients (10 SMA 1 and 6 SMA 2; 15 previously treated with nusinersen or risdiplam; 12 male) before and at variable time points after GRT. These values were related to motor scores (CHOP-Intend, HFMSE and RULM)., Results: Median age at GRT was 19 months (range 2-46 months). Median NfL of all patients before GRT was 39 pg/ml (range 0-663 pg/ml; normal values <25 pg/ml), increased significantly to 297 pg/ml (range 61-1,696 pg/ml; p<0,002) 1 month after GRT, and decreased to 49 pg/ml (range 24-151 pg/ml) after 6 months. Subjects pre-treated with nusinersen or risdiplam had lower baseline NfL levels than naïve patients (p<0,005), but absolute increases of NfL were similar in both groups. While motor scores were improved in 14 out of 18 SMA patients (78%) 6 months after GRT NfL values differed not significantly from those measured at baseline (p = 0,959)., Conclusion: Serum NfL showed a paradoxical transient increase after GRT in both, pre-treated and naïve patients, which may reflect an immunological reaction in the CNS related to transfection of neuronal cells by AAV9. The clinical meaning of this increase should be assessed in future studies. Our findings encourage regular monitoring of NfL in OA treated patients., Competing Interests: MF-B has received honoraria from Biogen, Roche and Novartis as an advisory board member and for lectures from Novartis. AH has received honoraria from Biogen, Roche and Novartis as an advisory board member and for lectures. CDW has received honoraria from Biogen as an advisory board member and for lectures and as an advisory member and consultant from Roche. She also received travel expenses from Biogen. CW has received honoraria from Biogen, Roche and Novartis as an advisory board member and for lectures. ZU has received honoraria and grants from Biogen as a consultant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Flotats-Bastardas, Bitzan, Grell, Martakis, Winter, Zemlin, Wurster, Uzelac, Weiß and Hahn.)

Background: Peripheral facial palsy (PFP) is a common neurologic symptom which can be triggered by pathogens, autoimmunity, trauma, tumors, cholesteatoma or further local conditions disturbing the peripheral section of the nerve. In general, its cause is often difficult to identify, remaining unknown in over two thirds of cases. As we have previously shown that the quantity and quality of pathogen-specific T cells change during active infections, we hypothesized that such changes may also help to identify the causative pathogen in PFPs of unknown origin., Methods: In this observational study, pathogen-specific T cells were quantified in blood samples of 55 patients with PFP and 23 healthy controls after stimulation with antigens from varicella-zoster virus (VZV), herpes-simplex viruses (HSV) or borrelia. T cells were further characterized by expression of the inhibitory surface molecule CTLA-4, as well as markers for differentiation (CD27) and proliferation (Ki67). Pathogen-specific antibody responses were analyzed using ELISA. Results were compared with conventional diagnostics., Results: Patients with PFP were more often HSV-seropositive than controls (p = 0.0003), whereas VZV- and borrelia-specific antibodies did not differ between groups. Although the quantity and general phenotypical characteristics of antigen-specific T cells did not differ either, expression of CTLA-4 and Ki67 was highly increased in VZV-specific T cells of 9 PFP patients, of which 5 showed typical signs of cutaneous zoster. In the remaining 4 patients, a causal relationship with VZV was possible but remained unclear by clinical standard diagnostics. A similar CTLA-4- and Ki67-expression profile of borrelia-specific T cells was also found in a patient with acute neuroborreliosis., Discussion: In conclusion, the high prevalence of HSV-seropositivity among PFP-patients may indicate an underestimation of HSV-involvement in PFP, even though HSV-specific T cell characteristics seem insufficient to identify HSV as a causative agent. In contrast, striking alterations in VZV- and borrelia-specific T cell phenotype and function may allow identification of VZV- and borrelia-triggered PFPs. If confirmed in larger studies, antigen-specific immune-phenotyping may have the potential to improve specificity of the clinical diagnosis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Pseudotumor cerebri (PTC) is defined as a rare disease with a pathological increase in intracranial pressure of unknown origin. The aim of this retrospective study was to establish a uniform diagnostic and therapeutic protocol for children and adolescents for the Saarland University Medical Center. Data from 28 patients with pseudotumor cerebri aged 0-17 years in the period 2008-2018 were retrospectively collected and statistically analyzed. The purpose of this study was to generate a better understanding of the clinical entity of pseudotumor cerebri in children and adolescents. Distinctive features, such as pubertal or adolescent age, female gender and obesity could be highlighted. The data collected in this study were used to develop an in-house standard for the diagnosis and treatment of children and adolescents with pseudotumor cerebri., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, ein Teil von Springer Nature.)

Background: Management and treatment of spinal muscular atrophy (SMA) has changed in recent years due to the introduction of novel transformative and potentially curative therapies resulting in the emergence of new disease phenotypes. Yet, little is known about the uptake and impact of these therapies in real-world clinical practice. The objective of this study was to describe current motor function, need of assistive devices, and therapeutic and supportive interventions provided by the healthcare system, as well as the socioeconomic situation of children and adults with different SMA phenotypes in Germany. We conducted a cross-sectional, observational study of German patients with genetically confirmed SMA identified and recruited via a nationwide SMA patient registry ( www.sma-register.de ) within the TREAT-NMD network. Study data was recorded directly from patient-caregiver pairs through a study questionnaire administered online via a dedicated study website., Results: The final study cohort consisted of 107 patients with SMA. Of these, 24 were children and 83 adults. In total, about 78% of all participants were taking medication for SMA (predominantly nusinersen and risdiplam). All children with SMA1 were able to sit and 27% of children with SMA2 were able to stand or walk. Impaired upper limb function, scoliosis and bulbar dysfunction were observed more frequently in patients with reduced lower limb performance. Physiotherapy, occupational therapy, and speech therapy, as well as the use of cough assists were less common than indicated by care guidelines. Family planning and educational and employment status appear to be related to motor skill impairment., Conclusions: We show that the natural history of disease has changed in Germany following improvements in SMA care and the introduction of novel therapies. Yet, a non-trivial proportion of patients remain untreated. We also identified considerable limitations in rehabilitation and respiratory care, as well as low labour-market participation among adults with SMA, calling for action to improve the current situation., (© 2023. The Author(s).)

5q-associated spinal muscular atrophy is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of spinal muscular atrophy patients, however, long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we report here real-world evidence on a broad spectrum of patients with early-onset spinal muscular atrophy treated with nusinersen focusing on effects regarding motor milestones, and respiratory and bulbar insufficiency during the first years of treatment. Within the SMArtCARE registry, all patients under treatment with nusinersen who never had the ability to sit independently before the start of treatment were identified for data analysis. The primary outcome of this analysis was the change in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and motor milestones considering World Health Organization criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset spinal muscular atrophy were included in the data analysis with a follow-up period of up to 38 months. We observed major improvements in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Improvements were greater in children >2 years of age at start of treatment than in older children. 24.5% of children gained the ability to sit independently. Major improvements were observed during the first 14 months of treatment. The need for intermittent ventilator support and tube feeding increased despite treatment with nusinersen. Our findings confirm the increasing real-world evidence that treatment with nusinersen has a dramatic influence on disease progression and survival in patients with early-onset spinal muscular atrophy. Major improvements in motor function are seen in children younger than 2 years at the start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months., Methods: SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function., Results: Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients., Conclusion: Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.

Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018-2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing.

Introduction: Neuroimmunological diseases such as autoimmune encephalitis (AE) or acquired demyelinating syndromes (ADS), can present with neurological symptoms and imaging features that are indistinguishable from mitochondrial diseases (MD) in particular at initial presentation., Methods: Retrospective analysis of the clinical, laboratory and neuroimaging features of five patients who presented with signs of a neuroimmunological disease but all had pathological pathogenic variants in genes related to mitochondrial energy metabolism., Results: Four patients presented with an acute neurological episode reminiscent of a possible AE and one patient with a suspected ADS at initial presentation. MRI findings were compatible with neuroimmunological diseases in all patients. In two children cerebrospinal fluid (CSF) studies revealed a mildly elevated cell count, two had elevated CSF lactate, none had oligoclonal bands (OCBs). All patients improved rapidly with intravenous steroids or immunoglobulins. Four patients had one or more relapses. Three patients showed worsening of their neurological symptoms with subsequent episodes and one patient died. Relapses in conjunction with new and progressive neurological symptoms, led to additional work-up which finally resulted in different genetic diagnosis of MD in all patients (MT-TL1, MT-ND5, APOA1-BP, HPDL, POLG)., Discussion: We would like to draw attention to a subset of patients with MD initially presenting with signs and symptoms mimicking neuroimmunological. Absence of CSF pleocytosis, elevated CSF lactate and progressive, relapsing course should trigger further (genetic) investigations in search of a MD even in patients with good response initially to immunomodulating therapies., Competing Interests: Declaration of competing interest A. Blaschek, Wegener-Panzer, A. Della-Marina, M. Flotats-Bastardas, T. Reinhardt, I. El Naggar, F Distelmaier, U. Schara-Schmidt, S. Wortmann, Theresa Brunet, Matia Wagner, Dimitri Smirnov, Holger Prokisch have no disclosures. K. Rostásy received speaker's honoraria from Merck and served on the advisory board of the PARADIGM study., (© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Background: The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months., Methods: SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM)., Results: Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score., Conclusion: Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity., (© 2022. The Author(s).)

Background: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups., Methods: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity., Findings: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings., Interpretation: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored., Funding: None., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests No author received financial support for the present manuscript. CW declares consulting fees from Novartis and Biogen (paid personally) and Roche (paid to institution); honoraria from Novartis and Biogen; and travel support from Biogen. AZ declares grants and travel support from Biogen; consulting fees and honoraria from Novartis, Roche, and Biogen; and advisory board participation for Novartis and Roche. JJ declares honoraria for review writing from Biogen; and travel support and personal fees for advisory board participation from Biogen, Roche, Novartis/Avexis, Sarepta Therapeutics, and PTC. GS declares payment for consulting from Novartis. MF-B declares consulting fees from Novartis Gene Therapy, Biogen, and Roche. CS declares training support from Biogen. HH declares support from the SMArtCARE registry (paid to institution) and payment for participation on advisory board from Novartis; and is a board member of the International Child Neurology Association. SI declares support from SMArtCARE (paid to institution) and payments for advisory board participation from Novartis. AP declares financial support from Biogen for the SMArtCARE registry; compensation for training activities from Biogen; and advisory board participation for Novartis Gene Therapy. WM-F declares consulting fees and honoraria from Novartis and Roche; honoraria from Biogen; and advisory board participation for Novartis and Roche. KV declares speaker's honoraria from Biogen and travel fees from Biogen and Santhera. AB declares speaker's honoraria from Biogen and Genzyme; travel support from Merck group; and advisory board participation for Novartis. MS declares payments for lectures from Novartis, Biogen, and Genzyme. BW declares honoraria for lectures, interviews, and workshops from Novartis, Biogen, and Pfizer; travel support for meetings from Novartis and Biogen; and advisory board participation for Novartis and Biogen. BP declares support for advisory board participation from Novartis, Biogen, Roche, Zogenix, and PCT; payment for manuscript writing from Novartis; and payment for workshop from Biogen. GB declares consulting fee from PTC; honoraria for lectures and information events; payment for participation on advisory boards from PTC, Roche, Novartis, Pfizer, and Biogen; and being an unpaid consultant for Wiener Gesundheitsverbund (WiGeV), Austrian Social Insurance, and Austrian Department of Pharmaceutical Affairs. RAF declares consulting fees, payment for lecture, and travel support from Biogen; and payment for advisory board participation from AveXis/Novartis. CR declares consulting fees from Biogen, EISAI, Novartis, PTC, Roche, and UCB; and payment for participation on advisory boards from Biogen, Novartis, and Roche. MvdH declares payment for lecture from Avexis/Novartis, Biogen, and PTC; payment for manuscript writing from Biogen; and advisory board participation for Avexis/Novartis, Biogen, Roche, and Sarepta. AMK declares grants from the German Research Foundation; consulting fees from Covance; payment for lecture from Ethypharm; and advisory board participation from Novartis, GW Pharma, and Ethypharm. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Syncope in childhood and adolescence is frequent and in most cases benign. A thorough history taking, complete physical examination, electrocardiography and further diagnostic work-up as indicated should rule out possible cardiac syncope., Objective: To evaluate whether the diagnosis of syncope was performed according to the currently valid S2k guideline., Material and Methods: Retrospective study (January 2015-December 2017), University Children's Hospital of Saarland, Homburg, Germany. All patients aged 1-18 years presenting with the primary complaint of syncope were included., Results: In this study 262 patients presented with a history of syncope (161 female (61.5%), 101 male (38.5%), median age 12.5 ± 3.9 years). Of these, 183 (69.8%) were reflex syncopes, 36 (13.7%) presyncopes, 35 (13.4%) undefined and 8 (3.1%) cardiac syncope. Out of 262 patients, 43 (16.4%) were diagnosed in accordance with the published guidelines and 13/43 (30.2%) correctly received further diagnostic work-up. In 219/262 patients (83.6%) basic diagnostic testing was not sufficient and 135/219 (61.6%) were submitted to further unnecessary diagnostic tests., Conclusion: Better adherence to the syncope guidelines bears the potential to avoid unnecessary and costly auxiliary medical tests while correctly diagnosing patients with syncope.

Nusinersen, an antisense oligonucleotide enhancing the production of the survival motor neuron protein, is approved for the treatment of spinal muscular atrophy (SMA) but requires repetitive lumbar punctures. Application via a subcutaneous port connected to a permanent intrathecal catheter has been proposed as an alternative for patients with severe scoliosis, spinal fusion, or comorbidities, rendering serial interlaminar punctures complicated and risky. Since experience with this technique is sparse and follow-up data are lacking, we assessed feasibility, safety, and tolerability of this approach in eight patients with SMA II/SMA III receiving Nusinersen in a multicenter study. Median age at port implantation was 21 years (range: 10-30 years), and median follow-up time thereafter was 19 months (range: 7-24 months). Leakage of the port catheter occurred in two patients, promptly resolving after resuturing. No further complications such as infection, dislocation, kinking, or obstruction of the port were noted in any of the patients. These findings suggest that application via an intrathecal port and catheter system represents a safe and feasible option for Nusinersen treatment in subjects with SMA. However, to detect rare adverse events longer term follow-up in a larger study cohort is warranted., Competing Interests: None declared., (Thieme. All rights reserved.)

Neuromuscular disorders (NMDs) of Childhood onset are a genetically heterogeneous group of diseases affecting the anterior horn cell, the peripheral nerve, the neuromuscular junction, or the muscle. For many decades, treatment of NMDs has been exclusively symptomatic. But this has changed fundamentally in recent years due to the development of new drugs attempting either to ameliorate secondary pathophysiologic consequences or to modify the underlying genetic defect itself. While the effects on the course of disease are still modest in some NMDs (e.g., Duchenne muscular dystrophy), new therapies have substantially prolonged life expectancy and improved motor function in others (e.g., spinal muscular atrophy and infantile onset Pompe disease). This review summarizes recently approved medicaments and provides an outlook for new therapies that are on the horizon in this field., (Copyright © 2020 Flotats-Bastardas and Hahn.)

Aims: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by a mutation in the TSC1 or TSC2 gene with a broad spectrum of physical and psychological manifestations. The aim of the study was to examine incontinence, psychological problems, and adaptive behavior skills in patients with TSC., Methods: Through a worldwide TSC support group, 26 children (4-17 years) and 15 adults (18-50 years) with TSC were recruited (38.1% male, mean age 16.4 years). Parents or care-givers completed the Developmental Behavior Checklist (DBC), the Parental Questionnaire: Enuresis/urinary Incontinence, and the Vineland Adaptive Behavior Scales (3rd edition)., Results: A total of 60.0% of the participants had nocturnal enuresis (NE), 51.3% daytime urinary incontinence (DUI) and 52.4% fecal incontinence (FI). 65.4% of children and 50.0% of adults had a clinically relevant DBC score. Psychological symptoms were associated with at least one subtype of incontinence. The mean adaptive behavior composite (ABC) score of the patients was 57.2 (SD = 26.1), with 38.1% in the average or below-average range (IQ >70), 26.2% with a mild, 11.9% with a moderate and 23.8% with a severe/profound intellectual disability. The incontinence rate was significantly higher in the groups with a lower ABC score., Conclusion: A substantial proportion of patients with TSC are affected by incontinence and psychological symptoms. Incontinence was higher in persons with lower adaptive skills and those with at least one type of incontinence showed a significantly higher DBC score. As incontinence and psychological problems affect daily functioning and well-being, assessment, and treatment are recommended., (© 2020 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

Aim: To provide data on the inadequate use of emergency medical transports services (EMTS) in children and underlying contributing factors. Methods: This was a prospective single-center cohort study (01/2017-12/2017) performed at the Saarland University Children's Hospital, Homburg, Germany. Patients ≤20 years of age transported by EMTS for suspected acute illness/trauma were included and proportion of inadequate/adequate EMTS use, underlying contributing factors, and additional costs were analyzed. Results: Three hundred seventy-nine patients (mean age: 9.0 ± 6.3 years; 55.7% male, 44.3% female) were included in this study. The three most common reasons for EMTS use were: central nervous system (30.6%), respiratory system affection (14.0%), and traumas (13.2%). ETMS use was categorized as inadequate depending on physician's experience: senior physician (58.8%), pediatrician (54.9%), resident (52.7%). All three physicians considered 127 (33.5%) cases to be medically indicated for transportation by EMTS, and 177 (46.7%) to be medically not indicated. The following parameters were significantly associated with inadequate EMTS use: non-acute onset of symptoms (OR 2.5), parental perception as non-life-threatening (OR 1.7), and subsequent out-patient treatment (OR 4.0). Conversely, transport by an emergency physician (OR 3.5) and first time parental EMTS call (OR 1.7) were associated with adequate use of EMTS. Moreover, a significant relation existed between maternal, respectively, paternal educational status and inadequate EMTS use (each p = 0.01). Using multiple logistic regression analysis, non-acute onset of symptoms (OR 2.2) was associated with inadequate use of EMTS while first time parental EMTS call (OR 1.8), transport by an emergency physician (OR 3.3), and need for in-patient treatment (OR 4.0) were associated with adequate use of EMTS. Conclusion: A substantial number of pediatric EMTS is medically not indicated. Possibly, specific measures including multifaceted educational efforts may be helpful in reducing unnecessary EMTS use., (Copyright © 2019 Poryo, Burger, Wagenpfeil, Ziegler, Sauer, Flotats-Bastardas, Grundmann, Zemlin and Meyer.)

Aim: To assess the role of the TAND (tuberous sclerosis complex [TSC] associated neuropsychiatric disorders) checklist as a screening tool for neuropsychiatric pathology, to evaluate behavioral and psychiatric symptoms and related parental stress in children with TSC, and to analyze associations between parental stress, TAND findings, and TSC pathology., Method: This is a prospective cohort study including 22 individuals from a national TSC surveillance study in Germany using demographic and clinical data, the TAND checklist, the Child Behavior Checklist (CBCL), and the Parenting Stress Index (PSI)., Results: Mean (standard deviation) age at follow-up was 4 years (3 years 9 months), and 13/22 of patients were male. Seventeen children had epilepsy (focal: 9; generalized: 4; infantile spasms: 4). Developmental delay was diagnosed in 12/22 patients. The most prevalent TAND items were anxiety and mood swings in 10/22 children. At least one TAND item was reported by 17/22 patients, internalizing symptoms by 10/22, and externalizing symptoms by 11/22. In contrast, only one patient had a clinically relevant score in the CBCL scales. Of 22 parents, 12 reported clinically relevant parental stress due to both child and parenting factors. Higher total parental stress was associated with a higher TAND externalizing score ( r  = 0.49; p  = 0.028) and TAND total score ( r  = 0.51; p  = 0.016), a higher CBCL total score ( r  = 0.59; p  = 0.005), and the number of antiepileptic drugs ( r  = 0.50; p  = 0.017). Developmental delay was correlated with child stress factors ( r  = 0.48; p  = 0.023)., Interpretation: The TAND checklist appears to be a promising screening tool for neuropsychiatric problems in very young children with TSC. Parental stress in children with TSC is modified by TSC-related pathology, both neuropsychiatric and neurological., Competing Interests: The authors state that they have no interests that might be perceived as posing a conflict or bias., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Duchenne muscular dystrophy (DMD) is a severe X‑linked recessive neuromuscular disorder. In children without corticosteroid therapy, progressive muscular weakness is associated with loss of ambulation on average by the age of 9.5 years., Objective, Material and Methods: On the basis of current guidelines, a group of experts in this field defined a number of clinical parameters and examinations that should be performed on a regular basis to assess changes over time in non-ambulant patients., Results and Conclusion: To assess function of the upper extremities the Brooke upper extremity functional rating scale or the performance of upper limb test should be used. For assessment of pulmonary function measurement of forced vital capacity (FVC) is recommended. The extent of cardiac involvement can best be evaluated using cardiac magnetic resonance imaging (MRI), measurement of the ejection fraction (EF) and the left ventricular shortening fraction (LVSF) by echocardiography. The pediatric quality of life inventory should be used for assessment of quality of life. In addition, the body mass index (BMI), the number of infections and need for in-hospital treatment as well as early detection of orthopedic problems, most importantly the development of scoliosis should be monitored. After transition from pediatric to adult care DMD patients should be primarily cared for by adult neurologists and specialists in pulmonary and cardiac medicine.

About 15% of Duchenne muscular dystrophy (DMD) cases are caused by point mutations leading to premature stop codons and disrupted synthesis of the dystrophin protein. Stop codon read-through therapy is available with the drug Ataluren (Translarna® by PTC Therapeutics). Following positive results in ambulatory nmDMD (non-sense mutation Duchenne muscular dystrophy) patients, Ataluren received conditional approval in ambulant nmDMD patients by the EMA in 2014. However, there are limited data on non-ambulatory nmDMD patients treated with Ataluren. Here, we report our experience in four non-ambulatory nmDMD patients. Routine investigations included cardiac function, pulmonary function tests and muscle strength. We compared changes in left ventricular fractional shorting, forced volume vital capacity and BMI from two defined time periods (18-26-month period prior to and after Ataluren start). Mean age at loss of ambulation was 10.1 ± 0.5 years, mean age when initiating Ataluren treatment 14.1 ± 1.4 years. Serial echocardiography, pulmonary lung function tests, and assessment of muscle strength indicated mild attenuation of disease progression after initiation of Ataluren treatment. A possible side effect of Ataluren was a reduction in BMI. There were no adverse clinical effects or relevant abnormalities in routine laboratory values. We conclude that Ataluren appears to mildly ameliorate the clinical course in our patients with a good safety profile. However, larger clinical trials are required to assess the role of Ataluren and its long-term impact on disease progression in non-ambulant nmDMD patients.

Competing Interests: None.

Background: Tuberous Sclerosis Complex (TSC) is a rare multisystem disorder. In 2012 diagnostic criteria for TSC were revised. However, data on the incidence of TSC are limited., Methods: Prospective, national surveillance study in Germany over a 2-year-period (03/2015-02/2017) using current revised criteria for TSC. Patients up to the age of 18 years with a new diagnosis of definite or possible TSC (clinical and/or genetic) were included. The aims of this study were 1) to generate up-to-date data on the incidence of definite or possible TSC, 2) to assess age at first diagnosis, and 3) to compare these data with previous epidemiologic data., Results: In total, 86 patients met inclusion criteria (definite or possible TSC) with a median age at diagnosis of 6 months (range: 5 months before birth - 197 months of age). Among patients identified with features of TSC, 73.3% met criteria for definite diagnosis (median age: 7 months) and 26.7% met criteria for a possible diagnosis (median age: 3 months). 55.8% of patients were male. When excluding prenatally diagnosed patients, median age at diagnosis was 11 months with a range of 0 to 197 months. The 3 most common clinical features at diagnosis of TSC were central nervous system involvement in 73.3% patients (of these 95.2% experienced seizures), cutaneous involvement in 58.1% patients (with the most common lesion being hypomelanotic macules in 92%) and cardiac rhabdomyoma in half of the patients. Cardiac rhabdomyoma were detected by prenatal ultrasonography in 22.1% of patients. The presence of cardiac rhabdomyoma was associated with cardiac arrhythmias in 25.6% (about 13% of all diagnosed patients) in our cohort. The overall prevalence of seizure disorders was 69.8%. The annual incidence rate of TSC is estimated at a minimum of 1:17.785 live births. However correcting for underreporting, the estimated incidence rate of definite or possible TSC is approximately 1:6.760-1:13.520 live births in Germany., Conclusions: This is the first study that assessed prospectively the incidence rate of TSC in children and adolescents using the updated diagnostic criteria of 2012. This prospective surveillance study demonstrates a low age at first diagnosis (median: 6 months), likely due to antenatal detection of cardiac rhabdomyoma. Early diagnosis bears the potential for implementing effective therapies at an earlier stage.

Tuberous sclerosis complex (TSC) is a genetic disease with a significant morbidity and mortality. We conducted a retrospective analysis of two cohorts (Vall d'Hebron University Hospital [HVH], Barcelona, Spain, 1982-2015, and at Saarland University Medical Center [UKS], Homburg, Germany, 1998-2015) to assess prevalence and treatment of TSC associated manifestations and to evaluate if the follow-up was in line with published recommendations. This was considered if more than 15% of patients did not receive adequate examination with regard to potential organ involvement. A definite diagnosis was made in 52 patients (96%), and a possible diagnosis was made in 2 patients (4%). Thirty-four (63%) patients were from HVH and 20 (37%) from UKS. Median age at first presentation was 6 months (interquartile range: 0-38 months), and median time of follow-up was 6 years (interquartile range: 2-13 years). Clinical symptoms that led to a diagnosis of TSC were cardiac rhabdomyoma (22/54), epilepsy (20/54), and cutaneous manifestations (4/54). Assessment of neuropsychiatric, renal, and ocular manifestations was inadequate in both hospitals, whereas cutaneous manifestation was inadequate at UKS only. Our data demonstrate insufficient examinations in a substantial number of TSC patients with regard to neuropsychiatric, renal, ocular, and cutaneous manifestations. The recently published guidelines may prove valuable in establishing a more comprehensive approach., Competing Interests: Prof. Dr. Macaya-Ruiz reports other from Advisory board, outside the submitted work. All the other authors have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Providing comprehensive medical care for patients with rare diseases is both challenging and rewarding. We will give a short summary of the most relevant medical issues pertinent to this subject, and will illustrate some of these issues by sharing our experience in the care of patients with TSC disease., Competing Interests: Conflict of Interest: The authors have no conflict of interest to disclose., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Tuberous sclerosis complex (TSC) disease is a rare genetic, multi-organ disorder characterized by the occurrence of multiple hamartoma., Methods: In cooperation with ESPED, Germany, a prospective, epidemiological study was performed to assess the incidence of newly diagnosed TSC disease in patients ≤18 years in Germany. Moreover, the following parameters were assessed: 1. Age distribution at initial diagnosis; 2. Percentage of patients with in utero diagnosis of TSC; 3. Detailed description of pathological clinical findings; 4. Results from genetic testing., Results: In this one-year interim analysis, 84 electronic questionnaires were received, 17 of which did not contain complete sets of data and were not included in data analysis. Twenty-three of 67 questionnaires did not report TSC patients and 3 reports contained redundant data sets and were excluded. In total, 41 reports were included into data analysis (female: 23; male: 18); median age at first diagnosis was 6 months (range: 0-151 months). The three most common symptoms were: central nervous affection: 31/41 patients ((75.6 %); 29/31 with seizures); rhabdomyoma: in 20/41 (48.8 %); cutaneous affection: hypomelanotic maculae ("white spots"): 20/41 (48.8 %). The three following organ manifestations were seen most often in a comprehensive diagnostic work-up: rhabdomyoma: 23/41 ((56.1 %); cortical dysplasia: 22/41 (53.7 %); "white spots"): 20/41 (48.8 %). In 11/41 patients, cardiac rhabdomyoma were detected by ultrasonography prenatally. In 6 patients, a TSC-2 mutation was found while in 4 patients a TSC-1 mutation was noted; in 1 patient, genetic testing was negative., Conclusions: Based on our preliminary findings, the annual incidence rate for TSC disease is estimated at approximately 1:12,300 live births, but this is a very rough approximation.

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement including facial angiofibromas that often appear in early childhood. Here we report the case of a 12-year-old girl with widespread disfiguring facial angiofibromas that were successfully treated with topical rapamycin, a mTOR inhibitor. A sustained remission of skin lesions was documented in detail over a 3-year follow-up. This case highlights the fact that topical rapamycin is a useful option in treating TSC-associated skin lesions. Especially in medically complex patients topical treatment may lessen the need for surgical interventions, reducing the risks of surgery, its adverse effects and permanent scarring. However, there is no standard dose or formulation at present. Topical rapamycin appears safe, but long-term maintenance therapy is necessary to prevent facial lesions from regrowth.

Introduction: The study of polymicrogyria with magnetic resonance imaging (MRI) has made possible the report of several series of patients in which the main clinical manifestations differ considerably. The aims of the study were to review the literature and to know the clinical variability of the patients attended in a neuropediatric service., Patients and Methods: A retrospective study was conducted between 1989-2011 for the patients attended in our neuro-pediatric service and diagnosed of polymicrogyria by MRI., Results: On the totality of 44 patients having polymicrogyria, 9 did not satisfy de inclusion criteria (Barkovich's radiological criteria). The polymicrogyria was bilateral in 22/35 patients (1 frontal, 22 perisylvian) and unilateral in 13/35 (2 frontal, the rest perisylvian). All patients with bilateral polymicrogyria had intellectual disability, 71% had global development delay, 75% had oromotor disorder and 40% had epilepsy. Patients with unilateral polymicrogyria had the following symptoms: 65% intellectual disability, 55% global development delay, 55% oromotor disorder, 55% epilepsy and 2 patients where free of symptoms (the oldest 2 year old). The initial symptoms were depending upon the age: the oromotor disorder was the most common in the newborn period, global development delay if the symptoms started before 2 years old and after 2 years epilepsy was the initial most common symptom., Conclusion: In our study the most common symptom was intellectual disability (independently of the type of poly-microgyria), followed by oromotor disorder and, with fewer proportion, epilepsy (in contrast with other series).

Patients with type 1 diabetes and poor metabolic control can develop hepatomegaly due to intrahepatic glycogen deposition. If these patients also have elevated liver enzymes, dyslipidemia, cushingoid features and delayed growth or sexual maturation, Mauriac syndrome can be diagnosed. This disorder is common and reversible with optimization of insulin therapy. We report three adolescents with type 1 diabetes and a long-standing history of poor glycemic control, who developed hepatomegaly, elevated liver enzymes and dyslipidemia with preserved liver function. One of these patients also had delayed growth and another had hypogonadotropic hypogonadism. Liver ultrasound showed changes suggestive of glycogenosis. In all three patients, optimization of insulin therapy achieved good glycemic control and reversed the manifestations within 2 weeks. The etiology of Mauriac syndrome is controversial since both prolonged hyperglycemia and hyperinsulinization produce glycogen accumulation in the liver. Hypercortisolism (due to ketosis or hypoglycemia) contributes to glycogen storage and also causes growth and sexual maturation delay.