Publications by authors named "Kurt Schlachter"

10 Publications

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[Expert recommendation: treatment of nonambulatory patients with Duchenne muscular dystrophy].

Nervenarzt 2021 Apr 19;92(4):359-366. Epub 2020 Nov 19.

Friedrich-Baur-Institut, Neurologische Klinik und Poliklinik, Klinikum der Ludwig-Maximilians-Universität München, Ziemssenstr. 1, 80336, München, Deutschland.

Background: Duchenne muscular dystrophy (DMD) is the most frequent genetic neuromuscular disease in childhood with loss of ambulation usually occurring around the age of 9-11 years.

Objective, Material And Methods: Based on current guidelines and clinical trials, neuropediatric and neurological experts developed recommendations for the treatment of nonambulatory DMD patients focusing on drug treatment of adults. This advisory board was sponsored by PTC Therapeutics, the distributers of the substance ataluren.

Results And Conclusion: Loss of ambulation is heterogeneously defined across clinical trials. Among others, the need of a wheelchair, ambulation without mobility aids or maximum walking distance can be suitable parameters for assessment. Treatment of DMD patients at any stage of the disease is based on supportive and symptomatic measures, which should be continued after loss of ambulation. In addition, disease-modifying drugs are available for the treatment of DMD and glucocorticoids are the usual standard of care treatment even beyond the loss of ambulation. Ataluren, a potentially dystrophin restorative, disease-modifying treatment, has been approved for patients with DMD due to a nonsense mutation (nmDMD), which applies to approximately 13% of DMD patients and is usually combined with steroids. Clinical data from the STRIDE registry demonstrated a delayed disease progression even after loss of ambulation. Currently, no reliable data are available for exon skipping approaches in adult DMD patients. The antioxidant idebenone could be an option in nonambulant adolescent patients not treated with glucocorticoids and without other therapeutic options. A combination treatment of idebenone and glucocorticoids is currently being investigated in a clinical trial. Add-on treatment with idebenone in addition to ataluren may be considered for nonambulant nmDMD patients. Some of the discussed treatment options are still in clinical trials or there are not enough data for older DMD patients; therefore, these expert recommendations correspond to evidence class IV.
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http://dx.doi.org/10.1007/s00115-020-01019-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026471PMC
April 2021

Treatment with Nusinersen - Challenges Regarding the Indication for Children with SMA Type 1.

J Neuromuscul Dis 2020 ;7(1):41-46

Department of Neuropediatrics, Children's Hospital 1, University of Duisburg-Essen, Essen, Germany.

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.
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http://dx.doi.org/10.3233/JND-190441DOI Listing
October 2020

[Non-ambulatory patients with Duchenne muscular dystrophy : Recommendations for monitoring disease progression and course of treatment].

Nervenarzt 2019 Aug;90(8):817-823

Klinik für Allgemeine Pädiatrie und Neonatologie, Sektion Neuropädiatrie, Universitätsklinikum des Saarlandes, Geb. 9, 66421, Homburg, Deutschland.

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.
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http://dx.doi.org/10.1007/s00115-019-0754-yDOI Listing
August 2019

Effectiveness of antiepileptic therapy in patients with PCDH19 mutations.

Seizure 2016 Feb 6;35:106-10. Epub 2016 Jan 6.

Kinderklinik, Stauferklinik, Schwäbisch Gmünd, Germany.

Purpose: PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations.

Methods: We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2-27 years (mean age 10.6 years).

Results: The most effective drugs after 3 months were clobazam and bromide, with a responder rate of 68% and 67%, respectively, where response was defined as seizure reduction of at least 50%. Defining long-term response as the proportion of responders after 12 months of treatment with a given drug in relation to the number of patients treated for at least 3 months, the most effective drugs after 12 months were again bromide and clobazam, with a long-term response of 50% and 43%, respectively. Seventy-four percent of the patients became seizure-free for at least 3 months, 47% for at least one year.

Significance: The most effective drugs in patients with PCDH19 mutations were bromide and clobazam. Although epilepsy in PCDH19 mutations is often pharmacoresistant, three quarters of the patients became seizure-free for at least for 3 months and half of them for at least one year. However, assessing the effectiveness of the drugs is difficult because a possible age-dependent spontaneous seizure remission must be considered.
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http://dx.doi.org/10.1016/j.seizure.2016.01.006DOI Listing
February 2016

Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies: first experiences.

Neuropediatrics 2015 Apr 2;46(2):110-6. Epub 2015 Mar 2.

Department of Pediatric Neurology and Neurological Rehabilitation, Schön Klinik Vogtareuth, Vogtareuth, Germany.

Objective: This article aims to report the first clinical experiences concerning effectiveness and tolerability of perampanel (PER) in a pediatric population with refractory epilepsies.

Patients And Methods: This nonsponsored, observational, retrospective survey was conducted through collaboration with multiple centers in Europe. The clinical course of the first pediatric patients treated in these centers with PER was documented with the help of a questionnaire completed by the treating physicians. Effectiveness and adverse effects were evaluated. The study population consisted of 58 patients (mean age, 10.5 years; range, 2-17 years), suffering from various refractory epilepsies, classified as focal epilepsy (n = 36), unclassified generalized epilepsy (n = 12), Lennox-Gastaut syndrome (n = 5), West syndrome (n = 3), and Dravet syndrome (n = 2).

Results: The response rate (≥ 50% seizure reduction) after the first 3 months of therapy was 31% (18/58 patients) in total. Complete seizure control was achieved in five patients (9% overall). Aggravation of seizures occurred in five cases (9%). The most frequently occurring adverse effects were reduced vigilance or fatigue (n = 16) and behavioral changes (n = 14).

Discussion: PER seems to be effective also in children and adolescents with pharmaco-refractory epilepsies. Tolerability was acceptable.
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http://dx.doi.org/10.1055/s-0035-1546276DOI Listing
April 2015

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.

Brain 2013 Oct 6;136(Pt 10):3140-50. Epub 2013 Sep 6.

1 NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
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http://dx.doi.org/10.1093/brain/awt233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784283PMC
October 2013

Neuropsychological profile of children after an episode of neuroborreliosis.

Neuropediatrics 2013 Dec 6;44(6):346-53. Epub 2013 Aug 6.

Department of Pediatrics I, Division of Pediatric Neurology, Medical University Innsbruck, Innsbruck, Austria.

Background: In the majority of patients with Lyme neuroborreliosis (LNB), neurological symptoms are transient. The extent of neuropsychological and neuropsychiatric problems in children is not well researched.

Objectives: The study aimed to investigate cognitive functions and behavioral problems in children after LNB.

Patients And Methods: A total of 20 children between 6 and 16 years of age with an episode of LNB at least 4 month before neuropsychological testing were enrolled in the study and compared with 20 healthy controls. Children with LNB had cranial nerve palsies or meningoencephalitis, immunoglobulin G and immunoglobulin M antibodies for Borrelia burgdorferi in the peripheral blood, pleocytosis in the cerebrospinal fluid (leukocytes > 10 cells/μL) and/or an intrathecal synthesis of antibodies for B. burgdorferi.Neuropsychological tests assessing intellectual skills, memory, and executive functions were used. Two parental questionnaires assessing behavior, psychiatric problems, and executive functions were administered.

Results: Intellectual skills, memory, and executive functions of children after an episode of LNB were within the normal range. In the subcategory of working memory, children after an episode of LNB performed worse than controls. The questionnaires did not reveal behavior or psychiatric problems, although there was a tendency that children after an episode of LNB had more physical complaints.

Conclusion: Neuropsychological deficits resulting from LNB in childhood are rare. Most children had a good cognitive, emotional, and behavioral outcome.
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http://dx.doi.org/10.1055/s-0033-1349724DOI Listing
December 2013

Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway.

Am J Hum Genet 2011 Dec;89(6):806-12

Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.

Thiamine pyrophosphate (TPP) is an essential cofactor of the cytosolic transketolase and of three mitochondrial enzymes involved in the oxidative decarboxylation of either pyruvate, α-ketoglutarate or branched chain amino acids. Thiamine is taken up by specific transporters into the cell and converted to the active TPP by thiamine pyrophosphokinase (TPK) in the cytosol from where it can be transported into mitochondria. Here, we report five individuals from three families presenting with variable degrees of ataxia, psychomotor retardation, progressive dystonia, and lactic acidosis. Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate but normal pyruvate dehydrogenase complex activity in the presence of excess TPP. A reduced concentration of TPP was found in the muscle and blood. Mutation analysis of TPK1 uncovered three missense, one splice-site, and one frameshift mutation resulting in decreased TPK protein levels.
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http://dx.doi.org/10.1016/j.ajhg.2011.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234371PMC
December 2011

Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures.

PLoS One 2010 Sep 16;5(9). Epub 2010 Sep 16.

INSERM UMR 910, University of Méditerranée, Marseille, France.

Background: Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE.

Methodology/principal Findings: A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS.

Conclusions/significance: The present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012740PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940893PMC
September 2010

Hyperhomocysteinemia in children treated with antiepileptic drugs is normalized by folic acid supplementation.

Epilepsia 2005 Oct;46(10):1677-83

Department of Pediatrics, Academic Teaching Hospital Landeskrankenhaus (LKH), Feldkirch, Austria.

Purpose: To assess the prevalence of hyperhomocysteinemia in pediatric patients treated with antiepileptic drugs (AEDs) and to evaluate the effect of folic acid supplementation on plasma total homocysteine (tHcy) concentrations in hyperhomocysteinemic patients.

Methods: 123 patients from three regional hospitals participated in the study. Patients with hyperhomocysteinemia were included in a 3-month double-blind randomized trial testing oral folic acid supplementation (1 mg/day) versus placebo.

Results: Hyperhomocysteinemia (tHcy >10.4 micromol/L) was present in 19 of 123 patients. Patients with hyperhomocysteinemia were older (13.7 +/- 4 vs. 11.0 +/- 3.9 years) and had significantly lower folate and cobalamin concentrations. Multidrug (two or more) AED treatment and duration of therapy correlated significantly with elevated total homocysteine (tHcy) and low folate. In contrast, polymorphisms in the methylene tetrahydrofolate reductase gene (MTHFR 677 C-->T, 1298 A-->C, 1793 G-->A) had no significant impact on tHcy. Nine of 19 patients with hyperhomocysteinemia were randomized to placebo, whereas the remaining 10 patients received folic acid supplementation. Folic acid supplementation resulted in a significant increase of folate and decrease of tHcy, whereas both parameters remained unchanged in the placebo group.

Conclusions: Hyperhomocysteinemia is present in 15.5% of children receiving long-term AED treatment. Multidrug treatment and long duration of therapy enhance the risk for hyperhomocysteinemia. Folic acid supplementation significantly reduces tHcy. We recommend assessment of serum folate and plasma tHcy in children receiving AEDs.
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http://dx.doi.org/10.1111/j.1528-1167.2005.00264.xDOI Listing
October 2005