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ZusammenfassungDie genetische Diagnostik bei an Epilepsie erkrankten Personen ist inzwischen weit verbreitet und unstrittig sinnhaft geworden. Die Kenntnis einer genetischen Ätiologie kann die Identifikation der Diagnose, genetische Beratung, Therapie und Prognoseeinschätzung der Grunderkrankung maßgeblich unterstützen. Methoden der Hochdurchsatz-Sequenzierung erlauben inzwischen eine rasche, umfassende und kosteneffektive Diagnostik. Diese aktuellen Empfehlungen der Kommission „Epilepsie und Genetik“ der Deutschen Gesellschaft für Epileptologie (DGfE) bauen auf den Empfehlungen der International League Against Epilepsie (ILAE) Commission on Genetics auf. Wir bieten einen praxisnahen Überblick über die Indikationsstellung, praktische Umsetzung, Befundbewertung, und Möglichkeiten der Präzisionsmedizin.

Little is known about clinical symptomatology and genetics of juvenile onset Pompe disease (JOPD). The aims of this study were to analyze how these children are diagnosed, what clinical problems they have, and how phenotype is related to genotype. To accomplish this, we analyzed retrospectively data of 34 patients diagnosed after their first and before completion of their 18th birthday. Median age at diagnosis was 3.9 (range 1.1–17) years. Eight patients (23.5%) developed initial symptoms in the first year, 12 (35%) between 1 and 7 years, and 6 (18%) thereafter. Eight (23.5%) had no clinical symptoms at the time of diagnosis. Indications for diagnostics were a positive family history in three (9%), hyperCKemia in eight (23.5%), motor developmental delay in three (9%), and muscle weakness and/or pain in 17 (50%). Rare clinical signs were failure to thrive, recurrent diarrhea, and suspected hepatopathy with glycogen storage. Thirty-two different mutations were identified. Twenty-seven patients (79.5%) carried the milder c.32–13T > G mutation, known to be associated with a broad range of phenotypes. Three out of eight patients manifesting within the first year of life showed generalized muscle weakness, hypertrophic cardiomyopathy, and had to be ventilated during the course of disease, thereby demonstrating clinical overlap with infantile onset Pompe disease.These findings demonstrate that the phenotype of JOPD is broad and that the differential is not only restricted to neuromuscular disorders. Genotypic analysis was useful to delineate subjects with early onset JOPD from those with IOPD, but overall genotype–phenotype correlation was poor.

Paediatric hydrocephalus is a result of a dysfunction of cerebrospinal fluid circulation, and it has diverse pathogeneses. This study investigates the epidemiology of paediatric hydrocephalus, as well as the influences of primary aetiology and implant type on treatment complications and the development of new therapeutic approaches and strategies.Between 2013 and 2018, a retrospective analysis of 131 children, who were suffering from hydrocephalus, was conducted. Medical charts, operative reports and clinical follow-up visits were reviewed. Statistical analysis was performed using t-test/ANOVA and Kruskal-Wallis test/Mann-Whitney U test.The most common pathogeneses of hydrocephalus among our patients were meningomyelocele-associated and posthaemorrhagic. The majority of patients received a programmable differential pressure valve (PPV, 77.8%) or a fixed differential pressure valve with a gravitational unit (FPgV, 14.8%). Among 333 shunt-associated surgeries, 66% of surgeries were revision surgeries and were performed because of mechanical shunt dysfunction (61%), infection (12%), or other reasons (27%). The median rate of revisions within one year for each patient was 0.15 (IQR25-75: 0.00-0.68) and was influenced by aetiology (p = 0.045) and valve type (p = 0.029). The highest rates were seen in patients with posthaemorrhagic hydrocephalus and in those with FPgVs; the lowest rates were seen in patients with meningomyelocele-associated hydrocephalus and PPVs. The occurrence of mechanical dysfunctions was correlated with FPgV patients (p = 0.014). Furthermore, the median time interval between initial shunt surgery and onset of infection was shorter than that between initial surgery and mechanical dysfunction (p = 0.033).Based on this research, we can state several factors that influence revision surgeries in paediatric shunt patients. With the assessment of patients' risk profiles, physicians can classify paediatric shunt patients and thus avoid unnecessary examinations or invasive procedures. Furthermore, medical providers can prevent revision surgeries if they choose shunt material in accordance with a patient's associated shunt complications.

The importance of nutritional supply for somatic growth and neurodevelopmental outcome in very-low-birthweight infants is an established medical strategy for reducing long-term morbidities. Our cohort study on rapid enteral feeding advances using a standardized protocol (STENA) previously demonstrated a 4-day reduction of parenteral nutrition. STENA did not impede the success of noninvasive ventilations strategies but significantly less infants required mechanical ventilation. Most importantly, STENA resulted in improved somatic growth at 36 weeks of gestation. Here, we evaluated our cohort for psychomotor outcomes and somatic growth at 2 years of age. n = 218 infants of the original cohort were followed-up (74.4%). Z-scores for weight and length did not differ but the benefits of STENA for head circumference persisted until the age of 2 years (p = 0.034). Concerning the psychomotor outcome, we neither found any statistically significant differences in the mental developmental index (MDI) (p = 0.738), norin the psychomotor developmental index (PDI) (p = 0.122). In conclusion, our data adds important insights on the topic of rapid enteral feeding advances and confirms the safety of STENA with respect to somatic growth and psychomotor outcome measures.

Objective This observational study reports on the postnatal mortality and 30-month outcome of children who underwent fully percutaneous fetoscopic repair of myelomeningocele (MMC) at a single center in Giessen, Germany. Methods Between October 2010 and August 2014, a total of 72 patients underwent fully percutaneous fetoscopic MMC closure at 21 + 0 to 29 + 1 (mean, 23 + 5) weeks' gestation. Of these, 52 (72%) participated in this study; however, 30-month mortality data are available for all 72 children. Children were examined at four timepoints: shortly after birth and at 3 months, 12 months and 30 months of corrected age. The patients underwent age-specific standardized neurological examinations and assessment of leg movements and ambulation at all timepoints. Cognitive and motor development were assessed using the Bayley Scales of Infant Development, second edition (BSID-II), at 30 months. Results All 72 children survived the intrauterine procedure, however, four (5.6%) infants died postnatally (including two of the 52 comprising the study cohort). Of the 52 patients included in the study, 11.5% were delivered before the 30th week of gestation (mean, 33 + 1 weeks) and, of the survivors, 48.1% had ventriculoperitoneal shunt placement. Of the 50 infants that were alive at 30 months, independent ambulation, without orthosis, was feasible for 46%. At 30 months of follow-up, 46% of children presented with a functional level that was at least two segments better than the anatomical level of the lesion. At 30 months, 70% of the children presented with BSID-II psychomotor development index score of ≥ 70 and 80% with BSID-II mental development index score of ≥ 70. Conclusion Intrauterine repair of MMC by percutaneous fetoscopy shows largely similar outcomes to those reported for open repair, with respect to mortality, prematurity, shunt-placement rates, motor and mental development and free ambulation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Paediatric hydrocephalus is a result of cerebrospinal fluid circulatory dysfunction and has diverse pathogeneses. This study investigates the epidemiology of paediatric hydrocephalus and influences of primary aetiology, type of implants, and of complications to develope new therapeutic approaches and strategies. Between 2013-2018 a retrospective analysis of 131 children, suffering from hydrocephalus, was conducted. Medical charts, operative reports and clinical follow-up visits were reviewed. Statistical analysis was performed using t-test/ANOVA and Kruksal-Wallis-test/ Mann-Whitney-U test. Most common pathogeneses of hydrocephalus among our patients were meningomyelocele associated and posthaemorrhagic. The majority received a programmable differential pressure valve (PP valve, 77.8%) or a fixed differential pressure valve with gravitational unit (FPG valve, 14.8%). Among 333 shunt associated surgeries 66% were performed because of mechanical shunt dysfunction (61%), infection (12%), or due to other reasons (27%). The median rate of revisions for each patient within one year was 0.15 (IQR25-75:0.00-0.68) and was influenced by aetiology (p=0.045) and used valves (p=0.029). The highest rates were seen in patients with posthaemorrhagic hydrocephalus and in those with FPG valve, the lowest in meningomyelocele associated hydrocephalus and PP valve. The occurrence of mechanical dysfunctions showed a relation to FPG valve (p=0.014). Furthermore, the median time interval between initial shunt surgery and infections was shorter than in mechanical dysfunctions (p=0.033). Conclusion: We could state several influence factors on revision surgeries in paediatric shunt patients. With the assessment of patients’ risk profiles, we can classify paediatric shunt patients and could avoid unnecessary examinations or invasive procedures. Furthermore, we could prevent revisions surgeries, if we choose shunt material in accordance with the patients’ associated shunt complications.

Zusammenfassung Fragestellung Ziel der prospektiven, multizentrischen Studie ist die Erfassung klinischer Charakteristika, des Ressourcenverbrauches sowie der Lebensqualität bei Patienten mit der Diagnose eines Dravet-Syndroms (DS) und deren Eltern in Deutschland. Methoden Die Datenerhebung erfolgte mit einem validierten retrospektiven Fragebogen über 3 bzw. 12 Monate sowie mit einem prospektiven Tagebuch über 3 Monate. Es wurden Daten zur Anfallssituation, Medikamenteneinnahme, Therapieinanspruchnahme sowie zu direkten und indirekten Kosten und zur Lebensqualität erhoben. Die Fragebögen und das Tagebuch wurden den Eltern über den Dravet-Syndrom e. V. sowie beteiligte Zentren ausgehändigt. Ergebnisse Der Fragebogen wurde von 93 Eltern der DS-Patienten und das Tagebuch von 77 ausgefüllt. Das mittlere Alter der Patienten betrug 10 Jahre (Spannweite 15 Monate bis 33,7 Jahre). Die Zeit bis zur Syndromdiagnose eines DS war in den letzten beiden Jahrzehnten deutlich kürzer. In den letzten 12 Monaten ereignete sich bei 95 % der Patienten mindestens ein epileptischer Anfall. Als anfallsauslösende Faktoren wurden Fieber (93,4 %), Aufregung (56 %), Schlafmangel (51,6 %) und starke körperliche Anstrengung (50,5 %) berichtet. Die Lebenszeitprävalenz des Status epilepticus lag bei 77 %, und bei 28 % war mindestens 1 Episode eines Status epilepticus innerhalb des letzten Jahres aufgetreten. Die Lebensqualität (QoL) der Patienten war niedriger als die der Allgemeinbevölkerung, und von 46 % der Eltern wurden Depressionssymptome berichtet. Die direkten Kosten in 3 Monaten betrugen 6043 € pro Patient. Den größten Kostenfaktor stellten die stationären Kosten dar (1702 €), gefolgt von den Leistungen für Pflege (1130 €), den Kosten für die antikonvulsiven Medikamente (892 €) und für Therapien (559 €). Bei den Müttern betrugen die gesamten indirekten Kosten 4399 € und bei den Vätern 391 € bezogen auf 3 Monate. Schlussfolgerung Das Dravet-Syndrom ist mit häufigen, oft therapierefraktären epileptischen Anfällen und Status epilepticus vergesellschaftet. Diese Studie zeigt die erhebliche Krankheitslast und die damit verbundenen Einschränkungen in der Lebensqualität sowie die hohen direkten und indirekten Kosten auf. Um eine Verbesserung der Lebensqualität bei Patienten mit DS und deren Eltern zu erreichen, bedarf es neuer Therapie- und Versorgungskonzepte.

Objective The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe. Methods Patient use of routine AEDs and emergency medications over 3–6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe. Results The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed. Significance This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3–6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.

We determined the prevalence of autoantibodies against an extended number of established and novel neural antigens in children and adolescents with suspected autoimmune encephalitis, epilepsy, single seizures, or marked epileptiform activity in electroencephalography (EEG). Prospectively, 103 patients were recruited aged between 0 and 18 years and 104 controls. A panel of 35 autoantibodies against neural cell-surface and intracellular antigens was screened. Sixteen of 103 patients (15.5%) showed a positive result for 1 or more autoantibodies, compared to 6 of 104 controls (5.8%, P = .02). Neurochondrin was identified as a possible new target of autoantibodies in 3 patients within this cohort, but none in controls. The patients showed severe behavioral disturbances, memory and cognitive impairment, episodes of reduced responsiveness, but no seizures, and normal MRI. Clinical findings, course, and treatment response of these 3 patients are presented.

Die Diagnose einer Epilepsie geht haufig mit relevanten Einschrankungen fur Patienten einher, wodurch eine Vielzahl verschiedener Probleme entstehen konnen, die einer gezielten und professionellen Beratung bedurfen. Seit 1996 existieren in einigen Bundeslandern spezialisierte Epilepsieberatungsstellen (EBS), die in solchen Fallen als Anlaufstelle dienen sollen. Ziel dieser prospektiven, multizentrischen Kohortenstudie an sechs EBS in Hessen und Unterfranken war es, Akzeptanz, Nachfrage und haufige Konsultationsgrunde von EBS zu erfassen und zu analysieren. Insgesamt wurden uber 12 Monate (06/2014 bis 05/2015) 435 Klienten, hiervon 74,3 % Erwachsene (n = 323, mittleres Alter 40,3 ± 14,7 Jahre; Spannweite 18–76 Jahre, 51,7 % weiblich) und 25,7 % Kinder und Jugendliche (n = 112, mittleres Alter 9,4 ± 4,8 Jahre; Spannweite 1–17 Jahre, 52,7 % weiblich) eingeschlossen. Im Mittel wurden 2,5 (Median 2,0; SD ± 2,8, Spannweite 1–20) ambulante Vorstellungen an EBS pro Jahr angegeben, wobei eine allgemeine Beratung zum Umgang mit Epilepsie (Erwachsene 55,7 %, Kinder 51,8 %), Aufklarung und Information uber die Erkrankung (43,7 % bzw. 41,1 %) und Hilfe bei der Beantragung von Hilfsleistungen (39,0 % bzw. 46,4 %) die haufigsten Vorstellungsgrunde waren. Die Distanz zwischen Wohnort und EBS war in Bayern signifikant kurzer als in Hessen (p

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Viele paroxysmal auftretende Phanomene bzw. Krankheiten konnen epileptischen Anfallen mehr oder minder ahneln und stellen somit relevante Differenzialdiagnosen dar, die dem Padiater bekannt sein mussen. Die Qualitat der Anamnese ist der entscheidende Faktor in der Diagnostik. Es konnte gezeigt werden, dass 10–20 % aller Patienten, die wegen einer therapierefraktaren Epilepsie in einem spezialisierten Zentrum vorgestellt werden und bereits mehrere Antiepileptika erhielten, an nichtepileptischen Anfallen leiden. Diese Patienten litten meist an Synkopen, psychogenen Storungen, Affektkrampfen oder Parasomnien. Die ubergeordnete Zuordnung einzelner Krankheiten kann unterschiedlich getroffen werden. Eine fur den klinischen Alltag benutzbare Einteilung gibt folgende ▶ Ubersicht.

Objective This observational study reports on the postnatal mortality and 30-month outcome of children who underwent fully percutaneous fetoscopic repair of myelomeningocele (MMC) at a single center in Giessen, Germany. Methods Between October 2010 and August 2014, a total of 72 patients underwent fully percutaneous fetoscopic MMC closure at 21 + 0 to 29 + 1 (mean, 23 + 5) weeks' gestation. Of these, 52 (72%) participated in this study; however, 30-month mortality data are available for all 72 children. Children were examined at four timepoints: shortly after birth and at 3 months, 12 months and 30 months of corrected age. The patients underwent age-specific standardized neurological examinations and assessment of leg movements and ambulation at all timepoints. Cognitive and motor development were assessed using the Bayley Scales of Infant Development, second edition (BSID-II), at 30 months. Results All 72 children survived the intrauterine procedure, however, four (5.6%) infants died postnatally (including two of the 52 comprising the study cohort). Of the 52 patients included in the study, 11.5% were delivered before the 30th week of gestation (mean, 33 + 1 weeks) and, of the survivors, 48.1% had ventriculoperitoneal shunt placement. Of the 50 infants that were alive at 30 months, independent ambulation, without orthosis, was feasible for 46%. At 30 months of follow-up, 46% of children presented with a functional level that was at least two segments better than the anatomical level of the lesion. At 30 months, 70% of the children presented with BSID-II psychomotor development index score of ≥ 70 and 80% with BSID-II mental development index score of ≥ 70. Conclusion Intrauterine repair of MMC by percutaneous fetoscopy shows largely similar outcomes to those reported for open repair, with respect to mortality, prematurity, shunt-placement rates, motor and mental development and free ambulation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition. Electronic supplementary material The online version of this article (doi:10.1007/s10048-017-0520-x) contains supplementary material, which is available to authorized users.

ZusammenfassungEpilepsien zählen zu den häufigsten neurologischen Erkrankungen mit etwa 600 000 Betroffenen in Deutschland. Symptome epileptischer Anfälle, die Vielzahl möglicher Epilepsieursachen und die unterschiedlichen Krankheitsverläufe erschweren sowohl die korrekte Diagnosestellung als auch die Auswahl einer geeigneten Therapie (Antikonvulsiva, epilepsiechirurgische Eingriffe, Neurostimulationsverfahren, ketogene Ernährungstherapien, Verhaltensstrategien u. a.). Zudem haben krankheitsspezifische Risiken sowie häufig auftretende Komorbiditäten nicht selten gravierende psychosoziale Konsequenzen. Daher wird bei der Versorgung von Menschen mit Epilepsie neben der vollständigen Anfallskontrolle ohne Nebenwirkungen und der Lebensqualität auch die Kontrolle bzw. Linderung typischer Begleiterkrankungen und Risiken angestrebt. Um diese Behandlungsziele zu erreichen, sind spezifische Fachkenntnisse und Untersuchungsmöglichkeiten erforderlich, die von spezialisierten Zentren vorgehalten werden. Epilepsiezentren sind als überregionale Kompetenzzentren definiert, die über spezielle Expertise und eine besondere Ausstattung zur ambulanten und stationären Versorgung von Patienten mit Epilepsien und verwandten Erkrankungen verfügen. Zu ihren Aufgaben zählen u. a. die umfassende Diagnostik, Differenzialdiagnostik und Therapie von Epilepsiepatienten sowie die multiprofessionelle und interdisziplinäre Beratung von Angehörigen und Eltern. Dieser Artikel fasst die diagnostischen und therapeutischen Herausforderungen bei der Versorgung von Menschen mit Epilepsien zusammen, beschreibt die personellen, apparativen und institutionellen Voraussetzungen von Epilepsiezentren und gibt eine Übersicht über die Vergütung epileptologischer Spezialleistungen nach G-DRG. Darüber hinaus werden Merkmale einzelner Epilepsiezentren in Deutschland skizziert sowie Perspektiven und Möglichkeiten zur Verbesserung der Versorgung von Epilepsiepatienten diskutiert.

Recent advances in the field of epilepsy genetics have led to an increased fraction of patients with epilepsies where the etiology of the disease could be identified. Nevertheless, there is some criticism regarding the use of epilepsy genetics because in many cases the identification of a pathogenetic mutation does not lead to an adaptation of therapy or to an improved prognosis. In addition, the interpretation of genetic results might be complicated due to the considerable numbers of variants of unclear significance. This publication presents the arguments in favour of a broad use of genetic investigations for children with epilepsies. Several diseases where a genetic diagnosis does in fact have direct therapeutic consequences are mentioned. In addition, the indirect impact of an established etiology, encompassing the avoidance of unnecessary diagnostic measures, possibility of genetic counselling, and the easing of the psychologic burden for the caregivers, should not be underestimated. The arguments in favour of broad genetic diagnostics prevail notwithstanding the lack of relevant new developments regarding the therapy.

Objective The treatment of a positional head deformity in infancy is a controversial issue. The aim of this study was to explore the effects of helmet therapy on positional plagiocephaly and brachycephaly. Patients and Methods We determined cranial vault shape parameters in 348 healthy children during the second year of life, combined them with preexisting data from more than 400 subjects younger than 12 months, and related retrospectively the data of 1,531 children obtained before and after treatment with individual molding helmets to these newly generated normative values. Results The number of subjects with cranial vault asymmetry values > 97th percentile decreased by 85.5% from 1,361 before to 197 (p 97th percentile declined by 87.7% from 1,353 to 167 (p 97th percentile diminished by 66.8% from 885 to 294 (p Conclusions These findings do not finally prove, but they support the idea that helmet treatment is effective and meaningful in preventing permanent head deformities in infants with severe deformation. The normative anthropometric data generated in this study will allow investigating the natural course and effects of various therapies on infant cranial shape objectively.

Inherited white matter disorders of the central nervous system frequently are degenerative and progressive clinical entities. They are classified into myelin disorders, including hypomyelination, dysmyelination, demyelination, and myelin vacuolization, but also astrocytopathies, leuko-axonopathies, microgliopathies, and leuko-vasculopathies. Hypomyelinating leukodystrophy is the main feature of Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD1). PMD- and PMLD1-affected patients display comparable neurological symptoms, including psychomotor developmental delay, spasticity, nystagmus, impairment of cognitive skills, sensorineural hearing loss, and different ophthalmological disabilities. While clinical features overlap, PMD and PMLD1 can be distinguished on the molecular genetic level. PMD is caused by mutations in the gene encoding for the proteolipid protein 1 (PLP1), whereas PMLD1 is associated with mutations in the gene encoding for the gap junction protein gamma 2 (GJC2). Here we present novel compound-heterozygous mutations in the GJC2 gene identified in two, unrelated infantile patients affected with PMLD1. The heterozygous frameshift mutations c.392dupC, p.H132Afs*6 and c.989delC, p.P330Rfs*141 were found in the first patient. The heterozygous nonsense variant c.291C>G, p.Y97*, as well as the heterozygous missense variant c.716T>C, p.V239A were detected in the second patient. All four variants were predicted to be damaging for structure and/or function of the GJC2 protein. Combinations of these genetic variants likely are pathogenic and resulted in the PMLD1-phenotype in the investigated children. In conclusion, our clinical and molecular findings confirmed the genotype-phenotype relationship between mutations in the GJC2 and PMLD1. The novel mutations of GJC2 described herein will help to further understand the pathogenic mechanism underlying PMLD1.

OBJECTIVE To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug-resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany. METHODS Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days). RESULTS Mean total direct costs were highest for DS patients (€4864 [median €3564] vs €3049 [median €1506] for DRE [excluding outliers], P = 0.01; and €1007 [median €311], P

The diagnosis of epilepsy is often accompanied by relevant restrictions for patients, which may result in disease-specific daily problems that need targeted and professional counseling. Specialized epilepsy counseling services (ECS) were introduced in some German states since 1996 to provide an additional and independent service for epilepsy-related problems. The objective of this prospective, multicenter cohort study at six ECS was to determine and analyze the acceptance, demand and frequent reasons for consultation in Hesse and Lower Franconia.A total of 435 clients were enrolled during the 12-month observation period (June 2014-May 2015) of which 74.3% were adults (n = 323, mean age 40.3 ± 14.7 years, range 18-76 years, 51.7% female) and 25.7% children and adolescents (n = 112, mean age 9.4 ± 4.8 years, range 1-17 years, 52.7% female). The mean number of outpatient consultations per year was 2.5 (median 2.0, SD ± 2.8, range 1-20), whereby a general counseling on dealing with epilepsy (adults 55.7%, children and adolescents 51.8%), clarification and information about the disease (43.7% and 41.1%, respectively) and assistance in applying for support (39.0% and 46.4%, respectively) were the most frequent issues. The distance from the place of residence to the ECS was significantly shorter in Lower Franconia compared to Hesse (p 0.002). Client satisfaction was high with a mean patient satisfaction questionnaire (ZUF-8) score of 29.0 (maximum score 32). Overall 96.4% of the clients rated the quality of counseling as good or very good and 96.6% would consider consulting the ECS again in case of new problems. In cases of threatened workplace, training position or situation at school, counseling helped to avoid negative consequences in 72.0% of cases.The ECS are frequently used, appreciated and effective institutions for adults and children with epilepsy as well as for their caregivers. The ECS complements the existing comprehensive specialized outpatient and inpatient care for epilepsy in Germany; however, in view of their limited numbers and inhomogeneous allocation, the number and the availability of ECS should be expanded on the national level.

Background: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. Results: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Conclusions: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Introduction Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany. Methods A validated 3–12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany. Results Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months–33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis. Conclusions This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.

Chudley–McCullough syndrome (CMS) is a rare autosomal recessive disorder characterized by sensorineural deafness, agenesis of the corpus callosum, frontal polymicrogyria, interhemispheric cyst, and ventricular enlargement. CMS is caused by mutations in the GPSM2 gene, but until now no more than eight different mutations are on record. We describe two dizygotic twins with a novel homozygous loss-of-function mutation (c.1093C > T; p.Arg365*). While one child developed hydrocephalus-prompting shunt implantation immediately after birth, the other sibling did not. The combination of sensorineural hearing loss and partial agenesis of the corpus callosum is a highly recognizable clinico-radiological entity that should prompt mutational analysis of the GPSM2 gene.

Objective To evaluate the need for postnatal neurosurgical intervention after fetoscopic patch coverage of spina bifida aperta (SBA). Methods This was a retrospective analysis of a cohort of 71 fetuses which underwent minimally invasive fetoscopic patch coverage of SBA between 21 + 0 and 29 + 1 weeks of gestation. Postnatal neurosurgical procedures were classified into two types: re-coverage of the SBA within the first 3 months following birth, and shunt placement as treatment of associated hydrocephalus within the first year. Results Location of the SBA was lumbosacral in 59 cases, lumbar in seven, thoracic in three and sacral in two. In total, 20/71 (28%) patients underwent early postnatal neurosurgical intervention by means of re-coverage of the SBA. This was performed because of cerebrospinal fluid leakage in seven (35%), adhesions with functional deterioration in three (15%), incomplete coverage in five (25%) and skin defect in five (25%) cases. Ventriculoperitoneal shunt placement within 1 year was required in 32 (45%) cases and was preceded by ventriculostomy in two. Three (4%) infants needed Chiari decompression surgery in the first 12 months following birth, because of syringomyelia or gait disturbance. Conclusions Fetoscopic patch coverage of SBA may require postnatal re-coverage in some cases. In most cases, conservative wound treatment shows good results, without requiring neurosurgical intervention. The low 1-year-shunt rate is comparable to data of the Management of Myelomeningocele Study and lower compared with published data of patients with postnatal only coverage of SBA. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

In der Aufklarung fokaler genetisch bedingter Epilepsiesyndrome wurden in den letzten drei Jahren grose Fortschritte erzielt. So wurden Defekte im DEPDC5-Gen, welches ein Protein codiert, das Bestandteil des GATOR1-Komplexes ist, der wiederum eine wichtige Rolle im mTOR-Signalweg spielt, als Ursache fokaler Epilepsien identifiziert. Interessanterweise wurden DEPDC5-Mutationen sowohl bei Kindern mit Rolando-Epilepsie als auch bei Patienten mit kortikalen Dysplasien gefunden. Bei der autosomal dominanten lateralen Temporallappenepilepsie wurde Reelin als ursachliches Gen in 17,5 % der untersuchten Familien identifiziert. Durch Metaanalyse mehrerer groser genomweiter Assoziationsstudien konnte belegt werden, dass Mutationen im SCN1A-Gen bedeutsam sind fur die Entstehung haufiger fokaler und generalisierter Epilepsien. Zudem wurde gezeigt, dass auch Mutationen im SCN3A-Gen selten ursachlich fur die Entstehung fokaler Epilepsien sein konnen. In einer Reihe von Studien, die sich mit den genetischen Ursachen bei typischer und atypischer Rolando-Epilepsie befasst haben, konnte nachgewiesen werden, dass Mutationen in den Genen GRIN2A, RBFOX1, RBFOX3 und DEPDC5 sowie eine bestimmte Copy Number Variation (CNV 16p11.2) bei insgesamt 12 % der Patienten pathogenetisch bedeutsam sind. Einzelne der identifizierten Genprodukte sind pharmakologisch beeinflussbar.

Background The diagnosis of epilepsy is accompanied by relevant personal, interpersonal, and professional restrictions for patients and their caregivers. Specialized epilepsy counseling services (ECS) have been introduced to inform, advise, and support patients with disease-related problems. Aim and scope The objective of this cross-sectional, multicenter study was to determine the demand, typical content, and outcomes of ECS in children, adolescents, and adults in two adjacent German regions of Hessen and Lower Franconia. All ECS sites in these regions participated in 2014 and 2015, offering a total population of 7.5 million inhabitants. Results A total number of 435 patients [323 adults (74.3%), 51.7% female, mean age: 40.3 ± 14.7 years and 112 children/adolescents (25.7%), 52.7% female, mean age: 9.4 ± 4.6 years] were enrolled at six ECS sites. The most common reasons for counseling were general information needs (n = 304; 69.9%), administrative help (n = 208; 47.8%), problems with education or work (n = 176; 40.5%), and recreational activities (n = 119; 27.3%). In addition, 6.2% reported epilepsy-related questions on family planning as a specific reason for desiring counseling. Recommendation by the treating physicians was the most frequent reason for receiving counseling through ECS (62.5%), and most patients preferred to receive a personal consultation (73.1%). Patient satisfaction as measured by the ZUF-8 client satisfaction score was high with a mean of 29.7 points (standard deviation: ± 2.7 points, median: 29.9 points), and 83.9% of patients said they would recommend ECS. Disease-related job loss or change in school was avoided in 72% of 82 patients. Suggestions for improvement of ECS included an extension of service hours (58.6%) and a better availability of more sites located nearby (32.8%). Conclusion Epilepsy counseling services are necessary, valued, and effective institutions for people with epilepsy complementing outpatient and inpatient care. To improve the care for people with epilepsy, access to and availability of ECS should be improved.