Good Outcome of Resective Epilepsy Surgery in a 1-Year-Old Child with Drug-Resistant Focal Epilepsy with a Novel Pathogenic COL4A1 Mutation.

Pathogenic variants in COL4A1, encoding the α chain of type IV collagen, have been associated with cerebrovascular pathology as well as malformations of cortical development, thereby causing structural epilepsy. This case illustrates successful resective epilepsy surgery in a 12-month-old girl with left occipital focal cortical dysplasia (FCD) associated with a heterozygous splice-donor variant in COL4A1. She presented with drug-resistant focal epilepsy with daily seizures from the age of 2 months, refractory to several combinations of antiseizure medications, as well as mild right-sided hemiparesis and developmental delay. All presurgical diagnostic modalities, including ictal and interictal electroencephalography, magnetic resonance imaging, and ictal fluorodeoxyglucose positron emission tomography, showed congruent findings, pointing toward one single left occipital epileptogenic zone (EZ). We performed a left occipital lobectomy, using intraoperative electrocorticography to confirm the boundaries of the EZ. After surgery, the patient has remained seizure free, and both cognitive and motor developments have improved. Histopathology of the resected brain tissue showed FCD type Ia. Resective epilepsy surgery can have a very good outcome, also in patients with genetic mutations in COL4A1, constituting a less invasive option than the previously used more radical surgical procedures such as hemispherectomy.

A Systematic Review of Seizure-Freedom Rates in Patients With Benign Epilepsy of Childhood With Centrotemporal Spikes Receiving Antiepileptic Drugs.

OBJECTIVES: The objective of this study was to evaluate seizure remission rates in patients with benign epilepsy of childhood with centrotemporal spikes (BECTS) receiving antiepileptic drugs. METHODS: PubMed and Web of Science were searched for studies on pharmacotherapy in patients with BECTS using free search terms or Medical Subject Headings. Only studies that used seizure-freedom rates as an indicator for pharmaceutical efficacy were considered. Different antiepileptic drugs were compared using the Fisher exact test for seizure-freedom rates. RESULTS: A total of 19 studies were included, 6 of them being randomized controlled trials. The randomized controlled trials included a total of 308 patients and covered sulthiame (n = 52), topiramate (n = 45), levetiracetam (n = 43), oxcarbazepine (n = 31), carbamazepine (n = 68), and clobazam (n = 18) as well as placebo (n = 35) and untreated control groups (n = 16). Treatment success rates were significantly higher in those children treated with sulthiame, levetiracetam, and clobazam compared with the children treated with carbamazepine, oxcarbazepine, or topiramate. CONCLUSIONS: The available literature suggests the use of sulthiame, levetiracetam, or clobazam as first-line agents for the treatment of BECTS.

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood.

Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.

Homoplasmy of the Mitochondrial DNA Mutation m.616T>C Leads to Mitochondrial Tubulointerstitial Kidney Disease and Encephalopathia.

Autosomal-dominant tubulointerstitial kidney disease -(ADTKD) describes tubulointerstitial kidney disease with autosomal-dominant inheritance. In 2017, the term mitochondrial tubulointerstitial kidney disease (MITKD) was introduced for tubulointerstitial kidney disease caused by mitochondrial DNA (mtDNA) mutations. To date, there are few mutations described in literature causing MITKD, one of them is m.616T>C. A 5-year-old girl presented with chronic renal insufficiency and epilepsia. At the age of 3 years, status epileptic occurred and evolved into epilepsia partialis continua. At the age of 5 years, chronic renal failure (CKD II-III) was diagnosed due to tubulointerstitial kidney disease. Urine analysis showed elevated fractional excretions of sodium and chloride. Kidneys were enlarged and hyperechogenic. Blood pressure was elevated. The family history was unremarkable for renal and/or neurological disorders. Genetic testing was performed and revealed homoplasmy of the substitution m.616T>C in our patient's mtDNA. This mutation has been shown to cause chronic tubulointerstitial kidney disease leading to end-stage renal disease (ESRD) and epilepsia formerly. MITKD is a rare mitochondrial disease leading to ESRD and should be suggested in patients with epilepsia and renal insufficiency.

Chewing induced reflex seizures ("eating epilepsy") and eye closure sensitivity as a common feature in pediatric patients with SYNGAP1 mutations: Review of literature and report of 8 cases.

PURPOSE: Heterozygous SYNGAP1 gene mutations have been associated with several forms of idiopathic generalized epilepsy, autism spectrum disorders and delay of psychomotor development. We report eight patients with a SYNGAP1 mutation and chewing/eating induced reflex seizures as new phenotype and compare them to other patients with eating epilepsy and genetic mutations. METHODS: Presentation of clinical and anamnestic features and retrospective analysis of Video-EEG data of a 4 year old index patient with SYNGAP1 mutation and chewing /eating induced seizures. Clinical and anamnestic features and home videos of seven additional patients (4 female; age: 4-14 years) with SYNGAP1 mutation and eating induced reflex seizures were compared. RESULTS: All reflex seizures of the index patient showed similar focal EEG pattern with 1-5 seconds high amplitude, irregular 3/sec spike-wave complexes with initiation from left temporo-occipital, right temporo-occipital or bi- occipital / temporo-occipital regions. Eyelid myoclonia, the most common seizure type in all 8 patients, were typically initiated by eating or other simple orofacial stimuli. In the index patient eye closure preceded eating induced-eyelid myoclonia in 30/38 seizures. CONCLUSION: The main clinical features of our patient (i.e. intellectual disability, epilepsy, autistic features) are compatible with previous reports on patients with SYNGAP1 mutations. This is the first complete description of eating induced seizures in association with SYNGAP1 mutations. Whether eye closure sensitivity (ECS) represents an independent reflex epileptic trait, as seen in other patients with idiopathic "generalized" epilepsies (IGE), or eye closure is part of a complex trigger mechanism in SYNGAP1 patients' remains to be elucidated.

Symptom patterns in childhood arterial ischemic stroke: Analysis of a population-based study in Germany.

HINTERGRUND: Die zeitliche Verzögerung zwischen Symptombeginn und Diagnose ist eine Herausforderung in der Behandlung von Kindern mit arteriell ischämischem Schlaganfall. Frühere Studien zur klinischen Präsentation beschäftigten sich v. a. mit kumulativen Symptomen. ZIELSETZUNG: Ziel dieser Studie ist es, mögliche Symptommuster aufzuzeigen. METHODEN: In einer aktiven Beobachtungsstudie zwischen 01/2015 und 12/2016 (ESPED-Studie) wurden Kinder mit Erstdiagnose eines arteriell ischämischen Schlaganfalls eingeschlossen. Isoliert auftretende Erstsymptome wurden verschiedenen Symptomkombinationen gegenübergestellt. Zudem wurde untersucht, inwieweit ein als "akut" oder "progredient" klassifiziertes Auftreten der Symptome Rückschlüsse auf die zugrundeliegende Ätiologie erlaubt. ERGEBNISSE: Es wurden 99 Kinder in die Studie eingeschlossen. Unabhängig vom Alter traten überwiegend fokale Symptome auf (86%). Krampfanfälle als Initialsymptom wurden insbesondere bei Säuglingen beschrieben (67%), wohin-gegen diffuse, unspezifische Symptome vor allem bei Vorschulkindern (38%) und älteren Kindern (59%) auftraten. Isoliert traten fokale Symptome bei 37 Kindern auf, 48 Kinder zeigten zusätzlich unspezifische Symptome, darunter auch 9 Kinder mit Krampfanfällen. Isolierte unspezifische Symptome zeigten sich lediglich bei 7 Kindern, 2 Kinder wurden nur mit Krampfanfällen symptomatisch. Die Akuität des Symptombeginns wurde bei 53/78 als "akut" und bei "25/78 Fällen als "progredient" klassifiziert, lieferte jedoch keinen Hinweis auf die zugrundeliegende Ätiologie. SCHLUSSFOLGERUNG: Jedes neue fokal neurologische Defizit sollte unabhängig vom Auftreten (isoliert oder kombiniert, akut oder progredient) an einen kindlichen Schlaganfall denken lassen. BACKGROUND: Time delay between onset of clinical symptoms and diagnosis is a challenge in childhood arterial ischemic stroke. Most previous studies reported cumulative symptoms. OBJECTIVE: We attempted to identify typical symptom patterns and assessed their emergence in childhood stroke. METHODS: Prospective active surveillance in ESPED, a hospital based Pediatric Surveillance Unit for rare diseases in Germany, between January 2015 and December 2016. Case definition: first diagnosis of a radiologically confirmed arterial ischemic stroke. Symptom patterns were identified as occurring in isolation or in combination. We distinguished acute vs. progressive onset. We ascertained risk factors to identify the possible etiology. RESULTS: 99 children with childhood arterial ischemic stroke were reported. Focal symptoms were the predominant presenting feature (86%), independent of age. Seizures were more often seen in infants < 1 year (67%), whereas diffuse symptoms were more present in pre-school children (38%) and older children (59%). 37 children had focal features alone and 48 additional non-specific features, including 9 with seizures. Isolated non-specific features accounted for 7 cases, and 2 children had (focal) seizures as the only symptom. In 77% of all cases at least one risk factor was identified. The emergence of symptoms was acute in 53/78 cases and progressive in 25/78 cases. The pattern of emergence was unrelated to the underlying etiology. CONCLUSIONS: Any new focal neurological deficit in isolation, or associated with seizures or further non-specific symptoms should alert to childhood stroke.

[The remains of the day: A working day in a university children's hospital]. / Was vom Tage übrig bleibt ­ Arbeitsalltag einer Universitätsmedizin für Kinder und Jugendliche.

BACKGROUND: Limited time available for direct patient contact and a lot of time required for administrative duties have been reported by physicians working in adult medicine. OBJECTIVE: To characterize the typical daily work routine in a major pediatric university hospital. MATERIALS AND METHODS: A self-administered questionnaire was completed by physicians in the University Children's Hospital, Munich. The questionnaire captured the time spent on direct patient contact and on administrative tasks as well as the physicians' clinical experience and the location where the respective work was actually carried out (inpatient ward, outpatient emergency department, specialized outpatient clinic or department for developmental medicine). RESULTS: Most physicians (91.7 %) reported daily working hours beyond the regular schedule of 8.5hours. The proportion of time dedicated to direct patient contact was 31.2 % (95 % confidence interval: 25.2-37.1). Considering the number of patients in the work units, the average amount of time available for each individual patient varied between 14 minutes in the pediatric ward and 52 minutes in the department for developmental medicine. The reported times spent on patient contact did not significantly differ between physicians with > 5 years and those with ≤ 5 years of clinical experience. CONCLUSION: Although physicians in a university pediatric hospital work long daily hours, only restricted time is available for direct patient contact defined as physical examination of the child and face-to-face communication with patients and families.

Associations between stress and migraine and tension-type headache: results from a school-based study in adolescents from grammar schools in Germany.

INTRODUCTION: Stress is considered the major contributor to migraine and tension-type headache in adolescents. Previous studies have focused on general stressors, whereas the aim of the present study was to investigate associations between individuals' stressful experiences and different types of headache. METHODS: Adolescents from 10th and 11th grades of grammar schools filled in questionnaires. Stressful experiences were measured with the Trier Inventory of Chronic Stress. Type of headache was classified according to the International Classification of Headache Disorders. Linear regressions, adjusted for sex and grade, were calculated to estimate differences in stress scores that can be attributed to migraine, tension-type headache or miscellaneous headache. RESULTS: A total of 1260 questionnaires were analysed. Tension-type headache, migraine and co-existing migraine plus tension-type headache were found in 48.7%, 10.2% and 19.8% of the participants. In subjects with migraine or co-existing migraine plus tension-type headache, high increases in stress scores were found in all investigated dimensions, whereas much weaker and inconsistent associations were found in subjects with tension-type headache only. CONCLUSIONS: The characteristic of migraine is more associated with stressful experiences than this is the case for tension-type headache. This suggests that adolescent migraine patients might especially benefit from behavioural interventions regarding stress.

Associations of diet and lifestyle with headache in high-school students: results from a cross-sectional study.

BACKGROUND: Diet and lifestyle are seen as factors which influence headache in adults. However, population-based studies on this issue in adolescents are rare. OBJECTIVE: Aim of the present study was to investigate associations between diet and lifestyle factors and different types of headache, ie, migraine and tension-type headache (TTH) in adolescents. METHODS: A total of 1260 adolescents from the 10th and 11th grades of high schools filled in questionnaires on intake of meals, coffee, nonalcoholic and alcoholic drinks, smoking, and physical activity. Type of headache was classified according to the International Classification of Headache Disorders - 2nd edition. Multiple logistic regression models, adjusted for sex and grade, were calculated. RESULTS: High consumption of cocktails (odds ratio = 3.4; 95% confidence interval 1.9-6.0) and coffee (2.4; 1.3-4.7), smoking (2.7; 1.4-5.1), and lack of physical activity (2.2; 1.3-3.7) were significantly associated with migraine plus TTH episodes, consumption of coffee and physical inactivity particularly with migraine (3.4; 1.6-7.0 and 4.2; 2.2-7.9, respectively) and physical inactivity with TTH (1.7; 1.1-2.7). Skipping of meals or insufficient fluid intake were not associated with any type of headache. CONCLUSIONS: Adolescents with any type of headache might benefit from regular physical activity and low consumption of alcoholic drinks, while for migraine patients a low consumption of coffee should additionally be recommended. Intervention studies are warranted to assess whether psycho-educational programs conferring knowledge of these associations will influence headache-triggering behavior and headache in adolescents.