Serum neurofilament light-chain levels in children with monophasic myelin oligodendrocyte glycoprotein-associated disease, multiple sclerosis, and other acquired demyelinating syndrome.

OBJECTIVE: To assess the diagnostic and prognostic potential of serum neurofilament light chain (sNfL) in children with first acquired demyelinating syndrome (ADS). METHODS: We selected 129 children with first ADS including 19 children with myelin oligodendrocyte glycoprotein (MOG)-antibody associated disease (MOGAD), 36 MOG/AQP4-seronegative ADS, and 74 with multiple sclerosis (MS) from the BIOMARKER study cohort. All children had a complete set of clinical, radiological, laboratory data and serum for NfL measurement using a highly sensitive digital ELISA (SIMOA). A control group of 35 children with non-inflammatory neurological diseases was included. sNfL levels were compared across patient groups according to clinical, laboratory, neuroradiological features and outcome after 2 years. RESULTS: sNfL levels were significantly increased in MOGAD, seronegative ADS and MS compared to controls (p-value < 0.001), in particular in children with an acute disseminated encephalomyelitis (ADEM)-like magnetic resonance imaging (MRI) pattern (p < 0.001) or longitudinally extensive myelitis (p < 0.01). In pediatric MS, elevated sNfL levels were significantly associated with higher numbers of cerebral (p < 0.001) and presence of spinal (p < 0.05) MRI lesions at baseline and predicted a higher number of relapses (p < 0.05). CONCLUSION: sNfL levels are significantly elevated in all three studied pediatric ADS subtypes indicating neuroaxonal injury. In pediatric MS high levels of sNfL are associated with risk factors for disease progression.

Accuracy of Flash Glucose Monitoring in a Patient with Dravet Syndrome on a Ketogenic Diet.

We herein report the case of a 3-year-old girl with severe myoclonic epilepsy of infancy known as Dravet syndrome (DS) on a ketogenic diet (KD) whose glucose concentrations were controlled by using a flash glucose monitoring system. Two-hundred ninety-three events of moderate hypoglycemia with a minimum of 45 mg/dL, not related to day or night, were recorded during the observational period. Hypoglycemia rate declined from 24.5% of all measurements to 11.8% over time; one hypoglycemia-associated seizure and one seizure due to ketone concentrations below the therapeutic range were observed. In summary, this case report broadens our understanding of hypoglycemia risk in patients with DS on a KD. Especially in childhood, the painless and easy detection of low glucose concentrations might lead to improved cognitive performance, and the reduction of hypoglycemia-induced seizures.

Co-infection of SARS CoV-2 and influenza A in a Pediatric Patient in Germany.

In December 2019 a novel coronavirus was firstly encountered in Wuhan/China with a massive outbreak of fatal pneumonia leading to a pandemic declared by the World Health Organization in March 2020 (WHO Dashboard COVID-19. [WHO web site]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019), affecting mainly elderly adults with underlying co-morbidities. Clinical course in children below the age of 10 years is considered to be mild or even with subclinical signs (Sinha IP, Ha et al. The Lancet Respiratory medicine 2020;27;S2213-2600(20) 30152-1). We describe a 4 month old infant with co-infection of SARS CoV-2 and influenza A virus.

Comparing modalities of conducting the six-minute walk test in healthy children and adolescents.

BACKGROUND: The 6-minute walk test (6MWT) in children can be performed in the conventional way, or by using a measuring wheel. This study aimed to compare these test modalities and to determine influencing factors. METHODS: The study included 317 healthy children (172 boys) between 6 and 15 years from elementary schools and high schools, who were randomly assigned to perform a 6MWT either with or without a measuring wheel according to the guidelines of the American Thoracic Society. The 6-minute walk distance (6MWD) was compared between the two measuring modalities as well as different school types. RESULTS: The use of a measuring wheel during the 6MWT led to a significantly greater 6MWD compared to conventional walking. Students of sports schools walked substantially farther than those attending general high schools, irrespective of test modality. In multivariate regression analysis height, post-test heart rate, male sex and the measuring wheel itself were all independently associated with greater 6MWD. CONCLUSIONS: The use of a measuring wheel during a 6MWT reflects physical performance in children and adolescents more accurately as it includes the stretch of way around the cones during lap turns. Test modalities and sports background should be taken into account, especially when performing longitudinal monitoring and multicenter studies.

Pediatric Maxillary Osteomyelitis: A Case Report of a Rare Entity.

Maxillary osteomyelitis is a rare disease, especially in the pediatric population. We present a case of maxillary osteomyelitis in an eight-year-old girl with favorable outcome. Diagnosis was based on magnetic resonance imaging as well as on direct inspection intra operatively. Treatment should be based primarily on clinical signs (e.g. loose teeth). Teeth should not been extracted if healthy.

Quality of Life and Fitness in Children and Adolescents with Epilepsy (EpiFit).

Objective The objective of this study was to evaluate the correlation between fitness and health-related quality of life (HRQoL) in children with idiopathic epilepsy compared with a healthy matched control group. Methods In this study, 107 children conducted a 6-minute walk test, anthropometric parameters were measured, and HRQoL was assessed using a standardized questionnaire (KINDL-R). Children were divided into two groups: (1) the patient group (n = 48) and (2) the healthy control group (n = 59). Results HRQoL of children with focal epilepsy was greater when compared with healthy children and children with generalized epilepsy. A significant association could be demonstrated for the 6-minute walk distance and mental wellbeing in children with epilepsy but not in healthy children. Furthermore, a negative correlation between the HRQoL and the amount of time spent in front of TV and computer in children with epilepsy and healthy children was seen. In children with focal epilepsy, a significant negative correlation could be shown between school sport and mental wellbeing as well as between school sport and self-esteem. Conclusion HRQoL in children with idiopathic epilepsy is significantly associated with physical fitness and might be positively influenced by an adequate education of patients and parents, a reduction of consumption of computer and TV in combination with age- and disease-adapted physical activity and sports.

Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families.

Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the γ-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase. While several dozens of patients with glutathione synthetase deficiency have been reported, with hemolytic anemia representing the clinical key feature, 5-oxoprolinase deficiency due to OPLAH mutations is less frequent and so far has not attracted much attention. This has prompted us to investigate the clinical phenotype as well as the underlying genotype in patients from 14 families of various ethnic backgrounds who underwent diagnostic mutation analysis following the detection of 5-oxoprolinuria. In all patients with 5-oxoprolinuria studied, bi-allelic mutations in OPLAH were indicated. An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes. It is remarkable, that all 20 mutations identified were novel and private to the respective families. Clinical features were highly variable and in several sib pairs, did not segregate with 5-oxoprolinuria. Although a pathogenic role of 5-oxoprolinase deficiency remains possible, this is not supported by our findings. Additional patient ascertainment and long-term follow-up is needed to establish the benign nature of this inborn error of metabolism. It is important that all symptomatic patients with persistently elevated levels of 5-oxoproline and no obvious explanation are investigated for the genetic etiology.

A Novel Variant in the HINT1 Gene in a Girl with Autosomal Recessive Axonal Neuropathy with Neuromyotonia: Thorough Neurological Examination Gives the Clue.

We report a girl with autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) who presented with asymmetric gait impairment, foot drop, and action myotonia on fast handgrip. Electrophysiological studies showed symmetrical axonal motor greater than sensory neuropathy, and neuromyotonic discharges on needle electromyography. ARAN-NM was confirmed by molecular genetic testing, which revealed a novel homozygous missense variant c.100G > A [p.(Glu34Lys)] in HINT1. This case shows that the diagnosis of ARAN-NM, as a new entity, has to be considered in the differential diagnosis of polyneuropathy in combination with neuromyotonia/action myotonia in children, even with asymmetric clinical presentation.

Sex-, age-, and height-specific reference curves for the 6-min walk test in healthy children and adolescents.

UNLABELLED: The 6-min walk test is a simple and accurate method to measure functional exercise capacity in children. We provide smooth reference curves for the modified 6-min walk test in 696 healthy children and adolescents aged 4-19 years, enabling calculation of sex-, age-, and height-specific Z-scores. CONCLUSION: These reference curves will allow more accurate grading of mobility and exercise capacity in sick or disabled children and monitoring the effects of intervention or treatment.

Activities of daily living in children with hemiparesis: influence of cognitive abilities and motor competence.

PURPOSE: The aim of the article is to investigate whether motor competence and cognitive abilities influence the quality of performance of activities of daily living (ADL) in children with hemiparesis. Patients and METHODS: A total of 20 children with hemiparesis (age, 6-12 years; 11 congenital, 9 acquired during childhood) were studied. Motor competence was assessed with the Assisting Hand Assessment, cognitive abilities with the German version of the Wechsler Intelligence Scale for Children IV, and the quality of ADL performance with the Assessment of Motor and Process Skills (AMPS). RESULTS: The motor skills scale of the AMPS correlated with motor competence, and the process skills scale of the AMPS correlated with cognitive abilities. CONCLUSION: The quality of ADL performance is influenced not only by motor competence but also by the cognitive abilities of a hemiparetic child. This suggests that, in addition to motor-oriented training programs, an optimal therapy for hemiparetic children should also consider cognitive approaches.

Reproductive endocrine health in pubertal females with epilepsy on antiepileptic drugs: time to screen?

OBJECTIVES: Although previous studies suggest that valproate (VPA) may induce reproductive endocrine disorders, the effects of newer antiepileptic drugs (AEDs) on reproductive endocrine health have not been widely investigated and compared with those of older AEDs. Therefore, this multicenter cross-sectional study aimed to evaluate the prevalence of reproductive endocrine dysfunctions in pubertal females with epilepsy receiving VPA, lamotrigine (LTG), or levetiracetam (LEV) monotherapy. PATIENTS AND METHODS: Pubertal girls on VPA (n = 11), LTG (n = 8), or LEV (n = 13) monotherapy for at least 6 months were recruited. Healthy sex-matched and age-matched subjects were enrolled as controls (n = 32). Each participant underwent a comprehensive physical examination concerning signs of hyperandrogenism. The Ferriman-Gallwey score of hirsutism was assessed. In addition, all patients completed a standardized questionnaire regarding epilepsy, menstrual cycle, and hirsutism features. Adiposity indices were measured and weight gain was documented for each subject. RESULTS: Hirsutism score, occurrence of hyperandrogenism features, and adiposity indices were significantly higher in the VPA group when compared with LEV and control groups. VPA therapy was more frequently associated with weight gain when compared with LTG and controls, whereas no significant differences with regard to signs of hyperandrogenism were found between VPA and LTG groups. Furthermore, no differences in menstrual disorders were observed between groups. CONCLUSIONS: Pubertal girls with epilepsy receiving VPA monotherapy were more likely to develop signs of hyperandrogenism, that is, hirsutism and acanthosis, than those on LEV or controls. However, no differences in occurrence of menstrual disorders and other reproductive dysfunctions were found between VPA, LTG, LEV, and control groups. These findings do not allow us to clearly determine whether or not VPA, LEV, and LTG monotherapies considerably affect reproductive endocrine health in pubertal girls with epilepsy. Therefore, further prospective studies of larger sample sizes are needed to establish if screening tests should be recommended.

Use of intrathecal baclofen in children and adolescents: interdisciplinary consensus table 2013.

In recent years, intrathecal baclofen (ITB) has attained an important role in the treatment of severe spasticity and dystonia in children. There are principal differences between the use of ITB in children and its use in neurology and oncology in adults. Here, we present a consensus report on best practice for the treatment of severe spastic and dystonic movement disorders with ITB. Using a problem-orientated approach to integrate theories and methods, the consensus was developed by an interdisciplinary group of experienced ITB users and experts in the field of movement disorders involving 14 German centers. On the basis of the data pooled from more than 400 patients, the authors have summarized their experience and supporting evidence in tabular form to provide a concise, but still a comprehensive information base that represents our current understanding regarding ITB treatment options in children and adolescents.

Primary Headache Is Related to Reduced Health-Related Quality of Life in Children with Epilepsy.

Headache is a frequent comorbidity in patients with epilepsy. Data are sparse regarding the distribution of headache types in children with epilepsy (CWE). We aimed to assess the prevalence of primary headache types and their influence on health-related quality of life (QoL) in CWE. CWE filled out a validated headache questionnaire to assess migraine (MIG), tension-type headache (TTH), trigeminal-autonomic cephalalgia (TAC), or, if the criteria were not fulfilled, non-classifiable headache (NCH). QoL was measured using both patient and parent versions of a validated questionnaire. Of 119 CWE (59 female; 11.5 ± 3.1 y), headache was found in 46 (38.7%). Sixteen (34.8%) patients showed MIG, 9 (19.6%) patients TTH, and 21 (45.7%) patients described NCH. More girls reported headache (χ2 = 5.4, p = 0.02) when compared to boys. Overall, QoL was reduced in patients with headache from both the patients' and parents' points of view (70.8% [39.6; 87.5] vs. 77.0% [46.9; 95.8], p = 0.002; 71,9% [33.3; 87.5] vs. 78,1% [54.2; 95.8], p = 0.003). Headache is common among CWE with MIG as the most prevalent primary headache type and higher rates in female patients. Importantly, patients and their parents perceive a reduced overall QoL when suffering from headache.

Pulsatile corticoid therapy reduces interictal epileptic activity burden in children with genetic drug-resistant epilepsy.

OBJECTIVE: Corticosteroids and adrenocorticotropic hormone (ACTH) are the therapy of choice to treat infantile spasms. However, systematic studies about their use in other types of childhood epilepsies remain rare and ACTH can have serious side effects. This study compares the interictal epileptic activity (IEA) burden (% of electroencephalography (EEG) time with IEDs) in children with genetic drug-resistant epilepsy before and after a standardized treatment with pulsatile corticoid therapy (PCT). METHODS: Children with drug-resistant epilepsy underwent a standardized protocol for PCT with cycles of high-dose dexamethasone (20 mg/m2 body surface) intravenously. Patients were hospitalized for 3 days per PCT cycle and EEGs were obtained before initiation of treatment (baseline) and during the hospitalization around the time of every second cycle. EEG recordings during sleep and wakefulness were obtained. IEA burden was compared before and after PCT. Secondary outcome measures included the sleep spindle rate, the seizure frequency and subjective evaluation in a standardized interview. RESULTS: In the cohort of 24 children (10 female, 6.2 ± 3.4 years), IEA burden was lower in the EEG after PCT compared to the baseline (baseline: 5.4% [0.7-97.3] vs. after PCT: 1.5% [0-96.9], p = 0.001, d = -0.41). Sleep physiology expressed by sleep spindles improved after PCT with enhanced fast spindle rates (0.8/min [0-2.2] vs. 1.5/min [0.2-3.4], p = 0.045, d = 0.36). Seizure frequency was decreased in 17 of the 24 patients (70.8%) with one patient achieving seizure freedom. The majority of patients improved in quality of life (79.2%), and sleep (81.3%). No serious adverse effects were documented. SIGNIFICANCE: This study systematically assessed the effect of PCT in children with genetic / suspected genetic drug-resistant epilepsy. PCT was found to not only reduce the IEA burden but also increase sleep spindle rates, which are important for cognitive functioning. PLAIN LANGUAGE SUMMARY: In this study, children with a form of epilepsy, which is resistant against antiseizure medication, received a systematic treatment with corticosteroids over multiple cycles in the hospital. It was found that not only the epileptic activity was reduced but also the sleep of the patients was improved after the treatment. These findings could provide the basis for extending the use of corticosteroids in children with epilepsy.

Primary headache types in adult epilepsy patients.

BACKGROUND: Headache is among the most common comorbidities in epilepsy. This study examined the distribution of different primary headache disorders in a large cohort of patients with diagnosed epilepsy. Headache types were analysed with regard to gender, type of epilepsy and antiepileptic drugs (AEDs). METHODS: In this prospective single-centre study, 500 patients with epilepsy (250 female, mean age: 45.52 ± 17.26 years) were evaluated with regards to primary headache types using a validated German headache questionnaire categorizing for migraine (MIG), tension-type headache (TTH) or trigeminal autonomic cephalalgias (TAC), their combinations and unclassifiable headache. Data regarding type of epilepsy, seizure-associated headache, AED treatment and seizure freedom were collected. RESULTS: Of 500 patients with epilepsy, 163 (32.6%) patients (108 female and 55 male) reported suffering from headaches at least 1 day per month. MIG (without aura, with aura) and TTH were the most frequent headache type (MIG 33.1%, TTH 33.1%). Female epilepsy patients reported headaches significantly more often than male patients (x2 = 8.20, p = 0.0042). In contrast, the type of epilepsy did not significantly affect headache distribution. Of 163 patients with headache, 66 (40.5%) patients reported seizure-associated headache and AEDs were used by 157 patients. Of importance, patients with AED monotherapy suffered from MIG less often when compared to patients on polytherapy (x2 = 4.79, p = 0.028). CONCLUSION: MIG and TTH are the most common headache types in epilepsy patients and headache is more frequent among female epilepsy patients. Monotherapy in AEDs might have a beneficial effect on the frequency of headache compared to polytherapy.

Simultaneous online SPE-LC-MS/MS quantification of six widely used synthetic progestins in human plasma.

Co-administration of synthetic progestin containing hormonal contraceptives (HCs) and antiepileptic drugs (AEDs) is a common clinical situation which needs specific considerations due to drug interactions. Several studies have demonstrated that lamotrigine plasma levels are significantly decreased during co-medication with HCs, and that this interaction is associated with increased seizure frequency in most of the cases. Additionally, an increase in contraceptive failure and unintended pregnancy could be observed during co-medication. Hence, monitoring of progestin plasma levels in patients with AED co-medication is of interest. A rapid and reliable online solid-phase extraction-high performance liquid chromatography-tandem mass spectrometry (online SPE-LC-MS/MS) method using gradient elution in the LC domain was established and validated for the simultaneous quantitative determination of gestodene, dienogest, drospirenone, etonogestrel, cyproterone acetate, and levonorgestrel in human plasma. The online SPE-LC-MS/MS method covered a quantification concentration range of 5-100 ng/ml for dienogest, 1-100 ng/ml for etonogestrel and 2-100 ng/ml for all other analytes. Stable isotope-labeled internal standards were used for analyte quantification based on selected reaction monitoring experiments. Inter- and intra-assay precision and accuracy were determined from quality control (QC) samples at the lower limits of quantification and at low, medium, and high concentration levels within the calibration range. Inter-assay reproducibility at the QC levels was better than 10% (relative standard deviation, RSD), accuracy at these levels ranged from -3.7% to 11.3%. Total extraction efficiency, tested at three concentrations, ranged from 92.5% to 106.4%. Matrix interferences were excluded by post-column infusion experiments. To prove the applicability of the assay in clinical cohorts, a sample set (n = 298) stemming from study patients under AED/oral HC co-medication was screened for progestin plasma levels. This method has to be considered a research-use-only assay and must not be used for diagnostic or therapeutic purposes, since it did not undergo formal performance evaluation in the sense of the IVD directive (98/79/EG) of the European Community.

Monitoring Glucose Concentrations in Children with Epilepsy on a Ketogenic Diet.

Ketogenic diet (KD) and pulsatile dexamethasone therapy (PDT) are commonly used in the treatment of children with drug resistant epilepsy. Potential side effects of the KD are hypoglycemia, whereas PDT might lead to hyperglycemia. One practical option to measure glucose concentrations regularly is the flash glucose monitoring system (FGM). In this single-center study in Germany, two pediatric patients with epilepsy (age: 6.0 and 6.8 years) received FGM from the beginning of the KD over six months, in the year 2020, and one patient (9.8 years) was observed for one month on PDT and switched to the KD thereafter. Glucose concentrations were measured by using an FGM system and capillary blood measurement. Seizure frequency, changes in cognition, motor performance, social behavior, and sleep quality were evaluated. The mean hypoglycemia rate per day (65 mg/dL and lower) declined significantly in patient 1 and 2 after three months. Patient 3 showed in total seven hyperglycemic events during PDT. Patient 1 became seizure free. Improvement of attention and memory performance were reported. FGM during the KD as a treatment for drug resistant epilepsies in childhood is a practical option to explore and to avoid hypoglycemia during the KD and hyperglycemia during PDT.

Six-minute walk distance in overweight children and adolescents: effects of a weight-reducing program.

OBJECTIVE: To assess the significance of consecutive six-minute walk tests (6MWTs) during a weight reduction program. STUDY DESIGN: Overweight children and adolescents (n = 113; mean ± standard deviation age, 12.9 ± 2.0 years; 64 girls) performed a standardized 6MWT at the beginning and end of an in-patient weight reduction program consisting of exercise, diet, and educational and psychological support. Their 6-minute walk distance (6MWD) was compared with age- and sex-matched normal-weight children (n = 353). RESULTS: Preintervention 6MWD averaged 93% of control subjects (631 ± 88 m versus 675 ± 70 m, P < .001) and increased significantly to 667 ± 90 m (P < .001) after 27 ± 7 days of intervention (99% of control subjects; P = .260). Participants reduced their body weight from 80.9 ± 19.8 kg to 75.6 ± 19.0 kg, body mass index (BMI) percentile from 98.2 ± 2.1% to 96.8 ± 3.8%, and BMI-standard deviation score from 2.37 ± 0.6 to 2.13 ± 0.6 (P < .001 for each variable). BMI-standard deviation score, height, and the change in heart rate during the 6MWT were significant independent predictors of the 6MWD at preintervention and at post intervention time points (P < .001 each). CONCLUSIONS: The 6MWD increases during a weight reduction program, indicating improvement of physical fitness and decreased metabolic demand during daily activities in overweight children. The 6MWT represents a practical and reliable assessment tool for exercise performance in overweight children and adolescents.

Old and new antiepileptic drugs during pregnancy and lactation--report of a case.

We describe a case of a woman with epilepsy treated with primidone/phenobarbital (so-called "old" antiepileptic drug) and levetiracetam (so-called "new" antiepileptic drug) who was discouraged from breastfeeding, resulting in clinically significant withdrawal seizures in her newborn. As a consequence, even when two or more antiepileptic drugs are needed for the treatment of women with epilepsy, breastfeeding should be recommended, mothers should be informed about the possibility of drug effects on the neonate, and infants of mothers treated with primidone/phenobarbital should be closely monitored for possible signs of sedation.