Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia.

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.

[Transition to adult care for patients with epilepsy]. / Transition bei Epilepsie.

The transition of children and adolescents with epilepsy to the adult healthcare system presents many challenges. The disease is frequently accompanied by cognitive and developmental impairments that make it difficult to achieve self-management of the disease. Seizures are often associated with a loss of consciousness; therefore, conversations regarding medical history often take place only between the physician and the parents. The children and adolescents then usually have a very little knowledge about their disease and do not learn to talk about their seizures and other disease-related problems. Childhood epilepsies are partly caused by rare genetic diseases, and neurologists usually have little experience with these diseases. In the past many of these etiologies were underdiagnosed in pediatrics and never reclassified during adulthood. An improvement of this situation requires long-term assistance over numerous years for the young patients to learn more about their own disease and the healthcare structures for adults. They should also be trained in how to talk about their medical problems with the doctor (physician-patient communication). At the medical level, a well-structured transfer of clinical findings, EEGs, imaging findings, etiologies, the current seizure situation, and the history of therapeutic measures is required. This article provides useful recommendations and information about existing programs and materials to support the management of transition.

Expanded phenotype of AARS1-related white matter disease.

PURPOSE: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease. METHODS: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts. RESULTS: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes. CONCLUSION: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.

Seizure-alerting behavior in dogs owned by people experiencing seizures.

INTRODUCTION: The unpredictability of epileptic seizures is considered an important threat to the quality of life of a person with epilepsy. Currently, however, there are no tools for seizure prediction that can be applied to the domestic setting. Although the information about seizure-alert dogs - dogs that display changes in behavior before a seizure that are interpreted by the owner as an alert - is mostly anecdotal; living with an alerting dog (AD) has been reported to improve quality of life of the owner by reducing the stress originating from the unpredictability of epileptic seizures and, sometimes, diminishing the seizure frequency. AIM OF THE STUDY: The aim of the study was to investigate, at an international level, the behaviors displayed by trained and untrained dogs that are able to anticipate seizures and to identify patient- and dog-related factors associated with the presence or absence of alerting behavior. METHODOLOGY: An online questionnaire for dog owners with seizures was designed. Information about the participants (demographics, seizure type, presence of preictal symptoms) and their dogs (demographics, behavior around the time of seizures) was collected. In addition, two validated scales were included to measure the human-dog relationship (Monash Dog-Owner Relationship scale (MDORS)) and five different traits of the dogs' personality (Monash Canine Personality Questionnaire refined (MCPQ-R)). RESULTS: Two hundred and twenty-seven responses of people experiencing seizures were received from six participant countries: 132 from people with dogs that had started alerting spontaneously, 10 from owners of trained AD, and the rest from owners of dogs that did not display any alerting behavior (nonalerting dog (NAD)). Individuals' gender, age, or seizure type did not predict the presence of alerting behavior in their dogs. People who indicated that they experience preictal symptoms were more likely to have a spontaneously AD. The owner-dog bond was significantly higher with ADs compared with NADs, and ADs scored significantly higher than NADs in the personality traits "Amicability", "Motivation", and "Training focus". CONCLUSION: This study collected a large group of dog owners with seizures reporting behavioral changes in their dogs before their seizures occurred. This was associated with the presence of preictal symptoms. The seizure-alerting behavior of the dog may have a positive influence on the bond between the owner and the dog.

Differences in Cerebellar Volume as a Diagnostic and Prognostic Biomarker in Children and Adolescents With Epilepsy of Unknown Etiology.

INTRODUCTION AND OBJECTIVE: Epilepsy is one of the most common brain diseases during childhood and adolescence. Atrophy in different brain areas is possible during epilepsy. This study aimed to verify whether cerebellar volume differences could be detected by volume analysis using magnetic resonance imaging (MRI) in children with epilepsy. METHOD: In this retrospective study, 41 children (3.1-18.8 years) with epilepsy of unknown etiology were included (duration of epilepsy 1.9 ± 3 years). A cranial MRI with a volumetric 3-dimensional, T1-weighted sequence was used for volume analysis. The MRIs of 26 patients with headache (5.3-17.1 years) were analyzed for comparison. A volume analysis of the cerebellum was performed using region-based morphometry. Total cerebellar volume, total white and gray matter volume, and 48 regional lobules (L), separated into white and gray matter, were calculated. Cerebellar volumes are presented in relative ratios as the volume fraction of cerebellar volume to total intracranial volume: CV/TIV. RESULTS: The ratio of overall white matter volume was significantly lower in the case group (23.93 × 10-3, P = .039). A significantly lower ratio of regional white matter volume was detected in LV right (P = .031) and left (P = .014), in LVIIIB right (P = .011) and left (P = .019), and in LVIIIA left (P = .009). CONCLUSION: Our results emphasize that volume analysis of the total cerebellar volume alone is insufficient to characterize cerebellar differences in children with epilepsy. Rather, in specific cerebellar region volume analysis using region-based morphometry, children with epilepsy showed significantly lower regional volumes of lobules, which are important for sensorimotor function (LV, LVIII) and higher cognitive function (crus I).

Pharmacology and drug interactions of cannabinoids.

Cannabinoids include a variety of substances, of which cannabidiol (CBD) is the main substance investigated for the treatment of epilepsy, and this will be the focus in the present review. CBD preparations exist in various forms. There are significant differences in quality control regarding content and reproducibility for an approved drug versus herbal preparations. Cannabidiol has challenging pharmacological properties, and pharmaceutical and pharmacokinetic aspects will depend on the formulation or preparation of a certain product. This article will focus on the characteristics, pharmacokinetic challenges, and interactions of standardised CBD-containing drugs based on evidence from clinical and pharmacokinetic studies.

Epilepsy and cannabidiol: a guide to treatment.

The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.

Strain Ultrasound Elastography of Muscles in Healthy Children and Healthy Adults. / Strain-Ultraschallelastografie der Muskulatur bei muskelgesunden Kindern und Erwachsenen.

PURPOSE: Standardized application and evaluation of the strain ultrasound elastography method (USE) by means of a strain color scale (SCS) and a strain ratio analysis. To determine differences in muscle elasticity in healthy children and adults. MATERIALS AND METHODS: Initially Mm. biceps brachii, Mm. recti femoris and Mm. gastrocnemii of 22 healthy adults were examined before and after exercise. Secondly measurements were obtained at rest in 21 healthy children. RESULTS: There was a difference in muscle elasticity between the upper and lower extremity. Muscle elasticity tends to be higher after exercise in healthy adults. SCS and strain ratio analysis show a similar trend. In comparison to adults, healthy children show lower muscle elasticity at rest using both analysis methods. CONCLUSION: Strain elastography is an easy to perform, cost-effective, non-invasive method to determine muscle stiffness, if the conditions of standardized measurements are given. KEY POINTS: · It is possible to perform standardized measurements with the strain elastography method in healthy adults and children. · Strain color scale as well as strain ratio analysis are appropriate tools to interpret the elastogrammes. · strain elastography shows higher elasticity in adults' muscles after exercise. · strain elastography shows higher elasticity in adults' muscles than in muscles of healthy children. CITATION FORMAT: · Wenz H, Dieckmann A, Lehmann T et al. Strain Ultrasound Elastography of Muscles in Healthy Children and Healthy Adults. Fortschr Röntgenstr 2019; 191: 1091 - 1098.

Effects of Levetiracetam and Sulthiame on EEG in benign epilepsy with centrotemporal spikes: A randomized controlled trial.

PURPOSE: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG. METHODS: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated. RESULTS: Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures. CONCLUSION: Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures.

[Do subclinical epileptiform discharges really affect short-term memory in children?]. / Beeinträchtigen subklinische epileptische Entladungen wirklich das Kurzzeitgedächtnis von Kindern?

OBJECTIVE: Deficits in concentration, specific developmental disorders, and behaviour problems often impair the educational abilities of children and adolescents with epilepsy, even if the subjects are seizure-free. The impact of subclinical epileptiform discharges that persist despite adequate antiepileptic treatment is not yet understood. Some studies suggest that these lead to simultaneous transitory cognitive impairment, thereby affecting short-term memory functions. This study examines the impact of subclinical discharges on memory functions. METHOD: 40 seizure-free children (10.3 +/- 3.5 years) with subclinical epileptiform discharges were examined by means of computerized EEG-coupled tests focussing on visuo-spatial and verbal short-term memory, in order to assess the temporal relation between discharges and test performance. RESULTS: No significant differences in cognitive performance were detected in phases with and without epileptiform discharges; neither discharges > 1.5 sec, nor multiple discharges within a test impaired performance. Moreover, performance was independent of the localisation of discharges and of the time of their occurrence during the test. CONCLUSIONS: The present study showed no association between subclinical epileptiform discharges and error rates as indicators of transient cognitive impairment in visuo-spatial and verbal short-term memory. Hence, other mechanisms have to be taken into account to explain the known cognitive deficits in patients with epilepsy.

Levetiracetam in children with refractory epilepsy: a multicenter open label study in Germany.

PURPOSE: To evaluate the efficacy and tolerability of Levetiracetam (LEV) in a large pediatric cohort with drug-resistant epilepsy from a prospective multicenter observational study. METHODS: We report the results of a multicenter observational survey of a cohort of 285 pediatric patients (mean: 9.9 years, range: 0; 6-17; 11) with refractory generalized and focal epilepsy who received Levetiracetam as an add-on open label treatment trial. The average duration of epilepsy was 6.0 years and the patients were treated with a mean of 7.0 antiepileptic drugs (AED) before LEV was introduced. RESULTS: No serious persistent adverse events were reported. Reversible colitis and an apnoea syndrome in a child with phosphorylase-A-kinase-deficiency were noted. Mild to moderate side effects were reported in 128 patients (44.9%), consisting most frequently of somnolence (23.9%), general behavioral changes (15.4%), aggression (10.5%) and sleep disturbances (3.2%). In 209 patients, efficacy was analyzed over a treatment period of at least 12 weeks compared to a baseline of 2 weeks. Thirteen patients (6.2%) became seizure free, 39 (18.7%) responded with a seizure reduction of more than 50% following introduction of LEV. No response to LEV was reported in 65.1% (n=136). A decrease of initial treatment effect was seen in 37 patients (17.8%) while in 6.7% the seizure frequency doubled to the baseline (n=14). In seven patients (3.3%), the effect of LEV on seizure frequency could not be evaluated. A positive psychotropic effect was observed in 18 patients (8.6%). Mental retardation was associated with poor response and associated with more side effects and earlier discontinuation of LEV therapy. CONCLUSION: LEV is a well-tolerated new AED that may effectively improve seizure control as an add-on drug in resistant epilepsy in childhood with good tolerability. However, neurologically handicapped children appear at increased risk for reversible neurocognitive side effects and have a poorer treatment response.

Intrauterine growth restriction improves cerebral O2 utilization during hypercapnic hypoxia in newborn piglets.

Data are scant regarding the capacity of cerebrovascular regulation during asphyxia for prevention of brain oxygen deficit in intrauterine growth-restricted (IUGR) newborns. We tested the hypothesis that IUGR improves the ability of neonates to withstand critical periods of severe asphyxia by optimizing brain oxygen supply. Studies were conducted to examine the effects of IUGR on cerebral blood flow (CBF) regulation and oxygen consumption (cerebral metabolic rate for oxygen, CMRO(2)) at different stages of asphyxia (hypercapnic hypoxaemia) in comparison to pure hypoxia (normocapnic hypoxaemia). We used 1-day-old anaesthetized and ventilated piglets. Animals were divided into normal weight (NW) piglets (n = 47; aged 11-26 h, body weight 1481 +/- 121 g) and IUGR piglets (n = 48; aged 13-28 h, body weight 806 +/- 42 g) according to their birth weight. Different stages of hypoxaemia were induced for 1 h by appropriate lowering of the inspired fraction of oxygen (moderate hypoxia: = 31-34 mmHg; severe hypoxia: = 20-22 mmHg). Fourteen NW and 16 IUGR piglets received additionally 9% CO(2) in the breathing gas, so that a of 74-80 mmHg resulted (hypoxia/hypercapnia groups). Eight NW and nine IUGR animals served as untreated controls. Furthermore, affinity of haemoglobin for oxygen was measured under hypoxic and asphyxic conditions. During asphyxia cerebral oxygen extraction was markedly increased in IUGR animals (P < 0.05). This resulted in a significantly diminished CMRO(2)-related increase of CBF at gradually reduced arterial oxygen content (P < 0.05). Therefore, an enhanced effectivity in oxygen availability appeared in newborn IUGR piglets under graded asphyxia by improved cerebral oxygen utilization (P < 0.05). This was not supported by related O(2) affinity of haemoglobin. Thus, IUGR newborns are more capable to ensure brain O(2) demand during asphyxia (hypercapnic hypoxia) than NW neonates.

Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets.

BACKGROUND: Perinatal hypoxia-ischemia (HI) is associated with delayed cerebral damage, which involves receptor-mediated excitotoxicity. Until now, successful interventions to reduce excitotoxicity early after HI in experimental settings failed to transform into clinical applications owing to negative side effects. A promising new approach using the anticonvulsant Topiramate (TPM) has shown to be effective to reduce brain damage after early HI in a rodent model of combined TPM-hypothermia. Here, we used TPM solely administered 1 h after HI in a neonatal piglet model in order to verify possible neuroprotection. METHODS: Newborn piglets were subjected to HI by transient occlusion of carotid arteries and hypotension (62-65% of baseline). Fifteen minutes later, an additional reduction of the inspired oxygen fraction to 0.06 was performed for 13 min. One cohort (VEHICLE, n = 8) received saline solution i.v. 1 h after HI and then twice a day. Two further cohorts were treated at same times with TPM (HI-TPM10, n = 8, loading dose 20 mg/kg; maintenance dose 10 mg/kg/day; HI-TPM20, n = 8, loading dose 50 mg/kg; maintenance dose 20 mg/kg/day). Untreated animals (CONTROL, n = 8) received all experimental procedures except HI. Animals were monitored 3 days after HI concerning occurrence of seizures as well as neurological and behavioral functions. After 72 h, the brains were perfused and processed to assess neuronal loss and DNA-fragments (TUNEL staining). RESULTS: There was a significant reduction of neuronal cell loss in HI-TPM20 animals. However, apoptosis was increased in the frontal white matter of HI-TPM20 animals. CONCLUSIONS: Exclusive TPM treatment shows neuroprotection in newborn piglets after HI.

Early diagnosis of cerebral involvement in Sturge-Weber syndrome using high-resolution BOLD MR venography.

Sturge-Weber syndrome (SWS) is a congenital disorder characterized by a vascular birthmark and neurological abnormalities. Typical imaging findings using MRI or CT are superficial cerebral calcification, atrophy and leptomeningeal enhancement. We present a neonate diagnosed with SWS because of a port-wine stain. In the absence of neurological symptoms the first MRI was performed when he was 4 months old, and follow-up MRI studies were performed after his first seizure at the age of 12 months. MRI was performed using standard sequences before and after administration of IV gadolinium. A high-resolution T2*-weighted, rf-spoiled 3D gradient-echo sequence with first-order flow compensation in all three directions was used for additional venographic imaging [blood-oxygen-level-dependent (BOLD) venography]. The initial conventional MRI sequences did not demonstrate any abnormality, but BOLD venography identified leptomeningeal internal veins. Follow-up MRI after the first onset of seizures demonstrated strong leptomeningeal enhancement, while BOLD venography revealed pathological medullary and subependymal veins as well as deep venous structures. At this time there were the first signs of atrophy and CT showed marginal calcifications. This report demonstrates that high-resolution BOLD MR venography allows early diagnosis of venous anomalies in SWS, making early therapeutic intervention possible.

Diffusion tensor imaging in children and adolescents with tuberous sclerosis.

BACKGROUND: Tuberous sclerosis (TS) is characterised by benign hamartomatous lesions in many organs. Diffusion tensor imaging (DTI) can detect microstructural changes in pathological processes. OBJECTIVE: To determine apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps in children with TS and to investigate the diffusion properties in cortical tubers, white-matter lesions, perilesional white matter, and contralateral normal-appearing white matter, and to compare the results with ADC and FA maps of normal age- and sex-matched volunteers. MATERIALS AND METHODS: Seven children and adolescents (age range 2-20 years) suffering from TS were included. MRI was performed on a 1.5-T scanner using a transmit/receive coil with T1-W and T2-W spin-echo and FLAIR sequences. DT images were acquired by using a single-shot echo-planar pulse sequence. Diffusion gradients were applied in six different directions with a b value of 1,000 s/mm(2). RESULTS: ADC was higher in cortical tubers than in the corresponding cortical location of controls. ADC values were higher and FA values were lower in white-matter lesions and perilesional white matter than in both the contralateral normal-appearing white matter of patients and in controls. There were no significant differences for both ADC and FA values in the normal-appearing white matter of patients with TS compared to controls. CONCLUSIONS: DTI provides important information about cortical tubers, white-matter abnormalities, and perilesional white matter in patients with TS.

Effect of routine MR imaging of the brain at 1.5 T on subsequent magnetoencephalography: results in nine volunteers.

PURPOSE: To investigate whether routine magnetic resonance (MR) imaging of the brain with a whole-body 1.5-T imager affects the results of subsequent magnetoencephalography (MEG). MATERIALS AND METHODS: Nine healthy volunteers (six women, mean age of 23 years, age range of 20-27 years; three men, mean age of 24 years, age range of 23-25 years) underwent one MEG session before and two MEG sessions after MR imaging of the brain. The first MEG session was completed about 20 minutes before brain MR imaging began, the second MEG session (MEG 2) was performed within 30 minutes after MR imaging, and the third MEG session was performed 2 hours after MEG 2. Each MEG session involved measurement of spontaneous brain activity and, in seven patients, of brain activity during stimulation of the median nerve. MR imaging included T1- and T2-weighted fast spin-echo and gradient-echo sequences applied with a 1.5-T clinical imager. Data were compared by using a repeated-measures analysis of variance (general linear model) both with and without Greenhouse-Geisser correction. RESULTS: MEG signals were detected and measured without difficulty in all volunteers. No statistically significant difference was seen between estimated noise at MEG before and after MR imaging (P =.588 with correction, P =.665 without correction). MEG records obtained in all volunteers enabled localization of evoked response to median nerve stimulation before and after MR imaging. No measurable differences were observed between relative power spectra of spontaneous brain activity before and after MR imaging (P >.290 with correction, P >or=.295 without correction). CONCLUSION: No measurable effect of 1.5-T brain MR imaging on subsequent MEG was detected.