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.