Expectations of patient associations from a French Center for Rare Epilepsies.

Rare epilepsy centers, also called reference centers in France, have the mission to coordinate care for rare diseases, improve knowledge, and conduct research on rare diseases. Dissemination of knowledge is conducted in collaboration with patient associations. In just a few years, the Internet and social media have become the main source for news and knowledge. We conducted a survey about the use of social media and the expectations of patient associations from a rare epilepsy center. From the 29 associations on our website, 18 (62%) answered the survey, representing about 9000 members. All of the patient associations use social media. Facebook is used by all of them, and most of them also used additional social media channels. 13/18 (72%) associations found that it was easy to get in touch with our center and almost all partner associations were satisfied with the information published on our website (17/18, 94%). Eight patient associations (8/15, 53%) expected more information from us regarding scientific news (10/13) and clinical trials (8/13). Despite the existence of an active website and a monthly newsletter, the family associations interacting with our rare epilepsy center still want to collaborate even more with us. The use of social media by the rare epilepsy centers might help to fill the gap of the knowledge dissemination.

Considering safety and patient tolerance in the use of ketogenic diet in the management of refractory and super-refractory status epilepticus: a systematic review.

INTRODUCTION: Early use of the ketogenic diet (KD) is described as having a particular interest for super-refractory status epilepticus and febrile infection-related epilepsy syndrome. The authors conducted a systematic review of the available data on the KD for refractory and super-refractory status epilepticus. AREAS COVERED: Following a systematic bibliographic search, the authors found 15 published papers: 2 prospective and 13 retrospective studies. Most often, the primary aim of the retrospective studies was the efficacy evaluation of the KD for refractory or super-refractory status epilepticus. Four studies focused on the use of KD for NORSE/FIRES. These initial studies suggested that KD was effective in these conditions, and that it showed mild and manageable side effects. EXPERT OPINION: The published studies provided enough preliminary data to validate the feasibility and safety of the use of KD for refractory and super-refractory status epilepticus. Further studies demonstrating the efficacy of the KD in these indications are needed. Possible design and endpoints are discussed.

Views of adolescents and their parents on mobile apps for epilepsy self-management.

INTRODUCTION: New technologies are ubiquitous in our everyday lives, and this is especially true for teenagers. Very few mobile apps have been designed for adolescents with epilepsy. In order to better understand their expectations as well as those of their parents, we conducted a survey on this topic. METHODS: The survey consisted of an anonymous self-administered questionnaire that was distributed to adolescents with epilepsy aged 10 to 18 years old and their parents. Questionnaires contained 15 questions including 8 multiple choice questions, 5 groups of multiple questions with a rating scale ranging from 1 to 6, and 2 open-ended questions covering the scope of the interest of epilepsy self-management apps, seizure and epilepsy management, antiseizure medications, and information on epilepsy. RESULTS: Surveys were answered by 17 teenagers and 19 parents. It showed that adolescents embrace new technologies. Parents' highest expectations regarding mobile apps contents were seizure management and emergency information, while adolescents were expecting contents on epilepsy daily life, as well as a tool that would improve antiseizure medication compliance. CONCLUSION: Parents and adolescents' expectations on the content of an epilepsy app were different.

History of dietary treatment from Wilder's hypothesis to the first open studies in the 1920s.

In the ketogenic diet (KD) history, Wilder is often mentioned as the first author to report on the use of KD for patients with epilepsy. Our article aimed to understand how Wilder formulated the hypothesis of the KD effectiveness for patients with epilepsy, and how the KD was used and spread in the 1920s. In 1921, Wilder published two articles on the effects of ketonemia on epilepsy. He first reported on the interest of fasting for patients with epilepsy, suggesting that the benefits of fasting on seizures might be dependent on ketonemia. He then hypothesized that equally good results could be obtained with a KD, very rich in fat and very low in carbohydrate, which would provoke ketogenesis, and observed the effects of this diet on three patients for the first time. Following the publication of Wilder articles, 9 papers on KD were published during the 1920s, involving more than 400 patients with epilepsy. Ketogenic diet therapies (KDT) are now evidence-based treatments of epilepsy. Available experimental data do not confirm the role of ketosis as the unique mechanism of the KD. The KD is still explored to understand all the underlying mechanisms.

History of dietary treatment: Guelpa & Marie first report of intermittent fasting for epilepsy in 1911.

We analyzed the article of Guelpa & Marie, published in 1911 and often quoted in the history of dietary treatment, as the basis for the use of ketogenic diet to mimic fasting. In this paper, the authors treated 21 patients with a diet consisting of daily administration of 30 g of sodium sulphate for 4 days, with unlimited aqueous beverage and no food, followed by a vegetarian diet restricted to half of the ordinary intake. This is the first report of intermittent fasting as treatment strategy for epilepsy. In this case series, 15 patients did not follow properly the diet while 2 improved temporary before they quitted the diet and 4 presented an improvement.

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

Clinical Practice Guidelines for Rare Diseases: The Orphanet Database.

Clinical practice guidelines (CPGs) for rare diseases (RDs) are scarce, may be difficult to identify through Internet searches and may vary in quality depending on the source and methodology used. In order to contribute to the improvement of the diagnosis, treatment and care of patients, Orphanet (www.orpha.net) has set up a procedure for the selection, quality evaluation and dissemination of CPGs, with the aim to provide easy access to relevant, accurate and specific recommendations for the management of RDs. This article provides an analysis of selected CPGs by medical domain coverage, prevalence of diseases, languages and type of producer, and addresses the variability in CPG quality and availability. CPGs are identified via bibliographic databases, websites of research networks, expert centres or medical societies. They are assessed according to quality criteria derived from the Appraisal of Guidelines, REsearch and Evaluation (AGREE II) Instrument. Only open access CPGs and documents for which permission from the copyright holders has been obtained are disseminated on the Orphanet website. From January 2012 to July 2015, 277 CPGs were disseminated, representing coverage of 1,122 groups of diseases, diseases or subtypes in the Orphanet database. No language restriction is applied, and so far 10 languages are represented, with a predominance of CPGs in English, French and German (92% of all CPGs). A large proportion of diseases with identified CPGs belong to rare oncologic, neurologic, hematologic diseases or developmental anomalies. The Orphanet project on CPG collection, evaluation and dissemination is a continuous process, with regular addition of new guidelines, and updates. CPGs meeting the quality criteria are integrated to the Orphanet database of rare diseases, together with other types of textual information and the appropriate services for patients, researchers and healthcare professionals in 40 countries.

Updating temporal expectancy of an aversive event engages striatal plasticity under amygdala control.

Pavlovian aversive conditioning requires learning of the association between a conditioned stimulus (CS) and an unconditioned, aversive stimulus (US) but also involves encoding the time interval between the two stimuli. The neurobiological bases of this time interval learning are unknown. Here, we show that in rats, the dorsal striatum and basal amygdala belong to a common functional network underlying temporal expectancy and learning of a CS-US interval. Importantly, changes in coherence between striatum and amygdala local field potentials (LFPs) were found to couple these structures during interval estimation within the lower range of the theta rhythm (3-6 Hz). Strikingly, we also show that a change to the CS-US time interval results in long-term changes in cortico-striatal synaptic efficacy under the control of the amygdala. Collectively, this study reveals physiological correlates of plasticity mechanisms of interval timing that take place in the striatum and are regulated by the amygdala.

Temporal sensitivity changes with extended training in a bisection task in a transgenic rat model.

The present study investigated temporal perception in a Huntington disease transgenic rat model using a temporal bisection procedure. After initial discrimination training in which animals learned to press one lever after a 2-s tone duration, and the other lever after a 8-s tone duration for food reward, the bisection procedure was implemented in which intermediate durations with no available reinforcement were interspersed with trials with the anchor durations. Bisection tests were repeated in a longitudinal design from 4 to 8 months of age. The results showed that response latencies evolved from a monotonic step-function to an inverted U-shaped function with repeated testing, a precursor of non-responding on trials with intermediate durations. We inferred that temporal sensitivity and incentive motivation combined to control the transformation of the bisection task from a two-choice task at the outset of testing to a three-choice task with repeated testing. Changes in the structure of the task and/or continued training were accompanied by improvement in temporal sensitivity. In sum, the present data highlight the possible joint roles of temporal and non-temporal factors in the temporal bisection task, and suggested that non-temporal factors may compensate for deficits in temporal processing.

Behavioral and in vivo electrophysiological evidence for presymptomatic alteration of prefrontostriatal processing in the transgenic rat model for huntington disease.

Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4- to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta-burst stimulation (TBS) were assessed. Results showed an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after TBS in homozygous transgenic rats. Results from the heterozygous animals mostly fell between wild-type and homozygous transgenic rats. Our results suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the present study provides the first behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD.