New paradigms for the treatment of pediatric monogenic epilepsies: Progressing toward precision medicine

Despite the availability of 28 antiseizure medications (ASMs), one-third of people with epilepsy fail to achieve sustained freedom from seizures. Clinical outcome is even poorer for children with developmental and epileptic encephalopathies (DEEs), many of which are due to single-gene mutations. Discovery of causative genes, however, has paved the way to understanding the molecular mechanism underlying these epilepsies, and to the rational application, or development, of precision treatments aimed at correcting the specific functional defects or their consequences. This article provides an overview of current progress toward precision medicine (PM) in the management of monogenic pediatric epilepsies, by focusing on four different scenarios, namely (a) rational selection of ASMs targeting specifically the underlying pathogenetic mechanisms; (b) development of targeted therapies based on novel molecules; (c) use of dietary treatments or food constituents aimed at correcting specific metabolic defects; and (d) repurposing of medications originally approved for other indications. This article is part of the Special Issue "Severe Infantile Epilepsies"

Cannabidiol treatment for refractory epilepsies in pediatrics

Cannabis extracts in oil are becoming increasingly available, and, during the last years, there has been growing public and scientific interest about therapeutic properties of these compounds for the treatment of several neurologic diseases, not just epilepsy. The discovered role of the endocannabinoid system in epileptogenesis has provided the basis to investigate the pharmacological use of exogenously produced cannabinoids, to treat epilepsy. Although, physicians show reluctance to recommend Cannabis extracts given the lack of high-quality safety available data, from literature data cannabidiol (CBD) results to be a promising and safe anticonvulsant drug with low side-effect. In particular, according to early studies, CBD can reduce the frequency of seizures and lead to improvements in quality of life in children affected by refractory epilepsy. So, for these reasons, the detailed study of the interactions between CBD and anticonvulsant drugs (AEDs) administered simultaneously in polytherapy, is arousing increasing interest, to clarify and to assess the incidence of adverse effects and the relation between dose escalation and quality of life measures. To date, in pediatric age, CBD efficacy and safety is not supported by well-designed trials and strong scientific evidence are not available. These studies are either retrospective or small-scale observational and only during the last years Class I evidence data for a pure form of CBD have been available, as demonstrated in placebo-controlled RCTs for patients affected by Lennox-Gastaut syndrome and Dravet syndrome. It is necessary to investigate CBD safety, pharmacokinetics and interaction with other AEDs alongside performing double-blinded placebo-controlled trials to obtain conclusive data on its efficacy and safety in the most frequent epilepsies in children, not just in the epileptic encephalopathy. This review was aimed to revise the available data to describe the scientific evidence for CBD in Pediatric Epilepsies

Changing Times for CLN2 Disease: The Era of Enzyme Replacement Therapy

Nicola Specchio, Nicola Pietrafusa, Marina Trivisano Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyCorrespondence: Nicola SpecchioDepartment of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyTel +39 0669592645Fax +39 0668592463Email [email protected]: Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a progressive neurodegenerative disease that results in early-onset, severe, progressive, neurological disabilities, leading to death in late childhood or early adolescence. Management has relied on symptomatic care, and supportive and palliative strategies, but the approval of the enzyme replacement therapy cerliponase alfa in the USA and Europe in 2017 brought different treatment opportunities. We describe the natural history of CLN2 disease, its diagnosis and management, and the preclinical and clinical development of cerliponase alfa. A PubMed search was undertaken for cerliponase alfa and rhTPP1 to identify preclinical and clinical studies. The hallmark-presenting symptoms of CLN2 disease are unprovoked seizures and a history of language delay, and progression involves motor dysfunction, and cognitive and visual decline. Cerliponase alfa has shown efficacy and tolerability in mouse and canine models of CLN2 disease when delivered intracerebroventricularly. Administration of cerliponase alfa in patients with CLN2 disease has led to significant reductions in the rate of decline of motor and language functions in comparison with a natural history population. The approval of cerliponase alfa has brought a new era for CLN2 disease, highlighting the need to understand different patterns of disease progression and clinical needs in treated patients.Keywords: neuronal ceroid lipofuscinosis type 2, TPP1, cerliponase alfa, late infantile, seizure

Characterisation of CASPR2 deficiency disorder - a syndrome involving autism, epilepsy and language impairment

Background Heterozygous mutations in CNTNAP2 have been identified in patients with a range of complex phenotypes including intellectual disability, autism and schizophrenia. However heterozygous CNTNAP2 mutations are also common in the normal population. Conversely, homozygous mutations are rare and have not been found in unaffected individuals. Case presentation We describe a consanguineous family carrying a deletion in CNTNAP2 predicted to abolish function of its protein product, CASPR2. Affected family members show epilepsy, facial dysmorphisms, severe intellectual disability and impaired language. We compared these patients with previously reported individuals carrying homozygous mutations in CNTNAP2 and identified a highly recognisable phenotype. Conclusions We propose that CASPR2 loss produces a syndrome involving early-onset refractory epilepsy, intellectual disability, language impairment and autistic features that can be recognized as CASPR2 deficiency disorder. Further screening for homozygous patients meeting these criteria, together with detailed phenotypic investigations will be crucial for understanding the contribution of CNTNAP2 to normal and disrupted development

A cross-sectional survey among physicians on internet use for epilepsy-related information

Objective: We investigated views towards the Internet in a sample of Italian healthcare specialists involved in epilepsy field, to identify factors associated with the attitude of being influenced by information found on the Internet. Methods: This study was a self-administered survey conducted in a group of members of the Italian Chapter of the International League Against Epilepsy (ILAE) in January 2018. Results: 184 questionnaires were analyzed. 97.8 % of responders reported to seek online information on epilepsy. The Internet was most frequently searched to obtain new information (69.9 %) or to confirm a diagnostic or therapeutic decision (37.3 %). The influence of consulting the Internet on clinical practice was associated with registration to social network(s) (OR: 2.94; 95 %CI: 1.28-6.76; p = 0.011), higher frequency of Internet use (OR: 3.66; 95 %CI: 1.56-9.21; p = 0.006) and higher confidence in reliability of online information (OR: 2.61; 95 %CI: 1.09-6.26; p = 0.031). No association was found with age, sex, years in epilepsy practice or easiness to find online information. Conclusion: Internet is frequently used among healthcare professionals involved in the epilepsy to obtain information about this disease. The attitude of being influenced by the Internet for diagnostic and/or therapeutic decisions in epilepsy is independent on age and years of experience in epilepsy, and probably reflects an individual approach towards the Web

Neuronal Ceroid Lipofuscinosis: Potential for Targeted Therapy

Neuronal ceroid lipofuscinosis (NCLs) is a group of inherited neurodegenerative lysosomal storage diseases that together represent the most common cause of dementia in children. Phenotypically, patients have visual impairment, cognitive and motor decline, epilepsy, and premature death. A primary challenge is to halt and/or reverse these diseases, towards which developments in potential effective therapies are encouraging. Many treatments, including enzyme replacement therapy (for CLN1 and CLN2 diseases), stem-cell therapy (for CLN1, CLN2, and CLN8 diseases), gene therapy vector (for CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN10, and CLN11 diseases), and pharmacological drugs (for CLN1, CLN2, CLN3, and CLN6 diseases) have been evaluated for safety and efficacy in pre-clinical and clinical studies. Currently, cerliponase alpha for CLN2 disease is the only approved therapy for NCL. Lacking is any study of potential treatments for CLN4, CLN9, CLN12, CLN13 or CLN14 diseases. This review provides an overview of genetics for each CLN disease, and we discuss the current understanding from pre-clinical and clinical study of potential therapeutics. Various therapeutic interventions have been studied in many experimental animal models. Combination of treatments may be useful to slow or even halt disease progression; however, few therapies are unlikely to even partially reverse the disease and a complete reversal is currently improbable. Early diagnosis to allow initiation of therapy, when indicated, during asymptomatic stages is more important than ever

Peri-ictal water drinking: a rare automatic behaviour in temporal lobe epilepsy

Peri-ictal water drinking (PIWD) has been reported as the action of drinking during or within two minutes of an electroclinical seizure. It is considered a peri-ictal vegetative symptom, evident both during childhood and adulthood epilepsy. The aim of this paper was to describe the clinical and electroencephalographic features of two new adult subjects suffering from symptomatic temporal lobe epilepsy with episodes of PIWD recorded by VIDEO-EEG and to review literature data in order to better define this peculiar event during seizures, a rare and probably underestimated semiological sign. To date, 51 cases with focal epilepsy and seizures associated with PIWD have been reported. All patients presented with temporal lobe epilepsy. All cases but one had symptomatic epilepsy. Most of the patients had an involvement of the right hemisphere. Water drinking was reported as an ictal sign in the majority of patients, and less frequently was reported as postictal. We believe that PIWD might be considered a rare automatic behaviour, like other automatisms. Automatisms are more frequently described in patients with temporal lobe epilepsy. PIWD was reported also to have lateralizing significance in the non-dominant temporal lobe, however, because of its rarity, this finding remains unclear