Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions

Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation. In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox-Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10 years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes. In this paper, we describe the current state of orphan drug development for rare epilepsies. We identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug. We provide some suggestions for future improvements in orphan drug development such as promoting paediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes

Perampanel outcomes at different stages of treatment in people with focal and generalized epilepsy treated in clinical practice: Evidence from the PERMIT study

IntroductionThe PERMIT study is the largest pooled analysis of perampanel (PER) clinical practice data conducted to date.MethodsThis post-hoc analysis of PERMIT investigated the effectiveness, safety and tolerability of PER when used as early add-on therapy (after failure of one or two previous antiseizure medications) in comparison with late add-on therapy (after failure of three or more previous antiseizure medications). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness was assessed by seizure type (total seizures, focal seizures, generalized tonic-clonic seizures [GTCS]) and assessments included seizure freedom rate and responder rate. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs.ResultsThe Full Analysis Set included 1184 and 2861 PWE treated with PER as early and late add-on therapy, respectively. Compared to the late add-on subgroup, the early add-on subgroup was characterized by later mean age at epilepsy onset, shorter mean duration of epilepsy, lower rates of intellectual disability and psychiatric comorbidity, and lower frequency of seizures per month, suggesting a less severe form of epilepsy in this subgroup. After 12 months, retention was significantly higher in the early versus late add-on subgroup (67.7% vs. 62.4%; p = 0.004). At the last visit, responder rates in the early versus late add-on subgroup were significantly higher for total seizures (68.2% vs. 39.3%; p &amp;lt; 0.001), focal seizures (65.0% vs. 36.8%; p &amp;lt; 0.001) and GTCS (83.7% vs. 67.2%; p &amp;lt; 0.001), as were seizure freedom rates (total seizures, 35.9% vs. 11.9% [p &amp;lt; 0.001]; focal seizures, 29.4% vs. 8.7% [p &amp;lt; 0.001]; GTCS, 69.0% vs. 48.1% [p &amp;lt; 0.001]). Incidence of AEs was significantly lower in the early versus late add-on subgroup (42.1% vs. 54.7%; p &amp;lt; 0.001), as was the rate of discontinuation due to AEs over 12 months (15.0% vs. 18.1%; p = 0.031).DiscussionThis study demonstrated that PER was effective and generally well tolerated when initiated as early or late add-on therapy, but it was significantly more effective and better tolerated when initiated early. These findings support PER's use as a broad-spectrum, early add-on therapy for use in PWE with focal and generalized seizures.</jats:sec

International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions

The 2017 International League Against Epilepsy classification has defined a three-tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self-limited focal epilepsies, comprising four syndromes: self-limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic-atonic seizures, Lennox-Gastaut syndrome, developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep, hemiconvulsion-hemiplegia-epilepsy syndrome, and febrile infection-related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations

Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens A Randomized Clinical Trial

IMPORTANCE Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. OBJECTIVE To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. INTERVENTIONS Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. MAIN OUTCOMES AND MEASURES The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. RESULTS A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. CONCLUSIONS AND RELEVANCE Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT0292689

A simple blood test expedites the diagnosis of GLUT1 deficiency syndrome

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Fungal volatile organic compounds: emphasis on their plant growth-promoting

Fungal volatile organic compounds (VOCs) commonly formed bioactive interface between plants and countless of microorganisms on the above- and below-ground plant-fungus interactions. Fungal-plant interactions symbolize intriguingly biochemical complex and challenging scenarios that are discovered by metabolomic approaches. Remarkably secondary metabolites (SMs) played a significant role in the virulence and existence with plant-fungal pathogen interaction; only 25% of the fungal gene clusters have been functionally identified, even though these numbers are too low as compared with plant secondary metabolites. The current insights on fungal VOCs are conducted under lab environments and to apply small numbers of microbes; its molecules have significant effects on growth, development, and defense system of plants. Many fungal VOCs supported dynamic processes, leading to countless interactions between plants, antagonists, and mutualistic symbionts. The fundamental role of fungal VOCs at field level is required for better understanding, so more studies will offer further constructive scientific evidences that can show the cost-effectiveness of ecofriendly and ecologically produced fungal VOCs for crop welfare

Overdiagnosis and overtreatment of early detected prostate cancer

Early detection of prostate cancer is associated with the diagnosis of a considerable proportion of cancers that are indolent, and that will hardly ever become symptomatic during lifetime. Such overdiagnosis should be avoided in all forms of screening because of potential adverse psychological and somatic side effects. The main threat of overdiagnosis is overtreatment of indolent disease. Men with prostate cancer that is likely to be indolent may be offered active surveillance. Evaluation of active surveillance studies and validation of new biological parameters for risk assessment are expected

International consensus recommendations for management of new onset refractory status epilepticus including febrile infection-related epilepsy syndrome: Statements and supporting evidence

Objective: This study was undertaken to develop consensus-based recommendations for the management of adult and pediatric patients with new onset refractory status epilepticus (NORSE)/febrile infection-related epilepsy syndrome (FIRES) based on best evidence and experience. Methods: The Delphi methodology was followed. A facilitator group of nine experts was established, who defined the scope, users, and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment, and research directions were generated, which were then rated on a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was ≥7 and inappropriate if the median score was ≤3. The analysis of evidence was mapped to the results of each statement included in the Delphi survey. Results: Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: (1) disease characteristics; (2) diagnostic testing and sampling; (3) acute treatment; (4) treatment in the postacute phase; and (5) research, registries, and future directions in NORSE/FIRES. The detailed results and discussion of all 85 statements are outlined herein. A corresponding summary of findings and practical flowsheets are presented in a companion article. Significance: This detailed analysis offers insight into the supporting evidence and the current gaps in the literature that are associated with expert consensus statements related to NORSE/FIRES. The recommendations generated by this consensus can be used as a guide for the diagnosis, evaluation, and management of patients with NORSE/FIRES, and for planning of future research

International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017–2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients

The role of inflammation in epilepsy.

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis