New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN.

Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of a large repertoire of membrane proteins, especially ion channels. Unique complements of coexpressed ion channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that are tailored for diverse physiological contributions, and dysfunction of any component may induce a disease state. A crucial parameter controlling cell excitability is the resting membrane potential (RMP) set by extra- and intracellular concentrations of ions, mainly Na+, K+, and Cl-, and their passive permeation across the cell membrane through leak ion channels. Indeed, dysregulation of RMP causes significant effects on cellular excitability. This review describes the molecular and physiological properties of the Na+ leak channel NALCN, which associates with its accessory subunits UNC-79, UNC-80, and NLF-1/FAM155 to conduct depolarizing background Na+ currents in various excitable cell types, especially neurons. Studies of animal models clearly demonstrate that NALCN contributes to fundamental physiological processes in the nervous system including the control of respiratory rhythm, circadian rhythm, sleep, and locomotor behavior. Furthermore, dysfunction of NALCN and its subunits is associated with severe pathological states in humans. The critical involvement of NALCN in physiology is now well established, but its study has been hampered by the lack of specific drugs that can block or agonize NALCN currents in vitro and in vivo. Molecular tools and animal models are now available to accelerate our understanding of how NALCN contributes to key physiological functions and the development of novel therapies for NALCN channelopathies.

Comprehensive scoping review of fenfluramine's role in managing generalized tonic-clonic seizures in developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) are characterized by pharmacoresistant seizures and developmental delay. Patients with DEEs experience multiple seizure types, including tonic-clonic seizures (TCS) that can be generalized tonic-clonic (GTCS) or focal evolving to bilateral tonic-clonic (FBTCS). Fenfluramine (FFA) has demonstrated efficacy in reduction of TCS in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and other DEEs. Using the PRISMA-ScR (Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Review) guidelines, we performed a scoping review to describe changes in TCS in patients treated with FFA. A comprehensive search of five literature databases was conducted up to February 14, 2023. Studies were included if they reported change in GTCS or TCS (but not FBTCS) after treatment with FFA in patients with DEEs. Duplicate patients and studies with unclear efficacy data were excluded. Fourteen of 422 studies met the eligibility criteria. Data extracted and evaluated by expert clinicians identified 421 unique patients with DS (in nine studies), CDKL5 deficiency disorder, SCN8A-related disorder, LGS, SCN1B-related disorder, and other DEEs. The median percent reduction in GTCS or TCS from baseline was available in 10 studies (n = 328) and ranged from 47.2% to 100%. Following FFA treatment, 10 studies (n = 144) reported ≥50% reduction in GTCS or TCS from baseline in 72% of patients; in nine of those (n = 112), 54% and 29% of patients achieved ≥75% and 100% reduction in GTCS or TCS from baseline, respectively. Overall, this analysis highlighted improvements in GTCS or TCS frequency when patients were treated with FFA regardless of the DEE evaluated. Future studies may confirm the impact of FFA on TCS reduction and on decreased premature mortality risk (including sudden unexpected death in epilepsy), improvement in comorbidities and everyday executive function, decreased health care costs, and improvement in quality of life.

Long-term evaluation of anterior thalamic deep brain stimulation for epilepsy in the European MORE registry.

OBJECTIVE: Short-term outcomes of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) were reported for people with drug-resistant focal epilepsy (PwE). Because long-term data are still scarce, the Medtronic Registry for Epilepsy (MORE) evaluated clinical routine application of ANT-DBS. METHODS: In this multicenter registry, PwE with ANT-DBS were followed up for safety, efficacy, and battery longevity. Follow-up ended after 5 years or upon study closure. Clinical characteristics and stimulation settings were compared between PwE with no benefit, improvers, and responders, that is, PwE with average monthly seizure frequency reduction rates of ≥50%. RESULTS: Of 170 eligible PwE, 104, 62, and 49 completed the 3-, 4-, and 5-year follow-up, respectively. Most discontinuations (68%) were due to planned study closure as follow-up beyond 2 years was optional. The 5-year follow-up cohort had a median seizure frequency reduction from 16 per month at baseline to 7.9 per month at 5-year follow-up (p < .001), with most-pronounced effects on focal-to-bilateral tonic-clonic seizures (n = 15, 77% reduction, p = .008). At last follow-up (median 3.5 years), 41% (69/170) of PwE were responders. Unifocal epilepsy (p = .035) and a negative history of epilepsy surgery (p = .002) were associated with larger average monthly seizure frequency reductions. Stimulation settings did not differ between response groups. In 179 implanted PwE, DBS-related adverse events (AEs, n = 225) and serious AEs (n = 75) included deterioration in epilepsy or seizure frequency/severity/type (33; 14 serious), memory/cognitive impairment (29; 3 serious), and depression (13; 4 serious). Five deaths occurred (none were ANT-DBS related). Most AEs (76.3%) manifested within the first 2 years after implantation. Activa PC depletion (n = 37) occurred on average after 45 months. SIGNIFICANCE: MORE provides further evidence for the long-term application of ANT-DBS in clinical routine practice. Although clinical benefits increased over time, side effects occurred mainly during the first 2 years. Identified outcome modifiers can help inform PwE selection and management.

Developmental epileptic encephalopathy in DLG4-related synaptopathy.

OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. METHODS: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. RESULTS: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants. SIGNIFICANCE: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.

ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Prospective multicenter study of continuous tonic-clonic seizure monitoring on Apple Watch in epilepsy monitoring units and ambulatory environments.

OBJECTIVE: Evaluate the performance of a custom application developed for tonic-clonic seizure (TCS) monitoring on a consumer-wearable (Apple Watch) device. METHODS: Participants with a history of convulsive epileptic seizures were recruited for either Epilepsy Monitoring Unit (EMU) or ambulatory (AMB) monitoring; participants without epilepsy (normal controls [NC]) were also enrolled in the AMB group. Both EMU and AMB participants wore an Apple Watch with a research app that continuously recorded accelerometer and photoplethysmography (PPG) signals, and ran a fixed-and-frozen tonic-clonic seizure detection algorithm during the testing period. This algorithm had been previously developed and validated using a separate training dataset. All EMU convulsive events were validated by video-electroencephalography (video-EEG); AMB events were validated by caregiver reporting and follow-ups. Device performance was characterized and compared to prior monitoring devices through sensitivity, false alarm rate (FAR; false-alarms per 24 h), precision, and detection delay (latency). RESULTS: The EMU group had 85 participants (4,279 h, 19 TCS from 15 participants) enrolled across four EMUs; the AMB group had 21 participants (13 outpatient, 8 NC, 6,735 h, 10 TCS from 3 participants). All but one AMB participant completed the study. Device performance in the EMU group included a sensitivity of 100 % [95 % confidence interval (CI) 79-100 %]; an FAR of 0.05 [0.02, 0.08] per 24 h; a precision of 68 % [48 %, 83 %]; and a latency of 32.07 s [standard deviation (std) 10.22 s]. The AMB group had a sensitivity of 100 % [66-100 %]; an FAR of 0.13 [0.08, 0.24] per 24 h; a precision of 22 % [11 %, 37 %]; and a latency of 37.38 s [13.24 s]. Notably, a single AMB participant was responsible for 8 of 31 false alarms. The AMB FAR excluding this participant was 0.10 [0.07, 0.14] per 24 h. DISCUSSION: This study demonstrates the practicability of TCS monitoring on a popular consumer wearable (Apple Watch) in daily use for people with epilepsy. The monitoring app had a high sensitivity and a substantially lower FAR than previously reported in both EMU and AMB environments.

What have we learned from the real-world efficacy of FFA in DS and LGS? A post-marketing study in clinical practice.

OBJECTIVE: To evaluate the effectiveness and tolerability of fenfluramine (FFA) in routine clinical practice treating real-world populations with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). METHODS: This was a retrospective analysis of patients with DS or LGS who initiated FFA treatment from 2018 to 2022 at a single center. Patient demographics, medical history, seizure characteristics, and treatment outcomes were collected from electronic medical records. Duration of FFA treatment, dosage regimens, seizure frequency, seizure severity, improvements in cognitive, social, and motor outcomes, and adverse events were extracted and analyzed. Effectiveness was assessed using ≥50 % sustained reduction in monthly seizure frequency vs baseline for ≥2 consecutive months at 12 months; seizure freedom was a secondary measure. RESULTS: Seizure frequency data was available for 56 of 68 patients included in the study. At 12 months, 50 patients (89.3 %) remained on FFA treatment; 58 % of these patients achieved a ≥50 % sustained response and 10 % experienced seizure freedom. Cognitive, motor, and social improvement were noted in 70.7 %, 36.2 %, and 27.6 % of patients, respectively. The total number of concomitant antiseizure medications was reduced by ≥1 in 29.4 % of patients. No differences were found between DS and LGS patients in these outcomes; age at start of FFA and age at the 12-month timepoint did not have an effect. At least one AE was experienced by 59.7% of patients; in 86.5% of the cases, AEs were plausibly related to treatment. While 70.3% of AEs were self-resolving and 81.8% of the remaining patients experienced mild AEs, 1 patient experienced a serious AE unrelated to FFA which resulted in the patient's death. There were no cases of pulmonary arterial hypertension or ventricular heart disease. SIGNIFICANCE: The effectiveness and tolerability of FFA treatment in patients with DS or LGS in this retrospective analysis of real-world data were consistent with those seen in randomized clinical trials.

Health care concerns in parents of children with different genetic developmental and epileptic encephalopathies: A qualitative study.

AIM: To describe the experiences and unmet medical care needs of a group of parents of children with developmental and epileptic encephalopathies (DEEs) caused by the SCN1A, KCNQ2, CDKL5, PCDH19, and GNAO1 variants. METHOD: A qualitative descriptive study was conducted. Participants were recruited using purposeful sampling. The inclusion criteria consisted of parents of children with DEEs caused by the SCN1A, KCNQ2, CDKL5, PCDH19, or GNAO1 variants, aged between 4 and 10 years old. In total, 21 parents were included. Data were acquired via researcher field notes and in-depth interviews. A thematic analysis was performed. RESULTS: Three main themes were identified: (1) managing symptoms: epileptic seizures are experienced with great uncertainty and are accompanied by cognitive, behavioural, and motor symptoms; (2) accepting treatment: the ideal medication regimen is a challenge and the decision to withdraw or start a new therapy falls on the parents; and (3) therapeutic relationship and medical care: behaviours related to the health professional can hinder the therapeutic relationship with the parents. Parents are apprehensive about going to the emergency department. INTERPRETATION: Professionals in emergency departments should acquire better knowledge of DEEs, welcome parents, and improve treatment for the children. The results of this study can serve as a starting point for a roadmap of relevant caregiver-reported outcomes in DEEs, to be implemented with new clinical trials and aetiology-targeted therapies. WHAT THIS PAPER ADDS: Epileptic seizures are the symptom that is most experienced and feared by parents. The medication regime has no defined protocol and the decision to withdraw a medication is frequently left to parents.

GPI-anchoring disorders and the heart: Is cardiomyopathy an overlooked feature?

Glycosylphosphatidylinositol anchoring disorders (GPI-ADs) are a subgroup of congenital disorders of glycosylation. GPI biosynthesis requires proteins encoded by over 30 genes of which 24 genes are linked to neurodevelopmental disorders. Patients, especially those with PIGA-encephalopathy, have a high risk of premature mortality which sometimes is attributed to cardiomyopathy. We aimed to explore the occurrence of cardiomyopathy among patients with GPI-ADs and to raise awareness about this potentially lethal feature. Unpublished patients with genetically proven GPI-ADs and cardiomyopathy were identified through an international collaboration and recruited through the respective clinicians. We also reviewed the literature for published patients with cardiomyopathy and GPI-AD and contacted the corresponding authors for additional information. We identified four novel and unrelated patients with GPI-AD and cardiomyopathy. Cardiomyopathy was diagnosed before adulthood and was the cause of early demise in two patients. Only one patients underwent cardiac workup after being diagnosed with a GPI-AD. All were diagnosed with PIGA-encephalopathy and three had a disease-causing variant at the same residue. The literature reports five additional children with GPI-AD related cardiomyopathy, three of which died before adulthood. We have shown that patients with GPI-ADs are at risk of developing cardiomyopathy and that regular cardiac workup with echocardiography is necessary.

Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS). METHODS: Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. RESULTS: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n = 241) and -50.5% at Month 15 (n = 142, p < .0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was -45.9% (n = 192, p = .0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p < .0001, n = 106) and 35.8% (p < .0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%-44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%-41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. SIGNIFICANCE: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.

DNA methylation-based classification of malformations of cortical development in the human brain.

Malformations of cortical development (MCD) comprise a broad spectrum of structural brain lesions frequently associated with epilepsy. Disease definition and diagnosis remain challenging and are often prone to arbitrary judgment. Molecular classification of histopathological entities may help rationalize the diagnostic process. We present a retrospective, multi-center analysis of genome-wide DNA methylation from human brain specimens obtained from epilepsy surgery using EPIC 850 K BeadChip arrays. A total of 308 samples were included in the study. In the reference cohort, 239 formalin-fixed and paraffin-embedded (FFPE) tissue samples were histopathologically classified as MCD, including 12 major subtype pathologies. They were compared to 15 FFPE samples from surgical non-MCD cortices and 11 FFPE samples from post-mortem non-epilepsy controls. We applied three different statistical approaches to decipher the DNA methylation pattern of histopathological MCD entities, i.e., pairwise comparison, machine learning, and deep learning algorithms. Our deep learning model, which represented a shallow neuronal network, achieved the highest level of accuracy. A test cohort of 43 independent surgical samples from different epilepsy centers was used to test the precision of our DNA methylation-based MCD classifier. All samples from the test cohort were accurately assigned to their disease classes by the algorithm. These data demonstrate DNA methylation-based MCD classification suitability across major histopathological entities amenable to epilepsy surgery and age groups and will help establish an integrated diagnostic classification scheme for epilepsy-associated MCD.

Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis.

OBJECTIVE: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications. METHODS: We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time-to-nth seizure), using a post hoc time-to-event (TTE) analysis of data from two Phase 3 placebo-controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2-19 years were randomized to placebo or adjunctive fenfluramine (Study 1: .7 mg/kg/day or .2 mg/kg/day; Study 2: .4 mg/kg/day with stiripentol). Data were analyzed by Kaplan-Meier TTE curves and waterfall plots. RESULTS: The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7 mg/kg/day, 60%; fenfluramine .2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine .4 mg/kg/day, 58%; placebo, 2%). Median time-to-nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7 mg/kg/day, 13 weeks; .2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine .4 mg/kg/day, 13 weeks; placebo, 5 weeks; p < .001). Longest duration of convulsive seizure-free days was increased in active groups versus the placebo group (Study 1: fenfluramine .7 and .2 mg/kg/day, 25.0 and 15.0 days; placebo, 9.5 days [p = .0001; p = .0352]; Study 2: fenfluramine .4 mg/kg/day, 22.0 days; placebo, 13.0 days [p = .004]). The most common adverse events included decreased appetite, pyrexia, upper respiratory tract infection, diarrhea, and fatigue. SIGNIFICANCE: These data demonstrate that fenfluramine can significantly reduce day-to-day seizure burden in patients with DS, providing prolonged periods of convulsive seizure-free days, which may help reduce the physical and emotional disease toll while improving health-related QOL for patients and caregivers.

Perampanel monotherapy for the treatment of epilepsy: Clinical trial and real-world evidence.

Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration's (FDA's) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries. As there are key differences in clinical evidence of perampanel as adjunctive therapy vs monotherapy, we review the clinical outcomes of perampanel when administered as primary or secondary monotherapy. Eight publications reporting the efficacy and safety outcomes of perampanel monotherapy in clinical trial and real-world settings were selected during our literature search and are included; these comprise three Eisai-sponsored studies in patients with epilepsy: one prospective, open-label, Phase III clinical trial of patients with newly diagnosed epilepsy (Study 342 [FREEDOM]) and two retrospective, real-world Phase IV studies of patients with epilepsy who received perampanel during routine clinical care (Studies 504 and 506 [PROVE]); and five retrospective, real-world studies in patients with epilepsy who were prescribed perampanel during routine clinical care. Results from these studies demonstrated that seizure freedom may be achieved following treatment with perampanel monotherapy (either primary or secondary), with favorable retention rates and safety profiles. Overall, the clinical evidence supports the use of perampanel monotherapy both in newly diagnosed patients and in those who have been unable to control their seizures with other ASMs.

The contribution of fenfluramine to the treatment of Dravet syndrome in Spain through Multi-Criteria Decision Analysis.

INTRODUCTION: Dravet Syndrome (DS) is a severe, developmental epileptic encephalopathy (DEE) that begins in infancy and is characterized by pharmaco-resistant epilepsy and neurodevelopmental delay. Despite available antiseizure medications (ASMs), there is a need for new therapeutic options with greater efficacy in reducing seizure frequency and with adequate safety and tolerability profiles. Fenfluramine is a new ASM for the treatment of seizures associated with DS as add-on therapy to other ASMs for patients aged 2 years and older. Fenfluramine decreases seizure frequency, prolongs periods of seizure freedom potentially helping to reduce risk of Sudden Unexpected Death in Epilepsy (SUDEP) and improves patient cognitive abilities positively impacting on patients' Quality of Life (QoL). Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders. The aim of this study was to determine the relative value contribution of fenfluramine for the treatment of DS in Spain using MCDA. METHOD: A literature review was performed to populate an adapted a MCDA framework for orphan-drug evaluation in Spain. A panel of ten Spanish experts, including neurologists, hospital pharmacists, patient representatives and decision-makers, scored four comparative evidence matrices. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. RESULTS: Dravet syndrome is considered a severe, rare disease with significant unmet needs. Fenfluramine is perceived to have a higher efficacy profile than all available alternatives, with a better safety profile than stiripentol and topiramate and to provide improved QoL versus studied alternatives. Fenfluramine results in lower other medical costs in comparison with stiripentol and clobazam. Participants perceived that fenfluramine could lead to indirect costs savings compared to available alternatives due to its efficacy in controlling seizures. Overall, fenfluramine's therapeutic impact on patients with DS is considered high and supported by high-quality evidence. CONCLUSIONS: Based on reflective MCDA, fenfluramine is considered to add greater benefit in terms of efficacy, safety and QoL when compared with available ASMs.

Outcomes from a Spanish Expanded Access Program on cannabidiol treatment in pediatric and adult patients with epilepsy.

AIM: To evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP). METHODS: This was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. RESULTS: One hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together. CONCLUSIONS: Cannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.

Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study.

AIM: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy. METHOD: Participants with genetically confirmed GPI deficiency were treated with oral pyridoxine or P5P as compassionate use in an agreed-upon clinical regimen. Pyridoxine (20-30 mg/kg/day) was used for 3 months. Baseline evaluation included 4 weeks of prospective seizure data and one video electroencephalogram (EEG). Seizure frequency was captured daily. The EEG was repeated after reaching maximum dosage of pyridoxine. Pyridoxine was switched to P5P (20-30 mg/kg/day) if seizure burden was unchanged after 3 months' treatment. Another EEG was done after 3 months of P5P treatment. Primary outcome measures were reduction of seizure frequency and EEG improvements. RESULTS: Seven participants (one female, six males; age range 5-23 year; mean age 11 years 10 months, SD 5 year 2 months) were included. The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency. All had drug-resistant epilepsy and neurodevelopmental impairment. We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom. No remarkable changes in electrophysiological findings were observed in 6 out of 7 participants treated with pyridoxine or P5P when comparing the baseline and follow-up EEGs. INTERPRETATION: We observed no long-lasting electrophysiological improvements during treatment but pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. WHAT THIS PAPER ADDS: Inherited glycosylphosphatidylinositol (GPI) deficiency often causes early-onset and drug-resistant epilepsy. Vitamin B6 is a potential disease-specific treatment; however, efficacy and safety are ill-defined. Pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. Pyridoxine and P5P could prove to be a useful treatment in some individuals with inherited GPI deficiency and epilepsy.

Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. METHODS: Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. RESULTS: Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

Initiating antiepilepsy treatment: An update of expert consensus in Spain.

Following publication in 2014 of the International League Against Epilepsy (ILAE) official report changing the definition of epilepsy, a number of questions remain unresolved in regard to deciding when to start treatment and to the choice of a particular antiseizure medication (ASM). This study uses a Delphi method to update consensus among a panel of experts on the initiation of epilepsy treatment in order to provide insight regarding those questions. The study was undertaken in four phases. Firstly, a multi-center steering committee met to review relevant bibliography and to draft a questionnaire. Secondly, a panel of neurologists specialized in epilepsy was selected and convened. Thirdly, an online survey was carried out in two rounds. Fourthly, the final results were discussed at a face-to-face meeting of the steering committee to draw conclusions. The final questionnaire focused on three independent sections: the decision to commence ASM in different clinical situations, the choice of initial monotherapy depending on the type of epilepsy and the patient's age/sex (including childbearing potential), and the choice of initial monotherapy depending on comorbidity. In these two latter sections, fourteen ASMs approved for monotherapy use by the EMA and available in Spain were considered. Regarding the decision as to when to commence treatment, the results show agreement exists to initiate treatment following a first generalized tonic-clonic seizure or a focal seizure if the electroencephalography (EEG) reveals epileptiform activity, if the MRI reveals a lesion, or when it occurs in elderly patients. With respect to the choice of initial monotherapy depending on the type of epilepsy and the patient's age/sex profile, it is agreed to avoid valproic acid (VPA) in women with childbearing potential, with levetiracetam (LEV) and lamotrigine (LTG) being the preferable options in generalized epilepsy. In focal epilepsy, the options are broader, particularly in men, and include the most recent ASMs approved for monotherapy. In the elderly, LEV, lacosamide (LCM), eslicarbazepine acetate (ESL) and LTG are considered the most suitable drugs for initiating treatment. With regard to comorbidities, the recommendation is to avoid enzyme inducing ASMs, with LEV, the most recent ASMs approved for monotherapy and LTG being the preferred options. In conclusion, as the ILAE definition states, there are different situations that lead to treatment initiation after a first seizure. When choosing the first ASM, the type of epilepsy, childbearing potential and drug-drug interaction are key factors.

Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort.

OBJECTIVE: This study was aimed to analyze the effectiveness of sodium channel blockers (SCBs) in CDKL5 deficiency disorder (CDD)-related epilepsy. METHODS: A retrospective, observational study was performed, including patients with CDD diagnosis evaluated between 2016 and 2019 at three tertiary Epilepsy Centers. Demographic, electroclinical and genetic features, as well as ASM treatments and their outcomes were analyzed, with special focus on SCBs. RESULTS: Twenty-one patients evaluated at three tertiary Epilepsy Centers were included, of which 19 presented with epilepsy (90.5%); all had pathogenic mutations of CDKL5. Six patients (31.6%) were classified as SCB responders (more than 50% reduction), four being currently seizure free (mean seizure-free period of 8 years). Most frequent SCB drugs were oxcarbazepine (OXC), carbamazepine (CBZ), and lacosamide (LCM). None of them presented relevant adverse events. In contrast, three patients showed seizure aggravation in the non-responder group. When comparing both groups, responders had statistically significant younger age at SCB treatment and epilepsy onset, higher proportion of focal epileptiform activity and less frequent history of West syndrome. CONCLUSIONS: The results of this study indicate that treatment with SCBs might be effective and safe in a subset of patients with CDD-related epilepsy.

Identifying key unmet needs and value drivers in the treatment of focal-onset seizures (FOS) in patients with drug-resistant epilepsy (DRE) in Spain through Multi-Criteria Decision Analysis (MCDA).

INTRODUCTION: Epilepsy is a serious neurological disease, ranking high in the top causes of disability. Approximately 40% of patients with epilepsy are pharmacoresistant after their seizures failed at least two antiseizure medications (ASMs). Adult patients experiencing focal-onset seizures (FOS) account for approximately 60% of all patients with epilepsy and they are more likely to become drug-resistant epilepsy (DRE) than those with generalized onset. Drug-resistant epilepsy is associated with mortality, morbidity, and reduced quality of life. The information available on the clinical management, health outcomes, and unmet needs of the disease within the Spanish healthcare environment is very limited. Multi-Criteria Decision Analysis (MCDA) allows determination of what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner and from the perspective of relevant stakeholders. PURPOSE: The aim of this study was to identify the burden of DRE (clinical, quality of life, and economic) and the unmet needs in Spain and to determine what represents value in the treatment of FOS in DRE patients from the perspective of Spanish epileptologists. METHODS: The steps taken to carry out the MCDA were based on previously published good methodological practices. A systematic literature review (combining biomedical databases and gray literature sources) was performed between March and April 2020. Results were reviewed and validated with three epileptologists in June 2020 and used to develop a MCDA value framework, adapted for FOS in DRE, composed of 12 quantitative criteria and 3 contextual criteria. A group of six Spanish epileptologists from four Spanish regions were trained in MCDA methodology before individually validating value criteria (and their definitions based on literature review findings) and assigned relative weights using an ordinal 6-points scale. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. RESULTS: Drug-resistant epilepsy is considered a very severe health problem with important unmet needs affecting a considerably sized population. While safety and impact on quality of life of available ASMs are considered adequate, efficacy remains insufficient for patients to achieve seizure freedom and maintain it over time. Hence, the therapeutic benefit of pharmacological treatments currently used is regarded as suboptimal. Drug-resistant epilepsy management is associated with moderate pharmacological, relevant direct medical and high indirect costs. Quality of evidence available for current treatments is moderate. It is considered that DRE does not currently stand as a key priority for the Spanish healthcare system. CONCLUSIONS: Drug-resistant epilepsy is considered a very severe health problem associated with relevant unmet needs. These include the lack of availability of specific treatment protocols, the need to improve early diagnosis by increasing the number of referrals to specialized epilepsy units and the availability of specific ASMs with improved efficacy and safety profiles, allowing to reach treatment objectives. Reflective MCDA provided a standardized, transparent approach to evaluate multiple criteria ascertaining what represents value from a holistic point of view and from the perspective of clinical experts, facilitating decision-making.