Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

CNS Drugs, Journal Year: 2022, Volume and Issue: 36(10), P. 1079 - 1111

Published: Oct. 1, 2022

The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood significant neurodevelopmental comorbidities. latter include intellectual disability, delay, behavioural problems including attention-deficit hyperactivity disorder autism spectrum disorder, psychiatric anxiety depression, speech impairment sleep problems. Classical examples Dravet syndrome, Lennox–Gastaut syndrome tuberous sclerosis complex. mainstay treatment is multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated psychobehavioural adverse events, effects (negative or positive) on cognition sleep. We have performed targeted literature review commonly used to discuss latest evidence their behaviour, mood, cognition, sedation valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) everolimus. Bromide, felbamate other sodium channel are discussed briefly. Overall, current suggest that LEV, PER lesser extent BRV events aggressiveness irritability; TPM ZNS language cognitive dulling/memory Patients history comorbidities may more at risk developing events. Topiramate negative some aspects cognition; CBD, FFA, LTG positive effects, while remaining do not appear detrimental effect. All certain extent, which pronounced during uptitration. Cannabidiol, pregabalin improvements sleep, insomnia, VPA, TPM, LCM effects. There was variability for each ASM: many first-generation second-generation ASMs, there scant documented evidence; extensive use suggests favourable tolerability safety (e.g. VPA); third-generation tend most robust over several years (TPM, PER, ZNS, BRV), still being generated newer such as CBD FFA. Finally, we how variety factors affect behaviour untangling associations between underlying those challenging. In particular, enormous heterogeneity cognitive, impairments complex change naturally time; lack standardised instruments evaluating these outcomes encephalopathies, reliance subjective evaluations proxy (caregivers); regimes involving well drugs.

Language: Английский

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Dravet syndrome: A systematic literature review of the illness burden

Epilepsia Open, Journal Year: 2023, Volume and Issue: 8(4), P. 1256 - 1270

Published: Sept. 26, 2023

Abstract We performed a systematic literature review and narrative synthesis according to pre‐registered protocol (Prospero: CRD42022376561) identify the evidence associated with burden of illness in Dravet syndrome (DS), developmental epileptic encephalopathy characterized by drug‐resistant epilepsy neurocognitive neurobehavioral impairment. searched MEDLINE, Embase, APA PsychInfo, Cochrane's database reviews, Epistemonikos from inception June 2022. Non‐interventional studies reporting on epidemiology (incidence, prevalence, mortality), patient caregiver health‐related quality life (HRQoL), direct indirect costs healthcare resource utilization were eligible. Two reviewers independently carried out screening. Pre‐specified data extracted was conducted. Overall, 49 met inclusion criteria. The incidence varied 1:15 400–1:40 900, prevalence 1.5 per 100 000 6.5 000. Mortality reported 3.7%–20.8% DS patients, most commonly due sudden unexpected death status epilepticus. Patient HRQoL, assessed caregivers, lower than non‐DS patients; mean scores (0 [worst] 100/1 [best]) 62.1 for Kiddy KINDL/Kid‐KINDL, 46.5–54.7 PedsQL 0.42 EQ‐5D‐5L. Caregivers, especially mothers, severely affected, impacts their time, energy, sleep, career, finances, while siblings also affected. Symptoms depression 47%–70% caregivers. Mean total high across all studies, ranging $11 048 $77 914 year (PPPY), inpatient admissions being key cost driver studies. related lost productivity only three publications, approximately $19 $20 PPPY ($17 596 mothers vs $1564 fathers). High seizure higher utilization, poorer HRQoL. system, society is profound, reflecting severe nature syndrome. Future will be able assess impact that newly approved therapies have reducing DS.

Language: Английский

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Fenfluramine: a plethora of mechanisms?

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: May 12, 2023

Developmental and epileptic encephalopathies are rare, treatment-resistant epilepsies with high seizure burden non-seizure comorbidities. The antiseizure medication (ASM) fenfluramine is an effective treatment for reducing frequency, ameliorating comorbidities, potentially risk of sudden unexpected death in epilepsy (SUDEP) patients Dravet syndrome Lennox-Gastaut syndrome, among other rare epilepsies. Fenfluramine has a unique mechanism action (MOA) ASMs. Its primary MOA currently described as dual-action sigma-1 receptor serotonergic activity; however, mechanisms may be involved. Here, we conduct extensive review the literature to identify all previously fenfluramine. We also consider how these play role reports clinical benefit outcomes, including SUDEP everyday executive function. Our highlights importance serotonin maintaining balance between excitatory (glutamatergic) inhibitory (γ-aminobutyric acid [GABA]-ergic) neural networks, suggests that represent pharmacological MOAs seizures, SUDEP. describe ancillary roles GABA neurotransmission, noradrenergic endocrine system (especially such progesterone derivatives neuroactive steroids). Dopaminergic activity underlies appetite reduction, common side effect treatment, but any involvement reduction remains speculative. Further research underway evaluate promising new biological pathways A better understanding comorbidities allow rational drug design and/or improved decision-making when prescribing multi-ASM regimens.

Language: Английский

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Pharmacotherapy for Dravet Syndrome: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Drugs, Journal Year: 2023, Volume and Issue: 83(15), P. 1409 - 1424

Published: Sept. 11, 2023

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed recent years with the approval new antiseizure medications (ASMs). aim this study was to estimate comparative efficacy tolerability ASMs for treatment associated using network meta-analysis (NMA). Studies were identified conducting systematic search (week 4, January 2023) MEDLINE (accessed PubMed), EMBASE, Cochrane Central Register Controlled Trials (CENTRAL), US National Institutes Health Clinical Registry ( http://www.clinicaltrials.gov ) databases. Any randomized, controlled, double- or single-blinded, parallel-group comparing at least one ASM therapy against placebo, another ASM, different dose same participants diagnosis identified. outcomes proportions ≥ 50% (seizure response) 100% reduction freedom) baseline convulsive seizure frequency during maintenance period. included patients who withdrew from any reason experienced adverse event (AE). Effect sizes estimated meta-analyses within frequentist framework. Eight placebo-controlled trials included, active add-on treatments stiripentol (n = 2), pharmaceutical-grade cannabidiol 3), fenfluramine hydrochloride soticlestat 1). studies recruited 680 participants, whom 409 randomized (stiripentol 33, 228, 122, 26) 271 placebo. Pharmaceutical-grade lower rate response than (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07–0.54), higher (OR 14.07, CI 2.57–76.87). No statistically significant differences emerged across freedom outcome. Stiripentol probability drug discontinuation 0.45, 0.04–5.69), proportion experiencing AE 0.22, 0.06–0.78). had risk occurrence 75.72, 3.59–1598.58). found high-quality evidence four DS. There exists first-class that documents stiripentol, cannabidiol, hydrochloride, DS, allows discussion about expected regarding profiles.

Language: Английский

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Comparative efficacy and safety of stiripentol, cannabidiol and fenfluramine as first‐line add‐on therapies for seizures in Dravet syndrome: A network meta‐analysis

Epilepsia Open, Journal Year: 2024, Volume and Issue: 9(2), P. 689 - 703

Published: March 1, 2024

Abstract Objectives Stiripentol, fenfluramine, and cannabidiol are licensed add‐on therapies to treat seizures in Dravet Syndrome (DS). There no direct or indirect comparisons assessing their full dose regimens, across different jurisdictions, as first‐line DS. Methods We conducted a systematic review frequentist network meta‐analysis (NMA) of randomized controlled trial (RCT) data for DS therapies. compared the proportions patients experiencing: reductions from baseline monthly convulsive seizure frequency (MCSF) ≥50% (clinically meaningful), ≥75% (profound), 100% (seizure‐free); serious adverse events (SAEs); discontinuations due AEs. Results identified relevant two placebo‐controlled RCTs each drug. Stiripentol 50 mg/kg/day fenfluramine 0.7 had similar efficacy achieving meaningful) (profound) MCSF (absolute risk difference [RD] stiripentol versus 1% [95% confidence interval: −20% 22%; p = 0.93] 6% [−15% 27%; 0.59], respectively), both were statistically superior ( < 0.05) regimens (10 20 mg/kg/day, with/irrespective clobazam) these outcomes. was seizure‐free intervals (RD 26% [CI: 8% 44%; 0.01]) cannabidiol. significant differences experiencing SAEs. The AEs lower stiripentol, although trials shorter. Significance This NMA RCT indicates therapy DS, is at least effective more than reducing seizures. No incidence SAEs between three agents observed, but may have These results inform clinical decision‐making continued development guidelines treatment people with Plain Language Summary study drugs (stiripentol, cannabidiol) used alongside other medications managing severe type epilepsy called found that similarly best drug stopping completely based on available data. All rates side effects, chance being stopped effects. information can help guide choices

Language: Английский

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Adaptive functioning and neurodevelopment in patients with Dravet syndrome: 12-month interim analysis of the BUTTERFLY observational study

Epilepsy & Behavior, Journal Year: 2024, Volume and Issue: 151, P. 109604 - 109604

Published: Jan. 13, 2024

The BUTTERFLY observational study aims to elucidate the natural trajectory of Dravet syndrome (DS) and associated comorbidities in order establish a baseline for clinical therapies. We present 12-month interim analysis study.

Language: Английский

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A Highly Sensitive Triple Quad LC–MS/MS Method Development and Validation for the Determination of Bexicaserin (LP352) in Human Plasma and Urine Matrices

Biomedical Chromatography, Journal Year: 2025, Volume and Issue: 39(2)

Published: Jan. 17, 2025

ABSTRACT Bexicaserin is a highly selective agonist at the 5‐HT 2c receptor in clinical development for treatment of seizures associated with developmental and epileptic encephalopathies (DEEs). We report an LC–MS/MS method quantitative estimation bexicaserin human plasma urine. The sample preparation involves extraction internal standard ( 13 CD 2 ‐bexicaserin; IS) from 150 μL 50 urine using solid phase method. chromatographic separation IS was achieved on Poroshell EC‐C18 column 5 min gradient program. calibration curve ranged 0.1 to 100 ng/mL 1.0 1000 Intraday interday precision accuracy, linearity, matrix effect, recovery, carry‐over, dilution integrity, battery stability studies, incurred reanalysis were performed both intraday accuracy well within acceptable limits matrices. Stability studies showed that stable bench 24 h, autosampler over 54 five freeze–thaw cycles, long‐term storage −20°C −80°C > 368 days. validated methods successfully applied study.

Language: Английский

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A multicenter cohort study on the efficacy, retention, and tolerability of cenobamate in patients with developmental and epileptic encephalopathies

Epilepsia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

This study was undertaken to evaluate retention and treatment characteristics of cenobamate (CNB) in patients with developmental epileptic encephalopathies (DEEs) clinical practice. multicenter, retrospective cohort recruited all DEEs who started CNB between October 2020 April 2023 at participating epilepsy centers. A total 41 (mean age = 28.3 ± 13.1 years, median 26 range 4-73 years; 24 male [58.5%]) were treated CNB. Of these, 33 had Lennox-Gastaut syndrome, seven tuberous sclerosis complex, one Dravet syndrome. The number antiseizure medications (ASMs) enrollment three, a eight failed ASMs the past. rate for 94.9% 3 months, 82.9% 6 72.4% 12 months follow-up. Cumulative exposure 477 (39.2 years). Efficacy (50% responder rate) 39% including 7.3% seizure-free patients. Long-term, 50% 34.5% (seizure-free [10.3%]). There no difference response regarding sex, (adult vs. children), previous concomitant ASMs, or first target dose Treatment-emergent adverse events predominantly sedation dizziness observed 58.5% Children adolescents showed comparable efficacy, retention, tolerability compared adults. findings from this open-label, suggest that may be effective some DEEs. Its overall use seems safe well tolerated. We similar response, event profiles children

Language: Английский

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Dravet syndrome: Advances in etiology, clinical presentation, and treatment

Epilepsy Research, Journal Year: 2022, Volume and Issue: 188, P. 107041 - 107041

Published: Oct. 29, 2022

Language: Английский

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The pharmacological treatment of epilepsy in adults

Epileptic Disorders, Journal Year: 2023, Volume and Issue: 25(5), P. 649 - 669

Published: June 30, 2023

The pharmacological treatment of epilepsy entails several critical decisions that need to be based on an individual careful risk-benefit analysis. These include when initiate and with which antiseizure medication (ASM). With more than 25 ASMs the market, physicians have opportunities tailor patients´ needs. ASM selection is primarily patient's type spectrum efficacy, but other factors must considered. age, sex, comorbidities, concomitant medications mention most important. Individual susceptibility adverse drug effects, ease use, costs, personal preferences should also taken into account. Once has been selected, next step decide target maintenance dose a titration scheme reach this dose. When clinical circumstances permit, slow generally preferred since it associated improved tolerability. adjusted response aiming at lowest effective Therapeutic monitoring can value in efforts establish optimal If first monotherapy fails control seizures without significant will gradually switch alternative monotherapy, or sometimes add another ASM. add-on considered, combining different modes action usually recommended. Misdiagnosis epilepsy, non-adherence suboptimal dosing are frequent causes failure excluded before patient regarded as drug-resistant. Other modalities, including surgery, neuromodulation, dietary therapies, considered for truly drug-resistant patients. After some years seizure freedom, question withdrawal often arises. Although successful many, risks decision needs

Language: Английский

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