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

CNS Drugs, Год журнала: 2022, Номер 36(10), С. 1079 - 1111

Опубликована: Окт. 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.

Язык: Английский

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Dravet syndrome: A systematic literature review of the illness burden

Epilepsia Open, Год журнала: 2023, Номер 8(4), С. 1256 - 1270

Опубликована: Сен. 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.

Язык: Английский

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Fenfluramine: a plethora of mechanisms?

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Май 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.

Язык: Английский

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

Drugs, Год журнала: 2023, Номер 83(15), С. 1409 - 1424

Опубликована: Сен. 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.

Язык: Английский

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Unveiling the role of histone deacetylases in neurological diseases: focus on epilepsy

Biomarker Research, Год журнала: 2024, Номер 12(1)

Опубликована: Ноя. 19, 2024

Abstract Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons poses great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it urgent need explore other potential mechanism develop novel approach delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), versatile epigenetic regulators responsible gene transcription via binding histones or non-histone substrates, have grabbed considerable attention in drug discovery. There also substantial evidences supporting aberrant expressions and/activities HDAC isoforms reported epilepsy inhibitors (HDACi) been purposes this condition. However, specific mechanisms underlying role HDACs progression not fully understood. Herein, we reviewed basic information HDACs, summarized recent findings associated with roles diverse subunits discussed regulatory which affected development epilepsy. Additionally, provided brief discussion on as promising targets treatment, serving valuable reference study clinical translation field.

Язык: 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, Год журнала: 2024, Номер 9(2), С. 689 - 703

Опубликована: Март 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

Язык: Английский

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

Epilepsy Research, Год журнала: 2022, Номер 188, С. 107041 - 107041

Опубликована: Окт. 29, 2022

Язык: Английский

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The pharmacological treatment of epilepsy in adults

Epileptic Disorders, Год журнала: 2023, Номер 25(5), С. 649 - 669

Опубликована: Июнь 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

Язык: Английский

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Fenfluramine: A Review in Dravet and Lennox-Gastaut Syndromes

Drugs, Год журнала: 2023, Номер 83(10), С. 923 - 934

Опубликована: Июнь 15, 2023

Fenfluramine (Fintepla®) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting activity in the serotonergic system coupled positive allosteric modulation effects at sigma-1 receptors. Originally approved for use high doses as appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before investigated low adjunctive ASM patients developmental epileptic encephalopathies, including Dravet syndrome (DS) Lennox-Gastaut (LGS) who have pharmacoresistant seizures. In clinical trials, treatment fenfluramine markedly reduced convulsive seizure frequency DS that were sustained up 3 years, drop LGS 1 year. Notably, also associated clinically meaningful improvements aspects everyday executive functioning (EF) not entirely explainable by reduction alone. Furthermore, generally well tolerated with, importantly, no reports VHD or PAH. Thus, effective seizures may improve EF some patients. Emerging infancy childhood, respectively, are severe encephalopathies. They characterized frequently 'pharmacoresistant' [i.e. cannot be controlled ≥ 2 medications (ASMs)] that, along cognitive behavioural comorbidities, can major impact on quality life (and their caregivers/family members) they grow. distinctive dual action, used doses. trials LGS, adding existing regimen produced significant reductions (EF; i.e. ability regulate cognition, emotions and/or behaviour). Importantly, there evidence complications previously observed suppressant. Adjunctive well-tolerated

Язык: Английский

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Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies

Therapeutic Advances in Neurological Disorders, Год журнала: 2023, Номер 16

Опубликована: Янв. 1, 2023

Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset often intractable seizures developmental delay/regression, include Dravet syndrome Lennox–Gastaut (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol ganaxolone antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability preventing the functional recycling voltage-gated sodium channels from inactivated resting state. It licensed adjunctive treatment associated LGS. Fenfluramine increases extracellular serotonin levels may reduce via activation receptors positive modulation sigma-1 receptor. Stiripentol a allosteric modulator type-A gamma-aminobutyric acid (GABA A ) receptors. As broad-spectrum inhibitor cytochrome P450 enzymes, its effects additionally arise through pharmacokinetic interactions co-administered ASMs. in patients taking clobazam and/or valproate. The mechanism(s) remains largely unclear although multiple targets proposed, including transient receptor potential vanilloid 1, G protein-coupled 55 equilibrative nucleoside transporter 1. Cannabidiol as conjunction LGS, tuberous sclerosis complex. Like at GABA has recently USA cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding causes DEEs driven research into use other novel repurposed agents. Putative ASMs currently clinical development soticlestat, carisbamate, verapamil, radiprodil, clemizole lorcaserin.

Язык: Английский

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