Current Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 31(4), P. 388 - 392
Published: March 22, 2023
The neurosteroids progesterone and allopregnanolone control numerous neuroprotective functions in neural tissues, including inhibition of epileptic seizures cell death. Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) (GNX) is the 3β- methylated synthetic analog an allosteric GABAA positive modulator. reduces frequency CDD-associated seizures.
Language: Английский
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
Citations
95
Epilepsy & Behavior, Journal Year: 2025, Volume and Issue: 164, P. 110261 - 110261
Published: Jan. 23, 2025
Language: Английский
Citations
2
Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 234, P. 108035 - 108035
Published: Nov. 16, 2021
Language: Английский
Citations
71
Epilepsia, Journal Year: 2022, Volume and Issue: 63(10), P. 2671 - 2683
Published: July 16, 2022
Abstract Objective Dravet syndrome (DS) and Lennox–Gastaut (LGS) are rare treatment‐resistant childhood epilepsies classed as developmental epileptic encephalopathies. ELEKTRA investigated the efficacy safety of soticlestat (TAK‐935) adjunctive therapy in children with DS or LGS (NCT03650452). Methods was a phase 2, randomized, double‐blind, placebo‐controlled study (≤300 mg twice daily, weight‐adjusted) (aged 2–17 years) DS, demonstrating three more convulsive seizures/month, LGS, four drop seizures/month at baseline. The 20‐week treatment period comprised an 8‐week dose‐optimization 12‐week maintenance period. Efficacy endpoints included change from baseline seizure frequency versus placebo. Safety assessments incidence treatment‐emergent adverse events (TEAEs). Results enrolled 141 participants; 126 (89%) completed study. modified intent‐to‐treat population 139 participants who received one doses drug had (DS, n = 51; 88). achieved its primary endpoint: combined soticlestat‐treated demonstrated placebo‐adjusted median reduction 30.21% during ( p .0008, 139). During this period, reductions frequencies 50.00% .0002; patients DS) 17.08% .1160; LGS), respectively, were observed. TEAE incidences similar between (80.3%) placebo (74.3%) groups mostly mild moderate severity. Serious TEAEs reported by 15.5% 18.6% receiving placebo, respectively. ≥5% difference lethargy constipation. No deaths reported. Significance Soticlestat resulted statistically significant, clinically meaningful (combined patient population) (DS cohort). Drop showed nonstatistically significant numerical LGS. profile consistent previous studies.
Language: Английский
Citations
54
Pharmacology Biochemistry and Behavior, Journal Year: 2022, Volume and Issue: 213, P. 173321 - 173321
Published: Jan. 15, 2022
Language: Английский
Citations
40
Orphanet Journal of Rare Diseases, Journal Year: 2023, Volume and Issue: 18(1)
Published: March 1, 2023
Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with multiple seizure types starting in childhood, typical slow spike-wave pattern on electroencephalogram, cognitive dysfunction.We performed systematic literature review according to the PRISMA guidelines identify, synthesize appraise burden of illness LGS (including "probable" LGS). Studies were identified searching MEDLINE, Embase APA PsychInfo, Cochrane's database reviews, Epistemonikos. The outcomes epidemiology (incidence, prevalence or mortality), direct indirect costs, healthcare resource utilization, patient caregiver health-related quality life (HRQoL).The search 22 publications evaluating (n = 10), costs 10) and/or HRQoL 5). No studies reporting identified. With no specific ICD code for many regions, several had rely upon methods identify their populations (e.g., algorithms insurance claims databases There was heterogeneity between how defined, size populations, ages patients length follow-up period. varied from 4.2 60.8 per 100,000 people across probable 2.9-28 confirmed/narrow definition LGS. associated high mortality rates compared general population population. Healthcare utilization substantial all studies. Mean annual person $24,048 $80,545 studies, home-based care inpatient significant cost drivers. showed that caregivers adversely affected, although only few In addition, suggested events higher worse HRQoL. risk bias low moderate most studies.LGS featuring resistant seizures More research needed, especially burden, where there notable lack
Language: Английский
Citations
32
Epilepsia, Journal Year: 2024, Volume and Issue: 65(5), P. 1240 - 1263
Published: Jan. 22, 2024
Dravet syndrome (DS) and Lennox-Gastaut (LGS) are rare developmental epileptic encephalopathies associated with seizure nonseizure symptoms. A comprehensive understanding of how many individuals affected globally, the diagnostic journey they face, extent mortality these conditions is lacking. Here, we summarize evaluate published data on epidemiology DS LGS in terms prevalence, incidence, diagnosis, genetic mutations, sudden unexpected death epilepsy (SUDEP) rates. The full study protocol registered PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided only, 17 seven both. Case definitions varied considerably across studies, particularly for LGS. Incidence prevalence estimates per 100 000 generally higher than (LGS: incidence proportion = 14.5-28, 5.8-60.8; DS: 2.2-6.5, 1.2-6.5). Diagnostic delay was frequently reported LGS, a wider age range at diagnosis (DS, 1.6-9.2 years; 2-15 years). Genetic by 63 studies; all screened SCN1A variants, only one specifically focused Individuals had estimate 1000 person-years 15.84; 6.12) lower median death. SUDEP most cause DS. Only four studies information none which included SUDEP. This systematic review highlights paucity epidemiological available especially demonstrating need further research adoption standardized criteria.
Language: Английский
Citations
15
Epilepsia, Journal Year: 2024, Volume and Issue: 65(5), P. 1224 - 1239
Published: March 8, 2024
Abstract Fully elucidating the burden that Lennox–Gastaut syndrome (LGS) places on individuals with disease and their caregivers is critical to improving outcomes quality of life (QoL). This systematic literature review evaluated global illness LGS, including clinical symptom burden, care requirements, QoL, comorbidities, caregiver economic treatment (PROSPERO ID: CRD42022317413). MEDLINE, Embase, Cochrane Library were searched for articles met predetermined criteria. After screening 1442 deduplicated supplementary manual searches, 113 included review. A high LGS was identified, seizure frequency nonseizure symptoms (including developmental delay intellectual disability) leading low QoL substantial requirements latter daily function assistance mobility, eating, toileting. Multiple comorbidities disorders having highest prevalence. Although based few studies, a also which associated physical problems fatigue sleep disturbances), social isolation, poor mental health, financial difficulties. Most analyses focused direct costs arose predominantly from medically treated events, inpatient costs, medication requirements. Pharmacoresistance common, many required polytherapy changes over time. Few studies humanistic burden. Quality concerns noted sample representativeness, outcome measures, reporting clarity. In summary, individuals, caregivers, health systems may be alleviated by reducing These findings highlight need greater understanding better definitions broad spectrum development treatments alleviate symptoms.
Language: Английский
Citations
9
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
Citations
1
Drugs, Journal Year: 2023, Volume and Issue: 83(10), P. 923 - 934
Published: June 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
Language: Английский
Citations
19