Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies

Gesche, Joanna; Khanevski, Marina; Solberg, Carl; Beier, Christoph P.

doi:10.1111/epi.13702

Cited by 54 publications

(54 citation statements)

References 14 publications

(20 reference statements)

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“…Addition of perampanel led to improvements in seizure outcomes, regardless of concomitant AEDs. Even in patients previously treated with (and presumably failed) valproic acid (which is a strong predictor of refractory seizures in IGE), 43% were free of absence seizures and 54% were free of all seizures at 1 year. Consistent with previous findings with perampanel when added to levetiracetam, the specific concomitant AEDs did not tend to affect the incidence of AEs.…”

Section: Discussionmentioning

confidence: 99%

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12‐month GENERAL study

et al. 2018

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Summary Objective To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE). Methods This multicenter, retrospective, 1‐year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ≥12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included. Results The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic–clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure‐free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add‐on (after ≤2 prior AEDs) than late (≥3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent. Significance In routine clinical care of patients with IGE, perampanel improved seizure outcomes for GTCS, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real‐world evidence with perampanel across different seizure types in IGE.

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Section: Discussionmentioning

confidence: 99%

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12‐month GENERAL study

et al. 2018

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“…Patients were classified as 'pseudo-resistant', 'drugresistant' and 'non-resistant' as described by Gesche et al [16]. Estimation of incidence and prevalence was based on the entire population on Funen (Data S1).…”

Section: Patient Cohort and Analysesmentioning

confidence: 99%

Epidemiology and outcome of idiopathic generalized epilepsy in adults

Gesche

Christensen

Hjalgrim³

et al. 2020

Euro J of Neurology

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Background and purpose Drug‐resistant idiopathic generalized epilepsy (IGE) remains challenging despite a favourable overall prognosis of IGE, and little is known about basic epidemiology and long‐term outcome of drug‐resistant IGE. The aim of the study was to describe the incidence, prevalence and outcome of IGE in an unbiased, population‐based cohort. Methods In 2014–2018, all patients (≥17 years) with IGE inhabiting the island of Funen (496 000 inhabitants) were recruited. The socioeconomic and clinical information available for 406 individuals was assessed. Median follow‐up was 15 years. Results The average IGE incidence (2008–2017) was 2.9/100 000 inhabitants/year. The point prevalence of identifiable IGE patients was 1.0/1000 adults (juvenile myoclonic epilepsy 0.4/1000; absence epilepsy 0.3/1000, epilepsy with generalized tonic–clonic seizures alone 0.3/1000); 92.1% of the patients were diagnosed before 25 years of age. When correcting for unequal age distribution in the cohort, 1102 people on the island of Funen fulfilled the diagnostic criteria for IGE at the age of 25 (estimated prevalence 2.7/1000 adults). In the year before data closure, 121 patients reported seizures. Fifty patients met the definition of drug‐resistant IGE (12.1% of the cohort, 4.5% of the estimated 1102 IGE patients). The average seizure burden of all patients with drug‐resistant IGE was 2.2 generalized tonic–clonic seizures per year; only 14 patients suffered more than two generalized tonic–clonic seizures per year. Drug‐resistant IGE was associated with an increased risk of requiring treatment for affective disorders and a reduced probability of working full time. Conclusion Idiopathic generalized epilepsy was associated with a low risk of persistent drug‐resistant seizures requiring specialist medical attention. Drug resistance was associated with a negative socioeconomic outcome.

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“…Previous studies have indicated that approximately one-third of patients are non-responsive to VPA (8,9), and the reason for this phenomenon remains elusive. Recently, Gesche et al (10) have demonstrated that resistance to VPA has a specificity of 100% regarding the identification of genetic generalized epileptic patients. Consequently, it is important to elucidate the mechanism underlying VPA efficacy and identify biomarkers predictive of VPA responses.…”

Section: Introductionmentioning

confidence: 99%

RNA‑seq analysis of blood of valproic acid‑responsive and non‑responsive pediatric patients with epilepsy

Wang

2019

Exp Ther Med

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Epilepsy is the most common chronic neurological disorder, affecting ~70 million individuals worldwide. However, approximately one-third of the patients are refractory to epilepsy medication. Of note, 100% of patients with genetic epilepsy who are resistant to the traditional drug, valproic acid (VPA), are also refractory to the other anti-epileptic drugs. The aim of the present study was to compare the transcriptomes in VPA responders and non-responders, to explore the mechanism of action of VPA and identify possible biomarkers to predict VPA resistance. Thus, RNA-seq was employed for transcriptomic analysis, differentially expressed genes (DEGs) were analyzed using Cuffdiff software and the DAVID database was used to infer the functions of the DEGs. A protein-protein interaction network was obtained using STRING and visualized with Cytoscape. A total of 389 DEGs between VPA-responsive and non-responsive pediatric patients were identified. Of these genes, 227 were upregulated and 162 were downregulated. The upregulated DEGs were largely associated with cytokines, chemokines and chemokine receptor-binding factors, whereas the downregulated DEGs were associated with cation channels, iron ion binding proteins, and immunoglobulin E receptors. In the pathway analysis, the toll-like receptor signaling pathway, pathways in cancer, and cytokine-cytokine receptor interaction were mostly enriched by the DEGs. Furthermore, three modules were identified by protein-protein interaction analysis, and the potential hub genes, chemokine (C-C motif) ligand 3 and 4, chemokine (C-X-C motif) ligand 9, tumor necrosis factor-α and interleukin-1β, which are known to be closely associated with epilepsy, were identified. These specific chemokines may participate in processes associated with VPA resistance and may be potential biomarkers for monitoring the efficacy of VPA.

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Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies

Cited by 54 publications

References 14 publications

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12‐month GENERAL study

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12‐month GENERAL study

Epidemiology and outcome of idiopathic generalized epilepsy in adults

RNA‑seq analysis of blood of valproic acid‑responsive and non‑responsive pediatric patients with epilepsy

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