Persistent treatment resistance in genetic generalized epilepsy: A long‐term outcome study in a tertiary epilepsy center

Abstract

Objective: To assess prognostic patterns and investigate clinical and electroencephalography (EEG) variables associated with persistent treatment resistance in a population of genetic generalized epilepsy (GGE) patients with a long-term follow-up. Methods: Data from GGE patients followed from 1975 to 2019 were reviewed retrospectively. Subjects with a follow-up >10 years, starting from epilepsy diagnosis, were included. Persistent treatment resistance was defined as the absence of any period of remission ≥1 year despite treatment with two appropriate and adequate antiepileptic drugs (AEDs). Results: One hundred ninety-nine patients were included. The median age was 39.5 years (interquartile range [IQR] 30-49) and the median follow-up was 27 years (IQR 18-35). The most common syndrome was juvenile myoclonic epilepsy (JME), diagnosed in 44.2% of patients. During follow-up, 163 subjects (81.9%) experienced 3-year remission from any seizure type, whereas 5-and 10-year remission occurred in 141 (70.8%) and 92 (46.2%) cases, respectively. The most common prognostic pattern was a relapsing-remitting course, observed in 80 patients (40.2%), whereas 29 (14.6%) displayed persistent treatment resistance. According to multivariable logistic regression analysis, febrile seizures (FS), specific EEG patterns (namely generalized paroxysmal fast activity, GPFA) and valproate (VPA) resistance were the only variables significantly associated with persistent treatment resistance. JME was the only epilepsy syndrome statistically associated with persistent treatment resistance in univariable logistic regression analysis. Significance: Persistent treatment resistance was observed in almost 15% of GGE patients followed in a tertiary epilepsy center. A worse outcome was associated with specific clinical variables (JME, FS) and EEG patterns (GPFA).

Generalized Fast Discharges Along the Genetic Generalized Epilepsy Spectrum: Clinical and Prognostic Significance

“…Regarding electrophysiological characteristics, the described EEG patterns were analyzed in terms of morphology and frequency and in relation to physiological state. The prominent occurrence of GPFA during sleep (especially during the N2 stage) was confirmed in our cohort ( 2 , 24 ). Previous authors have hypothesized that NREM sleep could represent a permissive neural environment for the production of GPFA, possibly in relation to the prominent occurrence of slow oscillations during this physiological state, which have been demonstrated to help facilitate fast activity bursts both in animal models and in LGS patients ( 29 – 31 ).…”

“…These findings were corroborated by our multivariable analysis, which confirmed GPFA/GPT as a significant independent predictor of both drug-resistant GGE and of a reduced chance of achieving 2-year seizure remission at the last medical observation. Overall, our data seem to support that EEG fast discharges represent an EEG biomarker of more difficult-to-treat GGE ( 6 , 24 , 25 ). However, the lack of systematic paEEG use at epilepsy onset prevented us from understanding whether generalized fast discharges represent an endophenotypic trait of more refractory GGE from its very onset or an epiphenomenon of prolonged unremitting seizures during the epilepsy course.…”

Etiology‐specific response to antiseizure medication in focal epilepsy

“…Estimating seizure outcome in epilepsy is of high importance with regard to counseling patients on overall prognosis and tailoring treatment decisions. Approximately 60%–70% of people with epilepsy (PwE) achieve seizure freedom with antiseizure medication (ASM); in mono‐ or polytherapy, treatment success in focal epilepsy (57%–62% seizure‐free) 1,2 is generally lower as compared to genetic generalized epilepsy (68%–85%) 1,3,4 . Beyond seizure control, equipollent therapeutic goals for PwE comprise minimal adverse effects of ASM and overall low interference of ASM with the patient's lifestyle, 5 both of which may be achieved by a preferably low drug load.…”

Seizure outcome trajectories in a well‐defined cohort of newly diagnosed juvenile myoclonic epilepsy patients

“…Seizure remission has been demonstrated to be a dynamic process during patient follow‐up, and great differences exist in terms of time delay from epilepsy onset to medication response 16–18 . Moreover, a considerable percentage of GGE patients has been shown to experience seizure relapse after periods of remission independent of ASM withdrawal 19–21 and no authors have investigated the time course of spontaneous relapse or the factors associated with recurring seizures in JME patients.…”