Paolo Tinuper

Purpose: To evaluate the long-term efficacy of vagus nerve stimulation (VNS) in reducing tonic-clonic seizures (TCS), drop attacks, and seizure clusters in adults with drug-resistant epilepsy (DRE). Methods: This retrospective, single-center study included adults with DRE who received VNS and had ≥ 12 months of follow-up. Data were collected pre-implantation (T0), at 12 months (T1), and last follow-up (T2). Outcomes included reduction in total seizure frequency and severity, frequency of TCS and drop attacks, and frequency/duration of seizure clusters. Battery replacement and tolerability were also assessed. Results: Eighty-seven subjects (51 males, median age 33 at T0) with a mean follow-up of 8 years were analyzed. At T2, 54% showed reduced total seizure frequency and 71% reported decreased severity/duration. Among those with baseline TCS, 75% (T1)–80.6% (T2) had frequency reduction, with 20.6% seizure-free at T2. Drop attacks improved in > 70% of cases, with resolution in 21.8% at T2. Over 80% with seizure clusters reported decreased frequency/duration at both T1 and T2. Response rates for specific seizure types significantly exceeded non-response ( p < 0.001). Battery replacement was required in 85.7% near depletion. Side effects occurred in 49.4%, mostly mild/transient; major complications were rare. Conclusion: VNS exerts a robust effect on the most disabling seizures—TCS, drop attacks, and seizure clusters—surpassing its impact on overall seizure burden. Benefits appear within the first year and persist long term. These findings support a more tailored approach to VNS candidate selection, advocating earlier use in patients with refractory, harmful seizures not eligible for curative surgery.

Objective: The AMPA study (Study 501; NCT04257604) was a multicenter, prospective, 12‐month observational study in Italy that evaluated the effectiveness and safety of adjunctive perampanel in patients with focal‐onset seizures (FOS), with or without focal to bilateral tonic–clonic seizures (FBTCS). Methods: Patients aged ≥12 years with insufficiently controlled FOS, with or without FBTCS, receiving 1–3 anti‐seizure medications (ASMs) were prescribed adjunctive perampanel per the approved indication. The primary endpoint was the median percent change in total seizure frequency per 28 days from baseline at Month 6. Baseline seizure frequency per 28 days was calculated using seizure diaries and/or medical records of seizures occurring in the 8 weeks prior to the baseline visit while patients were receiving 1–3 ASMs. Treatment‐emergent adverse events (TEAEs), including serious TEAEs, were monitored for up to 12 months. Results: Of the 240 patients enrolled in the study, 234 were included in the Full and Safety Analysis Sets. Median age (minimum, maximum) was 36.0 years (12, 84) and 51.3% ( n = 120/234) were female. The majority of patients (77.8% [ n = 182/234]) received ≥2 concomitant ASMs at baseline, with the most common being carbamazepine (33.8% [ n = 79/234]). The median percent reduction in total seizure frequency per 28 days from baseline (95% confidence interval) was 55.4% (46.7%–66.7%) at Month 6. Overall, the retention rate was 57.3% ( n = 134/234) following 12 months of treatment. During the study, the overall incidence of TEAEs was 56.4% ( n = 132/234), with the most frequently reported TEAE being dizziness/vertigo (21.8% [ n = 51/234]). Serious TEAEs were experienced by 6.0% ( n = 14/234) of patients and no deaths were reported during the 12‐month treatment period. Significance: Data from the AMPA study suggest that adjunctive perampanel is associated with improvement in seizure control and with good retention rates and tolerability in a real‐world clinical setting. These findings further support the use of adjunctive perampanel as a suitable treatment option for adolescent and adult patients with epilepsy. Plain Language Summary: Our study looked at teenage and adult patients with epilepsy in Italy who took the study drug, called perampanel, as well as the epilepsy treatments they had already been prescribed. After 12 months, 134 out of 234 patients were still using perampanel. Patients taking perampanel had fewer seizures than they did before they started taking perampanel. Side effects occurred in 132 patients (most commonly dizziness/vertigo, irritability, and sleepiness) and caused 45 of them to withdraw from the study. Perampanel was a suitable treatment option for teenage and adult patients with epilepsy.

Background: Ictal bradycardia (IB) and asystole (IA) represent a rare but potentially harmful feature of epileptic seizures. The aim of this study was to study IB/IA in patients with sleep-related hypermotor epilepsy (SHE). Methods: We retrospectively included cases with video-EEG-confirmed SHE who attended our Institute up to January 2021. We reviewed the ictal polysomnography recordings focusing on ECG and identified cases with IB (R-R interval ≥ 2 s or a ≥10% decrease of baseline heart rate) and IA (R-R interval ≥ 4 s). Results: We included 200 patients (123 males, 61.5%), with a mean age of 42 ± 16 years. Twenty patients (20%) had focal cortical dysplasia (FCD) on brain MRI. Eighteen (out of 104 tested, 17.3%) carried pathogenic variants (mTOR pathway, n = 10, nAchR subunits, n = 4, KCNT1, n = 4). We identified IB/IA in four cases (2%): three had IA (mean 10 s) and one had IB. Three patients had FCD (left fronto-insular region, left amygdala, right mid-temporal gyrus) and two had pathogenic variants in DEPDC5; both features were more prevalent in patients with IB/IA than those without (p = 0.003 and p = 0.037, respectively). Conclusions: We identified IB/IA in 2% of patients with SHE and showed that this subgroup more frequently had FCD on brain MRI and pathogenic variants in genes related to the mTOR pathway.

Background Non-convulsive status epilepticus (NCSE) is a time-dependent neurological disorder often misdiagnosed in the emergency setting. Electroencephalography (EEG) is often not available on a 24/7 basis, and Salzburg criteria may at times miss the diagnosis. Here, we tested the accuracy of hyperperfusion on CT perfusion imaging (CTP) in the identification of NCSE against Salzburg criteria, to define its potential role in a pragmatic diagnostic workflow. Methods We enrolled consecutive patients with suspected acute seizure or seizure disorder undergoing brain imaging with CTP and EEG from January 2021 to March 2023. EEG recordings, Salzburg criteria and CTP hyperperfusion were rated and adjudicated by two independent experts blinded to patient status. A reference standard including all clinical, lab, imaging, EEG and therapeutic data was used to adjudicate NCSE diagnosis. Sensitivity, specificity, diagnostic accuracy, positive and negative predictive values (NPV) were calculated for CTP hyperperfusion and Salzburg criteria versus NCSE adjudicated according to reference standard. Results Seventy-seven patients were enrolled. Among 21 NCSE cases, 17 were adjudicated according to Salzburg criteria (81%) and 4 received NCSE diagnosis according to reference standard. Agreement between EEG and CTP emerged in 16/21 NCSE cases, reaching sublobar level in 37.5% of cases. Receiver operator curve analysis suggested good accuracy for CTP hyperperfusion for the diagnosis of NCSE (AUROC 0.79, 95% CI 0.69 to 0.89). CTP hyperperfusion had a high NPV for NCSE (NPV 0.97, 95% CI 0.86 to 1). Conclusion CTP hyperperfusion may be implemented in the emergency fast-track to rule out NCSE, given very high NPV. Further validation studies are needed to evaluate CTP application in real-world setting for NCSE codes.

We propose an instructive figure that summarized the classification of epilepsy syndromes according to the 2022 report of the ILAE Task Force on Nosology and Definitions. Our aim is to present on the same figure different concepts such as the names of epilepsy syndromes, their extreme and classical ages of onset, their epilepsy types (generalized, focal, or generalized and focal) but also their membership in groups of epilepsy syndromes as for self‐limited or developmental and epileptic encephalopathies. With this figure, we provide an interactive tool, as supplementary data, helping to present this classification and link it to electro‐clinical mandatory, alerts, and exclusionary criteria of each syndrome, in accordance with the ILAE position papers on syndromes classification and nosology. This report may be used as an illustrative tool for teaching epilepsy syndromes and as a practical and comprehensive aid for the classification of epilepsy individuals' syndromes.

Objective: Nonconvulsive status epilepticus (NCSE) is misdiagnosed in >50% of cases in the emergency department. Computed tomographic perfusion (CTP) has been implemented in the hyperacute setting to detect seizure‐induced hyperperfusion. However, the diagnostic value of CTP is limited by the lack of thresholds for hyperperfusion and high interrater variability. This pilot case–control study aims at identifying the diagnostic value of reverse Tmax (rTmax) in differentiating NCSE from acute ischemic stroke in the hyperacute setting.Methods: We enrolled patients with NCSE (Salzburg criteria‐based diagnosis) and stroke cases 1:1 matched for clinical features and time of presentation. CTP standard maps (mean transit time [MTT]–cerebral blood volume–cerebral blood flow [CBF]) and rTmax maps were elaborated and rated by two experts in CTP blinded to the final diagnosis. Hyperperfusion was adjudicated for standard CTP maps as an increase in CBF and a decrease in MTT, and for rTmax as the presence of a black area on 3‐, 2‐, and 1‐s threshold maps. Cronbach alpha was used for interrater agreement; receiver operating curve analysis was run to measure accuracy with area under the curve.Results: Overall, 34 patients were included (17 NCSE, 17 stroke; time from onset to imaging = 2 h for both groups). People with NCSE were older and more frequently had a history of epilepsy. NCSE patients had hyperperfusion on rTmax maps in 11 of 17 cases versus zero of 17 in stroke. Intra‐ and interrater reliability was higher for rTmax than for standard CTP maps (κ = 1 vs. κ = .6). rTmax was 82% (95%CI = 67–97%) accurate in predicting NCSE versus stroke in the hyperacute setting. Agreement between neuroimaging and electroencephalography (EEG) was limited at a hemispheric level for standard CTP maps, whereas rTMax had agreement with EEG largely reaching the sublobar level.Significance: rTmax mapping might represent a reliable tool to spot NCSE‐induced hyperperfusion with a threshold‐based reproducible approach. Further studies are needed for validation and implementation in the differential diagnosis of focal neurological deficit in the hyperacute setting.

Epilepsy with auditory features (EAF) is a focal epilepsy belonging to the focal epileptic syndromes with onset at variable age according to the new ILAE Classification. It is characterized by seizures with auditory aura or receptive aphasia suggesting a lateral temporal lobe involvement of the epileptic discharge. Etiological factors underlying EAF are largely unknown. In the familial cases with an autosomal dominant pattern of inheritance several genes have been involved, among which the first discovered, LGI1, was thought to be predominant. However, increasing evidence now points to a multifactorial etiology, as familial and sporadic EAF share a virtually identical electro-clinical characterization and only a few have a documented genetic etiology. Patients with EAF usually have an unremarkable neurological examination and a good response to antiseizure medications. However, it must be underscored that total remission might be lower than expected and that treatment withdrawal might lead to relapses. Thus, a proper understanding of this condition is in order for better patient treatment and counseling. Further studies are still required to further characterize the many facets of EAF.

Background and Objectives To assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort. Methods Of 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.” Results Sixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories. Discussion The application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.