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Background: Although people with late onset epilepsy of unknown etiology (LOEU) are at higher risk of cognitive decline compared to the general population, we still lack affordable tools to predict and stratify their risk of dementia. Objective: This pilot-study investigates the potential application of electroencephalography (EEG) network small-world (SW) properties in predicting cognitive decline among patients with LOEU. Methods: People diagnosed with LOEU and normal cognitive examination at the time of epilepsy diagnosis were included. Cerebrospinal fluid biomarkers, brain imaging, and neuropsychological assessment were performed at the time of epilepsy diagnosis. Baseline EEG was analyzed for SW properties. Patients were followed-up over time with neuropsychological testing to define the trajectory of cognitive decline. Results: Over 5.1 years of follow-up, among 24 patients diagnosed with LOEU, 62.5% were female, mean age was 65.3 years, thirteen developed mild cognitive impairment (MCI), and four developed dementia. Patients with LOEU developing MCI had lower values of SW coefficients in the delta (p = 0.03) band and higher SW values in the alpha frequency bands (p = 0.02) compared to patients having normal cognition at last follow-up. The two separate ANOVAs, for low and alpha bands, confirmed an interaction between SW and cognitive decline at follow-up. A similar gradient was confirmed for patients developing dementia compared to those with normal cognitive function as well as to those developing MCI. Conclusion: Baseline EEG analysis through SW is worth investigating as an affordable, widely available tool to stratify LOEU patients for their risk of cognitive decline.

Although amyloid pathology plays a role in epilepsy, little is known about the relationship between beta amyloid and progression to Alzheimer's disease (AD) among patients with late-onset epilepsy of unknown origin (LOEU). This multicenter, observational, prospective study enrolled 40 consecutive nondemented adults diagnosed with LOEU, together with 43 age- and sex-matched healthy controls. All patients completed neuropsychological tests, core CSF AD biomarkers assessment (Aβ1-42, total tau, and phosphorylated tau), and follow-up for a mean of 3 years to verify cognitive decline. Despite age and baseline cognitive performance were similar to healthy controls, patients with LOEU had significant prevalence of CSF pathological Aβ1-42 (

Objective Autoantibody‐mediated forms of encephalitis (AE) include neurological disorders characterized by subacute memory loss, movement disorders, and, often, frequent, focal epileptic seizures. Yet, the electrophysiological effects of these autoantibodies on neuronal function have received little attention. In this study, we assessed the effects of CSF containing autoantibodies on intrinsic and extrinsic properties of hippocampal neurons, to define their epileptogenic potential. Methods We compared the effects of CSF containing leucine‐rich glioma inactivated 1 (LGI1), contactin‐associated protein‐like 2 (CASPR2), and γ‐aminobutyric acid receptor B (GABABR) antibodies on ex vivo electrophysiological parameters after stereotactic hippocampal inoculation into mice. Whole‐cell patch‐clamp and extracellular recordings from CA1 pyramidal neurons and CA3‐CA1 field recordings in ex vivo murine brain slices were used to study neuronal function. Results By comparison to control CSF, AE CSFs increased the probability of glutamate release from CA3 neurons. In addition, LGI1‐ and CASPR2 antibodies containing CSFs induced epileptiform activity at a population level following Schaffer collateral stimulation. CASPR2 antibody containing CSF was also associated with higher spontaneous firing of CA1 pyramidal neurons. On the contrary, GABABR antibody containing CSF did not elicit changes in intrinsic neuronal activity and field potentials. Interpretation Using patient CSF, we have demonstrated that the AE‐associated antibodies against LGI1 and CASPR2 are able to increase hippocampal CA1 neuron excitability, facilitating epileptiform activity. These findings provide in vivo pathogenic insights into neuronal dysfunction in these conditions.

Introduction Epilepsy has a growing frequency, particularly in the elderly. Several triggers may cause late-onset epilepsy; however, more than 20% of epilepsies, manifesting in the elderly, has an unknown etiology. Although cognition is frequently altered in patients affected by epilepsy, there is a paucity of studies specifically evaluating cognition in patients affected by late-onset epilepsy. The aim of the present study was to assess the cognitive profile of patients affected by late-onset epilepsy with an unknown etiology and followed for 12 months. Methods Patients affected by diagnosed late-onset epilepsy with unknown etiology were included in this observation. All patients were evaluated at the time of diagnosis (baseline) and at follow-up (12 months later). We distributed patients in subgroups based on seizure type (focal seizures [FS], secondarily generalized seizures [SGS], primarily generalized seizures [GS]) and antiepileptic drug (AED) regimen (mono- vs. polytherapy). Cognition was evaluated through standardized neuropsychological testing. Results Fifty-eight patients were included in this observation and distributed in three groups: 29 affected by FS, 14 affected by SGS, 15 affected by GS. Forty-five patients were in monotherapy, and 13 in polytherapy. The most frequent treatments were levetiracetam (n = 12), valproic acid (VPA) (n = 9), carbamazepine (n = 9), and oxcarbazepine (n = 7). We documented a significant decrease of Mini-Mental State Examination (MMSE) and memory scores at follow-up in the whole group. Verbal learning decreased exclusively in VPA users. Conclusion Patients affected by late-onset epilepsy with unknown etiology showed a significant decline of cognition at follow-up, independently from number and efficacy of AEDs received. These results deserve verification in larger longitudinal cohorts.

Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales. Forty-nine patients aged 36.6 ± 15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2–12 mg (5.3 ± 2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4–6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy. Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the ‘Action myoclonus’ section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness. PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.

The efficacy of levetiracetam (LEV) in controlling seizures in patients with brain tumor-related epilepsy (BTRE) depends on tumoral expression of synaptic vesicle protein 2A (SV2A). Although LEV is generally well tolerated, neuropsychiatric adverse events (NPAEs) might occur, limiting compliance and seizure control. We aimed to assess the influence of tumoral SV2A expression on the occurrence of LEV-related NPAEs in patients with glioma.Specimens from patients enrolled in the multicenter COMPO study, with glioma and BTRE treated with LEV, undergoing neurosurgery were retrieved. Immunohistochemistry-based expression of SV2A in tumoral and peritumoral tissue was scored in a four-point scale from absent (score = 0) to strong (score = 3). Low immunoreactivity (IR) corresponded to scores 2. Staining ratios (tumoral SV2A IR/peritumoral SV2A IR) were grouped into low (≤ 0.5) and high ( 0.5). NPAEs were assessed longitudinally with the Neuropsychiatry Inventory 12 test (NPI-12).Overall, 18 patients were eligible for analysis. All received LEV monotherapy, with 67% developing NPAEs. Patients with NPAEs had significantly lower median SV2A intensity score compared to patients without NPAEs (score 1 vs 0, p = 0.025). Low staining ratio (≤ 0.5) associated with higher NPAE occurrence compared to SR 0.5 (85.7% vs 0%, p 0.01). A SR ≤ 0.5 predicted a consistent increase in risk of NPAEs (OR 45.0; 95% CI 1.8-1128; p = 0.02).Our results suggest that SV2A expression in tumoral and peritumoral tissue correlates with the occurrence of LEV-related NPAEs. Thus, considering that SV2A expression also influences LEV effectiveness, SV2A staining might help in tailoring treatment to patients.

The intertwining between epilepsy, sleep disorders and beta amyloid pathology has been progressively highlighted, as early identification and stratification of patients at high risk of cognitive decline is the need of the hour. Modification of the sleep-wake activity, such as sleep impairment or excessive daytime sleepiness, can critically affect cerebral beta amyloid levels. Both mice models and human studies have demonstrated a substantial increase in the burden of beta amyloid pathology after sleep-deprivation, with potential negative effects partially restored by sleep recovery. The accumulation of beta amyloid has been shown to be an early event in the course of Alzheimer's disease dementia. Beta amyloid accumulation has been linked to epileptic seizures epileptic seizures, with beta amyloid being itself pro-epileptogenic in mice models already at oligomeric stage, well before plaque deposition. Further supporting a potential relationship between beta amyloid and epilepsy: i) seizures happen in 1 out of oofut 10 patients with Alzheimer's disease in the prodromal stage, ii) epileptic activity accelerates cognitive decline in Alzheimer's disease, iii) people with late-onset epilepsy present a critically high risk of developing dementia. In this Review we highlight the role of beta amyloid as a potential shared mechanisms between sleep disorders, late-onset epilepsy, and cognitive decline.