Molecular Chaperones and miRNAs in Epilepsy: Pathogenic Implications and Therapeutic Prospects.

Epilepsy is a pathologic condition with high prevalence and devastating consequences for the patient and its entourage. Means for accurate diagnosis of type, patient monitoring for predicting seizures and follow up, and efficacious treatment are desperately needed. To improve this adverse outcome, miRNAs and the chaperone system (CS) are promising targets to understand pathogenic mechanisms and for developing theranostics applications. miRNAs implicated in conditions known or suspected to favor seizures such as neuroinflammation, to promote epileptic tolerance and neuronal survival, to regulate seizures, and others showing variations in expression levels related to seizures are promising candidates as useful biomarkers for diagnosis and patient monitoring, and as targets for developing novel therapies. Components of the CS are also promising as biomarkers and as therapeutic targets, since they participate in epileptogenic pathways and in cytoprotective mechanisms in various epileptogenic brain areas, even if what they do and how is not yet clear. The data in this review should help in the identification of molecular targets among the discussed miRNAs and CS components for research aiming at understanding epileptogenic mechanisms and, subsequently, develop means for predicting/preventing seizures and treating the disease.

Do neurologists agree in diagnosing drug resistance in adults with focal epilepsy?

OBJECTIVE: To evaluate interrater agreement in categorizing treatment outcomes and drug responsiveness status according to the International League Against Epilepsy (ILAE) definition of drug-resistant epilepsy. METHODS: A total of 1053 adults with focal epilepsy considered by the investigators to meet ILAE criteria for drug resistance were enrolled consecutively at 43 centers and followed up prospectively for 18-34 months. Treatment outcomes for all antiepileptic drugs (AEDs) used up to enrollment (retrospective assessment), and on an AED newly introduced at enrollment, were categorized by individual investigators and by 2 rotating members of a 16-member expert panel (EP) that reviewed the patient records independently. Interrater agreement was tested by Cohen's kappa (k) statistics and rated according to Landis and Koch's criteria. RESULTS: Agreement between EP members in categorizing outcomes on the newly introduced AED was almost perfect (90.1%, k = 0.84, 95% confidence interval [CI] 0.80-0.87), whereas agreement between the EP and individual investigators was moderate (70.4%, k = 0.57, 95% CI 0.53-0.61). Similarly, categorization of outcomes on previously used AEDs was almost perfect between EP members (91.7%, k = 0.83, 95% CI 0.81-0.84) and moderate between the EP and investigators (68.2%, k = 0.50, 95% CI 0.48-0.52). Disagreement was related predominantly to outcomes considered to be treatment failures by the investigators but categorized as undetermined by the EP. Overall, 19% of patients classified as having drug-resistant epilepsy by the investigators were considered by the EP to have "undefined responsiveness." SIGNIFICANCE: Interrater agreement in categorizing treatment outcomes according to ILAE criteria ranges from moderate to almost perfect. Nearly 1 in 5 patients considered by enrolling neurologists to be "drug-resistant" were classified by the EP as having "undefined responsiveness."

Social cognition dysfunctions in patients with epilepsy: Evidence from patients with temporal lobe and idiopathic generalized epilepsies.

BACKGROUND AND AIM: Despite an extensive literature on cognitive impairments in focal and generalized epilepsy, only a few number of studies specifically explored social cognition disorders in epilepsy syndromes. The aim of our study was to investigate social cognition abilities in patients with temporal lobe epilepsy (TLE) and in patients with idiopathic generalized epilepsy (IGE). MATERIALS AND METHODS: Thirty-nine patients (21 patients with TLE and 18 patients with IGE) and 21 matched healthy controls (HCs) were recruited. All subjects underwent a basic neuropsychological battery plus two experimental tasks evaluating emotion recognition from facial expression (Ekman-60-Faces test, Ek-60F) and mental state attribution (Story-based Empathy Task, SET). In particular, the latter is a newly developed task that assesses the ability to infer others' intentions (i.e., intention attribution - IA) and emotions (i.e., emotion attribution - EA) compared with a control condition of physical causality (i.e., causal inferences - CI). RESULTS: Compared with HCs, patients with TLE showed significantly lower performances on both social cognition tasks. In particular, all SET subconditions as well as the recognition of negative emotions were significantly impaired in patients with TLE vs. HCs. On the contrary, patients with IGE showed impairments on anger recognition only without any deficit at the SET task. DISCUSSION: Emotion recognition deficits occur in patients with epilepsy, possibly because of a global disruption of a pathway involving frontal, temporal, and limbic regions. Impairments of mental state attribution specifically characterize the neuropsychological profile of patients with TLE in the context of the in-depth temporal dysfunction typical of such patients. CONCLUSION: Impairments of socioemotional processing have to be considered as part of the neuropsychological assessment in both TLE and IGE in view of a correct management and for future therapeutic interventions.

Fibromyalgia: Could hyperbaric oxygen therapy make the difference? Our experience.

Fibromyalgia is a rare disease, difficult to diagnose and to treat. We think that hyperbaric oxygen therapy could improve its signs and symptoms although more evidences have to be accumulated.

A retrospective multicentric study on the effectiveness of intravenous brivaracetam in seizure clusters: Data from the Italian experience.

OBJECTIVE: Nearly half of people with epilepsy (PWE) are expected to develop seizure clusters (SC), with the subsequent risk of hospitalization. The aim of the present study was to evaluate the use, effectiveness and safety of intravenous (IV) brivaracetam (BRV) in the treatment of SC. METHODS: Retrospective multicentric study of patients with SC (≥ 2 seizures/24 h) who received IV BRV. Data collection occurred from January 2019 to April 2022 in 25 Italian neurology units. Primary efficacy outcome was seizure freedom up to 24 h from BRV administration. We also evaluated the risk of evolution into Status Epilepticus (SE) at 6, 12 and 24 h after treatment initiation. A Cox regression model was used to identify outcome predictors. RESULTS: 97 patients were included (mean age 62 years), 74 (76%) of whom had a history of epilepsy (with drug resistant seizures in 49% of cases). BRV was administered as first line treatment in 16% of the episodes, while it was used as first or second drug after benzodiazepines failure in 49% and 35% of episodes, respectively. On the one hand, 58% patients were seizure free at 24 h after BRV administration and no other rescue medications were used in 75 out of 97 cases (77%) On the other hand, SC evolved into SE in 17% of cases. A higher probability of seizure relapse and/or evolution into SE was observed in patients without a prior history of epilepsy (HR 2.0; 95% CI 1.03 - 4.1) and in case of BRV administration as second/third line drug (HR 3.2; 95% CI 1.1 - 9.7). No severe treatment emergent adverse events were observed. SIGNIFICANCE: In our cohort, IV BRV resulted to be well tolerated for the treatment of SC and it could be considered as a treatment option, particularly in case of in-hospital onset. However, the underlying etiology seems to be the main outcome predictor.

Intravenous brivaracetam in status epilepticus: A multicentric retrospective study in Italy.

PURPOSE: to evaluate the use, effectiveness, and adverse events of intravenous brivaracetam (BRV) in status epilepticus (SE). METHODS: a retrospective multicentric study involving 24 Italian neurology units was performed from March 2018 to June 2020. A shared case report form was used across participating centres to limit biases of retrospective data collection. Diagnosis and classification of SE followed the 2015 ILAE proposal. We considered a trial with BRV a success when it was the last administered drug prior the clinical and/or EEG resolution of seizures, and the SE did not recur during hospital observation. In addition, we considered cases with early response, defined as SE resolved within 6 h after BRV administration. RESULTS: 56 patients were included (mean age 62 years; 57 % male). A previous diagnosis of epilepsy was present in 21 (38 %). Regarding SE etiology classification 46 % were acute symptomatic, 18 % remote and 16 % progressive symptomatic. SE episodes with prominent motor features were the majority (80 %). BRV was administered as first drug after benzodiazepine failure in 21 % episodes, while it was used as the second or the third (or more) drug in the 38 % and 38 % of episodes respectively. The median loading dose was 100 mg (range 50-300 mg). BRV was effective in 32 cases (57 %). An early response was documented in 22 patients (39 % of the whole sample). The use of the BRV within 6 h from SE onset was independently associated to an early SE resolution (OR 32; 95 % CI 3.39-202; p = 0.002). No severe treatment emergent adverse events were observed. CONCLUSION: BRV proved to be useful and safe for the treatment of SE. Time to seizures resolution appears shorter when it is administered in the early phases of SE.

Relation between sexual dysfunctions and epilepsy, type of epilepsy, type of antiepileptic drugs: a prospective study.

INTRODUCTION: The aim of this study was to evaluate the incidence of sexual dysfunctions in males with epilepsy, the type of epilepsy, the frequency of seizures, the type of antiepileptic drugs (AEDs), the serum hormonal profile and the presence of psychiatric comorbidity. METHODS: Sixty-one patients focused on type of epilepsy, frequency of seizures, AEDs, hormonal profile and presence of mood disorders. We excluded all patients with severe neurologic and psychiatric impairment and patient who were not able to fill questionnaires. Mean age was 31.2 years (range 18-50 years); 31 patients (50.8%) had an idiopathic generalised epilepsy and 30 (49.2%) a focal epilepsy; among them, latter 18 (60%) had probably symptomatic type and 12 (40%) symptomatic type. Sexual functions were evaluated by "International Inventory of Erectile Function" questionnaire. RESULTS: Out of 61 enrolled patients, 22 (36.7%) showed sexual dysfunctions: erectile dysfunctions in 14 (23%), orgasmic dysfunctions in (11.5%) and sexual drive dysfunctions in 12 (19.7%). Out of 61 patients, 36 were subjected to blood measurement of sexual hormones and 21 (58.3%) showed hormonal modifications. CONCLUSIONS: Sexual dysfunction are present in 36.7% of enrolled males with epilepsy; there is any association between sexual dysfunctions and various AEDs in the treatment, except for carbamazepine (CBZ); there is not any association between sexual dysfunctions and frequency of seizures; hormonal changes are associated with sexual dysfunction in males with epilepsy treated with AEDs but not with the orgasmic dysfunction; there is not any association between hormonal changes and type of AEDs, except for CBZ; depression is associated with sexual dysfunctions.

Validation Study of Italian Version of Inventory for Déjà Vu Experiences Assessment (I-IDEA): A Screening Tool to Detect Déjà Vu Phenomenon in Italian Healthy Individuals.

The Inventory Déjà Vu Experiences Assessment (IDEA) is the only screening instrument proposed to evaluate the Déjà vu (DV) experience. Here, we intended to validate the Italian version of IDEA (I-IDEA) and at the same time to investigate the incidence and subjective qualities of the DV phenomenon in healthy Italian adult individuals on basis of an Italian multicentre observational study. In this study, we report normative data on the I-IDEA, collected on a sample of 542 Italian healthy subjects aging between 18-70 years (average age: 40) with a formal educational from 1-19 years. From September 2013 to March 2016, we recruited 542 healthy volunteers from 10 outpatient neurological clinics in Italy. All participants (i.e., family members of neurological patients enrolled, medical students, physicians) had no neurological or psychiatric illness and gave their informed consent to participate in the study. All subjects enrolled self-administered the questionnaire and they were able to complete I-IDEA test without any support. In total, 396 (73%) of the 542 healthy controls experienced the DV phenomenon. The frequency of DV was inversely related to age as well as to derealisation, jamais vu, precognitive dreams, depersonalization, paranormal activity, remembering dreams, travel frequency, and daydreams (all p < 0.012). The Italian version of IDEA maintains good properties, thus confirming that this instrument is reliable for detecting and characterising the DV phenomenon.

Excessive Daytime Sleepiness and Sleep Disorders in a Population of Patients with Epilepsy: a Case-Control Study.

BACKGROUND AND PURPOSE: There are several primary causes for excessive daytime sleepiness (EDS) and sleep disorders in patients with epilepsy. Up to now, studies in the literature report conflicting data in terms of both prevalence and aetiology. The aim of our study was therefore to evaluate the prevalence of EDS and some sleep disorders in a population of patients with epilepsy treated with no more than two antiepileptic drugs (AEDs). We also investigated the role of the depression of mood as a variable that can negatively affect EDS. METHODS: We prospectively and consecutively recruited 99 patients with a diagnosis of epilepsy, sleep disorders and EDS, belonging to the Centre for Epilepsy of the Department of Experimental Biomedicine and Clinical Neurosciences of the University of Palermo. 61.6% of patients recruited were suffering from focal epilepsy, and 38.3% from generalized epilepsy. 68.6% were undertaking monotherapy and 27.2% were drug resistant. Patients were matched for sex and age (+/- 5 years) with 96 non epileptic controls recruited from high school students, college students, relatives and friends of the medical team that conducted the study. EDS was found in 11.1% of patients with epilepsy. Clinical evaluation of sleep disorders was performed using validated questionnaires to investigate excessive daytime sleepiness (EDS), insomnia, Restless Legs Syndrome (RLS) and Obstructive Sleep Apnoea Syndrome (OSAS). In a second phase of the study, 43 of the investigated patients and 34 controls - after giving their consent - underwent a polysomnographic examination by "Compumedics Somtè". RESULTS: Our study shows a statistically significant difference between cases and controls with regard to the prevalence of RLS (p = 0.022) and severity of OSAS with an increased risk in moderate-severe forms of epilepsy (odd ratio [OR] 2.5) most significantly associated with male gender (p = 0.04) and focal epilepsy (OR 3.8) with PSG seizures (0.02). Moreover, a statistically significant difference was demonstrated about mood disorders (p = 0.001) among patients with epilepsy and non epileptic controls. Sleepiness in patients with epilepsy seems to be particularly related to both the depression of mood (p = 0.01) and the presence of OSAS (p = 0.03), as well as to a higher mean age (p = 0.006) and a longer duration of illness (p = 0.04). CONCLUSIONS: Our results confirm that drowsiness trouble frequently complained by patients with epilepsy, is particularly related not only to the presence of OSAS but also to the depression of mood.