Relationship between saliva and plasma rufinamide concentrations in patients with epilepsy.

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r2  = .78, P < .0001), but concentrations in saliva were moderately lower than those in plasma (mean saliva to plasma ratio = 0.7 ± 0.2). In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. Patients receiving valproic acid comedication had higher dose-normalized plasma rufinamide levels than patients comedicated with drugs devoid of strong enzyme-inducing or enzyme-inhibiting activity. Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.

Electroencephalography during SARS-CoV-2 outbreak: practical recommendations from the task force of the Italian Society of Neurophysiology (SINC), the Italian League Against Epilepsy (LICE), and the Italian Association of Neurophysiology Technologists (AITN).

BACKGROUND: During COVID-19 lockdown, non-urgent medical procedures were suspended. Grade of urgency of electroencephalography (EEG) may vary according to the clinical indication, setting, and status of infection of SARS-CoV-2 virus. "Italian Society of Clinical Neurophysiology" (SINC), "Italian League Against Epilepsy" (LICE), and the "Italian Association of Neurophysiology Technologists" (AITN) aimed to provide clinical and technical recommendation for EEG indications and recording standards in this pandemic era. METHODS: Presidents of SINC, LICE, and AITN endorsed three members per each society to formulate recommendations: classification of the degree of urgency of EEG clinical indications, management and behavior of physicians and neurophysiology technologists, hygiene and personal protection standards, and use of technical equipment. RESULTS: Scientific societies endorsed a paper conveying the recommendation for EEG execution in accordance with clinical urgency, setting (inpatients/outpatients), status of SARS-CoV-2 virus infection (positive, negative and uncertain), and phase of governmental restrictions (phase 1 and 2). Briefly, in phase 1, EEG was recommended only for those acute/subacute neurological symptoms where EEG is necessary for diagnosis, prognosis, or therapy. Outpatient examinations should be avoided in phase 1, while they should be recommended in urgent cases in phase 2 when they could prevent an emergency room access. Reduction of staff contacts must be encouraged through rescheduling job shifts. The use of disposable electrodes and dedicated EEG devices for COVID-19-positive patients are recommended. CONCLUSIONS: During the different phases of COVID-19 pandemic, the EEG should be reserved for patients really benefiting from its execution in terms of diagnosis, treatment, prognosis, and avoidance of emergency room access.

Electroencephalography at the time of Covid-19 pandemic in Italy.

OBJECTIVE: During the Covid-19 pandemic, government restrictions limited health care to urgent needs. Neurophysiology centers had to suddenly reschedule their activities, with a lack of specific recommendations about electroencephalography (EEG) execution. During the pandemic phase 1, we launched an online survey to understand the flaws and strengths of the EEG management in Italy at the time of Covid-19 pandemic. METHODS: A 45-item online survey (published from April 16 to 30, 2020), endorsed by the Italian Society of Clinical Neurophysiology (SINC), the Italian League Against epilepsy (LICE), and the Italian Association of Neurophysiology technologists (AITN), collected EEG management data (EEG's number and type, indications, personnel and patients safety, devices' sanification) during the Covid-19 pandemic. RESULTS: We received responses from 206 centers. The number of EEGs performed was reduced by 76 ± 20%, and several types of specific EEG (video-EEG, ambulatory-EEG, LTM, polysomnography) were reduced at a minimum. Half of the centers performed inpatient EEGs only for urgencies. Repetitive seizures, encephalitis, and non-convulsive status epilepticus were the most common indications. Covid-19-positive patients received less EEG than negative ones (p < 0.0001). EEG requests came mainly not only from neurologists (n = 176) but also from general practitioners (n = 40), emergentists (n = 79), intensivists (n = 72), and other specialists (n = 53). Those centers which continued performing outpatient EEG examinations were instructed to perform the EEG after a Covid-19-related symptom screening for patients and using personal protective equipment (PPE) through all the procedure. Inpatient EEGs were performed using FFP2/FFP3 masks by neurophysiology technologists in only 50% of cases. Patients executed hyperventilation only for real clinical needs, but often (56%) with a mask. CONCLUSIONS: Italian neurophysiology centers strongly adhered to government restrictions of lockdown. Some issues emerged, ranging from the evaluation of a proper indication for EEG, technical procedures of EEG recording, and protection of neurophysiology technicians.

Validated outcome of treatment changes according to International League Against Epilepsy criteria in adults with drug-resistant focal epilepsy.

OBJECTIVE: Although many studies have attempted to describe treatment outcomes in patients with drug-resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug-resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria. METHODS: This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug-resistant by the investigators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP). RESULTS: A seizure-free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as having a "treatment failure" as compared to the judgment of the investigator (46.7% vs 62.9%, P < 0.001), because many more patients were rated as "undetermined outcome" (45.6% vs 27.7%, P < 0.001); 19.3% of the recruited patients were not considered drug-resistant by the EP. SIGNIFICANCE: This study validates the use of ILAE treatment outcome criteria in a real-life setting, providing validated estimates of seizure freedom in patients with drug-resistant focal epilepsy in relation to the number of previously failed AEDs. Fewer than one in 10 patients achieved seizure freedom on a newly introduced AED over the study period. Pseudo drug resistance could be identified in one of five cases.

Valproate and female patients: Prescribing attitudes of Italian epileptologists.

INTRODUCTION: After the European Medicines Agency (EMA) warning on the use of valproate (VPA) in female patients, we explored the antiepileptic drug (AED) prescribing attitudes of Italian epileptologists with regard to sex and VPA use in patients with epilepsy. MATERIAL AND METHODS: A specifically designed 30-item questionnaire was distributed at the annual multicenter meeting of the Italian League Against Epilepsy (LICE), held in Rome on January 2018. One hundred and sixty-nine physicians answered the questionnaire. RESULTS: In females, VPA was significantly less prescribed as first-choice AED in childhood absence epilepsy (22% females vs 64% males, p < 0.001), Dravet syndrome (54% vs 71%, p = 0.01), juvenile myoclonic epilepsy (JME) (2% vs 74%, p < 0.001), and undetermined epilepsy (0% vs 32%, p < 0.001). Ninety-six percent of the respondents inform teenage girls of the detrimental effects of intrauterine exposure to VPA; 74% recommend contraceptive measures when prescribing VPA. All the respondents stated that they were aware of the recommendations on VPA in female patients, and 64% claimed to have had difficulties in implementing them. CONCLUSIONS: The main challenges were represented by women with JME, who were seizure-free on VPA and failed to respond to levetiracetam and lamotrigine, and by little girls for whom VPA was considered the best choice. According to many Italian epileptologists, the decision to withdraw VPA should be shared with the patient.

Italian Wikipedia and epilepsy: An infodemiological study of online information-seeking behavior.

Wikipedia is the most commonly accessed source of health information by both healthcare professionals and the lay public worldwide. We aimed to evaluate information-seeking behavior of Internet users searching the Italian Wikipedia for articles related to epilepsy and its treatment. Using Pageviews Analysis, we assessed the total and mean monthly views of articles from the Italian Wikipedia devoted to epilepsy, epileptic syndromes, seizure type, and antiepileptic drugs (AEDs) from January 1, 2015 to October 31, 2017. We compared the views of the article on epilepsy with those of articles focusing on Alzheimer's disease, migraine, multiple sclerosis, syncope, and stroke and adjusted all results for crude disease prevalence. With the only exception of the article on multiple sclerosis, the adjusted views for the Italian Wikipedia article on epilepsy were higher than those for the other neurological disorders. The most viewed articles on seizure type were devoted to tonic-clonic seizure, typical absence seizure, tonic convulsive seizures, and clonic convulsive seizures. The most frequently accessed articles on epilepsy syndromes were about temporal lobe epilepsy and Lennox-Gastaut syndrome. The most frequently viewed articles on AEDs were devoted to valproic acid, carbamazepine, and levetiracetam. Wikipedia searches seem to mirror patients' fears and worries about epilepsy more than its actual epidemiology. The ultimate reasons for searching online remain unknown. Epileptologists and epilepsy scientific societies should make greater efforts to work jointly with Wikipedia to convey more accurate and up-to-date information about epilepsy.

A prospective study of direct medical costs in a large cohort of consecutively enrolled patients with refractory epilepsy in Italy.

OBJECTIVE: To evaluate direct medical costs and their predictors in patients with refractory epilepsy enrolled into the SOPHIE study (Study of Outcomes of PHarmacoresistance In Epilepsy) in Italy. METHODS: Adults and children with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers and followed for 18 months. At entry, all subjects underwent a structured interview and a medical examination, and were asked to keep records of diagnostic examinations, laboratory tests, specialist consultations, treatments, hospital admissions, and day-hospital days during follow-up. Study visits included assessments every 6 months of seizure frequency, health-related quality of life (Quality of Life in Epilepsy Inventory 31), medication-related adverse events (Adverse Event Profile) and mood state (Beck Depression Inventory-II). Cost items were priced by applying Italian tariffs. Cost estimates were adjusted to 2013 values. RESULTS: Of 1,124 enrolled individuals, 1,040 completed follow-up. Average annual cost per patient was € 4,677. The highest cost was for antiepileptic drug (AED) treatment (50%), followed by hospital admissions (29% of overall costs). AED polytherapy, seizure frequency during follow-up, grade III pharmacoresistance, medical and psychiatric comorbidities, and occurrence of status epilepticus during follow-up were identified as significant predictors of higher costs. Age between 6 and 11 years, and genetic (idiopathic) generalized epilepsies were associated with the lowest costs. Costs showed prominent variation across centers, largely due to differences in the clinical characteristics of cohorts enrolled at each center and the prescribing of second-generation AEDs. Individual outliers associated with high costs related to hospital admissions had a major influence on costs in many centers. SIGNIFICANCE: Refractory epilepsy is associated with high costs that affect individuals and society. Costs differ across centers in relation to the characteristics of patients and the extent of use of more expensive, second-generation AEDs. Epilepsy-specific costs cannot be easily differentiated from costs related to comorbidities.

Comprehensive educational plan for patients with epilepsy and comorbidity (EDU-COM): a pragmatic randomised trial.

BACKGROUND: The impact of educational strategies in the management of adverse treatment effects and drug interactions in adult patients with epilepsy with comorbidities remains undetermined. OBJECTIVE: The EDU-COM study is a randomised, pragmatic trial investigating the effect of a patient-tailored educational plan in patients with epilepsy with comorbidity. METHODS: 174 adult patients with epilepsy with chronic comorbidities, multiple-drug therapy and reporting at least one adverse treatment effect and/or drug interaction at study entry were randomly assigned to the educational plan or usual care. The primary endpoint was the number of patients becoming free from adverse treatment events and/or drug interactions after a 6-month follow-up. The number of adverse treatment events and drug interactions, health-related quality of life (HRQOL) summary score changes and the monetary costs of medical contacts and drugs were assessed as secondary outcomes. RESULTS: The primary endpoint was met by 44.0% of patients receiving the educational plan versus 28.9% of those on usual care (p=0.0399). The control group reported a significantly higher risk not to meet successfully the primary endpoint at the end of the study: OR (95% CI) of 2.29 (1.03 to 5.09). A separate analysis on drug adverse effects and drug interactions showed that the latter were more sensitive to the effect of educational treatment. Quality of life and costs were not significantly different in the two groups. CONCLUSIONS: A patient-tailored educational strategy is effective in reducing drug-related problems (particularly drug interactions) in epilepsy patients with chronic comorbidities, without adding significant monetary costs. Registered at ClinicalTrials.gov, identifier NCT01804322, (http://www.clinicaltrials.gov).

Late-Onset Focal Epilepsy: Electroclinical Features and Prognostic Role of Leukoaraiosis.

The aim of this study was to describe the electroclinical and prognostic characteristics, and to investigate the role of leukoaraiosis in outpatients with new-onset elderly focal epilepsy aged ≥60 years, referred to a tertiary epilepsy center between 2005 and December 31, 2020. Among the 720 patients who were referred to the center, we retrospectively selected 162 consecutive outpatients, with a first referral for recent-onset focal epilepsy of unknown cause (UC) or structural cause (SC), and collected a clinical and standard-Electroencephalogram (S-EEG), 24-h ambulatory EEG (A-EEG), and neuroimaging data. We also analyzed the seizure prognosis after titration of the first antiseizure medication (ASM). One hundred and four UC and 58 SC patients, followed up for 5.8 ± 5.3 years (mean ± SD), were included. Compared with the SC group, the patients with UC showed a predominance of focal seizures with impaired awareness (51.9% of cases) and focal to bilateral tonic-clonic seizures during sleep (25%); conversely, the SC group, more frequently, had focal to bilateral tonic-clonic seizures during wakefulness (39.6%) and focal aware seizures (25.8%) (p < 0.0001). Oral or gestural automatisms were prevalent in UC epilepsy (20.2 vs. 6.9% in the SC group, p = 0.04). In UC compared to patients with SC, interictal epileptiform discharges showed a preferential temporal lobe localization (p = 0.0007), low expression on S-EEG, and marked activation during deep Non-Rapid Eye Movement (NREM) sleep (p = 0.003). An overall good treatment response was found in the whole sample, with a probability of seizure freedom of 68.9% for 1 year. The cumulative probability of seizure freedom was significantly higher in the UC compared with the SC group (p < 0.0001). The prognosis was worsened by leukoaraiosis (p = 0.012). In the late-onset focal epilepsy of unknown cause, electroclinical findings suggest a temporal lobe origin of the seizures. This group showed a better prognosis compared with the patients with structural epilepsy. Leukoaraiosis, per se, negatively impacted on seizure prognosis.

Clinical and Instrumental Characterization of Patients With Late-Onset Epilepsy.

Epilepsy is classically considered a childhood disease. However, it represents the third most frequent neurological condition in the elderly, following stroke, and dementia. With the progressive aging of the general population, the number of patients with Late-Onset Epilepsy (LOE) is constantly growing, with important economic and social consequences, in particular for the more developed countries where the percentage of elderly people is higher. The most common causes of LOE are structural, mainly secondary to cerebrovascular or infectious diseases, brain tumors, trauma, and metabolic or toxic conditions. Moreover, there is a growing body of evidence linking LOE with neurodegenerative diseases, particularly Alzheimer's disease (AD). However, despite a thorough characterization, the causes of LOE remain unknown in a considerable portion of patients, thus termed as Late-Onset Epilepsy of Unknown origin (LOEU). In order to identify the possible causes of the disease, with an important impact in terms of treatment and prognosis, LOE patients should always undergo an exhaustive phenotypic characterization. In this work, we provide a detailed review of the main clinical and instrumental techniques for the adequate characterization of LOE patients in the clinical practice. This work aims to provide an easy and effective tool that supports routine activity of the clinicians facing LOE.

Use of cenobamate for the treatment of focal epilepsy: an Italian expert opinion paper.

INTRODUCTION: Cenobamate is a new antiseizure medication (ASM) recently introduced in the USA for the treatment of adults with focal-onset seizures. In March 2021, the European Commission authorized its use for the adjunctive treatment of focal-onset seizures with or without secondary generalization (focal seizures with or without progression to bilateral tonic-clonic seizures, according to current ILAE terminology) in adults with epilepsy not adequately controlled despite the treatment with at least two ASMs. AREAS COVERED: This review summarizes the mechanism of action, efficacy, and safety of Cenobamate. The authors provide their expert opinions on the use of this drug. EXPERT OPINION: The aim of this paper is to report on the Italian preliminary experience with the use of cenobamate, focusing on treatment goals, optimal dosing and titration schedules, strategies to minimize adverse effects, and identification of suitable candidates for treatment. There was agreement that slow titration may improve tolerability, and that clinically significant benefit can be achieved in many patients at relatively low doses. A favorable response to relatively low doses of cenobamate could be an early predictor of ultimate responsiveness. Overall, cenobamate is a welcome new treatment for adults with focal seizures resistant to conventional ASMs.

Determinants of health-related quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments.

PURPOSE: To evaluate the relative contribution of demographic and epilepsy-related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health-related quality of life (HRQOL) in adults with pharmacoresistant epilepsy. METHODS: Individuals with epilepsy whose seizures failed to respond to at least one AED were enrolled consecutively at 11 tertiary referral centers. HRQOL was assessed by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), AEs by the Adverse Event Profile (AEP), and depressive symptoms by the Beck Depression Inventory-II (BDI-II). Multivariate linear regression models were used to identify variables associated with QOLIE-31 total score and subscale scores. KEY FINDINGS: Of 933 enrolled individuals aged 16 years or older, 809 (87%) were able to complete the self-assessment instruments and were included in the analysis. Overall, 61% of the variance in QOLIE-31 scores was explained by the final model. The strongest predictors of HRQOL were AEP total scores (ß = -0.451, p < 0.001) and BDI-II scores (ß = -0.398, p < 0.001). These factors were also the strongest predictors of scores in each of the seven QOLIE-31 subscales. Other predictors of HRQOL were age (ß = -0.060, p = 0.008), lack of a driving license (ß = -0.053, p = 0.018), pharmacoresistance grade, with higher HRQOL in individuals who had failed only one AED (ß = 0.066, p = 0.004), and location of the enrolling center. Epilepsy-related variables (seizure frequency, occurrence of tonic-clonic seizures, age of epilepsy onset, disease duration) and number of AEDs had no significant predictive value on HRQOL. The AEP total score was the strongest negative predictor of HRQOL in the subgroup of 362 patients without depressive symptoms (BDI-II score <10), but even in this subgroup the BDI-II score was retained as a significant predictor. SIGNIFICANCE: In individuals with pharmacoresistant epilepsy, AEs of medication and depressive symptoms are far more important determinants of HRQOL than seizures themselves. When seizure freedom cannot be achieved, addressing depressive comorbidity and reducing the burden of AED toxicity is likely to be far more beneficial than interventions aimed at reducing the frequency of seizures.

Alternatives to valproate in girls and women of childbearing potential with Idiopathic Generalized Epilepsies: state of the art and guidance for the clinician proposed by the Epilepsy and Gender Commission of the Italian League Against Epilepsy (LICE).

Following recent European Medication Agency restrictions on valproate (VPA) use in girls and women of childbearing potential (WOCP), the Commission on Epilepsy and Gender of the Italian League against Epilepsy integrated current literature and legislative data in order to provide clinicians with guidance on antiseizure medication (ASM) prescription for Idiopathic Generalized Epilepsies (IGEs) in this population, avoiding VPA. We reviewed the updated literature on ASMs and examined the teratogenicity of those showing efficacy in IGEs. For all relevant ASMs, we considered the indications for use and the pregnancy and contraception-related recommendations given in the Italian Summary of Product Characteristics (SmPC) and on the websites of the European Medicines Agency (EMA) and other European Union (EU) countries' regulatory agencies. With the exception of absence seizures, the literature lacks high quality studies on ASMs in IGEs. In girls and WOCP, levetiracetam and lamotrigine should be considered the first-choice drugs in Generalized Tonic-Clonic Seizures Alone and in Juvenile Myoclonic Epilepsy, lamotrigine in Juvenile Absence Epilepsy, and ethosuximide in Childhood Absence Epilepsy. Although supported by the literature, several ASMs are off label, contraindicated or burdened by special warnings in pregnancy. Some discrepancies emerged between the various SmPC warnings for different brands of the same active principle. We provided a therapeutic algorithm for each IGE syndrome and highlighted the need for revised prescription rules, consistent with the latest literature data, uniformity of SmPC warnings for the same active principle, and more data on the efficacy of new ASMs in IGEs and their safety in pregnancy.

Long-term prognosis of juvenile myoclonic epilepsy: A systematic review searching for sex differences.

PURPOSE: Juvenile myoclonic epilepsy (JME), like other forms of idiopathic generalized epilepsy, shows a marked female predominance. However, few studies have specifically addressed the role of sex in its long-term prognosis. We performed a systematic review of the literature relevant to JME prognosis, focusing on sex-based differences in prognostic factors and outcome. METHODS: A comprehensive literature search of the PubMed and Scopus databases was performed, considering all articles up to April 2020 in which long-term prognosis in JME had been explored and sex differences in outcome or prognostic factors were specified. RESULTS: We included 25 articles published between 1984 and 2020. Sex differences in epilepsy outcome were explored by 21 of the 25 studies, but only three reported different outcomes in male vs female patients. All three found female sex to be associated with a later response to antiseizure medications, worse seizure control, and a higher risk of relapse in their entire study samples, which included JME patients. Eight studies found sex-based differences in possible predictors of long-term outcome: prolonged epileptiform EEG runs and the presence of eye closure sensitivity, both more frequent in women, were factors possibly linked to a poorer prognosis, as were praxis induction and generalized EEG asymmetric changes, which instead were more common in men. Valproate use, more frequent in men, was associated with a better outcome. CONCLUSION: Most studies do not highlight sex differences in JME prognosis. However, some sex specificities do emerge, especially with regard to particular reflex traits and EEG abnormalities. Finally, sex may condition therapeutic choices, and thus have a possible impact on long-term outcome.

Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox-Gastaut Syndrome.

Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox-Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.

Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug-refractory epilepsy.

PURPOSE: To evaluate the adverse effects (AEs) of antiepileptic drugs (AEDs) in adults with refractory epilepsy and their relationship with number of coprescribed AEDs and AED load. METHODS: Patients with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers. AEs were assessed through unstructured interview and the Adverse Event Profile (AEP) questionnaire. AED loads were calculated as the sum of prescribed daily dose (PDD)/defined daily dose (DDD) ratios for each coprescribed AED. RESULTS: Of 809 patients enrolled, 709 had localization-related epilepsy and 627 were on polytherapy. AED loads increased with increasing number of AEDs in the treatment regimen, from 1.2 +/- 0.5 for patients on monotherapy to 2.5 +/- 1, 3.7 +/- 1.1, and 4.7 +/- 1.1 for those on two, three, and > or =4 AEDs, respectively. The number of spontaneously reported AEs correlated with the number of AEs identified by the AEP (r = 0.27, p < 0.0001). AEP scores did not differ between patients with monotherapy and patients with polytherapy (42.8 +/- 11.7 vs. 42.6 +/- 11.2), and there was no correlation between AEP scores and AED load (r = -0.05, p = 0.16). CONCLUSIONS: AEs did not differ between monotherapy and polytherapy patients, and did not correlate with AED load, possibly as a result of physicians' intervention in individualizing treatment regimens. Taking into account the limitations of a cross-sectional survey, these findings are consistent with the hypothesis that AEs are determined more by individual susceptibility, type of AEDs used, and physicians' skills, than number of coprescribed AEDs and AED load.

Epileptic mechanisms in Charles Bonnet syndrome.

Epileptic phenomena are usually not considered a possible cause of prolonged hallucinatory states such as Charles Bonnet syndrome (CBS). A 65-year-old woman with previous right hemorrhagic strokes developed complex visual hallucinations (CVHs), featuring CBS, and delayed palinopsic phenomena, along with new neurological signs and worsening of existing deficits. Video/EEG/polygraphy monitoring revealed the presence of right-sided periodic lateralized epileptiform discharges of the "plus" type (PLEDs plus) and documented a focal seizure in close relation to a delayed palinopsia episode. Adjustment of antiepileptic drug treatment led to remission of the CVHs with simultaneous disappearance of PLEDs plus and epileptic seizures and return to previous neurological status. We discuss the role of continuous (PLEDs plus) and intermittent (focal seizures) epileptic activities in this episodic form of CBS, considering current theories on the genesis of CVHs. EEG assessment is recommended if CBS develops in a patient with unexplained worsening of existing neurological signs.

Does screening for adverse effects improve health outcomes in epilepsy? A randomized trial.

OBJECTIVE: To determine whether systematic screening for adverse effects of antiepileptic drugs (AEDs) reduces toxicity burden and improves health-related quality of life in patients with epilepsy. METHODS: Consecutive patients with uncontrolled seizures aged ≥16 years and a high Adverse Event Profile (AEP) score were randomized to 2 groups and followed up for 18 months at 11 referral centers. AEP scores were made available to treating physicians at all visits in the intervention group, but not in the control group. Co-primary endpoints were changes in AEP scores and Quality of Life Inventory for Epilepsy-31 (QOLIE-31) scores. RESULTS: Of 809 enrolled patients able to complete the AEP questionnaire, 222 had AEP scores ≥45 and were randomized to the intervention (n = 111) or control group (n = 111). A total of 206 patients completed the 18-month follow-up. Compared with baseline, AEP scores decreased on average by 7.2% at 6 months, 12.1% at 12 months, and 13.8% at 18 months in the intervention group (p < 0.0001), and by 7.7% at 6 months, 9.2% at 12 months, and 12.0% at 18 months in controls (p < 0.0001). QOLIE-31 scores also improved from baseline to final visit, with a mean 20.7% increase in the intervention group and a mean 24.9% increase in the control group (p < 0.0001). However, there were no statistically significant differences in outcomes between groups for the 2 co-primary variables. CONCLUSIONS: Contrary to findings from a previous study, systematic screening for adverse effects of AEDs using AEP scores did not lead to a reduced burden of toxicity over usual physician treatment. ITALIAN MEDICINES AGENCY AIFA IDENTIFIER: FARM52K2WM_003. CLINICALTRIALSGOV IDENTIFIER: NCT03939507 (registered retrospectively in 2019; the study was conducted during the 2006-2009 period and registration of clinical trials was not a widely established practice when this study was initiated). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the additional collection of formal questionnaires regarding adverse effects of AEDs does not reduce toxicity burden over usual physician treatment.

Changes in sex steroid levels in women with epilepsy on treatment: relationship with antiepileptic therapies and seizure frequency.

PURPOSE: Reproductive dysfunction in epilepsy is attributed to the seizures themselves and also to antiepileptic drugs (AEDs), which affect steroid production, binding, and metabolism. In turn, neuroactive steroids may influence neuronal excitability. A previous study in this cohort of consecutive women with epilepsy showed that patients with more frequent seizures had higher cortisol and lower dehydroepiandrosterone sulfate levels than those with rare or absent seizures. The present study was aimed at evaluating, in these same women, the possible relationship between some clinical parameters, seizure frequency, AED therapies, and sex hormone levels. METHODS: Estradiol (E2), progesterone (Pg), sex hormone-binding globulin (SHBG), and free estrogen index (FEI) were measured during the luteal phase in 113 consecutive females, 16-47 years old, with different epilepsy syndromes on enzyme-inducing AED (EIAED) and/or non-enzyme-inducing AED (NEIAED) treatments, and in 30 age-matched healthy women. Hormonal data were correlated with clinical parameters (age, epilepsy syndrome, disease onset, and duration), seizure frequency assessed on the basis of a seizure frequency score (SFS), and AED therapies. RESULTS: E2, Pg, and FEI were lower, whereas SHBG levels were higher in the epilepsy patients than in the controls. However, sex steroid and SHBG levels were not different between groups of patients categorized according to SFS. Therapies with EIAEDs accounted for changes in E2 levels and FEI. CONCLUSIONS: Despite globally decreased sex steroid levels in serum, actual hormone titers were not significantly correlated with SFS in consecutive epilepsy women; rather, these hormonal changes were explained by AED treatments, mainly when EIAED polytherapies were given.

Seizure frequency and sex steroids in women with partial epilepsy on antiepileptic therapy.

PURPOSE: Neuroactive sex steroids influence neuron excitability, which is enhanced by estradiol (E2) and decreased by progesterone (Pg). In epilepsy, the production, metabolism, biologic availability, and activity of sex hormones may be affected by seizures themselves or by antiepileptic drugs (AEDs). This cross-sectional observational study was aimed at evaluating the relationships between sex steroids, seizure frequency, and other clinical parameters in women with partial epilepsy (PE) on AED treatments. METHODS: Serum E2, Pg, sex hormone binding globulin (SHBG) levels, free E2 (fE2), and E2/Pg ratios were determined during the follicular and luteal phases in 72 adult women with PE, and in 30 healthy controls. Hormonal data were correlated with seizure frequency, age, body weight, body mass index (BMI), disease onset and duration, and AED therapies. RESULTS: In patients, E2, fE2, and Pg levels were lower in both ovarian phases, whereas those of SHBG were higher than in controls. No significant changes in hormone levels and in prevalence of anovulatory cycles were observed between patients grouped according to their seizure frequency. However, when compared with those in healthy controls, luteal fE2 and Pg levels were chiefly impaired in women with more frequent seizures, mostly undergoing AED polytherapies, but not in those with absent or rarer seizures. CONCLUSIONS: The actual changes in sex steroid levels and E2/Pg ratios did not explain an increased seizure frequency in adult women with AED-treated PE, but patients with more severe disease showed more relevant changes in their sex hormone profile and impaired Pg levels during the luteal phase.