Emerging roles of air pollution and meteorological factors in autoimmune eye diseases.

Autoimmune eye diseases (AEDs), a collection of autoimmune inflammatory ocular conditions resulting from the dysregulation of immune system at the ocular level, can target both intraocular and periorbital structures leading to severe visual deficit and blindness globally. The roles of air pollution and meteorological factors in the initiation and progression of AEDs have been increasingly attractive, among which the systemic and local mechanisms are both involved in. Exposure to excessive air pollution and extreme meteorological conditions including PM2.5/PM0.1, environmental tobacco smoke, insufficient sunshine, and high temperature, etc., can disturb Th17/Treg balance, regulate macrophage polarization, activate neutrophils, induce systemic inflammation and oxidative stress, decrease retinal blood flow, promote tissue fibrosis, activate sympathetic nervous system, adversely affect nutrients synthetization, as well as induce heat stress, therefore may together deteriorate AEDs. The crosstalk among inflammation, oxidative stress and dysregulated immune system appeared to be prominent. In the present review, we will concern and summarize the potential mechanisms underlying linkages of air pollution and meteorological factors to ocular autoimmune and inflammatory responses. Moreover, we concentrate on the specific roles of air pollutants and meteorological factors in several major AEDs including uveitis, Graves' ophthalmopathy (GO), ocular allergic disease (OAD), glaucoma, diabetic retinopathy (DR), etc.

Polymorphisms Affecting the Response to Novel Antiepileptic Drugs.

Epilepsy is one of the most frequent chronic neurologic disorders that affects nearly 1% of the population worldwide, especially in developing countries. Currently, several antiepileptic drugs (AEDs) are available for its therapy, and although the prognosis is good for most patients, 20%-30% amongst them do not reach seizure freedom. Numerous factors may explain AED-resistance such as sex, age, ethnicity, type of seizure, early epilepsy onset, suboptimal dosing, poor drug compliance, alcohol abuse, and in particular, genetic factors. Specifically, the interindividual differences in drug response can be caused by single nucleotide polymorphisms (SNPs) in genes encoding for drug efflux transporters, for the brain targets of AEDs, and for enzymes involved in drug metabolism. In this review, we used the PubMed database to retrieve studies that assessed the influence of SNPs on the pharmacokinetic (PK), pharmacodynamic (PD), and efficacy of new antiepileptic drugs. Our results showed that polymorphisms in the ABCB1, ABCC2, UGT1A4, UGT2B7, UGT2B15, CYP2C9, and CYP2C19 genes have an influence on the PK and efficacy of AEDs, suggesting that a genetic pre-evaluation of epileptic patients could help clinicians in prescribing a personalized treatment to improve the efficacy and the safety of the therapy.

Effects of age of onset and medication on cognitive performance and quality of life in patients with epilepsy.

Previous research shows that earlier age of onset of epilepsy and larger antiepileptic drug (AED) load are related to cognitive impairment and lower quality of life in patients with epilepsy. However, there has been a discrepancy in the specific cognitive domains that are affected and whether AED load is a significant contributor to the cognitive impairment. This study aimed to examine (a) the specific cognitive domains that are affected by age of epilepsy onset and (b) the effects of AED treatment and age of onset on cognition and quality of life. Participant data included scores on (1) the Wisconsin Card Sorting Test (WCST), (2) Digit Span subtest of the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV), (3) Test of Everyday Attention (TEA), (4) Brief Visuospatial Memory Test (BVMT), (5) Quality of Life in Epilepsy (QOLIE-31), (6) Beck Depression Inventory (BDI-2), and (7) a medical record review for drug treatment information. Earlier age of epilepsy onset predicted lower auditory attention span and working memory as assessed by digit span forward (DSF) and digit span backward (DSB). Additionally, larger AED load predicted lower visuospatial memory as assessed by BVMT-Delayed Recall (BVMT-DR). No relationship between either age of onset or AED load and quality of life in epilepsy was found. However, depression was highly correlated with quality of life. These results highlight the need to balance epilepsy control and AED effects, especially in early-onset epilepsy, and to gain awareness of the specific cognitive domains affected by epilepsy variables to effectively monitor and treat it.

Bone mineral density and fractures in institutionalised children with epilepsy and intellectual disability.

BACKGROUND: Long-term use of antiseizure drugs is associated with a low bone mineral density (BMD) and an increased fracture risk. The literature regarding institutionalised children on chronic antiseizure drugs is limited. Therefore, the aim of this cross-sectional study is to evaluate the prevalence of low BMD and the history of fractures in institutionalised children with epilepsy and intellectual disability (ID). METHODS: A dual-energy X-ray absorptiometry of lumbar spine (L1-L4) and hip was performed in 24 children, residing in a long-stay care facility in the Netherlands. Additionally, serum concentrations of albumin, calcium and 25-hydroxyvitamin D were determined. Data on fractures were retrospectively extracted from the medical files. RESULTS: Ages of the children (14 male and 10 female) ranged from 5 to 17 years with a mean age of 13.0 (±3.2). The criteria of the International Society for Clinical Densitometry (ISCD) were used for classification of bone mineral disorders. Eight (33.3%) children had a normal BMD (Z-score > - 2.0). Of the 16 children with a low BMD (Z-score ≤ - 2.0), three were diagnosed as osteoporotic, based on their fracture history. Ten children (41.7%) were reported to have at least one fracture in their medical history. Serum concentrations of albumin-corrected calcium (2.28-2.50 mmol/L) and (supplemented) vitamin D (16-137 nmol/L) were within the normal range. CONCLUSIONS: This study demonstrated that 67% of institutionalised children with epilepsy and ID had low BMD and 42% had a history of at least one fracture, despite supplementation of calcium and vitamin D in accordance with the Dutch guidelines.

Pharmacokinetic Drug-Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients.

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

Epileptogenesis and oncogenesis: An antineoplastic role for antiepileptic drugs in brain tumours?

The first description of epileptic seizures due to brain tumours occurred in 19th century. Nevertheless, after over one hundred years, scientific literature is still lacking on how epilepsy and its treatment can affect tumour burden, progression and clinical outcomes. In patients with brain tumours, epilepsy dramatically impacts their quality of life (QoL). Even antiepileptic therapy seems to affect tumor lesion development. Numerous studies suggest that certain actors involved in epileptogenesis (inflammatory changes, glutamate and its ionotropic and metabotropic receptors, GABA-A and its GABA-AR receptor, as well as certain ligand- and voltage-gated ion channel) may also contribute to tumorigenesis. Although some antiepileptic drugs (AEDs) are known operating on such mechanisms underlying epilepsy and tumor development, few preclinical and clinical studies have tried to investigate them as targets of pharmacological tools acting to control both phenomena. The primary aim of this review is to summarize known determinants and pathophysiological mechanisms of seizures, as well as of cell growth and spread, in patients with brain tumors. Therefore, a special focus will be provided on the anticancer effects of commonly prescribed AEDs (including levetiracetam, valproic acid, oxcarbazepine and others), with an overview of both preclinical and clinical data. Potential clinical applications of this finding are discussed.

Reproductive health in patients with epilepsy.

The aim of the present study was to review existing knowledge on the impact of epilepsy in reproductive health of both sexes. Extensive searches of relevant documentation published until February 2020 were retrieved from PubMed and Google Scholar literature in English or in other languages with an English abstract. In females, epilepsy may lead to estrogen and androgen level abnormalities. Women with epilepsy may develop Polycystic Ovaries Syndrome (PCOS), anovulatory cycles, and menstrual disorders. In men, epilepsy may cause sex hormone dysregulation and influence spermatogenesis. Males with epilepsy may also suffer from sexual dysfunction. Antiepileptic drugs (AEDs) have adverse effects on peripheral endocrine glands, influence hormones' biosynthesis and protein binding, diminish the bioactivity of serum sex hormones, and lead to secondary endocrine disorders related to changes concerning body weight and insulin sensitivity. Valproic acid (VPA) was the first recognized AED to cause disturbances potentially due to metabolic changes and increasing weight. Women taking VPA may develop PCOS, while men may have sperm abnormalities and/or sexual dysfunction. Liver enzyme inducing AEDs may also cause menstrual and sexual disorders in women and sexual dysfunction in men. Newer AEDs are much safer but studies still suggest reduced sexuality and erectile dysfunction.

Factors related to the adverse events of antiepileptic drugs.

OBJECTIVE: The aim of the present study was to explore the factors related to the severity of the adverse effects of antiepileptic drugs (AEDs), experienced by patients with epilepsy. MATERIALS AND METHODS: A case study was conducted in adult patients with epilepsy and followed up at the Epilepsy Outpatients of the University Hospital of Ioannina in Northwest Greece. The Adverse Event Profile (AEP) questionnaire for AEDs adverse effects assessment, the Defense style questionnaire (DSQ-88) and the Patient Health Questionnaire (PHQ-9) for depression' severity evaluation were used to estimate the severity of adverse effects, the defense style, and the depressive symptoms, respectively. RESULTS: Sixty-three patients with epilepsy (M/F:28/35), with a mean age of 37.6 ±â€¯13.41, were recruited in the study. The univariate analysis showed that both the Maladaptive style of defense and the PHQ-9 score were significantly associated with the AEP score. After multivariate regression analysis female gender, the load of AEDs, the PHQ-9 score, and the Adaptive defense style remained significant coefficients. CONCLUSION: There are also nonpharmacological factors that may contribute to the severity of the adverse effects of AEDs, experienced by the patients with epilepsy.

Seizures, Antiepileptic Drugs, and CKD.

There are 2 major categories of patients with seizures and chronic kidney disease (CKD): patients who develop acute symptomatic seizures in the setting of CKD and patients with epilepsy who at some point develop CKD. The incidence of uremic seizures with kidney failure is ∼10%. These seizures are often nonconvulsive and may mimic uremic encephalopathy. Recognition and management of such situations may be challenging for treating physicians who are non-neurologists. Furthermore, practitioners caring for patients with seizures with or without an established diagnosis of epilepsy in the setting of CKD frequently encounter challenges in the selection, loading, titration, and maintenance of antiepileptic drugs (AEDs) due to potentially altered pharmacokinetics of the AEDs. We review the pathophysiology of uremia, uremic seizures, and other neurologic complications of kidney failure; management approaches to the treatment of such complications; the relevant mechanisms of action and pharmacokinetics of AEDs with their use in CKD; and in particular, the management of AEDs in patients requiring hemodialysis therapy.

Long-term efficacy and safety of lacosamide and levetiracetam monotherapy in elderly patients with focal epilepsy: A retrospective study.

OBJECTIVES: Epilepsy management in elderly patients is often complex because of several concomitant comorbidities that may limit the use of some antiepileptic drugs (AEDs). Levetiracetam (LEV) is a second-generation AED widely used in elderly patients with epilepsy while lacosamide (LCM), which has been recently approved in European Union (EU) as monotherapy for the treatment of focal onset seizures, is affected by a scarcity of data in such frail population. This study is aimed at assessing the efficacy and the tolerability of LCM as monotherapy in elderly patients affected by focal onset epilepsy compared with those receiving LEV. METHODS: A retrospective chart review of patients aged ≥65 years suffering from focal onset seizures, with or without secondary generalization on LCM monotherapy or LEV monotherapy, was performed. Data regarding demographic characteristics, seizure type and etiology, LCM and LEV daily dose, number of lifetime AEDs, seizure frequency at baseline and at 12 months of follow-up, and seizure freedom rates were reported. RESULTS: In this observational retrospective study, 22 patients on LCM (10 males, 12 females, mean age: 76.23 ±â€¯7.5) and 24 patients on LEV (10 males, 14 females, mean age: 73.58 ±â€¯6.39) were enrolled. Mean LCM daily dose was 204.51 ±â€¯88.51 mg and mean LEV daily dose was 1281.25 ±â€¯378.15 mg. All patients had comorbidities on chronic treatment. At 12 months of follow-up, mean monthly seizure frequency reduced from 4.23 ±â€¯8.53 to 0.33 ±â€¯0.9 (p < .001) in LCM group and from 2.29 ±â€¯6.11 to 0.2 ±â€¯0.81 (p < .001) in LEV group. Furthermore, 16/22 (72.7%) LCM patients were seizure-free at 12 months of follow-up while seizure freedom was achieved by 17/24 (70.8%) patients in LEV group. DISCUSSION AND CONCLUSION: Epilepsy management in elderly patients is often challenging. In this retrospective real-life study, the efficacy and the tolerability of LCM as monotherapy was favorable even at low doses in older patients and comparable with LEV with a high rate of long-term seizure freedom. Considering the frequent comorbidities and the risk of drug-drug interactions, LCM monotherapy may be a valuable option in elderly patients with focal onset epilepsy because of its favorable pharmacokinetic profile.

Increased frequency of psychosis after second-generation antiepileptic drug administration in adults with focal epilepsy.

OBJECTIVE: Many studies show psychoses after some antiepileptic drug (AED) administrations (post-AED administration psychoses [PAP]). It remains uncertain about psychogenetic potential of each AED and effects of clinical state factors on PAP. We examined the relations between AED-related factors (types, generations, dosages, and concomitant AED) and PAP. METHODS: The clinical records of patients with focal epilepsy were retrospectively reviewed from eight adult epilepsy clinics, for every six-month period after administration of a new drug (either AED or non-AED) between 1981 and 2015. Characteristics of psychotic episodes, AED-related factors (type, daily dosage, and concomitant AED), and other state-related risk factors to psychosis (age, duration of epilepsy, history of psychosis, and seizure frequency) were examined. Psychogenetic risks of AED-related and state-related factors were analyzed with multifactorial procedures. RESULTS: Of 2067 patients with focal epilepsy, 5018 new drugs (4402 AEDs and 616 non-AEDs) were administered. Within the first six-month period, 89 patients exhibited 105 psychotic episodes (81 interictal and 24 postictal psychoses: 55 first episodes and 50 recurrences). With second-generation AED (SAED) administration, particularly topiramate and lamotrigine, frequency of psychosis was significantly increased. Daily dosage of AED was not significantly associated with psychosis. Psychosis tended to occur with a higher number of concomitant AED. Subsequent analysis with AED-related and general factors showed that SAED administrations and previous psychotic history were the most significant risks for PAP. CONCLUSION: Post-AED administration psychoses is associated with type of AED (SAED), rather than its dosage. Individual vulnerabilities are also associated with PAP.

Evolving dynamic networks: An underlying mechanism of drug resistance in epilepsy?

At least one-third of all people with epilepsy have seizures that remain poorly controlled despite an increasing number of available anti-epileptic drugs (AEDs). Often, there is an initial good response to a newly introduced AED, which may last up to months, eventually followed by the return of seizures thought to be due to the development of tolerance. We introduce a framework within which the interplay between AED response and brain networks can be explored to understand the development of tolerance. We use a computer model for seizure generation in the context of dynamic networks, which allows us to generate an 'in silico' electroencephalogram (EEG). This allows us to study the effect of changes in excitability network structure and intrinsic model properties on the overall seizure likelihood. Within this framework, tolerance to AEDs - return of seizure-like activity - may occur in 3 different scenarios: 1) the efficacy of the drug diminishes while the brain network remains relatively constant; 2) the efficacy of the drug remains constant, but connections between brain regions change; 3) the efficacy of the drug remains constant, but the intrinsic excitability within brain regions varies dynamically. We argue that these latter scenarios may contribute to a deeper understanding of how drug resistance to AEDs may occur.

Epilepsia partialis continua following a Western variant tick-borne encephalitis.

Epilepsia partialis continua (EPC) is a rare entity, first described in 1894 by Kozevnikov, as a variant of simple focal motor status epilepticus. EPC is most frequently characterized by motor symptoms, but as recently described, non-motor manifestations may occur, such as somatosensory symptoms or aura continua. EPC in adults has been attributed to various etiologies: infectious, vascular, neoplastic, and metabolic. According to the recent definition, we reported a case of EPC with behavioral symptoms, following a tick-borne encephalitis (TBE) contracted in an endemic area (North Eastern Italy). Patient's symptom was a poorly localized "whole body sensation", which is reported as a condition occurring only in frontal lobe epilepsy. Patient's EEG showed a left frontal predominance of epileptiform discharges. Literature highlighted the importance of the Far-eastern TBE variant as a cause of EPC, since no Western variant TBE cases are reported. In contrast to what was claimed so far, our case demonstrates that not only the Far-eastern TBE variant, but also Western variant TBE is a cause of EPC. Prognosis of EPC depends largely on the underlying etiology, and it is frequently drug-resistant. Our patient was treated with intravenous levetiracetam, with a subsequent clinical recovery and a disappearance of epileptiform discharges. The rapid clinic and electroencephalographic response to levetiracetam confirm that it can be a promising therapeutic option for treatment of EPC.

The role of ethnicity on pregnancy outcomes in women with epilepsy: The need for specific research.

The role of ethnicity on pregnancy outcomes of women with epilepsy (WWE) has received little research attention but is important to guide management. The aim of this review is to identify and describe current knowledge of ethnicity for WWE giving birth. Literature searches were performed with the following terms: ethnic/race combined with epilepsy/seizure, antiepileptic drugs (AED), and/or pregnancy, and combined them with congenital malformation, birth outcome, or pregnancy complication, with English language restriction in PubMed, EMBASE, and Web of Science. Both primary studies and review articles were included. Ethnicity disparities exist in specific congenital malformations, pregnancy complications, and birth outcomes among the general population. There is also ethnicity-related diversity of AED disposition. Information on ethnicity is rarely considered in studies about pregnant WWE. The association between ethnicity and pregnancy outcomes of WWE remains to be elucidated. The lack of data relating to ethnicity in pregnancy studies among WWE needs addressing. Knowledge of potential effects of ethnicity on pregnancy outcomes in WWE will help inform better clinical care around the world.

Value of clinical features to differentiate refractory epilepsy from mimics: a prospective longitudinal cohort study.

BACKGROUND AND PURPOSE: Misdiagnosis of refractory epilepsy (rE) is common and such patients experience a long diagnostic delay. Our aim was to identify key clinical/laboratory factors in order to obtain an alternative diagnosis in patients referred for rE. METHODS: Between January 2010 and December 2015, 125 consecutive patients with a diagnosis of rE were prospectively enrolled. All patients underwent a comprehensive neurological, neuropsychiatric and cardiological evaluation, and had an observation time of at least 1 year after the study entry. RESULTS: Diagnosis of rE was confirmed in 104/125 (83.2%) patients (55 women, mean age 38.8 ± 14.3 years). Thirteen/125 patients (10.4%, seven women, mean age 50.8 ± 20.9) were diagnosed with syncope, which was cardiac/cardio inhibitory in 9/13 (69%). The remaining 8/125 patients (6.4%, six women, mean age 41.2 ± 14.6 years) were diagnosed with psychogenic non-epileptic seizures. Age at onset had a high accuracy in differentiating patients with syncope from others, with the best cut-off age at 35 years and above. Abnormal brain magnetic resonance imaging (MRI) had a significant yield of about 70% in rE. A diagnostic model including age at onset and brain MRI was highly accurate in differentiating patients with syncope from others. In patients with cardiac/cardio inhibitory syncope, the point score of historical features was ≥1 and falsely favoured the diagnosis of epileptic seizures. CONCLUSIONS: This prospective cohort study identifies rE mimics who are at high risk of morbidity and mortality. rE starting in adulthood should raise a high suspicion of cardiac syncope. Brain MRI is accurate in differentiating rE from other conditions.

The differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on seizure frequency in patients with drug-resistant epilepsy - A randomized, double-blind, placebo-controlled trial.

OBJECTIVES: The omega-3 (n-3) fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are known to play an important role in maintenance and modulation of neuronal functions. There is evidence that omega-3 fatty acids may have anticonvulsant effects. The effect of DHA and EPA on seizure rate in patients with drug-resistant epilepsy (DRE) was investigated. METHODS: A double-blind, randomized, placebo-controlled clinical trial included ninety-nine (n = 99) subjects with DRE, aged 5-16 years (n = 85) and 17-45 years (n = 14). After randomization, subjects were given two, four, or six capsules per day of DHA (417.8 mg DHA and 50.8 mg EPA/capsule, n = 33), EPA (385.6 mg EPA and 81.2 mg DHA/capsule, n = 33), or placebo (high oleic acid sunflower oil, n = 33) for one year. The primary endpoint was the effect of treatment on rate of seizure. Random-effects negative binomial regression models were fitted to model the patients' total count of seizures per month. The treatment effects on seizure incidence rate ratio (IRR) were tested after controlling for the covariate effects of gender, age, rate of seizure per week at enrollment, type of seizure, and number of antiepileptic drug (AED) combinations used at enrollment. RESULTS: Fifty-nine subjects (n = 59) completed the study (59.6%). The average number of seizures per month were 9.7 ±â€¯1.2 in the EPA group, 11.7 ±â€¯1.5 in the DHA group, and 16.6 ±â€¯1.5 in the placebo group. Age, gender, and seizure-type adjusted seizure IRRs of the EPA and DHA groups compared with the placebo group were 0.61 (CI = 0.42-0.88, p = 0.008, 42% reduction) and 0.67 (CI = 0.46-1.0, p = 0.04, 39% reduction), respectively. There was no difference in IRR between the EPA and DHA groups (p = 0.56). Both treatment groups had a significantly higher number of seizure-free days compared with the placebo group (p < 0.05). SIGNIFICANCE: This study demonstrates that EPA and DHA are effective in reducing seizure frequency in patients with DRE.

Termination of pregnancy in women with epilepsy - A retrospective single center study.

Antiepileptic drugs (AEDs) are commonly prescribed to women of childbearing age. As 0.3%-0.7% of all pregnancies occur in women with epilepsy (WWE), the effect of recurrent seizures and teratogenicity on pregnancy outcome and the fetus have been widely studied. Most of these studies have focused on live births. A significant number of terminated pregnancies in WWE were ignored in past studies, thus reducing the calculated incidence of congenital malformations and possible influence of AED exposure. We scrutinized the medical records at our medical center for termination of pregnancy (TOP) in WWE for the years 2004-2016. Fifty-eight TOPs occurred in WWE during these years. Reasons for TOP included spontaneous abortions necessitating medical intervention (46.6%), patient's request (31.0%), medically recommended (10.3%), and unknown (12.1%).

Interactions between cannabidiol and commonly used antiepileptic drugs.

OBJECTIVE: To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs. METHODS: In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate. RESULTS: Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01). SIGNIFICANCE: Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.

Efficacy of Vagal Nerve Stimulation for Drug-Resistant Epilepsy: Is it the Stimulation or Medication?

BACKGROUND: Vagus nerve stimulation (VNS) therapy has been widely recognized as an alternative for the treatment of drug-resistant epilepsy, although modification of antiepileptic drugs (AEDs) during VNS treatment could explain the improvement in patients. METHODS: We retrospectively assessed the efficacy of VNS in 30 adult patients with epilepsy treated with >6 months of follow-up. The criteria for implantation were the following: (1) not a candidate for resective epilepsy surgery, (2) drug-resistant epilepsy, (3) impairment of quality of life, (4) no other option of treatment, and (5) patients with idiopathic generalized epilepsy who fail to be controlled with appropriate AEDs. We assessed sociodemographics, seizure etiology, seizure classification, and AEDs used during treatment with VNS. We assessed adverse effects and efficacy. Responder rate was defined as >50% seizure improvement from baseline. RESULTS: Thirty patients (females, 18; males, 12; age, 35.1±13.3 years) were included. After 6, 12, 24, and 36 months of follow-up, the response rates were: 13/30 (43%), 13/27 (48%), 9/22 (41%), and 8/16 (50%), respectively; none was seizure free. Fifty-seven percent, 33%, 59%, and 81% of patients had changes of medication type or dose at 6, 12, 24, and 36 months respectively. In the majority of patients, the change of medication consisted of an increase in the dose of AEDs. CONCLUSIONS: Our study shows that VNS is an effective therapy, although significant changes in medications were done along with the therapy; therefore, the real effect of VNS could be controversial.

Neuroprotection as a Potential Therapeutic Perspective in Neurodegenerative Diseases: Focus on Antiepileptic Drugs.

Neuroprotection is conceived as one of the potential tool to prevent or slow neuronal death and hence a therapeutic hope to treat neurodegenerative diseases, like Parkinson's and Alzheimer's diseases. Increase of oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation have been identified as main causes of neuronal death and adopted as targets to test experimentally the putative neuroprotective effects of various classes of drugs. Among these agents, antiepileptic drugs (AEDs), both the old and the newer generations, have shown to exert protective effects in different experimental models. Their mechanism of action is mediated mainly by modulating the activity of sodium, calcium and potassium channels as well as the glutamatergic and GABAergic (gamma-aminobutyric acid) synapses. Neurological pathologies in which a neuroprotective action of AEDs has been demonstrated in specific experimental models include: cerebral ischemia, Parkinson's disease, and Alzheimer's disease. Although the whole of experimental data indicating that neuroprotection can be achieved is remarkable and encouraging, no firm data have been produced in humans so far and, at the present time, neuroprotection still remains a challenge for the future.