Effect of drug treatment changes and seizure outcomes on depression and suicidality in adults with drug-resistant focal epilepsy.

OBJECTIVE: To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after the addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy. METHODS: Seven hundred seventy consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model. RESULTS: At baseline, 50% of patients had a positive screening test result for depression and 13% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. In addition, the number of ASMs taken at baseline correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients who were initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to the type of ASM introduced, sociodemographic variables, or seizure outcomes. SIGNIFICANCE: Almost 1 in 5 adults with drug-resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. At re-assessment 6 months later, 6.1% who screen initially negative for passive suicidal ideation become positive. These changes in screening status are independent of type of ASM introduced or seizure outcomes but correlate with psychiatric status at baseline.

Acute symptomatic seizures after stroke: A scoping review on primary prevention, treatment with antiseizure medications and drug discontinuation.

AIM: To evaluate and synthesize the evidence and knowledge gaps on primary prevention and treatment of post-stroke acute symptomatic seizures (ASSs) using antiseizure medications (ASMs). METHODS: We systematically searched of EMBASE, MEDLINE (accessed from PubMed), and the Cochrane Central Register of Controlled Trials (CENTRAL) to include randomized, double- or single-blinded trials (RCTs) on primary prophylaxis and treatment of post-stroke ASSs with ASMs. The risk of bias in the included studies was assessed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Two placebo-controlled RCTs (totaling 114 participants) evaluating valproate or levetiracetam as primary prophylaxis of ASSs due to hemorrhagic stroke were included. In one RCT, post-stroke ASS occurred in 1/36 patients (2.7%) on valproate and in 4/36 patients (7%) on placebo (p = 0.4). In the other RCT, ASSs were only electrographic and occurred in 3/19 (16%) with levetiracetam and in 10/23 (43%) with placebo (p = 0.043). We found no RCTs on the treatment of post-stroke ASSs or discontinuation of ASMs administered for the treatment of post-stroke ASSs. CONCLUSION: Evidence to support primary prophylaxis of ASSs is sparse and of very low quality and is insufficient to recommend it routinely. Secondary prevention of post-stroke ASSs is usually not recommended except in selected cases (the most relevant being acute symptomatic status epilepticus, which carries a high risk of subsequent poststroke seizures (PSE)). The choice of which ASM to administer and for how long is not based on solid RCT evidence. Management of post-stroke PSE should be done according to an evidence-based framework, considering the individuality of the patient and the pharmacological properties of the drugs.

Pharmacokinetic Interactions Between Antiseizure and Psychiatric Medications.

Antiseizure medications and drugs for psychiatric diseases are frequently used in combination. In this context, pharmacokinetic interactions between these drugs may occur. The vast majority of these interactions are primarily observed at a metabolic level and result from changes in the activity of the cytochrome P450 (CYP). Carbamazepine, phenytoin, and barbiturates induce the oxidative biotransformation and can consequently reduce the plasma concentrations of tricyclic antidepressants, many typical and atypical antipsychotics and some benzodiazepines. Newer antiseizure medications show a lower potential for clinically relevant interactions with drugs for psychiatric disease. The pharmacokinetics of many antiseizure medications is not influenced by antipsychotics and anxiolytics, while some newer antidepressants, namely fluoxetine, fluvoxamine and viloxazine, may inhibit CYP enzymes leading to increased serum concentrations of some antiseizure medications, including phenytoin and carbamazepine. Clinically relevant pharmacokinetic interactions may be anticipated by knowledge of CYP enzymes involved in the biotransformation of individual medications and of the influence of the specific comedication on the activity of these CYP enzymes. As a general rule, these interactions can be managed by careful evaluation of clinical response and, when indicated, individualized dosage adjustments guided by measurement of drugs serum concentrations, especially if pharmacokinetic interactions may cause any change in seizure control or signs of toxicity. Further studies are required to improve predictions of pharmacokinetic interactions between antiseizure medications and drugs for psychiatric diseases providing practical helps for clinicians in the clinical setting.

Drug-resistant epilepsy at the age extremes: Disentangling the underlying etiology.

The incidence of epilepsy is highest at the extreme age ranges: childhood and elderly age. The most common syndromes in these demographics - self-limited epilepsies of childhood and idiopathic generalized epilepsies in pediatric age, focal epilepsy with structural etiology in older people - are expected to be drug responsive. In this work, we focus on such epilepsy types, overviewing the complex clinical background of unexpected drug-resistance. For self-limited epilepsies of childhood and idiopathic generalized epilepsies, we illustrate drug-resistance resulting from syndrome misinterpretation, reason on possible unexpected courses of epilepsy, and explicate the influence of inappropriate treatments. For elderly-onset epilepsy, we show the challenges in differential diagnosis possibly leading to pseudoresistance and analyze how drug-resistant epilepsy can arise in stroke, neurocognitive disorders, brain tumors, and autoimmune encephalitis. In children and senior people, drug-resistance can be regarded as a hint to review the diagnosis or explore alternative therapeutic strategies. Refractory seizures are not only a therapeutic challenge, but also a cardinal sign not to be overlooked in syndromes commonly deemed to be drug-responsive.

Third-Generation Antiseizure Medications for Adjunctive Treatment of Focal-Onset Seizures in Adults: A Systematic Review and Network Meta-analysis.

BACKGROUND: Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs. OBJECTIVE: We estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA). METHODS: We systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA). RESULTS: Sixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11-3.66], ESL (OR 1.93, 95% CI 1.07-3.48), LCM (OR 1.86, 95% CI 1.04-3.32), and PER (OR 2.07, 95% CI 1.16-3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44-0.86) and LCM (OR 0.60, 95% CI 0.40-0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02-1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments. CONCLUSIONS: Cenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.

Cardiac adverse effects of antiseizure medications.

INTRODUCTION: Patients with severe epilepsy are at increased risk of cardiovascular disease and arrhythmias. Although antiseizure medications (ASMs) may have indirect protective effects against cardiovascular events by reducing seizure frequency and hence sudden death in epilepsy, some of them exert cardiotoxic effects. AREAS COVERED: Patients with epilepsy, mainly those with severe forms, are at higher risk of cardiac disease because their heart can have structural alterations and electrical instability as a consequence of repeated seizures. Some ASMs have direct protective effects through anti-inflammatory, antioxidant, hypotensive, and lipid-reducing properties. Antiseizure medications can also have toxic cardiac effects including both long-term consequences, such as the increased risk of atherogenesis and subsequent cardiovascular disease due to the influence on lipid profile and pro-inflammatory milieu, and immediate effects as the increased risk of potentially fatal arrhythmias due to the influence on ion channels. Sodium channel blocking ASMs may also affect cardiac sodium channels and this effect is particularly observed in subjects with genetic mutations in cardiac ion channels. Fenfluramine cause valvulopathies in obese subjects and this effect need to be evaluated in epilepsy patients. EXPERT OPINION: For the selection of treatment, cardiotoxic effects of ASMs should be considered; cardiac monitoring of treatment is advisable.

Critical Appraisal of Cenobamate as Adjunctive Treatment of Focal Seizures in Adults.

Cenobamate (CNB) is the latest antiseizure medication (ASM) authorized for the treatment of focal-onset seizures in adults. Although the precise mechanism of action of CNB is not yet fully understood, this drug inhibits the persistent, rather than transient, voltage-gated sodium channel currents and is a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, differently from benzodiazepines. CNB has a non-linear pharmacokinetic with a terminal half-life range of about 50/60 hours within the therapeutic dose range, which allows once daily administration. Cenobamate inhibits cytochrome P450 (CYP) 2C19 and induces CYP3A4 and 2B6, and hence can potentially interact with ASMs (eg, phenytoin, carbamazepine and clobazam) and no-ASMs drugs. In two randomized, double-blind, placebo-controlled trials in patients with focal epilepsies, CNB has shown a particularly good efficacy with a rate of seizure freedom of about 20% during the maintenance period in participants treated with the dose of 400 mg/day. The most common treatment-emergent adverse effects include central nervous system-related symptoms, like dizziness, diplopia, somnolence, and gait disturbances. Safety issues of particular interest are severe skin reactions (drug reaction with eosinophilia and systemic symptoms) and QT shortening, which contraindicates its use in subjects with familial short QT syndrome or in combination with other QT-shortening drugs. The recommended starting dose is 12.5 mg/day, which can be gradually titrated to the target dose (200 mg/day) and further increased up to 400 mg/day. There are several aspects of CNB that need to be still addressed, including the long-term efficacy and the efficacy in patients with generalized seizures. Ongoing studies will clarify these issues. The clinical relevance of the peculiar pharmacokinetics and the pattern of drug-drug interactions also require further investigation.

Drugs for patients with epilepsy and excessive daytime sleepiness.

Excessive daytime sleepiness (EDS) and attentional deficits are often observed in people with epilepsy. They may be the consequence of seizures and subclinical discharges as well as of comorbid conditions as obstructive sleep apnea/hypopnea syndrome (OSAS), attention deficit hyperactivity disorder (ADHD), or other less frequent disorders. Excessive daytime sleepiness may also be caused or worsened by antiseizure medications (ASMs). Several meta-analyses suggested that lamotrigine, lacosamide, and perhaps eslicarbazepine are less sedative than other traditional and new ASMs and, in patients prone to somnolence, might be preferred over ASMs with more sedative properties. In patients with severe EDS and/or ADHD, advantages and risks of a treatment with a psychostimulant need to be considered. Methylphenidate, modafinil, armodafinil, pitolisant, and solriamfetol are authorized for use in ADHD and EDS in patients with narcolepsy and some of them also in OSAS. These agents are off-label for the treatment of EDS associated with epilepsy. They do not have proconvulsant effects, although there are several possible risks for patients with epilepsy. The risks of cardiovascular events and psychiatric symptoms should be carefully evaluated as such disorders can coexist with epilepsy and be triggered by these agents. Finally, combination of psychostimulants with ASMs may be associated with several pharmacokinetic drug-drug interactions.

Pharmacology of Cenobamate: Mechanism of Action, Pharmacokinetics, Drug-Drug Interactions and Tolerability.

Cenobamate is one of the latest antiseizure medications (ASMs) developed for the treatment of focal onset seizures in adult patients. The recommended starting dose is 12.5 mg/day, titrated gradually to the target daily dose of 200 mg, which may be increased to a maximum of 400 mg/day based on clinical response. Although the high rate of seizure freedom observed in randomized, placebo-controlled clinical trials has resulted in exciting expectations, further clinical studies are needed to better define its clinical profile. Cenobamate is characterized by a peculiar pharmacology regarding both pharmacodynamics and pharmacokinetics. The mechanism of action has only partly been described, with the drug acting on voltage-gated sodium channels through a pronounced action on persistent rather than transient currents. Cenobamate also acts as a positive allosteric modulator of GABAA receptors independently from the benzodiazepine binding site. The bioavailability of cenobamate is not influenced by other drugs, except phenytoin; it can inhibit cytochrome P450 (CYP) 2C19 and induce CYP3A4 and 2B6, and hence can potentially interact with many drugs (e.g. dose adjustments may be required for lamotrigine, carbamazepine and clobazam). The pharmacokinetics of cenobamate are not linear and dosage increases imply a disproportional increase in plasma levels, particularly at doses higher than 300 mg. The most common and dose-related adverse effects associated with cenobamate include central nervous system-related symptoms, mainly somnolence, dizziness, diplopia, and disturbances in gait and coordination. A somewhat higher incidence of adverse events has been observed in patients concomitantly treated with sodium channel blockers. The most relevant safety issues are currently represented by the risk of severe skin reactions (apparently avoidable by a slow titration) and QT shortening (the drug is contraindicated in patients with familial short QT syndrome or taking QT-shortening drugs). Overall, cenobamate is a promising ASM with an intriguing and not fully understood mechanism of action; pharmacokinetic issues need to be considered in clinical practice.

Which treatment strategy in patients with epilepsy with focal seizures uncontrolled by the first anti-seizure medication?

There is no definite proven or accepted strategy in the management of patients with focal epilepsy uncontrolled by the first anti-seizure medication (ASM). Clinical studies failed to find a significant difference in efficacy or tolerability between alternative monotherapy and/or adjunctive therapy in these patients. A second ASM is often added, the efficacy of the combination is assessed, and the dose of the first drug can be gradually reduced and withdrawn. If seizures recur, the effective combination therapy can be reinstated. In this review, we discussed experimental and clinical data about the efficacy and tolerability of the most frequently used combinations of ASMs. Animal studies suggested that the most favorable combinations are those between ASMs with different or multiple mechanisms of action, whereas combining drugs with similar pharmacodynamic properties is often associated with additive or infra-additive efficacy and additive or synergistic toxicity. Clinical studies have shown that levetiracetam (LEV) can be favorably combined with the sodium channel blockers (SCBs) lacosamide (LCM) and lamotrigine (LTG). Lamotrigine is particularly effective when associated with valproate (VPA) and possibly with LEV and topiramate (TPM). Carbamazepine (CBZ) has negative pharmacokinetic interactions with several ASMs and should not be combined with other SCBs; it could be effectively and safely combined with gabapentin (GBP) and LEV. Valproic acid has enzyme inhibiting properties and can be cautiously used with SCBs; its combination with TPM or zonisamide (ZNS) may be associated with higher toxicity.

A review of pharmacokinetic drug interactions between antimicrobial and antiseizure medications in children.

Comorbidity between epilepsy and infectious diseases in children is frequent. Pharmacokinetic drug-drug interactions (DDIs) between antiseizure medications (ASMs) and anti-infectives can occur and influence their efficacy or cause toxicity. All potential DDIs between ASMs and antimicrobial agents used in children were identified through consultation of drug compendia. Clinical studies, case reports and summaries of product characteristics of all identified drugs were also searched. A typical example of a DDI that is often observed in children is that involving valproate (VPA) and carbapenem antibiotics. This DDI has a unique mechanism of action (inhibits the enzyme that catalyses the hydrolysis of VPA-glucuronide) and leads to a fall of around 60% of VPA level, associated with seizure recurrence. An example of bidirectional DDI involves the antimycotic voriconzole and several ASMs. Voriconazole is metabolized and is a strong inhibitor of cytochrome (CYP)3A4, CYP2C9/10 and CYP2C19. There is clinical evidence of induction of voriconazole metabolism with possible loss of its efficacy by phenytoin (PHT), while voriconazole increases the levels of PHT. Other ASMs that are inducers of these enzymes, such as carbamazepine (CBZ), phenobarbital, stiripentol and to a lesser degree, oxcarbazepine, might be predicted to decrease the level of voriconazole. Voriconazole might also be predicted to increase levels of cannabidiol, CBZ, lacosamide, midazolam, and zonisamide. DDIs between ASMs and some antiviral agents are potentially even more frequent and clinically relevant.

Pharmacokinetic drug interactions between antiseizure medications and drugs for comorbid diseases in children with epilepsy.

Introduction: Nearly 80% of children with epilepsy have one or more chronic comorbidities that require specific drug treatments in several cases. Drug-drug interactions (DDIs) between antiseizure medications (ASMs) and all other drugs (NON-ASMs) used to treat comorbid diseases may have serious consequences.Areas covered: All potential DDIs between 27 ASMs and all NON-ASMs used for oral chronic treatment of those disorders most often comorbid with epilepsy in children were searched for drug compendia. Clinical evidence of the identified DDIs was also searched in the literature. Forty-eight drugs have been identified as potential DDIs with at least one ASM. Most important DDIs are between some ASMs and omeprazole and pantoprazole (drugs for gastrointestinal disorders), ibuprofen and cyclobenzaprine (drugs for musculoskeletal disorders), loratidine, lumacaftor/ivacaftor, montelukast, and theophylline (drugs for respiratory system), levothyroxine, liothyronine and several corticosteroids (systemic hormonal preparations), almotriptan, dihydroergotamine, ergotamine, and several antipsychotics, antidepressants and anxiolytics (drugs for nervous diseases). Clinical evidence of the predicted DDIs was found in a minority of cases.Expert opinion: Treatment of children with epilepsy should be decided considering treatment of both seizures and comorbid diseases and aimed at minimizing the risk of DDIs between ASMs and NON-ASMs.

Appropriate use of generic and branded antiseizure medications in epilepsy: Updated recommendations from the Italian League Against Epilepsy (LICE).

Generic drugs are increasingly used to treat many diseases including epilepsy. The growing importance of generic antiseizure medications (ASMs) has led the ASMs commission of the Italian League Against Epilepsy (LICE) to review current evidence in the literature about efficacy and safety of these products. Recommendations from other scientific organizations have also been considered to provide an update of the LICE position about their utilization (List of Recommendations). Compared with the previous literature review, randomized controlled trials assessing bioequivalence among branded drugs and generics are currently available. Although some contrasting results have been reported, brand-to-generic switching was effective and tolerable in real-life settings, with similar adverse event ratios. Based on these findings, LICE concluded that, conforming to the rigorous regulation of USA and EU markets, generic ASMs are not inferior to the respective branded, providing a cost advantage for patients starting or replacing monotherapy or add-on, and for those with incomplete seizure control. Branded-to-generic (and vice versa) switching is not recommended (although applicable) during seizure remission, as well as the generic-to-other generic switching. Other recommendations focus on the appropriateness of therapeutic drug monitoring (TDM) when switching is required, paying attention to avoiding the erroneous switch between modified and immediate-release formulations during dispensation. Finally, to support patients' compliance, they should be assured of generics' safety and efficacy and carefully informed with practical advice, particularly when the switching is associated with aspect modifications (e.g. color and shape changes) of the pill or the packaging.

Practical use of pharmaceutically purified oral cannabidiol in Dravet syndrome and Lennox-Gastaut syndrome.

INTRODUCTION: Pharmaceutically purified oral cannabidiol (CBD) has been recently approved by the US Food and Drug Administration and European Medicines Agency as treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), which are severe and difficult-to-treat developmental and epileptic encephalopathies with onset in early childhood. AREAS COVERED: This review will critically review the pharmacokinetic properties of CBD, the interactions with antiseizure and non-antiseizure medications, and the main tolerability and safety issues to provide guidance for its use in everyday practice. EXPERT OPINION: CBD is metabolized in the liver and can influence the activity of enzymes involved in drug metabolism. The best characterized drug-drug interaction is between CBD and clobazam. The most common adverse events include somnolence, gastrointestinal discomfort, and increase in serum transaminases. High-grade purified CBD oral solution represents an effective therapeutic option in patients with DS and LGS. The findings cannot be extrapolated to other cannabis-based products, synthetic cannabinoids for medicinal use and non-medicinal cannabis and CBD derivatives.

Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis.

BACKGROUND: Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABAA receptors, binding at a non-benzodiazepine site. OBJECTIVE: We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques. METHODS: We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome. RESULTS: Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67-2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93-7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85-2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08-4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02-1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia. CONCLUSIONS: Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Antidepressant effect of vagal nerve stimulation in epilepsy patients: a systematic review.

BACKGROUND: Vagal nerve stimulation (VNS) is an effective palliative therapy in drug-resistant epileptic patients and is also approved as a therapy for treatment-resistant depression. Depression is a frequent comorbidity in epilepsy and it affects the quality of life of patients more than the seizure frequency itself. The aim of this systematic review is to analyze the available literature about the VNS effect on depressive symptoms in epileptic patients. MATERIAL AND METHODS: A comprehensive search of PubMed, Medline, Scopus, and Google Scholar was performed, and results were included up to January 2020. All studies concerning depressive symptom assessment in epileptic patients treated with VNS were included. RESULTS: Nine studies were included because they fulfilled inclusion criteria. Six out of nine papers reported a positive effect of VNS on depressive symptoms. Eight out of nine studies did not find any correlation between seizure reduction and depressive symptom amelioration, as induced by VNS. Clinical scales for depression, drug regimens, and age of patients were broadly different among the examined studies. CONCLUSIONS: Reviewed studies strongly suggest that VNS ameliorates depressive symptoms in drug-resistant epileptic patients and that the VNS effect on depression is uncorrelated to seizure response. However, more rigorous studies addressing this issue are encouraged.

Cannabidiol efficacy and clobazam status: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut syndrome using meta-analytical techniques. METHODS: We searched for randomized, placebo-controlled, single- or double-blinded trials. The proportion of patients who achieved ≥50% reduction from baseline in seizure frequency during the treatment period was assessed according to CLB status. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated. RESULTS: Four trials were included and enrolled 714 participants, 429 for the add-on CBD group and 285 for the add-on placebo group. Among CBD-treated patients, 240 (55.9%) were taking concomitant CLB (CLB-On) and 189 (44.1%) were not taking concomitant CLB (CLB-Off); in placebo-treated patients, 158 (55.4%) were CLB-On and 127 (44.6%) CLB-Off. The percentages of patients who had at least 50% reduction in seizure frequency during the treatment period were 29.1% in the CBD arm and 15.7% in the placebo group among CLB-Off patients (RR = 1.80, 95% CI = 1.12-2.90, P = .015). Among CBL-On patients, the ≥50% reduction in seizure frequency was found in 52.9% and 27.8% in the CBD and placebo groups, respectively (RR = 1.85, 95% CI = 1.40-2.44, P < .001). SIGNIFICANCE: CBD was associated with a higher rate of seizure response in comparison to placebo when added to the existing antiepileptic regimen both in patients taking and in those not taking concomitant CLB. The lack of randomization for CLB status and the limited sample size need to be considered in the interpretation of the findings.

Drug treatments in patients with cardiac diseases and epilepsy.

OBJECTIVE: Comorbidity between epilepsy and heart diseases is frequent. METHODS: All drugs classified within the group of drugs for cardiovascular system according to the Anatomical Therapeutic Chemical (ATC) classification system were reviewed for their effects on seizures or epilepsy. RESULTS: Several agents showed antiseizure properties in animal models of seizures and/or in patients with epilepsy and only few were proconvulsant. Drugs with anticonvulsant effects include mecamylamine and guanfacine (antihypertensive drugs), indapamide, amiloride, furosemide and bumetanide (diuretics), fasudil (peripheral vasodilator), bioflavonoids (vasoprotective drug), propranolol (beta blocking agent), isradipine, nimodipine, verapamil and diltiazem (calcium channel blockers: CCBs), fosinopril and zofenopril (agents acting on the renin-angiotensin system), several statins, and fenofibrate (lipid-modifying agents). Drugs with proconvulsant properties in experimental models or in patients include reserpine, buflomedil, naftidrofuryl, and clonidine and propranolol at high doses. Drug-drug interactions (DDI) between antiseizure medications (ASMs) and drugs for cardiovascular system were also searched in two leading publicly accessible drug compendia. The most important DDIs occur between enzyme-inducing (EI) ASMs and ivabradine, ranolazine, macitenan and between EI-ASMs and the CCBs felodipine, nicardipine, nisoldipine, and verapamil. Simvastatin and atorvastatin are the lipid-modifying agents with more DDIs with EI-ASMs. Several pharmacodynamic interactions have been also documented. DISCUSSION AND CONCLUSIONS: Available data show that the treatment of patients with epilepsy and vascular comorbidities is challenging and requires the appropriate knowledge of pharmacological properties of drugs and drug interactions.

Effects of Music Reading on Motor Cortex Excitability in Pianists: A Transcranial Magnetic Stimulation Study.

Neurophysiological studies suggest that music reading facilitates sensorimotor cortex. The aim of this study was to evaluate (1) whether in pianists, reading notes in bass and treble clef selectively enhances right and left primary motor cortex (M1) excitability; and (2) whether reading notes played with the thumb or little finger selectively modulates the excitability of specific muscles. Twenty musicians (11 pianists, 9 non-pianists) participated. Transcranial magnetic stimulation (TMS) was applied while subjects read the bass or the treble clef of sheets music and during the observation of a blank staff (baseline). When pianists read the treble clef, the excitability of the left M1 was higher compared to that recorded in the right M1. Moreover, in the treble clef condition motor evoked potentials (MEPs) induced by TMS of the left M1 were higher when pianists read notes to be played with the 5° finger (little finger) with respect to 1° finger (thumb) notes, whereas in the bass clef condition TMS of the right M1 induced higher MEPs for 1° finger note compared to 5° finger notes. No significant modulation was observed in non-pianists. These data support the view that music reading may induce specific inter- and intra-hemispheric modulation of the motor cortex excitability.

Efficacy of Tocilizumab in Limbic Encephalitis with Anti-CASPR2 Antibodies.

We report the case of a 64-year-old man who presented with subacute memory, balance impairment, behavioral and mood changes, and epileptic seizures. Magnetic resonance imaging (MRI) showed bilateral hippocampal abnormalities. Brain [18F]-FDG fluorodeoxyglucose positron emission tomography (PET) revealed hypometabolism in both the temporal lobe as well as in the left insular and parietal regions. The clinical and neuroradiological picture and the detection of anti-CASPR2 antibodies in serum oriented the diagnosis towards autoimmune limbic encephalitis. Intravenous high-dose steroid and immunoglobulin treatments were ineffective. We did not use rituximab for the presence of antibodies to HbcAg positivity. Tocilizumab given intravenously 8 mg/kg once a month for six months and then subcutaneously 162 mg every week for six months resulted in clinical and neuroradiological improvement. These data support the efficacy of tocilizumab in autoimmune limbic encephalitis associated with anti-CASPR2 antibodies, which has been sporadically reported in the literature.