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.

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.

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.

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.

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.

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.

Pharmacodynamic interactions of antiepileptic drugs: From bench to clinical practice.

BACKGROUND: Approximately 50% of patients do not achieve seizure control with antiepileptic drug (AED) monotherapy, and polytherapy, with more than one AED, is often required. To date, no evidence-based criteria on how to combine AEDs exist. OBJECTIVE: This narrative review aimed to provide critical findings of the available literature about the role of pharmacodynamic AEDs' interactions in patients whose epilepsies were treated with polytherapy. METHODS: Electronic databases, Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica dataBASE (EMBASE), were systematically searched to identify relevant studies on pharmacodynamic AEDs' interactions in patients with epilepsy. RESULTS AND CONCLUSION: Most data on AED combinations are coming from animal models and preclinical studies. Combining AEDs with different mechanisms of actions seems to have greater effectiveness and lower risk of adverse event development. Conversely, the combination of AEDs may cause pharmacodynamic synergistic effects that may result in not only increased efficacy but also more adverse effects. Despite some AED associations that have been proven to be effective in specific epilepsy/seizure type (e.g., phenobarbital+/phenytoin for tonic seizures and ethosiximide + valproate for absences; lamotrigine + valproate for various epilepsy/seizure types), no clear and definitive evidence exists about AED combinations in humans. Examples of pharmacodynamic interactions that possibly explain the synergistic effects on efficacy or adverse effects include the combination between vigabatrin or pregabalin and sodium channel blockers (supra-additive antiseizure effect) and lacosamide combined with other sodium channel blockers (infra-additive antiseizure effect and neurotoxicity synergistic). The pharmacodynamic lamotrigine-valproate interaction is also supported by synergistic adverse events. Therefore, well-designed double-blind prospective studies recruiting a sufficient number of patients possibly with a crossover design and carefully ascertain the role of pharmacokinetic interactions and variations of AEDs' levels in the blood are needed.

A survey on clinical pathways of patients with epilepsy and cerebrovascular diseases or brain tumors.

OBJECTIVE: Patients with seizures and epilepsies comorbid with cerebrovascular disorders (CVDs) or brain tumors (BTs) are managed by different specialists, including neurologists with expertise in epilepsy (epileptologists), CVDs, and neuro-oncology, as well as neurologists without special expertise (general neurologists), and also emergency room physicians (EPs), intensive care physicians, and neurosurgeons. It has never been studied how these specialists interact for the treatment of seizures or epilepsy in these patients. METHODS: A survey was used to investigate how patients with such comorbidities are managed in hospitals in Italy. RESULTS: One hundred and twenty-eight specialists from hospitals in all parts of Italy filled in a questionnaire. Epileptologists were in charge of treatment of epilepsy in about 50% of cases while acute seizures were treated mainly by general neurologists (52% of cases). Diagnostic, therapeutic, and assistance pathways (PDTAs) for CVD and BT epilepsies were declared by physicians in about half of the hospitals while in about a quarter, there were only informal agreements and, in the remaining hospitals, there were no agreements between specialists. CVD neurologists, specialists in internal medicine, and EP were most often in charge of treatment of epilepsy comorbid with CVD. General neurologists, neuro-oncologists, and neurosurgeons were included in teams that manage BT epilepsies while epileptologists were included only in a small percentage of hospitals. CONCLUSIONS: Clinical decisions on epilepsy or seizures in patients with such comorbidities are often handled by different specialists. A new team culture and PDTAs are needed to guarantee high standards of diagnostic and therapeutic procedures.

Clinical pathways of epileptic seizures and status epilepticus: results from a survey in Italy.

OBJECTIVE: Patients with seizures or status epilepticus (SE) access the hospital through emergency departments and may be admitted into different wards according to the level of care required. Clinicians with different expertise are in charge of taking critical therapeutic decisions. To date, very few studies have investigated the stage at which these patients are referred to neurologists or epileptologists and how guideline recommendations are applied in clinical practice. METHODS: A survey was used to investigate how patients with epileptic seizures or SE are managed in emergency and in subsequent hospital pathways in Italy. RESULTS: One hundred and seventy-seven physicians (mainly neurologists) from all parts of Italy filled in a questionnaire. Less than half of the participants (35%) answered that, in their hospital, patients with epilepsy were managed by epileptologists. The percentages were lower for patients presenting with acute seizures (21%) or SE (16%). Diagnostic, therapeutic, and assistance pathways (PDTA) for patients presenting with seizure(s) or SE were available for both conditions in about 50% of cases, while, in the rest of the hospitals, participants indicated informal agreements (about 25% of cases) or lack of any agreement (about 25% of cases) between clinicians. Professionals more often involved in PDTA were epileptologists/neurologists, emergency physicians, and intensivists. More than half ot the participants (55%) thought that organizational issues are the most important criticalities for such patients and need to be improved (61%). SIGNIFICANCE: There is a high variability in hospital clinical pathways for epilepsy in Italy.

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.

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.

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

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

Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis.

Second and third generation AEDs have been directly compared to controlled-release carbamazepine (CBZ-CR) as initial monotherapy for new-onset focal epilepsy. Conversely, no head-to-head trials have been performed. The aim of this study was to estimate the comparative efficacy and tolerability of the antiepileptic monotherapies in adults with newly diagnosed focal epilepsy through a network meta-analysis (NMA). Randomized, double-blinded, parallel group, monotherapy studies comparing any AED to CBZ-CR in adults with newly diagnosed untreated epilepsy with focal-onset seizures was identified. The outcome measures were the seizure freedom for 6 and 12 months, the occurrence of treatment-emergent adverse events (TEAEs), and the treatment withdrawal due to TEAEs. Mixed treatment comparisons were conducted by a Bayesian NMA using the Markov chain Monte Carlo methods. Effect sizes were calculated as odds ratios (ORs) with 95% credible intervals (CrIs). Four trials were included involving 2856 participants, 1445 for CBZ-CR and 1411 for the comparative AEDs. Monotherapy AEDs compared to CBR-CR were levetiracetam (LEV), zonisamide (ZNS), lacosamide (LCM), and eslicarbazepine acetate (ESL). There were no statistical differences in the 6- and 12-month seizure freedom and TEAEs occurrence between LEV, ZNS, LCM, ESL, and CBZ-CR In the analysis of drug withdrawal due to TEAEs, LCM treatment was associated with a significantly lower discontinuation rate than CBZ-CR (OR 0.659, 95% CrI 0.428-0.950). LEV, ZNS, LCM, and ESL are effective initial monotherapy treatments in adult patients with newly diagnosed focal epilepsy and represent suitable alternatives to CBZ-CR.

Comorbidity between epilepsy and cardiac arrhythmias: Implication for treatment.

Epilepsy is often comorbid with either neurological or nonneurological diseases. The association between epilepsy and cardiac arrhythmias is not infrequent, mostly in patients with severe forms of epilepsy or critically ill. Remarkably, these medical conditions share many similarities. Vascular and genetic disorders may predispose to both seizures and abnormalities of cardiac electrophysiology. Repeated and uncontrolled seizures may favor potentially life-threatening arrhythmias. Antiepileptic drugs (AEDs) may facilitate the occurrence of cardiac arrhythmias by acting on ionic channels at heart level. Antiarrhythmic drugs (AADs) can have effects on ionic channels expressed in the brain, as suggested by their efficacy in treating patients with rare forms of epilepsy; AADs may also be proconvulsant, mainly during their overdosage. In clinical practice, the AEDs with the lowest risk to influence cardiac electrophysiology are to be preferred in patients presenting with either seizures or arrhythmias. Traditional AEDs should be avoided because of their arrhythmogenic properties and enzyme-inducing effects, which may make ineffective the concomitant treatment with AADs. Some of the newer AEDs can rarely affect cardiac rhythm, and electrocardiogram (ECG) monitoring should be warranted.

Management of epilepsy in brain tumors.

Epilepsy in brain tumors (BTE) may require medical attention for a variety of unique concerns: epileptic seizures, possible serious adverse effects of antineoplastic and antiepileptic drugs (AEDs), physical disability, and/or neurocognitive disturbances correlated to tumor site. Guidelines for the management of tumor-related epilepsies are lacking. Treatment is not standardized, and overall management might differ according to different specialists. The aim of this document was to provide directives on the procedures to be adopted for a correct diagnostic-therapeutic path of the patient with BTE, evaluating indications, risks, and benefits. A board comprising neurologists, epileptologists, neurophysiologists, neuroradiologists, neurosurgeons, neuro-oncologists, neuropsychologists, and patients' representatives was formed. The board converted diagnostic and therapeutic problems into seventeen questions. A literature search was performed in September-October 2017, and a total of 7827 unique records were retrieved, of which 148 constituted the core literature. There is no evidence that histological type or localization of the brain tumor affects the response to an AED. The board recommended to avoid enzyme-inducing antiepileptic drugs because of their interference with antitumoral drugs and consider as first-choice newer generation drugs (among them, levetiracetam, lamotrigine, and topiramate). Valproic acid should also be considered. Both short-term and long-term prophylaxes are not recommended in primary and metastatic brain tumors. Management of seizures in patients with BTE should be multidisciplinary. The panel evidenced conflicting or lacking data regarding the role of EEG, the choice of therapeutic strategy, and timing to withdraw AEDs and recommended high-quality long-term studies to standardize BTE care.

Frequency of drug combinations between enzyme-inducing first-generation antiepileptic drugs and inducible drugs in patients with epilepsy.

OBJECTIVE: The objective of the study was to systematically assess, through the analysis of administrative data, the frequency of combinations of first-generation enzyme-inducing (EI) antiepileptic drugs (AEDs) with drugs frequently prescribed in patients with epilepsy whose metabolism is induced by EIAEDs. METHODS: From the population of Tuscany (a region in Italy of about 3,750,000 habitants), patients who had been treated with at least one first-generation EIAEDs (carbamazepine, phenytoin, phenobarbital, and primidone) and had received prescriptions of an inducible non-AED (NON-AED) included in a prespecified list of 103 inducible drugs were identified. RESULTS: At the index date, 9221 patients with epilepsy were treated with at least one traditional EIAED, and there were 2538 drug combinations between EIAEDs and NON-AEDs, which may result in potentially serious clinical consequences, and 3317 combinations with NON-AEDs that have their metabolism consistently increased. CONCLUSIONS: Patients with epilepsy treated with traditional EIAEDs are at a very high risk of drug interactions.

Do antiepileptic drugs increase the risk of infectious diseases? A meta-analysis of placebo-controlled studies.

AIMS: Experimental studies show that some antiepileptic drugs (AEDs) may modify natural immune defences, thus influencing the risk of developing infectious diseases. The aim of this meta-analysis was to explore whether AEDs as a class of drugs or singularly may increase risk of infectious diseases. METHODS: A meta-analysis of all randomized, double-blind, placebo-controlled trials (RCTs) investigating any AED in any condition was performed. All terms that could be coded in the System Organ Classes (SOCs) of infections and infestations using the Medical Dictionary for Regulatory Activities were recorded. Additional subanalyses were performed also pooling together AEDs sharing similar mechanisms of action. RESULTS: Two hundreds and sixty-nine double-blind, placebo-controlled studies were identified and, among them, 127 RCTs with 16 AEDs (brivaracetam, gabapentin, lacosamide, levetiracetam, lamotrigine, oxcarbazepine, perampanel, pregabalin, phenytoin, remacemide, retigabine, rufinamide, tiagabine, topiramate, valproate, zonisamide) reported at least one of 19 symptoms or diseases that could be included in the Medical Dictionary for Regulatory Activities SOC term infections and infestations. These terms were singularly recorded and then pooled together in the SOC term infection and infestation. Topiramate was significantly associated with an increased risk of infection (risk difference = 0.04; 95% confidence interval = 0.01/0.06), while oxcarbazepine was significantly associated with a lower risk (-0.005; -0.09/-0.01). Risk difference of all studies with all AEDs showed a slight, but significantly increased risk of infection (0.01; 0.00/0.002). Levetiracetam and brivaracetam RCTs, when pooled together, were associated with a significantly increased risk of infection (0.03; 0.01/0.05). CONCLUSIONS: Some AEDs are associated with a mild increased risk of infection.

Tolerability of new antiepileptic drugs: a network meta-analysis.

OBJECTIVE: The objective of this study was to perform a comparative assessment of tolerability of all licensed new antiepileptic drugs (AEDs) through a network meta-analysis (NMA) including all placebo-controlled double-blind clinical trials (RCTs) in all conditions in which these drugs have been tested. METHODS: NMA with a frequentist approach was used to compare proportions of patients withdrawing because of adverse events (AEs). Analyses were conducted for all therapeutic doses pooled and specifically for high therapeutic doses. Patients treated with non-therapeutic doses of each drug were excluded. RESULTS: A total of 195 RCTs were included in the current analysis, comprising a total of 28,013 patients treated with AEDs and 17,908 patients treated with placebo. RCTs included in the analysis were 8 for brivaracetam; 5 for eslicarbazepine; 22 for gabapentin; 7 for lacosamide; 14 for levetiracetam; 14 for lamotrigine; 6 for oxcarbazepine; 9 for perampanel; 50 for pregabalin; 5 for tiagabine; 36 for topiramate; 7 for zonisamide; 4 for gabapentin-extended formulation (ER); 2 each for levetiracetam-ER, lamotrigine-ER, and topiramate-ER; and 1 each for oxcarbazepine-ER and pregabalin-ER. Brivaracetam, gabapentin, gabapentin-ER, and levetiracetam had a significantly lower withdrawal rate compared to several other AEDs, while eslicarbazepine, lacosamide, oxcarbazepine, and topiramate had a higher withdrawal rate. Perampanel, lamotrigine, pregabalin, tiagabine, and zonisamide showed an intermediate pattern of tolerability. Additional analysis has been conducted through selection of highly recommended doses for each drug. This analysis has roughly confirmed results of head to head comparisons of the all-dose analysis, with some exceptions. A further analysis has been conducted after exclusion of RCTs in which patients were allocated to the therapeutic dose of the experimental drug without titration, and it failed to show clinically important differences. SIGNIFICANCE: Relevant differences in short-term tolerability of AEDs have been observed between AEDs. Brivaracetam, gabapentin, and levetiracetam show the best tolerability profile while other AEDs are at higher risk for intolerable adverse effects.