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.

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.

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.

Placebo and nocebo responses in drug trials of epilepsy.

Placebo response can be defined as any therapeutic change on placebo, while the nocebo response is any ill effect during placebo exposure. Several meta-analytic approaches have investigated the extent of placebo response in randomized, placebo-controlled, clinical trials of focal epilepsies. Placebo response rates (proportion of patients with ≥50% improvement of seizures versus baseline) ranging from 9.9% up to 15.2% have been reported. Interestingly, a sham response of 15.8% has been noted in trials of transcranial magnetic stimulation. Recently, nocebo response rates of 60.3% and 3.9% were noted, which were defined as the proportion of patients with adverse events (AEs) and those withdrawing because of intolerable AEs, respectively. Factors which were found to influence placebo response were as follows: the year of publication (with more recent studies showing higher rates of placebo response), some clinical characteristics of recruited patients (lower placebo response rates with a history of 7 or more prior lifetime AEDs, a high baseline seizure frequency, prior epilepsy surgery, and higher age at diagnosis), trial design and statistical analysis, and whether studies have been conducted in children or adults. Furthermore, placebo and nocebo rates were correlated with respective seizure outcome and adverse events of the experimental AED. Several mechanisms of placebo and nocebo responses are discussed. Specifically, the role of positive or negative expectations of patients and of investigators may influence the placebo and the nocebo response. Finally, recommendations are given on how to address placebo and nocebo responses in clinical practice.

"Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients".

BACKGROUND: Neurologic outcome after early or delayed carotid endarterectomy (CEA) has yet to be fully elucidated. The aim of this study was to determine 30-day neurologic improvement with respect to the timing of CEA in symptomatic patients. METHODS: Single-institution review of consecutive patients who underwent CEA for symptomatic carotid stenosis ≥60% in the period between January 2009 and November 2013. Patients recruited had acute neurologic impairment on presentation, defined as <5 points on the National Institutes of Health Stroke Scale (NIHSS). Patients were grouped according to time between the qualifying event and surgery (0-14 days, early CEA and 15-30 days, delayed CEA). Thirty-day neurologic status improvement was defined as a decrease (≥1) in the 30-day NIHSS score versus NIHSS score immediately before surgery. RESULTS: There were 100 and 222 patients in the early and delayed CEA groups, respectively. The type of qualifying symptoms (stroke versus transient ischemic attack rate) was similar and there were no significant differences in 30-day adverse outcome rates between the 2 cohorts. There were no deaths, 4 strokes (1.2%, 3 vs. 1; P = 0.091), and 4 myocardial infarcts (1.2%, 0 vs. 4; P = 0.315). Thirty-day improvement in neurologic status was associated with early CEA, very early CEA (48 hours), and NIHSS >2 before surgery, with an odds ratio of 4.9 (confidence interval [CI], 0.9-25.7; P = 0.03), 12.9 (CI, 1.4-115.7; P = 0.02), and 2.6 (CI, 1.7-4.1; P < 0.001), respectively. CONCLUSIONS: Our results suggest that reducing the time to intervention in selected (NIHSS <5) symptomatic patients is safe and associated with improved neurologic status.

Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P-glycoprotein) and can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥ 200 mg/day) and perampanel (at doses ≥ 8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.

The adverse event profile of lacosamide: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Defining the tolerability and safety profile of recently marketed antiepileptic drugs, such as lacosamide (LCM), is a prerequisite for their optimal utilization in clinical practice. We aimed to identify any adverse event (AE) associated with LCM treatment by conducting a systematic review and meta-analysis of all available randomized controlled trials (RCTs). We also evaluated the association of serious AEs with LCM, the proportion of study withdrawals due to intolerable AEs at different LCM doses, and whether the tolerability profile of LCM differs according to the disorder in which it was investigated. METHODS: We searched MEDLINE and Cochrane CENTRAL to May 2011 for LCM RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo-controlled, double-blind RCTs and investigated the therapeutic effects of oral LCM in adults with any condition. AEs were assessed for their association with LCM after identification/exclusion of synonyms, rare AEs, and non-assessable AEs. We used risk differences to evaluate the association of any (99% confidence intervals [CIs]) or serious AEs (95% CIs) with LCM and to investigate dose-response relationships of identified AEs. KEY FINDINGS: Ten RCTs (three in pharmacoresistant epilepsy, four in neuropathic pain, one in migraine, one in fibromyalgia, and one in knee osteoarthritis) were included in our study. Their duration varied from 12-18 weeks. The total number of patients included was 3,148. No serious AE was significantly associated with LCM treatment. Of 21 identified AEs, 11 (52%) were found to be significantly associated with LCM. The number of AEs significantly associated with LCM increased with increasing dose: one at 200 mg/day (dizziness); six at 400 mg/day (dizziness, vertigo, abnormal coordination, abnormal vision, nausea, and vomiting); nine at 600 mg/day (dizziness, vertigo, ataxia, balance disorder, diplopia, fatigue, nausea, vomiting, and tremor). The proportion of AE-related study withdrawals also significantly increased with increasing dose. LCM AEs tended to occur more frequently in patients with drug-resistant epilepsy compared with patients with other disorders. SIGNIFICANCE: A range of AEs suggestive of vestibulocerebellar dysfunction is significantly associated with LCM treatment and their incidence increases with increasing doses.

The adverse event profile of pregabalin across different disorders: a meta-analysis.

PURPOSE: In a recent meta-analysis of 38 double-blind randomized controlled trials (RCTs) comparing pregabalin (PGB) to placebo, we found 20 adverse events (AEs) to be significantly associated with PGB treatment. In the present study, we evaluated whether the incidence of these 20 AEs differs across distinct disorders in which PGB was investigated. METHODS: Among the 38 previously identified RCTs of PGB, we selected only those including a PGB 600 mg/day arm and subsequently classified them into four distinct groups according to the disorder in which PGB was investigated: (1) drug-resistant partial epilepsy, (2) psychiatric disorders, (3) fibromyalgia, and (4) neuropathic pain. We used risk differences (RDs) to quantify the placebo-corrected proportion of subjects discontinuing PGB due to intolerable AEs and to determine the placebo-corrected incidence of each of the 20 PGB AEs across the four disorders. RESULTS: Twenty-two RCTs were included in this study. Neither the proportion of subjects discontinuing PGB due to intolerable AEs nor the incidence of PGB AEs (with the exception of ataxia) differed significantly across the four disorders. Ataxia was more common in drug-resistant partial epilepsy compared to fibromyalgia. When limiting analyses to subjects on placebo, most vestibulo-cerebellar AEs (ataxia, diplopia, and blurred vision) were found to be more common in drug-resistant partial epilepsy compared to all other disorders. Diplopia and blurred vision were more common in epilepsy than in neuropathic pain; and ataxia had a higher incidence in epilepsy than in anxiety disorder and fibromyalgia. Among other CNS AEs, somnolence was more common in epilepsy compared to neuropathic pain and in anxiety disorders alone compared to neuropathic pain and fibromyalgia. Asthenia was also more common in epilepsy than in neuropathic pain and fibromyalgia. CONCLUSIONS: Although drug-resistant partial epilepsy is associated with a higher probability of developing vestibulo-cerebellar AEs, the risk for PGB toxicity does not differ across distinct disorders.

Idiosyncratic adverse reactions to antiepileptic drugs.

Idiosyncratic drug reactions may be defined as adverse effects that cannot be explained by the known mechanisms of action of the offending agent, do not occur at any dose in most patients, and develop mostly unpredictably in susceptible individuals only. These reactions are generally thought to account for up to 10% of all adverse drug reactions, but their frequency may be higher depending on the definition adopted. Idiosyncratic reactions are a major source of concern because they encompass most life-threatening effects of antiepileptic drugs (AEDs), as well as many other reactions requiring discontinuation of treatment. Based on the underlying mechanisms, idiosyncratic reactions can be differentiated into (1) immune-mediated hypersensitivity reactions, which may range from benign skin rashes to serious conditions such as drug-related rash with eosinophilia and systemic symptoms; (2) reactions involving unusual nonimmune-mediated individual susceptibility, often related to abnormal production or defective detoxification of reactive cytotoxic metabolites (as in valproate-induced liver toxicity); and (3) off-target pharmacology, whereby a drug interacts directly with a system other than that for which it is intended, an example being some types of AED-induced dyskinesias. Although no AED is free from the potential of inducing idiosyncratic reactions, the magnitude of risk and the most common manifestations vary from one drug to another, a consideration that impacts on treatment choices. Serious consequences of idiosyncratic reactions can be minimized by knowledge of risk factors, avoidance of specific AEDs in subpopulations at risk, cautious dose titration, and careful monitoring of clinical response.