Unraveling the links between circulating bioactive factors and epilepsy: A bidirectional Mendelian randomization study.

Epidemiological research has shown that a variety of circulating bioactive factors are associated with epilepsy, including macrophage colony-stimulating factor, interleukin-1ß, and tumor necrosis factor-α. To further investigate the associations between epilepsy and 41 inflammatory cytokines, this Mendelian randomization was performed. This study presents genome-wide association study summary data on 41 inflammatory cytokines and epilepsy. Epilepsy incorporates generalized and focal epilepsy. A two-sample Mendelian randomization method was used. In order to analyze causal relationships between exposures and outcomes, the inverse variance-weighted method was mainly used. The findings suggested that increased levels of interleukin-1 receptor antagonists and interleukin-5 may be significantly associated with increased risks of focal epilepsy (beta: 0.080, P = .043; beta: 0.083, P = .015). In addition, regulated upon activation normal T cell expressed and secreted factor and Macrophage colony-stimulating factor may be significantly associated with generalized epilepsy (beta: 0.110, P = .042; beta: -0.114, P = .024). Furthermore, inflammatory cytokines such as interleukin-10, interleukin-1ß, interleukin-1Ra, interleukin-7, tumor necrosis factor-α, and interferon-γ may be identified as the result of focal epilepsy (beta: 0.152, P = .031; beta: 0.214, P = .037; beta: 0.214, P = .047; beta: 0.222, P = .031; beta: 0.224, P = .025; beta: 0.161, P = .018). This study suggests that interleukin-5 and interleukin-1 receptor antagonists are potentially correlated factors with focal epilepsy etiology, macrophage colony-stimulating factor and regulated upon activation normal T cell expressed and secreted factor are potentially correlated factors with generalized epilepsy etiology, while several inflammatory cytokines possibly contribute to focal epilepsy development downstream.

Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.

OBJECTIVE: To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this clinical setting. METHODS: Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy. RESULTS: 10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. 9/23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (p<0.0001). Multivariate analysis identified six features which predicted autoantibody positivity (area under the curve=0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, MRI limbic system changes and the absence of conventional epilepsy risk factors. 11/14 (79%) patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score=0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (p<0.05). CONCLUSIONS: Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggests immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis.

Peripheral blood expression levels of inflammasome complex components in two different focal epilepsy syndromes.

BACKGROUND: Although the role of inflammation in epilepsy pathogenesis has been extensively investigated, the inflammasome complex, a key component of neuroinflammation, has been understudied in epilepsy patients. METHODS: To better understand the involvement of this system in epilepsy, levels of inflammasome complex components (NLRP1, NLRP3, CASP1, ASC), end-products of inflammasome complex activity [IL-1ß, IL-18, nitric oxide synthase (NOS) isoforms] and other inflammatory factors (NFκB, IL-6, TNF-α) were measured in peripheral blood of patients with focal epilepsy of unknown cause (FEoUC) (n = 47), mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (n = 35) and healthy controls using real time qPCR and/or ELISA. RESULTS: Inflammasome complex associated factors were either downregulated or unchanged in epilepsy patients. Likewise, flow cytometry studies failed to show an increase in ratios of NLRP3-expressing CD3+ and CD14+ peripheral blood mononuclear cells (PBMC) in epileptic patients. Anti-neuronal antibody positive epilepsy patients showed increased NLRP1 and neuronal NOS mRNA expression levels, whereas patients under poly-therapy showed reduced serum inflammasome levels. FEoUC patients demonstrated increased PBMC NFκB mRNA expression levels and serum IL-1ß and IL-6 levels. Both MTLE-HS and FEoUC patients displayed higher ratios of NFκB-expressing CD14+ PBMC than healthy controls. CONCLUSIONS: Although previous clinical studies have implicated increased inflammasome complex expression levels in epilepsy, our results indicate suppressed inflammasome complex activity in the peripheral blood of focal epilepsy patients. Alternatively, the IL-6-NFκB signaling pathway, appears to be activated in focal epilepsy, suggesting that factors of this pathway might be targeted for future theranostic applications.

Evaluation of zonisamide for the treatment of focal epilepsy: a review of pharmacokinetics, clinical efficacy and adverse effects.

Introduction: Zonisamide is a benzisoxazole with 3-methanesulfonamide side chain, chemically unrelated with other anticonvulsants, and approved as mono-therapy of newly diagnosed focal epilepsy with or without secondary generalization in adults or adjunctive therapy in the treatment of partial seizures, with or without secondary generalization, in adults, adolescents, and children aged 6 years and above.Areas covered: Pharmacokinetics, clinical efficacy, and the adverse effects of zonisamide are discussed in the article. The discussion is based on data from published preclinical studies, clinical trials, observational studies, systematic reviews, and approved summary of product characteristics.Expert opinion: Zonisamide is an anticonvulsant with multiple mechanisms of action on neuronal tissue, which achieves seizure freedom in more than 80% of patients with newly-onset focal epilepsy and in 6.2 to 18.1% of patients with focal onset seizures inadequately controlled by first-line anticonvulsants. Within the recommended dose range, it follows linear kinetic of elimination; it is metabolized in the liver by two cytochrome isoforms, so pharmacokinetic interactions are rare and with little clinical significance. Up to 10% of patients taking zonisamide will have problems with weight loss and more than 10% with irritability, confusion or depression, and long-lasting therapy may cause renal calculi in 1.2% of patients.

Is brivaracetam-induced elevation of carbamazepine-epoxide levels common and clinically relevant? - A case series.

Brivaracetam (BRV) was recently introduced for the treatment of patients with focal epilepsy. BRV undergoes relatively few interactions, but one of them leads to the elevation of carbamazepine (CBZ)-10,11-CBZ-epoxide (CBZ-E) if BRV is co-administered with CBZ. This interaction has been considered to be clinically negligible. We present a case series of nine patients. In eight of them, levetiracetam (LEV) was switched to BRV. In the remaining case, oxcarbazepine was replaced by CBZ and added to a stable BRV dose. A marked increase of CBZ-E occurred in every case and was associated with clinically relevant symptoms including blurred vision, diplopia, dizziness, or fatigue in three of them. However, in the remaining six, the elevated CBZ-E levels were not associated with any tolerability problems. The importance of CBZ-E for adverse events under CBZ may have been overemphasized in the past and is not clinically impairing in most cases treated with the combination of BRV and CBZ.

Elevation in plasma tRNA fragments precede seizures in human epilepsy.

Transfer RNAs (tRNAs) are a major class of noncoding RNA. Stress-induced cleavage of tRNA is highly conserved and results in tRNA fragments. Here we find specific tRNA fragments in plasma are associated with epilepsy. Small RNA sequencing of plasma samples collected during video-EEG monitoring of focal epilepsy patients identified significant differences in three tRNA fragments (5', 5'AlaTGC, and 5'GluCTC) from controls. Levels of these tRNA fragments were higher in pre-seizure than post-seizure samples, suggesting they may serve as biomarkers of seizure risk in epilepsy patients. In vitro studies confirmed that production and extracellular release of tRNA fragments was lower after epileptiform-like activity in hippocampal neurons. We designed PCR-based assays to quantify tRNA fragments in a cohort of pre- and post-seizure plasma samples from focal epilepsy patients and healthy controls (n = 32/group). Receiver operating characteristic analysis indicated that tRNA fragments potently distinguished pre- from post-seizure patients (area under the curve of 0.8-0.95). Elevated tRNA fragments levels were not detected in patients with psychogenic non-epileptic seizures, and did not result from medication tapering. This study identifies a novel class of epilepsy biomarker and reveals the potential existence of prodromal molecular patterns in blood that could be used to predict seizure risk.

Follow-up of patients with epilepsy harboring antiglycine receptor antibodies.

OBJECTIVE: The long-term follow-up of patients with epilepsy harboring autoantibodies against the glycine receptor (also glycine receptor antibodies or GlyR-Ab) is not well-known. Our aim was to investigate the 5-year prognosis and treatment response of patients with epilepsy who were seropositive for GlyR-Ab. METHODS: Clinical features; electroencephalogram (EEG), neuroradiological, and neuropathological findings; and treatment responses of patients with epilepsy with GlyR-Ab seropositivity were investigated. RESULTS: Thirteen (5.46%) of 238 patients with epilepsy were GlyR-Ab positive: focal epilepsy of unknown cause (FEoUC) was diagnosed in four (7.27%) out of 55 patients, mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) in five (4.5%) out of 111 patients, epileptic encephalopathy (EE) in two (4%) out of 50 patients, and status epilepticus (SE) in two (9.09%) out of 22 patients. None of the patients developed any other neurological symptoms or cancer during the 5-year follow-up. Seven of them had seizures that were resistant to antiepileptic drug (AED). Immunotherapy was used in two patients (with FEoUC and EE) improving seizure control. Three patients with MTLE-HS benefited from epilepsy surgery, and another patient with EE showed spontaneous remission. CONCLUSION: Glycine receptor antibodies are detected in a wide spectrum of epileptic disorders with unclear pathogenic significance. Two GlyR-Ab seropositive patients with AED-resistant epilepsy treated with intravenous immunoglobulin (IVIg) showed clear benefit from immunotherapy. Future studies will be valuable in determining the role of screening patients with drug-resistant epilepsy for GlyR-Ab in order to identify patients who may benefit or respond to immunotherapy.

Effect of anti-seizure drugs on serum S100B in patients with focal seizure: a randomized controlled trial.

PURPOSE: S100B, a cytokine produced by astrocytes, has been studied as a biomarker of glial and neuronal damage in epilepsy. The present study investigated the reliability of serum S100B as a biomarker and the effect of carbamazepine and oxcarbazepine on serum S100B in patients with focal seizure. METHODS: The present randomized, open-label, active-controlled, parallel design clinical trial (NCT02705768) conducted on 60 patients with focal seizure. After recruitment, clinical evaluations were performed including Chalfont-National Hospital seizure severity scale (NHS3), Quality of Life in Epilepsy Inventory (QOLIE-31) and serum S100B was estimated. Thirty healthy individuals were recruited for evaluation of serum S100B at baseline only. After randomization, the study groups received either tablet oxcarbazepine or tablet carbamazepine. At follow-up after 2 weeks, clinical status was checked and at 4 weeks, NHS3 and QOLIE-31 were scored along with serum S100B level estimation. RESULTS: Serum S100B level in patients with focal seizure increased significantly in comparison to healthy volunteers. The decrease in serum S100B was significantly higher with carbamazepine group (0.004; 95% CI 0.001-0.006; p = 0.01) over oxcarbazepine group. In logistic regression analysis, there was an increase in the log odds of 0.17 for focal seizure positivity against healthy controls if S100B level increases by 1 pg and area under curve obtained by ROC analysis was 0.96 (p < 0.001). CONCLUSION: Serum S100B increases in the patients with focal seizure and therapy with carbamazepine can decrease serum S100B level significantly over oxcarbazepine. Serum S100B can be used as a prognostic biomarker in a focal seizure.

Severe neonatal hyperbilirubinemia induces temporal and occipital lobe seizures.

To examine the origin of seizures induced by severe neonatal hyperbilirubinemia, The EEG characteristics of seizures were analyzed in newborns with and without severe neonatal hyperbilirubinemia. Fisher's exact test was used to determine the specificity. In total, 931 patients had a total serum bilirubin (TSB) level of 340-425 µmol/L, only 2 of whom had seizures. Compared to patients with hyperbilirubinemia and a TSB level of 340-425 µmol/L, those with a TSB level >425 µmol/L had a significant risk of seizure (OR = 213.2, 95% CI = 113.0-405.8, P<0.001). Of all 28 patients with severe hyperbilirubinemia and seizure, 26 had seizures that originated in the temporal and/or occipital lobe. In seizure patients without severe hyperbilirubinemia, origination in the temporal/occipital and other lobes occurred in 19 and 117 cases, respectively. Compared to the risk of seizure origination in the temporal and/or occipital lobe in other diseases, the risk in patients with severe hyperbilirubinemia was increased by approximately 80 times (OR = 80.1, 95% CI = 28.3-226.4, P<0.001). Severe neonatal hyperbilirubinemia can selectively induce temporal and occipital lobe seizures. This is the first report of a new syndrome with the same etiology and electrophysiological features as epilepsy.

[The clinical significance of the lamotrigine pharmacokinetic variability]. / Klinicheskoe znachenie farmakokineticheskoi variabel'nosti lamotridzhina.

AIM: To estimate pharmacokinetic variability of lamotrigine (LTG) and its clinical significance. MATERIAL AND METHODS: One hundred patients, including 74 women, aged from 18 to 77 years (38.23±14.37 years), with focal epilepsy were examined. Monotherapy with LTG was administered to 54 patients, duotherapy to 46 patients (LTG and valproic acid combination to 27 patients, LTG and liver enzymes inducers to 19 patients). Patients underwent procedures of therapeutic drug monitoring (TDM). Minimal (Cssmin) and maximal (Cssmax) steady-state LTG plasma concentrations, and concentration-to-weight ratio (CDR) were calculated. RESULTS AND CONCLUSION: In patients who used LTG in monotherapy, LTG Cssmin was 5.6±4.65 mg/l, Cssmax 7.59±5.54 mg/l. In the group that received LTG in combination with valproate, LTG Сssmin was 7.8 [5.4; 11.8] mg / l and Cssmax 11.4 [7.3; 15.3] mg/l. In the group that received LTG in combination with drug-inducers of glucuronidation, Cssmin was 2.5 [1.99; 4.32] mg/l, Cssmax 4.73 [2.91; 6.70] mg/l. Statistically significant differences in CDR parameter between groups with LTG monotherapy and duotherapy, both with inducer and with inhibitors, as well as between groups of duotherapy with inductors and with inhibitors were obtained. The results of the study indicate a pronounced pharmacokinetic variability of the LTG. Conducting TDM allows the establishment of individual therapeutic concentrations of LTG in blood plasma and setting a correction vector for antiepileptic therapy.

Vascular, inflammatory, and metabolic factors associated with cognition in aging persons with chronic epilepsy.

We examined cognition in aging persons with chronic epilepsy; characterized targeted vascular, inflammatory, and metabolic risk factors associated with abnormal cognitive aging in the general population; and examined associations between cognition and vascular, inflammatory, and metabolic health. Participants included 40 persons with chronic localization-related epilepsy and 152 controls, aged 54.6 and 55.3, respectively. Participants underwent neuropsychological assessment, clinical examination, and fasting blood evaluation for quantification of vascular status (systolic and diastolic blood pressure, obesity/body mass index [BMI], total and high-density lipoprotein [HDL] cholesterol level, and homocysteine), inflammatory markers (high sensitivity C-reactive protein [hs-CRP], and interleukin-6 [IL-6]), and metabolic status (insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], glucose). Epilepsy participants exhibited impairment across all cognitive factor scores (all p's < 0.0001); abnormalities in BMI (p = 0.049), hs-CRP (p = 0.046), HOMA-IR (p = 0.0040), and fasting glucose (p = 0.03), with significant relationships between higher HOMA-IR with poorer Immediate Memory (p = 0.03) and Visuospatial Ability (0.03); elevated hs-CRP with poorer Visuospatial (p = 0.035) and Verbal Ability (p = 0.06); elevated BMI with poorer Speed/Flexibility (p = 0.04), Visuospatial (p = 0.001) and Verbal Ability (p = 0.02); and lower HDL with poorer Verbal Learning/Delayed Memory (p = 0.01), Speed/Flexibility (p = 0.043), and Working Memory (p = 0.008). Aging persons with chronic epilepsy exhibit multiple abnormalities in metabolic, inflammatory, and vascular health that are associated with poorer cognitive function.

Anti-Neuronal Autoantibodies in Both Drug Responsive and Resistant Focal Seizures with Unknown Cause.

BACKGROUND: and Objective Autoimmunity is an emerging field of research in the etiology of different neurological disorders including epilepsy. We aimed to investigate the presence of neuronal autoantibodies in focal epilepsy with unknown cause and their clinical correlates in both drug-responsive and resistant patients. METHOD: Between 2009 and 2010 94 patients were prospectively enrolled, had their antibodies tested and clinically followed." An additional 50 age- and gender-matched controls were also tested for antibodies. Age at examination, gender, age at onset, seizure frequency, risk factors, seizure precipitants, and type of seizures were noted. Plasma obtained from patients was frozen at -80°C and analysed for autoantibodies against VGKC-complex, VGCC, GAD, LGI1, CASPR2, NMDA, AMPA and GABAB receptors with immunocytochemistry and radioimmunoassay as required. RESULTS: Thirteen (13.8%) patients, but none of the controls, had antibodies (p=0.003). Antibodies were directed against the uncharacterized components of VGKC-complex in 5 patients (5.3%), GAD in 4 patients (4.2%), NMDA-R in 1 patient (1%), AMPA-R in 1 patient (1%) and both GAD and VGKC-complex in 2 patients (2.1%). Prognosis of epilepsy, in subsequent follow-up, did not correlate to general presence of anti-neuronal antibodies with slightly more patients with antibodies epilepsy control than without (76.9% vs. 69.1%, not-statistically significant. Three patients with suspected active autoimmunity and epilepsy who were treated, showed a response to treatment with a reduction in the seizure frequency. Although most clinical features were identical between seropositive and seronegative patient groups, seropositive patients were more likely to have inflammatory/autoimmune disorders in their medical history. DISCUSSION: In keeping with previous studies, we have shown anti-neuronal antibodies in a proportion of focal epilepsy patients. Although autoimmunity might merely occur as a bystander effect in many chronic neurological disorders, association of anti-neuronal antibodies with good response to immunotherapy and coexisting autoimmune disorders suggests that anti-neuronal autoimmunity might participate in seizure formation at least in a subgroup of focal epilepsy patients. CONCLUSION: Immunity may play a role in some patients with unknown etiology regardless of prognosis and immunmodulatuar treatment may be helpful in seropositive group.

GC-MS-Based metabolomics discovers a shared serum metabolic characteristic among three types of epileptic seizures.

OBJECTIVE: Understanding the overall and common metabolic changes of seizures can provide novel clues for their control and prevention. Here, we aim to investigate the global metabolic feature of serum for three types of seizures. METHODS: We recruited 27 patients who had experienced a seizure within 48h (including 11 who had a generalized seizure, nine who had a generalized seizure secondary to partial seizure and seven who had a partial seizure) and 23 healthy controls. We analyzed the global metabolic changes of serum after seizures using gas chromatography-mass spectrometry-based metabolomics. Based on differential metabolites, the metabolic pathways and their potential to diagnose seizures were analyzed, and metabolic differences among three types of seizures were compared. RESULTS: The metabolic profiles of serum were distinctive between the seizure group and the controls but were not different among the three types of seizures. Compared to the controls, patients with seizures had higher levels of lactate, butanoic acid, proline and glutamate and lower levels of palmitic acid, linoleic acid, elaidic acid, trans-13-octadecenoic acid, stearic acid, citrate, cysteine, glutamine, asparagine, and glyceraldehyde in the serum. Furthermore, these differential metabolites had common change trends among the three types of seizures. Related pathophysiological processes reflected by these metabolites are energy deficit, inflammation, nervous excitation and neurotoxicity. Importantly, transamination inhibition is suspected to occur in seizures. Lactate, glyceraldehyde and trans-13-octadecenoic acid in serum jointly enabled a precision of 92.9% for diagnosing seizures. CONCLUSIONS: There is a common metabolic feature in three types of seizures. Lactate, glyceraldehyde and trans-13-octadecenoic acid levels jointly enable high-precision seizure diagnosis.

Changes in hormone and lipid levels in male patients with focal seizures when switched from carbamazepine to lacosamide as adjunctive treatment to levetiracetam: A small phase IIIb, prospective, multicenter, open-label trial.

Treatment with enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine (CBZ) can lead to changes in reproductive, endocrine, and lipid parameters, resulting in clinical symptoms for some patients. Previous studies indicate that these changes can be reversed by switching to a nonenzyme-inducing AED. Lacosamide is a newer-generation AED, not known to induce or strongly inhibit cytochrome P450 (CYP450) enzymes. In this phase IIIb, prospective, multicenter, open-label, single-arm trial (NCT01375374), the serum concentrations of CYP-related reproductive hormones, thyroid hormones, and lipids were assessed in otherwise healthy male patients with focal seizures (N=11), before and after a switch from CBZ (600-1200mg/day at baseline) to lacosamide (target dose: 400mg/day by the end of titration) as adjunctive treatment to the nonenzyme-inducing AED levetiracetam (LEV, stable dosage of >1000mg/day throughout). Cross titration took place over 4weeks, followed by an 8-week maintenance period. Serum measurements were conducted at baseline and at the end of maintenance. The median serum sex-hormone-binding globulin (SHBG) concentration was towards the higher end of the normal range at baseline and decreased following the switch (61.7 to 47.5nmol/L, N=10, p=0.027 by Wilcoxon signed-rank test). Free androgen index (100×testosterone/SHBG) and free thyroxine serum concentration increased (25.4 to 36.4 and 13.0 to 14.9pmol/L, respectively, both N=10 and p=0.002). At baseline, the median progesterone serum concentration was below the normal range (0.7nmol/L), whereas median cholesterol and low-density lipoprotein concentrations were above the normal range (5.5 and 3.6mmol/L, respectively). By the end of maintenance, all measured parameters were within the normal range. The safety and tolerability profile of lacosamide was consistent with that observed in previous studies. Furthermore, antiseizure efficacy appeared to be maintained, suggesting that deinduction of CYP enzymes following a switch from CBZ to lacosamide as adjunctive therapy to LEV is feasible within 8weeks and is associated with normalization of serum parameters.

Long-term effect of antiepileptic drug switch on serum lipids and C-reactive protein.

BACKGROUND: Prior studies have shown that switching patients from inducing antiepileptic drugs (AEDs) to lamotrigine, levetiracetam, or topiramate reduces serum lipids and C-reactive protein (CRP). These studies were all of short duration, and some drugs, such as zonisamide, have not been investigated. METHODS: We recruited 41 patients taking phenytoin or carbamazepine who were being switched to zonisamide, lamotrigine, or levetiracetam. We measured serum lipids and CRP before the switch, >6weeks after, and >6months after. An untreated control group (n=14) underwent similar measurement. We combined these data with those of our previous investigation (n=34 patients and 16 controls) of a very similar design. RESULTS: There were no differences in outcome measures between the two inducing AEDs nor among the three noninducing AEDs. Total cholesterol (TC), atherogenic lipids, and CRP were higher under inducer treatment than in controls. All measures were elevated under inducer treatment relative to noninducer treatment, including TC (24mg/dL higher, 95% CI: 17.5-29.9, p<0.001) and CRP (72% higher, 95% CI: 41%-111%, p<0.001). The difference between drug treatments was clinically meaningful for atherogenic lipids (16%, 95% CI: 11%-20%, p<0.001) but small for high-density lipoprotein cholesterol (5%, 95% CI: 1%-9%, p<0.05). All measures were stable between 6weeks and 6months after drug switch. CONCLUSIONS: We demonstrate that switching from inducing to noninducing AEDs produces an enduring reduction in serum lipids and CRP. These results provide further evidence that inducing AEDs may be associated with elevated vascular disease risk. These are the first vascular risk marker data in patients taking zonisamide, which shows a profile similar to that of other noninducing AEDs.

Ethical Considerations in Balancing Parental Autonomy With Protecting a Child With Epilepsy From Harm.

Neurologists are expected to accommodate parental decisions in the medical care for their child, unless the parental decision places the child at an unnecessary risk of serious harm. Sometimes, respect for parental autonomy is in conflict with the physician's professional obligation to protect the patient from harm and to optimize treatment for a particular disease or condition. This case illustrates an ethical dilemma created when the neurologist and parent disagree about the most appropriate medical treatment for a child with epilepsy. Viewing the disagreement within an ethical framework, however, provides the parties to the disagreement with an opportunity to understand the beliefs and motivations of everyone involved and creates the potential for an outcome based upon the child's best interest.

Perampanel efficacy and safety by gender: Subanalysis of phase III randomized clinical studies in subjects with partial seizures.

The antiepileptic drug (AED) perampanel is approved in ≥40 countries as adjunctive therapy for drug-resistant partial seizures in patients with epilepsy. This post hoc analysis of pooled data from three phase III, double-blind, randomized studies of perampanel examines between-gender differences in perampanel efficacy and safety. Of the 1,478 subjects in the pooled analysis (719 male, 759 female), 1,109 were included in the pharmacokinetic/pharmacodynamic analysis. Perampanel oral clearance was 17% lower in female than in male patients not receiving enzyme-inducing AEDs. Pooled efficacy analysis revealed that seizure frequency was reduced with perampanel treatment regardless of gender; a greater numerical reduction in seizure frequency and increased responder rates occurred in female participants at perampanel doses of 4, 8, and 12 mg. Tolerability was similar between groups, although common adverse events such as dizziness and headache occurred more frequently in female subjects. Modest elevations in perampanel exposure in female patients may result in meaningful between-gender differences in efficacy and safety; therefore, dosing should be individualized and clinical response monitored.

Absence of Liver Toxicity in Perampanel-Treated Subjects: Pooled results from partial seizure phase III perampanel clinical studies.

OBJECTIVE: The liver plays a major role in the metabolism and elimination of many antiepileptic drugs (AEDs), including perampanel. Some of the metabolites identified for perampanel are likely formed via reactive intermediates, which have the potential to covalently bind to protein and cause idiosyncratic toxicities, including hepatotoxicity. The approved AED perampanel is a selective, noncompetitive AMPA receptor antagonist. The safety and tolerability of perampanel have been well documented in 3 double-blind, randomized, placebo-controlled, phase III studies. Here we report the effects of perampanel on liver function in patients from the phase III studies to assess the potential for liver toxicity. METHODS: Following 6-week baseline, patients (≥12 years old) with drug-resistant partial seizures were randomized to once-daily double-blind treatment (6-week titration, 13-week maintenance) with 2, 4, 8, or 12mg perampanel (n=1038) or with placebo (n=442). Clinical laboratory tests for hepatobiliary laboratory parameters were evaluated at baseline and at end of treatment. These included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and total bilirubin. Treatment-emergent markedly abnormal values (an increase in NCI-CTC grade relative to baseline and a grade ≥2) and treatment-emergent adverse events (TEAEs) related to hepatobiliary parameters were also recorded. RESULTS: Mean hepatobiliary values were within normal ranges at baseline and end of treatment for all perampanel groups and placebo. Mean changes from baseline to end of treatment were small. The incidence of markedly abnormal results was very low for perampanel and placebo. TEAEs related to hepatobiliary parameters occurred in 0.4% of perampanel patients and 0% of placebo patients. Hepatobiliary disorders included cholelithiasis (n=3 in perampanel) and abnormal hepatic function (n=1 in perampanel). None of the events were serious or led to perampanel discontinuation. No subject had values that met the criteria for Hy's Law. CONCLUSION: Hepatobiliary laboratory data and related TEAEs were not notably different between perampanel and placebo treatment groups, and no dose-related trends were observed. Based on the laboratory results from the 3 Phase III studies, perampanel (2, 4, 8, and 12mg) demonstrated no clinically important effects on liver function tests, indicating perampanel is an AED with a low potential for drug-induced liver toxicity.

Effect of age and sex on lacosamide pharmacokinetics in healthy adult subjects and adults with focal epilepsy.

BACKGROUND AND OBJECTIVE: Age- and sex-related differences in body composition could affect the pharmacokinetic parameters of administered drugs. The purpose of this post hoc analysis was to investigate the influences of age and sex on the pharmacokinetics of lacosamide. METHODS: This post hoc analysis used pharmacokinetic data taken at steady state from (i) two phase I studies of oral lacosamide in healthy adult subjects (n = 66), and (ii) a population pharmacokinetic analysis carried out using data from two phase III studies of adjunctive oral lacosamide in adults (n = 565) with focal epilepsy taking 1-3 concomitant anti-epileptic drugs. Phase I data were stratified by age and sex as 'younger female' (aged 18-40 years), 'younger male' (aged 18-45 years) or 'elderly male/female' (aged ≥65 years), then normalized by body weight (lean body weight or fat-free mass), height or volume of distribution, and analysed using non-compartmental analysis. Population pharmacokinetic data were stratified by sex and analysed using a one-compartment model. RESULTS: Minor numerical differences between lacosamide exposure [the area under the concentration-time curve at steady state over the dosage interval (AUCτ,ss)] and the maximum plasma concentration at steady state (C max,ss) in subjects of different ages or sexes were noted. The differences could be explained by a scaling factor between the drug applied and the plasma concentration. Following normalization by lean body weight or volume of distribution, an analysis of relative bioavailability resulted in 90 % confidence intervals of the ratios for AUCτ,ss and C max,ss for age (elderly to younger) or sex (male to female) falling within the range accepted for equivalence (80-125 %); without normalization, the 90 % confidence intervals were outside this range. Minor numerical differences in lacosamide plasma concentrations were noted in the comparison between male and female patients (aged 16-71 years) with focal epilepsy. Simulations using different body weights demonstrated a minimal effect of body weight on lacosamide plasma concentrations in adult patients with focal epilepsy. CONCLUSION: Age and sex had no relevant effects on the rates of absorption and elimination of lacosamide in this post hoc analysis, as the minor numerical differences could be explained by the main scaling factor for body weight or volume of distribution. The pharmacokinetic profile of lacosamide was unaffected by age or sex in adults with focal epilepsy.