Objective
The study aim was to compare interictal encephalographic (EEG) functional network topology between people with well‐controlled idiopathic generalized epilepsy (WC‐IGE) and drug‐resistant ...IGE (DR‐IGE).
Methods
Nineteen participants with WC‐IGE, 18 with DR‐IGE, and 20 controls underwent a resting state, 64‐channel EEG. An artifact‐free epoch was bandpass filtered into the frequency range of high and low extended alpha. Weighted functional connectivity matrices were calculated. Mean degree, degree distribution variance, characteristic path length (L), clustering coefficient, small world index (SWI), and betweenness centrality were measured. A Kruskal–Wallis H‐test assessed effects across groups. Where significant differences were found, Bonferroni‐corrected Mann–Whitney pairwise comparisons were calculated.
Results
In the low alpha band (6–9 Hz), there was a significant difference in L at the three‐group level (p < .0001). This was lower in controls than both WC‐IGE and DR‐IGE (p < .0001 for both), with no difference in L between WC‐IGE and DR‐IGE. Mean degree (p = .031), degree distribution variance (p = .032), and SWI (p = .023) differed across the three groups in the high alpha band (10–12 Hz). Mean degree and degree distribution variance were lower in WC‐IGE than controls (p = .029 for both), and SWI was higher in WC‐IGE compared with controls (p = .038), with no differences in other pairwise comparisons.
Significance
IGE network topology is more regular in the low alpha frequency band, potentially reflecting a more vulnerable structure. WC‐IGE network topology is different from controls in the high alpha band. This may reflect drug‐induced network changes that have stabilized the WC‐IGE network by rendering it less likely to synchronize. These results are of potential importance in advancing the understanding of mechanisms of epilepsy drug resistance and as a possible basis for a biomarker of DR‐IGE.
Summary
The potentially serious outcomes from ingestion of and dependence on toxins make this an important topic for epileptologists. We must be aware of the potential for harm from compounds that ...may be freely available, yet patients may try to conceal their use. Problematic compounds may cause seizures either acutely or on withdrawal: Their use may reduce effectiveness of antiepileptic drugs, or may simply promote and enhance chaotic lifestyles. Any or all of these factors may worsen seizure control or even directly cause seizures. This article highlights the pathophysiology behind provoked seizures, provides clues to diagnosis, and then outlines the steps that clinicians should take to reduce the deleterious effects of toxic compounds.
The evaluation of the role of anomalous neuronal networks in epilepsy using a graph theoretical approach is of growing research interest. There is currently no consensus on optimal methods for ...performing network analysis, and it is possible that variations in study methodology account for diverging findings. This review focuses on global functional and structural interictal network characteristics in people with idiopathic generalized epilepsy (IGE) with the aim of appraising the methodological approaches used and assessing for meaningful consensus.
Thirteen studies were included in the review. Data were heterogenous and not suitable for meta-analysis. Overall, there is a suggestion that the cerebral neuronal networks of people with IGE have different global structural and functional characteristics to people without epilepsy. However, the nature of the aberrations is inconsistent with some studies demonstrating a more regular network configuration in IGE, and some, a more random topology. There is greater consistency when different data modalities and connectivity subtypes are compared separately, with a tendency towards increased small-worldness of networks in functional electroencephalography/magnetoencephalography (EEG/MEG) studies and decreased small-worldness of networks in structural studies.
Prominent variation in study design at all stages is likely to have contributed to differences in study outcomes. Despite increasing literature surrounding neuronal network analysis, systematic methodological studies are lacking. Absence of consensus in this area significantly limits comparison of results from different studies, and the ability to draw firm conclusions about network characteristics in IGE.
•The role of anomalous neuronal networks in epilepsy may be evaluated using graph theory.•Inter-ictal networks of people with IGE have different characteristics to people without epilepsy.•A standardized methodological framework, such as the approach suggested in the article, would improve study comparability.
Purpose: P‐glycoprotein (P‐gp) has been implicated in the causation of refractory epilepsy. The expression and efflux efficiency of P‐gp is influenced by a polymorphism (C3435T) in the encoding gene ...(MDR1). Recent evidence suggests that the homozygous C‐variant, which is associated with higher expression and increased activity of P‐gp, is more common in patients with pharmacoresistant epilepsy. We have investigated the prevalence of this polymorphism in a series of patients attending a specialist epilepsy clinic.
Methods: DNA samples were obtained from 400 patients, irrespective of seizure type or drug treatment. Genotype of the C3435T polymorphism was determined by traditional polymerase chain reaction (PCR) followed by restriction digest. Classification of response to treatment was determined in a blinded fashion by an independent physician. Results were expressed as genotype and allele frequencies per response group and compared by logistic regression analysis.
Results: In total, 170 patients were classified as responders, with ≥12 months seizure freedom on current treatment. The remaining 230 patients were classified as nonresponders. Comparison of responders and nonresponders revealed no significant difference in allele frequency (C vs. T; odds ratio, 1.03; 95% CI, 0.78–1.37; p = 0.83) or genotype frequency (CC vs TT; odds ratio, 1.07; 95% CI, 0.60–1.91; p = 0.81). Subanalyses of individual seizure types were similarly unremarkable.
Conclusions: This study failed to corroborate a previously reported association between the C3435T polymorphism in the human MDR1 gene and pharmacoresistant epilepsy. Whether the C3435T polymorphism can act as a marker for the natural history of treated epilepsy remains to be determined.
Levetiracetam (Keppra
, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran
, Eisai Co. Ltd, Tokyo, Japan) are licensed as monotherapy for focal epilepsy, and levetiracetam is increasingly used as a ...first-line treatment for generalised epilepsy, particularly for women of childbearing age. However, there is uncertainty as to whether or not they should be recommended as first-line treatments owing to a lack of evidence of clinical effectiveness and cost-effectiveness.
To compare the clinical effectiveness and cost-effectiveness of lamotrigine (Lamictal
, GlaxoSmithKline plc, Brentford, UK) (standard treatment) with levetiracetam and zonisamide (new treatments) for focal epilepsy, and to compare valproate (Epilim
, Sanofi SA, Paris, France) (standard treatment) with levetiracetam (new treatment) for generalised and unclassified epilepsy.
Two pragmatic randomised unblinded non-inferiority trials run in parallel.
Outpatient services in NHS hospitals throughout the UK.
Those aged ≥ 5 years with two or more spontaneous seizures that require anti-seizure medication.
Participants with focal epilepsy were randomised to receive lamotrigine, levetiracetam or zonisamide. Participants with generalised or unclassifiable epilepsy were randomised to receive valproate or levetiracetam. The randomisation method was minimisation using a web-based program.
The primary outcome was time to 12-month remission from seizures. For this outcome, and all other time-to-event outcomes, we report hazard ratios for the standard treatment compared with the new treatment. For the focal epilepsy trial, the non-inferiority limit (lamotrigine vs. new treatments) was 1.329. For the generalised and unclassified epilepsy trial, the non-inferiority limit (valproate vs. new treatments) was 1.314. Secondary outcomes included time to treatment failure, time to first seizure, time to 24-month remission, adverse reactions, quality of life and cost-effectiveness.
. A total of 990 participants were recruited, of whom 330 were randomised to receive lamotrigine, 332 were randomised to receive levetiracetam and 328 were randomised to receive zonisamide. Levetiracetam did not meet the criteria for non-inferiority (hazard ratio 1.329) in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio vs. lamotrigine 1.18, 97.5% confidence interval 0.95 to 1.47), but zonisamide did meet the criteria (hazard ratio vs. lamotrigine 1.03, 97.5% confidence interval 0.83 to 1.28). In the per-protocol analysis, lamotrigine was superior to both levetiracetam (hazard ratio 1.32, 95% confidence interval 1.05 to 1.66) and zonisamide (hazard ratio 1.37, 95% confidence interval 1.08 to 1.73). For time to treatment failure, lamotrigine was superior to levetiracetam (hazard ratio 0.60, 95% confidence interval 0.46 to 0.77) and zonisamide (hazard ratio 0.46, 95% confidence interval 0.36 to 0.60). Adverse reactions were reported by 33% of participants starting lamotrigine, 44% starting levetiracetam and 45% starting zonisamide. In the economic analysis, both levetiracetam and zonisamide were more costly and less effective than lamotrigine and were therefore dominated.
. Of 520 patients recruited, 260 were randomised to receive valproate and 260 were randomised to receive to levetiracetam. A total of 397 patients had generalised epilepsy and 123 had unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio 1.19, 95% confidence interval 0.96 to 1.47; non-inferiority margin 1.314). In the per-protocol analysis of time to 12-month remission, valproate was superior to levetiracetam (hazard ratio 1.68, 95% confidence interval 1.30 to 2.15). Valproate was superior to levetiracetam for time to treatment failure (hazard ratio 0.65, 95% confidence interval 0.50 to 0.83). Adverse reactions were reported by 37.4% of participants receiving valproate and 41.5% of those receiving levetiracetam. Levetiracetam was both more costly (incremental cost of £104, 95% central range -£587 to £1234) and less effective (incremental quality-adjusted life-year of -0.035, 95% central range -0.137 to 0.032) than valproate, and was therefore dominated. At a cost-effectiveness threshold of £20,000 per quality-adjusted life-year, levetiracetam was associated with a probability of 0.17 of being cost-effective.
The SANAD II trial was unblinded, which could have biased results by influencing decisions about dosing, treatment failure and the attribution of adverse reactions.
SANAD II data could now be included in an individual participant meta-analysis of similar trials, and future similar trials are required to assess the clinical effectiveness and cost-effectiveness of other new treatments, including lacosamide and perampanel.
- The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy.
- The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. For women of childbearing potential, these results inform discussions about the benefit (lower teratogenicity) and harm (worse seizure outcomes and higher treatment failure rate) of levetiracetam compared with valproate.
Current Controlled Trials ISRCTN30294119 and EudraCT 2012-001884-64.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 25, No. 75. See the NIHR Journals Library website for further project information.
Mortality in epilepsy Hitiris, Nikolas; Mohanraj, Rajiv; Norrie, John ...
Epilepsy & behavior,
05/2007, Letnik:
10, Številka:
3
Journal Article
Recenzirano
Abstract All studies report an increased mortality risk for people with epilepsy compared with the general population. Population-based studies have demonstrated that the increased mortality is often ...related to the cause of the epilepsy. Common etiologies include neoplasia, cerebrovascular disease, and pneumonia. Deaths in selected cohorts, such as sudden unexpected death in epilepsy (SUDEP), status epilepticus (SE), suicides, and accidents are more frequently epilepsy-related. SUDEP is a particular cause for concern in younger people, and whether and when SUDEP should be discussed with patients with epilepsy remain problematic issues. Risk factors for SUDEP include generalized tonic–clonic seizures, increased seizure frequency, concomitant learning disability, and antiepileptic drug polypharmacy. The overall incidence of SE may be increasing, although case fatality rates remain constant. Mortality is frequently secondary to acute symptomatic disorders. Poor compliance with treatment in patients with epilepsy accounts for a small proportion of deaths from SE. The incidence of suicide is increased, particularly for individuals with epilepsy and comorbid psychiatric conditions. Late mortality figures in patients undergoing epilepsy surgery vary and are likely to reflect differences in case selection. Future studies of mortality should be prospective and follow agreed guidelines to better quantify risk and causation in individual populations.
Abstract Background Seizures can lead to cardiac arrhythmias by a number of mechanisms including activation/inhibition of cortical autonomic centers, increase in vagal tone through activation of ...brainstem reflex centers, and respiratory failure. Ictal asystole (IA) is a potential mechanism underlying sudden unexpected death in epilepsy (SUDEP). We analyzed the clinical features of 5 patients who developed IA requiring pacemaker implantation. Methods Patients with ictal arrhythmias were identified from the video-telemetry and ambulatory EEG database at Greater Manchester Neurosciences Centre, as well as an independent epilepsy residential care facility. Only those who had IA requiring pacemaker implantation were included in the analysis. A total of 5 patients were identified. Results Of the 5 patients with IA, 4 were female. All 5 patients had focal epilepsy, and four had temporal lobe epilepsy. Ictal asystole occurred with focal seizures with impairment of awareness. Seizure onset was left-sided in 2 patients, right-sided in one, left-sided onset with switch of lateralization in one, and nonlateralized in one patient. Three patients had hippocampal sclerosis, one of whom had undergone epilepsy surgery, one had traumatic encephalomalacia of the temporal lobe, and one patient had no lesions detected on MRI. Interictal epileptiform activity was more pronounced during sleep in all patients. Asystole occurred in association with sleep-related seizures in 4 of 5 patients. Conclusions Ictal asystole (IA) occurred in association with sleep-related seizures in 4 out of 5 cases, predominantly in patients with temporal lobe epilepsy. These findings may be of relevance to SUDEP.
Clinical trials of new antiepileptic drugs (AEDs) include regulatory studies aimed at demonstrating efficacy and reasonable safety, post-marketing open-open label studies and longer term outcome ...studies. Regulatory trials involve a carefully selected population of patients and are conducted under rigorously standardised conditions. Data from such studies cannot often be translated into clinical practice. Pragmatic post-marketing studies using flexible dosing schedules allow clinicians to better judge the utility of the new drug in a wider population of patients with epilepsy and decide the most appropriate dosing schedules. This paper discusses some of the issues surrounding the measurement of efficacy of new AEDs in both pre- and post-marketing phases of their development.
All of the newer AEDs are initially used in patients with refractory partial seizures as adjunctive treatment. These trials are generally parallel-group studies although cross-over designs have been employed. The use of placebo-control is uncontroversial in this type of study. Efficacy endpoints are generally manipulations of seizure frequency on study drug compared to control. Global outcome measures and health related quality of life scores can also be used to measure efficacy.
As the standard AEDs are associated with a high rate of seizure remission in patients who receive them as monotherapy, demonstration of superior efficacy of a new agent in a comparative trial will require large numbers of patients in a design that takes into account the natural history of treated epilepsy. Comparing investigational agents to a standard AED in an ‘active-control’ study with demonstration of equivalent efficacy would seem to be an acceptable way of assessing efficacy of new AEDs in this population. Some regulators, however, do not accept equivalence as proof of efficacy and insist on demonstration of superiority compared to a control. The use of placebo alone in the control group is ethically dubious. Several innovative study designs have, therefore, been used to satisfy regulatory requirements, while maintaining patient safety including withdrawal to monotherapy using high versus low dose comparators.
Observational outcome studies provide the best opportunity of exploring the long-term utility of individual AEDs. Such studies largely follow standard clinical practice and need considerable time and resources. They can, however, yield valuable information about the effectiveness of AEDs in everyday clinical practice. Data from regulatory trials should be complemented by postmarketing studies and longer term studies of outcome to help clinicians decide the best way of utilising new AEDs and establishing their role in the therapeutic armamentarium.
Abstract Background Perampanel (PER) is a novel antiepileptic drug that inhibits the AMPA class of glutamate receptors. It has been available in the UK since September 2012. We undertook a ...retrospective analysis of efficacy and tolerability of PER in 47 patients with drug-refractory epilepsy attending a regional epilepsy service in the UK. Methods Demographic and clinical data of patients with refractory epilepsy prescribed PER were collected by review of records. Efficacy, as measured by responder rates (> 50% reduction in seizure frequency), retention rates, and adverse effects, was analyzed. Results Of the 47 patients prescribed PER, 39 (87%) had focal epilepsy, four (9%) had idiopathic generalized epilepsy, 3 (6%) had symptomatic generalized epilepsy, and 1 had unclassified epilepsy. Patients were taking a median of 2 AEDs (range: 1–5) when starting on PER. The median dose of PER was 8 mg (range: 2–12 mg). Thirteen (28%) patients were classed as responders, but no patients experienced sustained seizure freedom. Twenty-one (45%) patients had withdrawn from PER during the study period, with 16 (76%) of them withdrawing due to intolerable adverse effects, 4 due to inadequate seizure control, and 1 due to the combination of both. The most frequent adverse effects requiring withdrawal from PER were behavioral reactions including suicidal ideation (n = 2), aggressive behavior (n = 2), and both (n = 1). Conclusion In our experience, PER had a retention rate of 55% and a responder rate of 28%. Psychiatric adverse effects, including suicidal ideation, were the most common reasons for withdrawal.
Idiopathic generalized epilepsies (IGE) are characterized by generalized interictal epileptiform discharges (IEDs) on a normal background electroencephalography (EEG). However, the yield of IEDs can ...be low. Approximately 20% of patients with IGE fail to achieve seizure control with antiepileptic drug (AED) treatment. Currently, there are no reliable prognostic markers for early identification of drug-resistant epilepsy (DRE). We examined spectral power of the interictal EEG in patients with IGE and healthy controls, to identify potential diagnostic and prognostic biomarkers of IGE.
A 64-channel EEG was recorded under standard conditions in patients with well-controlled IGE (WC-IGE, n = 19), drug-resistant IGE (DR-IGE, n = 18), and age-matched controls (n = 20). After preprocessing, fast Fourier transform was performed to obtain 1D frequency spectra for each EEG channel. The 1D spectra (averaged over channels) and 2D topographic maps (averaged over canonical frequency bands) were computed for each participant. Power spectra in the 3 cohorts were compared using one-way analysis of variance (ANOVA), and power spectra images were compared using T-contrast tests. A post hoc analysis compared peak alpha power between the groups.
Compared with controls, participants with IGE had higher interictal EEG spectral power in the delta band in the midline central region, in the theta band in the midline, in the beta band over the left hemisphere, and in the gamma band over right hemisphere and left central regions. There were no differences in spectral power between cohorts with WC-IGE and DR-IGE. Peak alpha power was lower in WC-IGE and DR-IGE than controls.
Electroencephalography spectral power analysis could form part of a clinically useful diagnostic biomarker for IGE; however, it did not correlate with response to AED in this study.
•A 64 channel EEG was recorded 19 patients with well controlled IGE, 18 with drug resistant EEG and 20 control subjects.•Spectral power of interictal EEG was compared between the 3 groups•Compared to controls, patients with IGE had higher interictal EEG spectral power in the delta, theta, beta and gamma bands•There were no differences in spectral power between the well controlled and drug resistant IGE cohorts•EEG spectral power analysis could be useful in the diagnosis of IGE, but did not correlate with response to AED in this study
PDF
