The objective of the present study is to identify novel, time-indexed imaging biomarkers of epileptogenesis in mesial temporal lobe epilepsy (MTLE).Methods
We used high-resolution brain diffusion tensor imaging (DTI) of the translationally relevant methionine sulfoximine (MSO) brain infusion model of MTLE. MSO inhibits astroglial glutamine synthetase, which is deficient in the epileptogenic hippocampal formation of patients with MTLE. MSO-infused (epileptogenic) rats were compared with phosphate-buffered saline (PBS)–infused (nonepileptogenic) rats at early (3–4 days) and late (6–9 weeks) time points during epileptogenesis.Results
The epileptogenic rats exhibited significant changes in DTI-measured fractional anisotropy (FA) in numerous brain regions versus nonepileptogenic rats. Changes included decreases and increases in FA in regions such as the entorhinal-hippocampal area, amygdala, corpus callosum, thalamus, striatum, accumbens, and neocortex. The FA changes evolved over time as animals transitioned from early to late epileptogenesis. For example, some areas with significant decreases in FA early in epileptogenesis changed to significant increases late in epileptogenesis. Finally, the FA changes significantly correlated with the seizure load.Significance
Our results suggest (1) that high-resolution DTI can be used for early identification and tracking of the epileptogenic process in MTLE, and (2) that the process identified by DTI is present in multiple brain areas, even though infusion of MSO is restricted to the unilateral entorhinal-hippocampal region.
Psychiatric lifetime diagnoses are associated with a reduced chance of seizure freedom after temporal lobe surgery
To examine whether psychiatric comorbidity is a predictor of long-term seizure outcome following temporal lobe epilepsy surgery.Methods
A sample of 434 adult patients who received temporal lobe resection to treat epilepsy between 1991 and 2009 and were psychiatrically assessed before surgery were followed for 2 years to assess seizure outcome. Stepwise multivariate logistic regression analyses were used to assess the impact of psychiatric variables on complete seizure freedom (Engel class IA), and freedom from disabling seizures (Engel class I). Lifetime histories of three psychiatric syndromes (PS: psychosis; depression; other) and five personality disorders (PD: DSM-IV Clusters A, B, and C; organic personality disorder; other) were considered as predictors, complemented by age at onset, duration of epilepsy, type of lesion (mesiotemporal sclerosis vs. other), and year of surgery.Results
Seizure-freedom rates were significantly higher (p < 0.001) in patients with no history of PS or PD (N = 138; Engel class IA: 61.6%; Engel class I: 87.7%) than in those with any PS or PD (N = 296; Engel class IA: 39.5%; Engel class I: 58.8%). Particularly low seizure-freedom rates were found in patients with a diagnosis of psychosis (N = 32, Engel class IA: 21.9%; Engel class I: 40.6%), organic PD (N = 48, Engel class IA: 25.0%; Engel class I: 35.4%) or a double diagnosis of PS plus PD (N = 97; Engel class IA: 27.8%; Engel class I: 45.5%). No other variables emerged as significant risk factors in multivariate logistic regression analyses.Significance
Patients with and without psychiatric comorbidities can benefit from temporal lobe epilepsy surgery; however, psychiatric comorbidities are negatively associated with postoperative seizure-freedom rates. Surgical outcome is related to the type and extent of preoperative psychiatric morbidity, which underscores the prognostic value of presurgical psychiatric evaluation. The data support the argument that there are common pathogenetic mechanisms underlying both epilepsy and psychiatric conditions.
We aimed to compare long-term social outcomes in young adults with childhood-onset epilepsy (cases) with neurologically normal sibling controls.Methods
Long-term social outcomes were assessed at the 15-year follow-up of the Connecticut Study of Epilepsy, a community-based prospective cohort study of children with newly diagnosed epilepsy. Young adults with childhood-onset epilepsy with complicated (abnormal neurologic exam findings, abnormal brain imaging with lesion referable to epilepsy, intellectual disability (ID; IQ < 60) or informative history of neurologic insults to which the occurrence of epilepsy might be attributed), and uncomplicated epilepsy presentations were compared to healthy sibling controls. Age, gender, and matched-pair adjusted generalized linear models stratified by complicated epilepsy and 5-year seizure-free status estimated adjusted odds ratios (aORs) and 95% confidence intervals [CIs] for each outcome.Results
The 15-year follow-up included 361 individuals with epilepsy (59% of initial cases; N = 291 uncomplicated and N = 70 complicated epilepsy; mean age 22 years [standard deviation, SD 3.5]; mean epilepsy onset 6.2 years [SD 3.9]) and 173 controls. Social outcomes for cases with uncomplicated epilepsy with ≥5 years terminal remission were comparable to controls; cases with uncomplicated epilepsy <5 years seizure-free were more likely to be less productive (school/employment < 20 h/week) (aOR 3.63, 95% CI 1.83–7.20) and not to have a driver's license (aOR 6.25, 95% CI 2.85–13.72). Complicated cases with epilepsy <5 years seizure-free had worse outcomes across multiple domains; including not graduating high school (aOR 24.97, 95% CI 7.49–83.30), being un- or underemployed (<20 h/week) (aOR 11.06, 95% CI 4.44–27.57), being less productively engaged (aOR 15.71, 95% CI 6.88–35.88), and not living independently (aOR 10.24, 95% CI 3.98–26.36). Complicated cases without ID (N = 36) had worse outcomes with respect to productive engagement (aOR 6.02; 95% CI 2.48–14.58) compared to controls. Cases with complicated epilepsy were less likely to be driving compared to controls, irrespective of remission status or ID.Significance
In individuals with uncomplicated childhood-onset epilepsy presentations and 5-year terminal remission, young adult social outcomes are comparable to those of sibling controls. Complicated epilepsy, notable for intellectual disability, and seizure remission status are important prognostic indicators for long-term young adult social outcomes in childhood-onset epilepsy.
Derivation and initial validation of a surgical grading scale for the preliminary evaluation of adult patients with drug-resistant focal epilepsy
Presently, there is no simple method at initial presentation for identifying a patient's likelihood of progressing to surgery and a favorable outcome. The Epilepsy Surgery Grading Scale (ESGS) is a three-tier empirically derived mathematical scale with five categories: magnetic resonance imaging (MRI), electroencephalography (EEG), concordance (between MRI and EEG), semiology, and IQ designed to stratify patients with drug-resistant focal epilepsy based on their likelihood of proceeding to resective epilepsy surgery and achieving seizure freedom.Methods
In this cross-sectional study, we abstracted data from the charts of all patients admitted to the New York University Langone Medical Center (NYULMC) for presurgical evaluation or presented in surgical multidisciplinary conference (MDC) at the NYU Comprehensive Epilepsy Center (CEC) from 1/1/2007 to 7/31/2008 with focal epilepsy, who met minimal criteria for treatment resistance. We classified patients into ESGS Grade 1 (most favorable), Grade 2 (intermediate), and Grade 3 (least favorable candidates). Three cohorts were evaluated: all patients, patients presented in MDC, and patients who had resective surgery. The primary outcome measure was proceeding to surgery and seizure freedom.Results
Four hundred seven patients met eligibility criteria; 200 (49.1%) were presented in MDC and 113 (27.8%) underwent surgery. A significant difference was observed between Grades 1 and 3, Grades 1 and 2, and Grades 2 and 3 for all presurgical patients, and those presented in MDC, with Grade 1 patients having the highest likelihood of both having surgery and becoming seizure-free. There was no difference between Grades 1 and 2 among patients who had resective surgery.Significance
These results demonstrate that by systematically using basic information available during initial assessment, patients with drug-resistant epilepsy may be successfully stratified into clinically meaningful groups with varied prognosis. The ESGS may improve communication, facilitate decision making and early referral to a CEC, and allow patients and physicians to better manage expectations.
Fundraiser Simon Osborn claims to be “more mixed grill than Bear Grylls” as he gets ready to walk 184 miles of the River Thames
Epilepsy Research UK supporter and fundraiser Simon Osborn is training hard to get ready for a mammoth task. Simon is walking the entire length of the River Thames. The walk is a massive 184 miles. Simon, who has epilepsy himself, is walking most of the way on his own and he expects the whole walk to take around 10 days. In a recent interview given to the Banbury Guardian Simon described himself as “more mixed grill than Bear Grylls” but he is certainly a hero to us and has raised almost £2,000 so far.
Intracerebral delivery of the M2 polarizing cytokine interleukin 13 using mesenchymal stem cell implants in a model of temporal lobe epilepsy in mice
Neuroinflammation plays a critical role in the pathophysiology of mesial temporal lobe epilepsy. We aimed to evaluate whether intracerebral transplantation of interleukin 13–producing mesenchymal stem cells (IL-13 MSCs) induces an M2 microglia/macrophage activation phenotype in the hippocampus with an epileptogenic insult, thereby providing a neuroprotective environment with reduced epileptogenesis.Methods
Genetically engineered syngeneic IL-13 MSCs or vehicle was injected within the hippocampus 1 week before the intrahippocampal kainic acid–induced status epilepticus (SE) in C57BL/6J mice. Neuroinflammation was evaluated at disease onset as well as during the chronic epilepsy period (9 weeks). In addition, continuous video–electroencephalography (EEG) (vEEG) monitoring was obtained during the chronic epilepsy period (between 6 and 9 weeks after SE).Results
Evaluation of vEEG recordings suggested that IL-13 MSC grafts did not affect the severity and duration of SE or the seizure burden during the chronic epilepsy period, when compared to the vehicle treated SE mice. An M2-activation phenotype was induced in microglia/macrophages that infiltrated the -13 MSC graft site, as evidenced by the arginase1 expression at the graft site at both the 2-week and 9-week time-points. However, M2-activated immune cells were rarely observed outside the graft site and, accordingly, the neuroinflammatory response or cell loss related to SE induction was not altered by IL-13 MSC grafting. Moreover, an increase in the proportion of F4/80+ cells was observed in the IL-13 MSC group compared to the controls.Significance
Our data suggest that MSC-based IL-13 delivery to induce M2 glial activation does not provide any neuroprotective or disease-modifying effects in a mouse model of epilepsy. Moreover, use of cell grafting to deliver bioactive compounds for modulating neuroinflammation may have confounding effects in disease pathology of epilepsy due to the additional immune response generated by the grafted cells.
The International League Against Epilepsy (ILAE) has proposed to expand the definition of remission to 10 years seizure-free with the last 5 years off antiepileptic drugs (AEDs). We examined if a 10-year remission is needed to predict the lowest recurrence risk.Methods
The population-based study cohort consisted of 148 patients with new-onset childhood epilepsy living in the catchment area of Turku University Hospital. They were prospectively followed for 44 years (median). Patients in first remission were prospectively followed for the duration of remission or possible relapse at 2 years in remission with the last year without antiepileptic drugs (AEDs), at 5 years in remission with the last 2 years without AEDs, and at 10 years with the last 5 years without AEDs. For comparison of the proportions of relapsed patients within each remission category exact Clopper Pearson 95% confidence intervals were used.Results
The magnitude of the relapse rate estimates off AEDs did not significantly improve when remission increased from 2 years (2YR) to 5 years (5YR) and further to 10 years (10YR). However, 10YR was a more sensitive measure of no relapse than 2YR. Among patients with remission on or off AEDs, the ability to predict lower relapse rate increased markedly from 2 to 5 years, and again from 5 to 10 years. The risk of relapse was virtually the same estimated after 2YR off AEDs as after 10YR on or off AEDs, except for patients with generalized epilepsy whose 2YR off AEDs was a weaker predictor than 10YR on or off AEDs.Significance
Given the modest differences in relapse rates between the 5 years seizure-free with last 2 years off medications definition and the 10 years seizure-free with last 5 years off medications, and the adverse impact of not being considered in remission, we propose that a return to the 5-year definition may be warranted.
Adopting stress reduction techniques may lower the risk of epileptic seizures, according to a review article published in the scientific journal Seizure. The relationship between stress and epileptic seizures has been studied for many years and a number of scientific studies looking at this relationship have been published. Scientists have shown that stress can, not only increase the risk of sudden seizures, but in severe cases, can also increase the risk of epilepsy.
Stressful events that may trigger epileptic seizures include trauma, bereavement, natural disasters or war. It is tough that such stressors lead to higher anxiety levels in people, which in turn can trigger the development of seizures. However the exact mechanism of how stress may be triggering seizures in the brain is not well understood.
One of the authors of the study, Dr Heather Mc Kae at the University of Cincinnati said in a press release: “Stress is a subjective and highly individualised state of mental or emotional strain. Although it’s quite clear that stress is an important and common seizure precipitant, it remains difficult to obtain objective conclusions about a direct causal factor for individual epilepsy patients,”
For the present review, the scientists analysed 21 studies, which were published since 1980s, that looked into the relationship between stress and seizures.
“The earliest studies from the 1980s were primarily diaries of patients who described experiencing more seizures on ‘high-stress days’ than on ‘low-stress days,” said the co-author Dr Michael Privitera.
Other studies analysed functional magnetic resonance imaging (fMRI) data that allow scientists to identify areas of the brain that become highly active in response to external stimuli such as stressful visual and audio triggers.
The authors concluded that adopting stress reduction techniques such as controlled deep breathing, relaxation techniques, and exercise could improve people’s overall quality of life and reduce seizure frequency.
Further studies are needed however to better understand the mechanism that may link stress and seizures. This way doctors can make evidence-based recommendations about the benefits of stress reduction in reducing the risk of seizures.
Author: Dr Özge Özkaya
To report the reasons for discontinuation of contraceptive methods by women with epilepsy (WWE).Methods
These retrospective data come from a web-based survey regarding the contraceptive practices of 1,144 WWE in the community, ages 18–47 years. We determined the frequencies of contraceptive discontinuations and the reasons for discontinuation. We compared risk ratios for rates of discontinuation among contraceptive methods and categories. We used chi-square analysis to test the independence of discontinuation reasons among the various contraceptive methods and categories and when stratified by antiepileptic drug (AED) categories.Results
Nine hundred fifty-nine of 2,393 (40.6%) individual, reversible contraceptive methods were discontinued. One-half (51.8%) of the WWE who discontinued a method discontinued at least two methods. Hormonal contraception was discontinued most often (553/1,091, 50.7%) with a risk ratio of 1.94 (1.54–2.45, p < 0.0001) compared to intrauterine devices (IUDs), the category that was discontinued the least (57/227, 25.1%). Among all individual methods, the contraceptive patch was stopped most often (79.7%) and the progestin-IUD was stopped the least (20.1%). The top three reasons for discontinuation among all methods were reliability concerns (13.9%), menstrual problems (13.5%), and increased seizures (8.6%). There were significant differences among discontinuation rates and reasons when stratified by AED category for hormonal contraception but not for any other contraceptive category.Significance
Contraception counseling for WWE should consider the special experience profiles that are unique to this special population on systemic hormonal contraception.
An examination of biochemical parameters and their association with response to ketogenic dietary therapies
In the absence of specific metabolic disorders, accurate predictors of response to ketogenic dietary therapies (KDTs) for treating epilepsy are largely unknown. We hypothesized that specific biochemical parameters would be associated with the effectiveness of KDT in humans with epilepsy. The parameters tested were β-hydroxybutyrate, acetoacetate, nonesterified fatty acids, free and acylcarnitine profile, glucose, and glucose-ketone index (GKI).Methods
Biochemical results from routine blood tests conducted at baseline prior to initiation of KDT and at 3-month follow-up were obtained from 13 adults and 215 children with KDT response data from participating centers. One hundred thirty-two (57%) of 228 participants had some data at both baseline and 3 months; 52 (23%) of 228 had data only at baseline; 22 (10%) of 228 had data only at 3 months; and 22 (10%) of 228 had no data. KDT response was defined as ≥50% seizure reduction at 3-month follow-up.Results
Acetyl carnitine at baseline was significantly higher in responders (p < 0.007). It was not associated with response at 3-month follow-up. There was a trend for higher levels of free carnitine and other acylcarnitine esters at baseline and at 3-month follow-up in KDT responders. There was also a trend for greater differences in levels of propionyl carnitine and in β-hydroxybutyrate measured at baseline and 3-month follow-up in KDT responders. No other biochemical parameters were associated with response at any time point.Significance
Our finding that certain carnitine fractions, in particular baseline acetyl carnitine, are positively associated with greater efficacy of KDT is consistent with the theory that alterations in energy metabolism may play a role in the mechanisms of action of KDT.