Intracerebral electrographic activity following a single dose of diazepam nasal spray: A pilot study.

OBJECTIVE: Rescue benzodiazepine medication can be used to treat seizure clusters, which are intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern. The NeuroPace RNS® System is a device that detects abnormal electrographic activity through intracranial electrodes and administers electrical stimulation to control seizures. Reductions in electrographic activity over days to weeks have been associated with the longer-term efficacy of daily antiseizure medications (ASMs). In this pilot study, electrographic activity over hours to days was examined to assess the impact of a single dose of a proven rescue therapy (diazepam nasal spray) with a rapid onset of action. METHODS: Adult volunteers (>18 years old) with clinically indicated RNS (stable settings and ASM usage) received a weight-based dose of diazepam nasal spray in the absence of a clinical seizure. Descriptive statistics for a number of detections and a sum of durations of detections at 10-min, hourly, and 24-h intervals during the 7-day (predose) baseline period were calculated. Post-dose detections at each time interval were compared with the respective baseline-detection intervals using a 1 SD threshold. The number of long episodes that occurred after dosing also were compared with the baseline. RESULTS: Five participants were enrolled, and four completed the study; the excluded participant had recurrent seizures during the study. There were no consistent changes (difference >1 SD) in detections between post-dose and mean baseline values. Although variability was high (1 SD was often near or exceeded the mean), three participants showed possible trends for reductions in one or more electrographic variables following treatment. SIGNIFICANCE: RNS-assessed electrographic detections and durations were not shown to be sensitive measures of short-term effects associated with a single dose of rescue medication in this small group of participants. The variability of detections may have masked a measurable drug effect. PLAIN LANGUAGE SUMMARY: Rescue drugs are used to treat seizure clusters. Responsive neurostimulation (RNS) devices detect and record epilepsy brain waves and then send a pulse to help stop seizures. This pilot study looked at whether one dose of a rescue treatment changes brain activity detected by RNS. There was a very wide range of detections, which made it difficult to see if or how the drug changed brain activity. New studies should look at other types of brain activity, multiple doses, and larger patient groups.

Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy.

We performed a genome-wide association study (GWAS) to identify genetic variation associated with common forms of idiopathic generalized epilepsy (GE) and focal epilepsy (FE). Using a cohort of 2220 patients and 14,448 controls, we searched for single nucleotide polymorphisms (SNPs) associated with GE, FE and both forms combined. We did not find any SNPs that reached genome-wide statistical significance (p ≤ 5 × 10-8) when comparing all cases to all controls, and few SNPs of interest comparing FE cases to controls. However, we document multiple linked SNPs in the PADI6-PADI4 genes that reach genome-wide significance and are associated with disease when comparing GE cases alone to controls. PADI genes encode enzymes that deiminate arginine to citrulline in molecular pathways related to epigenetic regulation of histones and autoantibody formation. Although epilepsy genetics and treatment are focused strongly on ion channel and neurotransmitter mechanisms, these results suggest that epigenetic control of gene expression and the formation of autoantibodies may also play roles in epileptogenesis.

Coffee and cigarette smoking interactions with lamotrigine.

The objective of this analysis was to determine possible interactions between lamotrigine (LTG) and coffee or cigarette use. As part of the statistical analysis of factors influencing LTG pharmacokinetics (PK) in the Equigen chronic dose study, we collected prospective data from enrolled patients on their use of coffee and cigarettes. Subjects were part of a crossover replication study of generic LTG products with rigorous blood sampling and were instructed to not change their typical consumption of these products for the duration of the study. A total of 35 subjects were enrolled, with 33 subjects having sufficient data for analysis. Higher consumption of coffee was associated with a significantly lower area under the curve (AUC) and maximum concentration (Cmax) of lamotrigine (LTG). Higher cigarette use did not result in a significant change in AUC or Cmax. Coffee, but not cigarette use, either induces LTG metabolism or inhibits LTG absorption.

Characteristics of men with conversion disorder.

OBJECTIVE: Women comprise the majority of subjects with conversion disorders in nearly all studies. The authors previously identified 96 subjects with psychogenic non-epileptic seizures (PNES) and found that female sex, alexithymia and childhood trauma were strongly correlated with the development of PNES. In order to characterize men with PNES, the authors collected questionnaire data on a series of male subjects recruited from an epilepsy monitoring unit (EMU). METHODS: Only male patients admitted to the EMU were asked to complete the Toronto Alexithymia Scale-20 (TAS-20) and the Childhood Trauma Questionnaire (CTQ). Results were correlated with diagnosis at discharge, either epileptic seizures (ES) or PNES. RESULTS: Ninety-two subjects submitted complete questionnaire data. Sixty-nine subjects (74%) were diagnosed with ES, 13 subjects (14%) were diagnosed with PNES and 10 subjects (11%) had an undetermined diagnosis. There were no significant differences on the TAS-20 or the CTQ by diagnosis. CONCLUSION: In this sample of men admitted to an EMU there was no difference in the extent of alexithymia or childhood trauma between men with ES and PNES. There was a small number of men with a PNES diagnosis, which may have limited our ability to identify differences in the groups. The clear correlation of childhood trauma and alexithymia with development of conversion disorder in women could not be demonstrated in men.

Bioequivalence Between Generic and Branded Lamotrigine in People With Epilepsy: The EQUIGEN Randomized Clinical Trial.

Importance: Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs. Objective: To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products. Design, Setting, and Participants: The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses. Interventions: Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected. Main Outcomes and Measures: The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%). Results: Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-∞, 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0-∞, 0.36; P ≥ .76). Conclusions and Relevance: This study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs. Trial Registration: clinicaltrials.gov Identifier: NCT01733394.

Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges in Coma-Incidence and Interrater Reliability of Continuous EEG After a Standard Stimulation Protocol: A Prospective Study.

PURPOSE: Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) are often seen during continuous electroencephalographic (cEEG) monitoring in coma. Given their uncertain clinical significance, our prospective study evaluated incidence of SIRPIDs in comatose patients in the neuroscience intensive care unit (NSICU) who underwent a standard stimulation protocol and defined interreader reliability for cEEG. METHODS: Of 146 patients prospectively screened who underwent cEEG during a 6-month period, 53 patients were included and 93 patients were excluded. Our protocol used a sequence of auditory, mild tactile, and painful stimuli tested in a quiet room. Continuous electroencephalogram were then reviewed offline by blinded experts, with interrater agreement assessed by kappa statistic. By Pearson χ and Wilcoxon rank-sum tests, we then compared binary and numerical clinical features between those with and without SIRPIDs. RESULTS: Of 53 patients who underwent our protocol, one patient with a corrupt cEEG file was excluded. Traumatic brain injury was the most common diagnosis. Moderate interrater agreement was observed for 66 total stimulations: 20 patients (38.5%) had possible or definite SIRPIDs by minimum one reviewer. For 19 stimulations reviewed by a third reviewer, consensus was reached in 10 cases making the incidence of SIRPIDs 19.3% in our cohort. There was a moderate interrate agreement with kappa of 0.5 (95% confidence interval: 0.1, 0.7). Median intensive care unit stay was 15 days in patients with SIRPIDs versus 6.5 days in those without (P = 0.021). CONCLUSIONS: Our prospective study of SIRPIDs in the neuroscience intensive care unit found a 19% incidence by cEEG using a standard stimulation protocol, most often rhythmic delta activity, and showed a moderate interrater agreement.

Stress as a seizure precipitant: Identification, associated factors, and treatment options.

Stress is a common and important seizure precipitant reported by epilepsy patients. Studies to date have used different methodologies to identify relationships between epilepsy and stress. Several studies have identified anxiety, depression, and childhood trauma as being more common in patients with epilepsy who report stress as a seizure precipitant compared to patients with epilepsy who did not identify stress as a seizure precipitant. In one survey study it was found that a majority of patients with stress-triggered seizures had used some type of stress reduction method on their own and, of those who tried this, an even larger majority felt that these methods improved their seizures. Additionally, small to moderate sized prospective trials, including randomized clinical trials, using general stress reduction methods have shown promise in improving outcomes in patients with epilepsy, but results on seizure frequency have been inconsistent. Based on these studies, we recommend that when clinicians encounter patients who report stress as a seizure precipitant, these patients should be screened for a treatable mood disorder. Furthermore, although seizure reduction with stress reduction methods has not been proven in a randomized controlled trial, other important endpoints like quality of life were improved. Therefore, recommending stress reduction methods to patients with epilepsy appears to be a reasonable low risk adjunctive to standard treatments. The current review highlights the need for future research to help further clarify biological mechanisms of the stress-seizure relationship and emphasizes the need for larger randomized controlled trials to help develop evidence based treatment recommendations for our epilepsy patients.

Hypothalamic-pituitary-adrenocortical axis dysfunction in epilepsy.

Epilepsy is a common neurological disease, affecting 2.4million people in the US. Among the many different forms of the disease, temporal lobe epilepsy (TLE) is one of the most frequent in adults. Recent studies indicate the presence of a hyperactive hypothalamopituitary- adrenocortical (HPA) axis and elevated levels of glucocorticoids in TLE patients. Moreover, in these patients, stress is a commonly reported trigger of seizures, and stress-related psychopathologies, including depression and anxiety, are highly prevalent. Elevated glucocorticoids have been implicated in the development of stress-related psychopathologies. Similarly, excess glucocorticoids have been found to increase neuronal excitability, epileptiform activity and seizure susceptibility. Thus, patients with TLE may generate abnormal stress responses that both facilitate ictal discharges and increase vulnerability for the development of comorbid psychopathologies. Here, we will examine the evidence that the HPA axis is disrupted in TLE, consider potential mechanisms by which this might occur, and discuss the implications of HPA dysfunction for seizuretriggering and psychiatric comorbidities.

Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial.

BACKGROUND: Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. METHODS: The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200-800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, "high" vs "low"), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80-125%) in the analysis population. This study is registered with ClinicalTrials.gov\, number NCT01713777. FINDINGS: Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both Cmax and AUC were within equivalence limits (AUC 90% CI 98-103, Cmax 90% CI 99-105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. INTERPRETATION: Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. FUNDING: American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration.

Differences in paracingulate connectivity associated with epileptiform discharges and uncontrolled seizures in genetic generalized epilepsy.

OBJECTIVE: Patients with genetic generalized epilepsy (GGE) frequently continue to have seizures despite appropriate clinical management. GGE is associated with changes in the resting-state networks modulated by clinical factors such as duration of disease and response to treatment. However, the effect of generalized spike and wave discharges (GSWDs) and/or seizures on resting-state functional connectivity (RSFC) is not well understood. METHODS: We investigated the effects of GSWD frequency (in GGE patients), GGE (patients vs. healthy controls), and seizures (uncontrolled vs. controlled) on RSFC using seed-based voxel correlation in simultaneous electroencephalography (EEG) and resting-state functional magnetic resonance imaging (fMRI) (EEG/fMRI) data from 72 GGE patients (23 with uncontrolled seizures) and 38 healthy controls. We used seeds in paracingulate cortex, thalamus, cerebellum, and posterior cingulate cortex to examine changes in cortical-subcortical resting-state networks and the default mode network (DMN). We excluded from analyses time points surrounding GSWDs to avoid possible contamination of the resting state. RESULTS: (1) Higher frequency of GSWDs was associated with an increase in seed-based voxel correlation with cortical and subcortical brain regions associated with executive function, attention, and the DMN; (2) RSFC in patients with GGE, when compared to healthy controls, was increased between paracingulate cortex and anterior, but not posterior, thalamus; and (3) GGE patients with uncontrolled seizures exhibited decreased cerebellar RSFC. SIGNIFICANCE: Our findings in this large sample of patients with GGE (1) demonstrate an effect of interictal GSWDs on resting-state networks, (2) provide evidence that different thalamic nuclei may be affected differently by GGE, and (3) suggest that cerebellum is a modulator of ictogenic circuits.

Development of new treatment approaches for epilepsy: unmet needs and opportunities.

A working group was created to address clinical "gaps to care" as well as opportunities for development of new treatment approaches for epilepsy. The working group primarily comprised clinicians, trialists, and pharmacologists. The group identified a need for better animal models for both efficacy and tolerability, and noted that animal models for potential disease-modifying or antiepileptogenic effect should mirror conditions in human trials. For antiseizure drugs (ASDs), current animal models have not been validated with respect to their relationship to efficacy in common epilepsy syndromes. The group performed an "expert opinion" survey of perceived efficacy of the available ASDs, and identified a specific unmet need for ASDs to treat tonic-atonic and myoclonic seizures. No correlation has as yet been demonstrated between animal models of tolerability and adverse effects (AEs), versus tolerability in humans. There is a clear opportunity for improved therapies in relation to dose-related AEs. The group identified common and rare epilepsy syndromes that could represent opportunities for clinical trials. They identified opportunities for antiepileptogenic (AEG) therapies in both adults and children, acknowledging that the presence of a biomarker would substantially improve the chances of a successful trial. However, the group acknowledged that disease-modifying therapies (given after the first seizure or after the development of epilepsy) would be easier to study than AEG therapies.

Issues related to development of new antiseizure treatments.

This report represents a summary of the discussions led by the antiseizure treatment working group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Working Groups joint meeting in London (London Meeting). We review here what is currently known about the pharmacologic characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the National Institute of Neurological Disorders and Stroke (NINDS)-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacologic development. We also briefly address what we believe is necessary, going forward, to achieve the goal of stopping seizures in all patients, with a call to arms for funding agencies, the pharmaceutical industry, and basic researchers.

The incidence of seizures in patients undergoing therapeutic hypothermia after resuscitation from cardiac arrest.

STUDY OBJECTIVE: Non-convulsive seizures/status epilepticus occur in approximately 20% of comatose, non-cardiac arrest intensive care unit (ICU) patients, and are associated with increased mortality. The prevalence and clinical significance of seizures in comatose survivors of cardiac arrest undergoing therapeutic hypothermia is not well described. METHODS: At this urban level I trauma center, every patient undergoing therapeutic hypothermia is monitored with continuous video encephalography (cvEEG). We abstracted medical records for all cardiac arrest patients treated with therapeutic hypothermia during 2010. Clinical data were extracted in duplicate. cvEEGs were independently reviewed for seizures by two board-certified epileptologists. RESULTS: There were 33 patients treated with therapeutic hypothermia after cardiac arrest in 2010 who met inclusion criteria for this study. Median age was 58 (range 28-86 years), 63% were white, 55% were male, and 9% had a history of seizures or epilepsy. During cooling, seizures occurred in 5/33 patients (15%, 95%CI 6%-33%). 11/33 patients (33%, 95% CI 19%-52%) had seizures at some time during hospitalization. 13/33 (39%) survived to discharge and of these, 7/13 (54%) survived to 30 days. 9/11 patients with seizures died during hospitalization, compared with 11/22 patients without seizures (82% vs. 50%; difference 32%, CI 951%-63%). No patient with seizures was alive at 30 days. CONCLUSIONS: Seizures are common in comatose patients treated with therapeutic hypothermia after cardiac arrest. All patients with seizures were deceased within 30 days of discharge. Routine use of EEG monitoring could assist in early detection of seizures in this patient population, providing an opportunity for intervention to potentially improve outcomes.

Comparisons of childhood trauma, alexithymia, and defensive styles in patients with psychogenic non-epileptic seizures vs. epilepsy: Implications for the etiology of conversion disorder.

BACKGROUND: It has been theorized that conversion disorder is the result of emotion that cannot be experienced consciously as feeling states or put into words (i.e., alexithymia), but there is little confirming empirical evidence. We sought to characterize subjects with conversion disorder compared to subjects with a distinct medical illness, using the model of psychogenic non-epileptic seizures (PNES) vs. epilepsy (ES), on measures of childhood traumatic experience, alexithymia and maturity of psychological defensive strategies. METHODS: All subjects admitted to the Epilepsy Monitoring Unit of the University of Cincinnati Medical Center were offered self-report questionnaires (Childhood Trauma Questionnaire, Toronto Alexithymia Scale-20 and Response Evaluation Measure-71) at the outset of evaluation. Diagnosis of each subject was confirmed by video-EEG and we compared subjects with PNES to those with ES on these measures. RESULTS: 82 subjects had ES AND 96 had PNES. Those with PNES were significantly more likely to have experienced childhood trauma in all domains (p=.005 to p=.05), and were significantly more likely to have alexithymia (p=.0267). There was a significant difference in the capacity to identify feelings, and a trend towards significance in capacity to describe feelings. There were no differences in defensive styles between the two groups. CONCLUSIONS: PNES diagnosis was associated with female sex, higher alexithymia scores and higher rates of childhood trauma, but not with differences in defensive styles compared to ES. These findings add empirical evidence for theories regarding the cause of conversion disorder and may aid in the design of prospective treatment trials in patients with conversion disorder.

Reduced default mode network connectivity in treatment-resistant idiopathic generalized epilepsy.

PURPOSE: Idiopathic generalized epilepsy (IGE) resistant to treatment is common, but its neuronal correlates are not entirely understood. Therefore, the aim of this study was to examine resting-state default mode network (DMN) functional connectivity in patients with treatment-resistant IGE. METHODS: Treatment resistance was defined as continuing seizures despite an adequate dose of valproic acid (valproate, VPA). Data from 60 epilepsy patients and 38 healthy controls who underwent simultaneous electroencephalography (EEG) and resting-state functional magnetic resonance imaging (fMRI) were included (EEG/fMRI). Independent component analysis (ICA) and dual regression were used to quantify DMN connectivity. Confirmatory analysis using seed-based voxel correlation was performed. KEY FINDINGS: There was a significant reduction of DMN connectivity in patients with treatment-resistant epilepsy when compared to patients who were treatment responsive and healthy controls. Connectivity was negatively correlated with duration of epilepsy. SIGNIFICANCE: Our findings in this large sample of patients with IGE indicate the presence of reduced DMN connectivity in IGE and show that connectivity is further reduced in treatment-resistant epilepsy. DMN connectivity may be useful as a biomarker for treatment resistance.

The relationship between the localization of the generalized spike and wave discharge generators and the response to valproate.

PURPOSE: Up to 30% of patients with idiopathic generalized epilepsy (IGE) have seizures that are refractory to medication despite appropriate therapy that commonly includes valproate (VPA). The aim of this study was to compare patients with VPA-refractory and VPA-responsive IGE in order to determine whether there are group differences in generalized spike and wave discharge (GSWD) generators that may be associated with VPA resistance. METHODS: Of 89 IGE patients who underwent electroencephalography (EEG) combined with functional magnetic resonance imaging (fMRI; EEG/fMRI), 25 with GSWDs identified in EEG/fMRI data were included. Simultaneous acquisition of 64 channels of EEG data at 10 kHz was performed using an MRI-compatible EEG cap and amplifier at 4T. VPA resistance was defined as lack of seizure control despite therapeutic dose of VPA. KEY FINDINGS: The fMRI blood oxygen-level dependent (BOLD) correlates of GSWD in the entire group involved midline thalamus, frontal regions comprising Brodmann areas 6, 24, and 32, and temporal lobes diffusely. When VPA-responsive and VPA-resistant patients were compared, BOLD signal increases were noted in the VPA-resistant patients in medial frontal cortex, along the paracingulate gyrus (Montreal Neurological Institute; MNI x = 2, y = 13.6, z = 45.9), and anterior insula bilaterally (right MNI x = 37.6, y = 7.8, z = 0.6, left MNI x = -35.3, y = 13.6, z = -5.3). SIGNIFICANCE: Our findings support the hypothesis that VPA-resistant and VPA-responsive patients may have different GSWD generators. Furthermore, we hypothesize that these differences in GSWD generators may be the reason for different responses to VPA.

Behavioral intervention as an add-on therapy in epilepsy: designing a clinical trial.

Many patients with epilepsy continue to experience seizures despite taking medication, and stress is a commonly reported trigger for seizures in these individuals. Therefore, a behavioral therapy proven to be effective in epilepsy could be a valuable adjunct to current pharmacotherapy. The challenges in testing such a behavioral intervention for epilepsy are numerous, including lack of consensus about sham designs, maintaining the blind, and powering the study absent known effect sizes. Herein, we present the design of a randomized, controlled, double-blind trial of progressive muscle relaxation as an add-on therapy for refractory epilepsy. Progressive muscle relaxation, which involves the tensing and releasing of muscle groups one at a time, is a well-established technique that relaxes the body and mind, reduces stress, and may improve seizure control. Study design issues discussed may provide insights that will inform future behavioral research in epilepsy.

Semantic association investigated with functional MRI and independent component analysis.

Semantic association, an essential element of human language, enables discourse and inference. Neuroimaging studies have revealed localization and lateralization of semantic circuitry, making substantial contributions to cognitive neuroscience. However, because of methodological limitations, these investigations have only identified individual functional components rather than capturing the behavior of the entire network. To overcome these limitations, we have implemented group independent component analysis (ICA) to investigate the cognitive modules used by healthy adults performing the fMRI semantic decision task. When compared with the results of a standard general linear modeling (GLM) analysis, ICA detected several additional brain regions subserving semantic decision. Eight task-related group ICA maps were identified, including left inferior frontal gyrus (BA44/45), middle posterior temporal gyrus (BA39/22), angular gyrus/inferior parietal lobule (BA39/40), posterior cingulate (BA30), bilateral lingual gyrus (BA18/23), inferior frontal gyrus (L>R, BA47), hippocampus with parahippocampal gyrus (L>R, BA35/36), and anterior cingulate (BA32/24). Although most of the components were represented bilaterally, we found a single, highly left-lateralized component that included the inferior frontal gyrus and the medial and superior temporal gyri, the angular and supramarginal gyri, and the inferior parietal cortex. The presence of these spatially independent ICA components implies functional connectivity and can be equated with their modularity. These results are analyzed and presented in the framework of a biologically plausible theoretical model in preparation for similar analyses in patients with right- or left-hemispheric epilepsies.

Lessons learned from a comparison of language localisation using fMRI and electrocortical mapping: case studies of neocortical epilepsy patients.

Electrocortical mapping (ECM) is recognised as an established method for localisation of eloquent cortex in patients undergoing resective surgery for epilepsy management. Functional MRI (fMRI) has been utilised for language and other cortical function localisation. We describe language localisation in two patients using both ECM and fMRI. Co-registration of fMRI and ECM revealed that although two fMRI tasks localised multiple language areas, the verb generation task had an advantage over the semantic decision/tone decision task in that there was a clear overlap between the language areas identified by the verb generation task and ECM. In addition to the language areas detected by ECM, fMRI showed other language-related areas that may be important for post-operative language outcome. Therefore, fMRI may provide additional and complementary information to ECM in presurgical evaluation of patients with epilepsy. The correlation between fMRI and ECM may depend on the language testing methods utilised during the procedures.