Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia (FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography (EEG)–functional magnetic resonance imaging (fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high-frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high-field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose–positron emission tomography (FDG-PET) is highly sensitive for detecting FCD in MRI-negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin (mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet (KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation (VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment-resistant cases, initial evidence from novel approaches suggests that future success is possible.
To study the impact of childhood-onset epilepsy on a variety of outcomes across the life span.Methods
A population-based cohort of 245 subjects with childhood-onset epilepsy was assessed for outcomes at 45 years. In addition, 51 of 78 surviving subjects with uncomplicated epilepsy and 52 of 99 originally matched controls participated in a detailed evaluation including electroencephalography (EEG), imaging, and laboratory studies at 50 years.Results
Of 179 surviving subjects, 61% were in terminal 10-year remission and 43% in remission off medications. At 45 years, 95% of the idiopathic group, 72% of the cryptogenic group, and 47% of the remote symptomatic group were in terminal remission (p < 0.001). Abnormal neurologic signs were significantly more common in subjects with uncomplicated epilepsy than in controls. Mortality during period 1992–2012 was higher in subjects than in controls (9% vs. 1%, p = 0.02). The rate of 3T MRI abnormalities was higher in subjects than in controls (risk ratio [RR] 2.0; 1.3–3.1) specifically including findings considered markers of cerebrovascular disease (RR 2.5; 1.04–5.9). Even subjects with idiopathic epilepsy had higher rates of imaging abnormalities than controls (73% vs. 34%, p = 0.002).Significance
Long-term seizure outcomes are excellent and a function of etiology. The presence of imaging abnormalities suggestive of vascular disease may put these subjects at higher risk for clinically evident stroke and cognitive changes as they age.
Suppressing cAMP response element-binding protein transcription shortens the duration of status epilepticus and decreases the number of spontaneous seizures in the pilocarpine model of epilepsy
Current epilepsy therapies directed at altering the function of neurotransmitter receptors or ion channels, or release of synaptic vesicles fail to prevent seizures in approximately 30% of patients. A better understanding of the molecular mechanism underlying epilepsy is needed to provide new therapeutic targets. The activity of cyclic AMP (cAMP) response element-binding protein (CREB), a major transcription factor promoting CRE-mediated transcription, increases following a prolonged seizure called status epilepticus. It is also increased in the seizure focus of patients with medically intractable focal epilepsy. Herein we explored the effect of acute suppression of CREB activity on status epilepticus and spontaneous seizures in a chronic epilepsy model.Methods
Pilocarpine chemoconvulsant was used to induce status epilepticus. To suppress CREB activity, a transgenic mouse line expressing an inducible dominant negative mutant of CREB (CREBIR) with a serine to alanine 133 substitution was used. Status epilepticus and spontaneous seizures of transgenic and wild-type mice were analyzed using video–electroencephalography (EEG) to assess the effect of CREB suppression on seizures.Results
Our findings indicate that activation of CREBIR shortens the duration of status epilepticus. The frequency of spontaneous seizures decreased in mice with chronic epilepsy during CREBIR induction; however, the duration of the spontaneous seizures was unchanged. Of interest, we found significantly reduced levels of phospho-CREB Ser133 upon activation of CREBIR, supporting prior work suggesting that binding to the CRE site is important for CREB phosphorylation.Significance
Our results suggest that CRE transcription supports seizure activity both during status epilepticus and in spontaneous seizures. Thus, blocking of CRE transcription is a novel target for the treatment of epilepsy.
The European Forum on Epilepsy Research (ERF2013), which took place in Dublin, Ireland, on May 26–29, 2013, was designed to appraise epilepsy research priorities in Europe through consultation with clinical and basic scientists as well as representatives of lay organizations and health care providers. The ultimate goal was to provide a platform to improve the lives of persons with epilepsy by influencing the political agenda of the EU. The Forum highlighted the epidemiologic, medical, and social importance of epilepsy in Europe, and addressed three separate but closely related concepts. First, possibilities were explored as to how the stigma and social burden associated with epilepsy could be reduced through targeted initiatives at EU national and regional levels. Second, ways to ensure optimal standards of care throughout Europe were specifically discussed. Finally, a need for further funding in epilepsy research within the European Horizon 2020 funding programme was communicated to politicians and policymakers participating to the forum. Research topics discussed specifically included (1) epilepsy in the developing brain; (2) novel targets for innovative diagnostics and treatment of epilepsy; (3) what is required for prevention and cure of epilepsy; and (4) epilepsy and comorbidities, with a special focus on aging and mental health. This report provides a summary of recommendations that emerged at ERF2013 about how to (1) strengthen epilepsy research, (2) reduce the treatment gap, and (3) reduce the burden and stigma associated with epilepsy.
Half of the 6 million European citizens with epilepsy feel stigmatized and experience social exclusion, stressing the need for funding trans-European awareness campaigns and monitoring their impact on stigma, in line with the global commitment of the European Commission and with the recommendations made in the 2011 Written Declaration on Epilepsy. Epilepsy care has high rates of misdiagnosis and considerable variability in organization and quality across European countries, translating into huge societal cost (0.2% GDP) and stressing the need for cost-effective programs of harmonization and optimization of epilepsy care throughout Europe. There is currently no cure or prevention for epilepsy, and 30% of affected persons are not controlled by current treatments, stressing the need for pursuing research efforts in the field within Horizon 2020. Priorities should include (1) development of innovative biomarkers and therapeutic targets and strategies, from gene and cell-based therapies to technologically advanced surgical treatment; (2) addressing issues raised by pediatric and aging populations, as well as by specific etiologies and comorbidities such as traumatic brain injury (TBI) and cognitive dysfunction, toward more personalized medicine and prevention; and (3) translational studies and clinical trials built upon well-established European consortia.
Studies using quantitative neuroimaging have shown subtle abnormalities in patients with idiopathic generalized epilepsy (IGE). These findings have several locations, but the midline parasagittal structures are most commonly implicated. The cingulate cortex is related and may be involved. The objective of the current investigation was to perform a comprehensive analysis of the cingulate cortex using multiple quantitative structural neuroimaging techniques.Methods
Thirty-two patients (18 women, 30 ± 10 years) and 36 controls (18 women, 32 ± 11 years) were imaged by 3 Tesla magnetic resonance imaging (MRI). A volumetric three-dimensional (3D) sequence was acquired and used for this investigation. Regions-of-interest were selected and voxel-based morphometry (VBM) analyses compared the cingulate cortex of the two groups using Statistical Parametric Mapping (SPM8) and VBM8 software. Cortical analyses of the cingulate gyrus was performed using Freesurfer. Images were submitted to automatic processing using built-in routines and recommendations. Structural parameters were extracted for individual analyses, and comparisons between groups were restricted to the cingulate gyrus. Finally, shape analyses was performed on the anterior rostral, anterior caudal, posterior, and isthmus cingulate using spherical harmonic description (SPHARM).Results
VBM analyses of cingulate gyrus showed areas of gray matter atrophy, mainly in the anterior cingulate gyrus (972 mm3) and the isthmus (168 mm3). Individual analyses of the cingulate cortex were similar between patients with IGE and controls. Surface-based comparisons revealed abnormalities located mainly in the posterior cingulate cortex (718.12 mm2). Shape analyses demonstrated a predominance of anterior and posterior cingulate abnormalities.Significance
This study suggests that patients with IGE have structural abnormalities in the cingulate gyrus mainly localized at the anterior and posterior portions. This finding is subtle and variable among patients.
The brain aspartate-glutamate carrier (AGC1) is specifically expressed in neurons, where it transports aspartate from the mitochondria to the cytosol, and plays a role in transfer of nicotinamide adenine dinucleotide (NADH)-reducing equivalents into the mitochondria as a part of the malate-aspartate shuttle. Deficient function of AGC1 underlies an inborn error of metabolism that presents with severe hypotonia, arrested psychomotor development, and seizures from a few months of age. In AGC1 deficiency, there is secondary hypomyelination due to lack of N-acetylaspartate (NAA), which is normally generated by acetylation of aspartate in the neuron and required for fatty acid synthesis by the adjacent oligodendrocyte. Based on experiences from AGC2 deficiency, we predicted that reduced glycolysis should compensate for the metabolic defect and allow resumed myelination in AGC1 deficiency. Carbohydrate restriction was therefore initiated in a patient with AGC1 deficiency at 6 years of age by introducing a ketogenic diet. The response was dramatic, clinically as well as radiologically. Psychomotor development showed clear improvement, and magnetic resonance imaging (MRI) indicated resumed myelination. This is the first successful treatment of secondary hypomyelination reported. Because AGC1 is driven by the proton gradient generated by the neuronal mitochondrial respiratory chain, the results have potential relevance for secondary hypomyelination in general.
Question: A patient who is a commercial truck driver has a long history of snoring and daytime sleepiness. His physical exam was remarkable for obesity, prominent extremities, a large tongue,...
The photoparoxysmal response (PPR) involves rapid spread of epileptic activity from visual to parietal and frontal areas. We used a transcranial magnetic stimulation (TMS) technique to assess the physiologic connections between primary visual (V1) and motor (M1) areas in patients with idiopathic generalized epilepsy (IGE). We hypothesized that in PPR-positive patients, M1 would respond excessively to inputs from V1.Methods
Eleven photosensitive patients with IGE who had a PPR at the time of the study were compared with 10 similar patients without a PPR, and with 11 healthy subjects of similar age and sex. The connection between V1 and M1 was assessed in resting participants by delivering a conditioning stimulus (CS) over the phosphene hotspot of the visual cortex (intensity 90% phosphene threshold, PT) followed at random interstimulus intervals (ISIs; 15, 18, 21, 24, 27, 30, 35 and 40 msec) by a test stimulus (TS) over the left motor cortex to elicit a motor evoked potential (MEP) of ~1 mV from the right first dorsal interosseous muscle.Results
In healthy subjects, a CS over V1 suppressed M1 at ISIs between 18 and 40 msec. Similar effects occurred in IGE patients without a PPR. This was not true in PPR-positive IGE patients, in whom this type of physiologic inhibition was significantly (p < 0.05) reduced.Significance
IGE patients with a PPR have an overactive functional response of M1 to inputs traveling from V1. This may represent one core factor for the anterior spread of the PPR itself and for the origin of the abnormal epileptic motor phenomenon, such as myoclonus.
N-methyl-D-aspartate receptor NR2B Subunit Involved in Promoting Depression-like Behaviours in Lithium Chloride-Pilocarpine Chronic Rat Epilepsy Model
The assessment of neural networks in epilepsy has become increasingly relevant in the context of translational research, given that localized forms of epilepsy are more likely to be related to abnormal function within specific brain networks, as opposed to isolated focal brain pathology. It is notable that variability in clinical outcomes from epilepsy treatment may be a reflection of individual patterns of network abnormalities. As such, network endophenotypes may be important biomarkers for the diagnosis and treatment of epilepsy. Despite its exceptional potential, measuring abnormal networks in translational research has been thus far constrained by methodologic limitations. Fortunately, recent advancements in neuroscience, particularly in the field of connectomics, permit a detailed assessment of network organization, dynamics, and function at an individual level. Data from the personal connectome can be assessed using principled forms of network analyses based on graph theory, which may disclose patterns of organization that are prone to abnormal dynamics and epileptogenesis. Although the field of connectomics is relatively new, there is already a rapidly growing body of evidence to suggest that it can elucidate several important and fundamental aspects of abnormal networks to epilepsy. In this article, we provide a review of the emerging evidence from connectomics research regarding neural network architecture, dynamics, and function related to epilepsy. We discuss how connectomics may bring together pathophysiologic hypotheses from conceptual and basic models of epilepsy and in vivo biomarkers for clinical translational research. By providing neural network information unique to each individual, the field of connectomics may help to elucidate variability in clinical outcomes and open opportunities for personalized medicine approaches to epilepsy. Connectomics involves complex and rich data from each subject, thus collaborative efforts to enable the systematic and rigorous evaluation of this form of “big data” are paramount to leverage the full potential of this new approach.
The aim of our study was to evaluate the role of auras in preventing motor vehicle accidents (MVAs) among patients with medically refractory epilepsy. The Multicenter Study of Epilepsy Surgery database was used to perform a case–control study by identifying patients who had seizures while driving that led to MVAs (cases) and those who had seizures while driving without MVAs (controls). We compared presence of reliable auras and other aura-related features between the two groups. Two hundred fifteen of 553 patients reported having seizure(s) while driving; 74 were identified as “controls” and 141 as “cases.” The two groups had similar demographic and clinical features. The presence of reliable auras was not different between the two groups (67% in cases vs. 65% in controls; odds ratio [OR] 0.89, 95% confidence interval [CI] 0.49–1.61, p = 0.76). In addition, the groups did not differ in the proportion of patients who reported longer (>1 min) auras (OR 0.7, 95% CI 0.28–1.76, p = 0.47), or who thought that their auras were of sufficient duration to be protective (OR 1.19, 95% CI 0.62–2.00, p = 0.77). Our study questions the long-held belief of a protective role of reliable auras against MVAs in people with epilepsy.
Tuesday May 26, 2015, will be remembered as an historic day in the fight against epilepsy. On that date, the World Health Assembly approved unanimously the Resolution on the “Global Burden of Epilepsy and the Need for Coordinated Action at the Country Level to Address its Health, Social and Public Knowledge Implications,” which urges Member States to implement a coordinated action against epilepsy and its consequences. This event, which comes almost 20 years after the establishment of the Global Campaign against Epilepsy, is another landmark in the longstanding collaboration among the World Health Organization (WHO), the International League Against Epilepsy (ILAE), and the International Bureau for Epilepsy (IBE) in addressing the needs of people with epilepsy. It also acted as a catalyst for other professional societies, including the World Federation of Neurology (WFN), to join forces in promoting a common action against epilepsy. The Resolution did not happen by chance, but came at the end of a long journey that involved the hard and tireless work of many dedicated individuals around the globe.
Illness perceptions mediate the relationship between depression and quality of life in patients with epilepsy
The current study examined whether negative illness perceptions help explain the link between depression and quality of life. Seventy patients with epilepsy completed standardized self-report questionnaires measuring depression, illness perception, and quality of life (QOL). Illness perception statistically mediated the relationship between depression and QOL (Indirect effect (CI; confidence interval) = −.72, lower limit = −1.7, upper limit = −.22, p < .05). Results held with and without adjusting for potential confounding variables (age, sex, ethnicity, income, and seizure frequency) and when operationalizing depression as a continuous variable that indexed severity of symptoms or as a dichotomous variable that indexed criteria consistent with a diagnosis of major depressive disorder. This study is the first to suggest that illness perceptions may be a useful target in screening and intervention approaches in order to improve QOL among low-income, racially/ethnically diverse patients with epilepsy.
Near-transfer effects following working memory intervention (Cogmed) in children with symptomatic epilepsy: An open randomized clinical trial
Limited research exists regarding the effectiveness of educational and psychological interventions for improving commonly presenting cognitive impairments experienced by children with epilepsy. We evaluated the efficacy of a commercially available, computerized, working memory (WM) program (Cogmed) using a well-defined population of children with epilepsy.Methods
In this controlled trial, 77 children with symptomatic epilepsy (ages 6.5–15.5 years; 100% taking medication) with estimated intellectual ability greater than the 2nd percentile were randomly assigned to an intervention (n = 42) or waitlist-control (n = 35) group. Standardized assessments of attention and WM were administered pre- and posttraining or waitlist interval, 7 weeks apart.Results
Without intervention, participants displayed significant weaknesses in intelligence, attention, and WM compared to normative samples. After controlling for preintervention scores and intelligence, we found that significant treatment effects for the intervention group were evident for visual attention span, auditory WM, and visual-verbal WM. Intention-to-treat analyses (all participants) and sensitivity analyses (n = 37 and n = 21 for the intervention and waitlist-control groups, respectively) were highly similar, providing confidence to the results. Effect sizes for significant outcomes were large (greater than or equal to two thirds of the standard deviation of the normative-data). The clinical/demographic and functional factors studied did not elucidate who most benefits from training.Significance
This is the first study to evaluate the effectiveness of intervention to ameliorate WM deficits commonly experienced by children with symptomatic epilepsy. Results support group improvement on some untrained tasks immediately postintervention, demonstrating preliminary usefulness of Cogmed as a treatment option.