Enhanced long-term potentiation in mature rats in a model of epileptic spasms with betamethasone-priming and postnatal N-methyl-d-aspartate administration
Patients with epileptic spasms are at high risk for learning and memory impairment later in life. We examined whether synaptic plasticity is affected in the adult hippocampus, a structure responsible for learning and memory, using an animal model of epileptic spasms of unknown cause.Methods
We produced a rat model of N-methyl-d-aspartate (NMDA)–induced spasms combined with prenatal betamethasone administration. In 6- to 11-week-old rats, we evaluated the long-term potentiation (LTP) and general properties of synaptic transmission in pyramidal neurons in the CA1 area of the hippocampus in brain slices.Results
The magnitude of LTP by theta burst stimulation was significantly larger in adult rats with a history of infantile NMDA injections than in control rats and rats that received additional adrenocorticotropic hormone (ACTH) treatment. The frequency of spontaneous excitatory transmission, but not inhibitory transmission, was smaller in adult rats with a history of infantile NMDA injections.Significance
This study is the first to provide a basis for the alteration of synaptic plasticity and transmission in a model of epileptic spasms of unknown cause. Postnatal NMDA treatment causing epileptic spasms–like aberrant episodes in the early stage of life in rats has a latent influence on various forms of synaptic plasticity in the hippocampus. Our results provide a novel insight into cognitive impairment that appears later in life in patients with a history of epileptic spasms.
Environmental exposures impart powerful effects on vulnerability to many brain diseases, including epilepsy. Mesial temporal lobe epilepsy (MTLE) is a common form of epilepsy, and it is often accompanied by neuropsychiatric comorbidities. This study tests the hypothesis that environmental enrichment (EE) confers antiepileptogenic, psychoprotective, and neuroprotective effects in the amygdala kindling model of MTLE, and explores potential neurobiologic mechanisms.Methods
At weaning, male Wistar rats were allocated into either EE (large cages containing running wheels and toys; n = 43) or standard housing (SH; standard laboratory cages; n = 39) conditions. At P56, a bipolar electrode was implanted into the left amygdala, and rats underwent rapid amygdala kindling until experiencing five class V seizures (Racine scale, fully kindled). The elevated plus maze was used to assess anxiety. Postmortem histologic and molecular analyses investigated potential biologic mediators of effects.Results
EE significantly delayed kindling epileptogenesis, with EE rats requiring a significantly greater number of kindling stimulations to reach a fully kindled state compared to SH rats (p < 0.05). EE and kindling both reduced anxiety (p < 0.05). Timm's staining revealed significant reductions in aberrant mossy fiber sprouting in EE rats (p < 0.05), and these effects of EE were accompanied by reduced expression of TrkB and CRH genes.Significance
We identify beneficial effects of EE on vulnerability to limbic epileptogenesis and anxiety, and identify reduced pathologic neuroplasticity and plasticity-related gene expression as potential underlying mechanisms. Enhanced environmental stimulation represents a potential antiepileptogenic strategy that might also mitigate the common psychiatric comorbidities of MTLE.
Mutations in NPRL3, one of three genes that encode proteins of the mTORC1-regulating GATOR1 complex, have recently been reported to cause cortical dysplasia with focal epilepsy. We have now analyzed a multiplex epilepsy family by whole exome sequencing and identified a frameshift mutation (NM_001077350.2; c.1522delG; p.E508Rfs*46) within exon 13 of NPRL3. This truncating mutation causes an epilepsy phenotype characterized by early childhood onset of mainly nocturnal frontal lobe epilepsy. The penetrance in our family was low (three affected out of six mutation carriers), compared to families with either ion channel- or DEPDC5-associated familial nocturnal frontal lobe epilepsy. The absence of apparent structural brain abnormalities suggests that mutations in NPRL3 are not necessarily associated with focal cortical dysplasia but might be able to cause epilepsy by different, yet unknown pathomechanisms.
The influence of socioeconomic status on health resource utilization in pediatric epilepsy in a universal health insurance system
It is unknown if there is a disparity in health resource utilization (HRU) among children with epilepsy in a universal health insurance system. The aims of this study were to evaluate whether socioeconomic status (SES) influenced the pattern of HRU among children with epilepsy, and to determine if neurology visits were associated with emergency department (ED) visits and hospitalizations.Methods
Health administrative databases were used to identify HRU among children with epilepsy in Ontario, Canada. The frequency of neurology visits, ED visits, and hospitalizations were assessed for 1 year. SES was measured using dissemination area income and deprivation index. The association between SES and HRU was evaluated, adjusting for age, sex, residence, and comorbidities. Subsequently, we assessed whether neurology visits influenced ED visits and hospitalizations, adjusting for age, sex, residence, comorbidities, and SES.Results
Deprivation index was a more sensitive measure of disparity in HRU than dissemination area income. Status epilepticus–related ED visits and hospitalizations were most expensive but accounted for a small proportion of total costs. Higher deprivation was associated with fewer neurology visits (relative risk [RR] 0.85–0.89), more frequent ED visits (RR 1.08–1.36), and hospitalizations (RR 1.27). Increased neurology visits were associated with more frequent ED visits (RR 1.10) and hospitalizations (RR 1.15). The associations between neurology visits and ED visits as well as hospitalizations varied by deprivation index, in that neurology visits were associated with increased ED visits and hospitalizations and the increase was higher in the most deprived relative to the least deprived (all p < 0.0001).Significance
We found disparity in HRU by SES despite the universal health insurance system. More frequent neurology visits were associated with more frequent ED visits and hospitalizations after adjusting for SES, probably related to epilepsy severity. Our study identified an at-risk population for high resource use that may require additional support to reduce ED visits and hospitalizations.
To assess the diagnostic yield of 7T magnetic resonance imaging (MRI) in detecting and characterizing structural lesions in patients with intractable focal epilepsy and unrevealing conventional (1.5 or 3T) MRI.Methods
We conducted an observational clinical imaging study on 21 patients (17 adults and 4 children) with intractable focal epilepsy, exhibiting clinical and electroencephalographic features consistent with a single seizure-onset zone (SOZ) and unrevealing conventional MRI. Patients were enrolled at two tertiary epilepsy surgery centers and imaged at 7T, including whole brain (three-dimensional [3D] T1-weighted [T1W] fast-spoiled gradient echo (FSPGR), 3D susceptibility-weighted angiography [SWAN], 3D fluid-attenuated inversion recovery [FLAIR]) and targeted imaging (2D T2*-weighted dual-echo gradient-recalled echo [GRE] and 2D gray–white matter tissue border enhancement [TBE] fast spin echo inversion recovery [FSE-IR]). MRI studies at 1.5 or 3T deemed unrevealing at the referral center were reviewed by three experts in epilepsy imaging. Reviewers were provided information regarding the suspected localization of the SOZ. The same team subsequently reviewed 7T images. Agreement in imaging interpretation was reached through consensus-based discussions based on visual identification of structural abnormalities and their likely correlation with clinical and electrographic data.Results
7T MRI revealed structural lesions in 6 (29%) of 21 patients. The diagnostic gain in detection was obtained using GRE and FLAIR images. Four of the six patients with abnormal 7T underwent epilepsy surgery. Histopathology revealed focal cortical dysplasia (FCD) in all. In the remaining 15 patients (71%), 7T MRI remained unrevealing; 4 of the patients underwent epilepsy surgery and histopathologic evaluation revealed gliosis.Significance
7T MRI improves detection of epileptogenic FCD that is not visible at conventional field strengths. A dedicated protocol including whole brain FLAIR and GRE images at 7T targeted at the suspected SOZ increases the diagnostic yield.
PET hypermetabolism in medically resistant childhood epilepsy: Incidence, associations, and surgical outcome
We observed several children with medically resistant epilepsy demonstrating focal positron emission tomography (PET) hypermetabolism, a finding rarely reported and of questionable significance. We therefore retrospectively reviewed the incidence of hypermetabolic PET, and its relationship to electroencephalography (EEG) and magnetic resonance imaging (MRI) findings, and to the outcome of epilepsy surgery.Methods
We retrospectively reviewed 498 PET brain studies in patients with medically resistant childhood epilepsy for evidence of hypermetabolism. In patients with PET hypermetabolism, we correlated metabolic abnormality with the scalp EEG and MRI findings. In a subset of patients who underwent surgical resection, we further correlated the PET findings with histopathologic and surgical outcomes.Results
Focal PET hypermetabolism was identified in 33 (6.6%) of 498 studies. The region of hypermetabolism correlated with a spike count of ≥10 per minute in 26 of 32 concomitant scalp EEG studies and 18 of 21 lesions evident on MRI. In 17 patients who underwent surgical resection, PET hypermetabolism further correlated with regions revealing almost continuous epileptiform discharges on the intracranial EEG and with histopathologically malformative tissue. At a minimum follow-up of 1 year postsurgery (median 33 months), 7 (50%) of 14 patients had Engel's class I outcome, 4 patients had class II, and 2 had class III outcome, whereas one patient was unchanged. At last follow-up, seizure freedom was noted in five of seven patients with focal PET hypermetabolism alone versus three of eight patients with PET hypometabolism.Significance
Focal PET hypermetabolism is associated with high spike frequency on scalp EEG and can occur in the absence of ictal events during the peri-injection period. Correlation with intracranial EEG usually corroborates the highly epileptogenic pathophysiologic state. Cortical malformations constitute the most common pathologic substrate, and resection of the hypermetabolic PET region may facilitate favorable outcomes. These observations indicate that focal PET hypermetabolism is an important marker of the epileptogenic zone and may represent its epicenter.
The term epileptic encephalopathy (EE) denotes a process by which epileptic activity adversely affects brain function over and above the underlying etiology. Underlying mechanisms are poorly understood, but recent studies demonstrate that seizures and interictal epileptiform discharges can disrupt distributed neural networks that underpin cognitive functions, both temporarily and permanently. EE is just one of a number of factors that can affect development in epilepsy. The presence and relative contribution of EE to cognitive impairment is often difficult to separate from that of the underlying etiology or even effects of antiepileptic medication (AEM). This difficulty has led to the increasing use of the term EE to encapsulate “severe” epileptic syndromes, or etiologies associated with severe epilepsy and intellectual disability (ID), regardless of evidence that the epileptic process has impacted cognition. The use of the term EE in the literature to describe both the process of cognitive impairment by epileptic activity and as a category for severe epilepsy syndromes is creating confusion. We propose that use of the term EE be restricted to the central concept of a pervasive epileptic process disrupting development, and that the use of EE as a classifier be avoided. A different term is needed to encapsulate the broad and heterogenous group of patients with severe epilepsy and ID, for which the mechanisms may be unknown but are often closely related to the underlying genetic, metabolic, or structural etiology. An improved understanding of the mechanisms by which EE develops is of critical importance, potentially leading to identification of biomarkers for early detection and treatment.
Abnormal network topology in polymicrogyric cortex may predispose to seizures via abnormal network topology: An fMRI connectomics study
Polymicrogyria is a significant malformation of cortical development with a high incidence of epilepsy and cognitive deficits. Graph theoretic analysis is a useful approach to studying network organization in brain disorders. In this study, we used task-free functional magnetic resonance imaging (fMRI) data from four patients with polymicrogyria and refractory epilepsy. Gray matter masks from structural MRI data were parcellated into 1,024 network nodes. Functional “connectomes” were obtained based on fMRI time series between the parcellated network nodes; network analysis was conducted using clustering coefficient, path length, node degree, and participation coefficient. These graph metrics were compared between nodes within polymicrogyric cortex and normal brain tissue in contralateral homologous cortical regions. Polymicrogyric nodes showed significantly increased clustering coefficient and characteristic path length. This is the first study using functional connectivity analysis in polymicrogyria—our results indicate a shift toward a regular network topology in polymicrogyric nodes. Regularized network topology has been demonstrated previously in patients with focal epilepsy and during focal seizures. Thus, we postulate that these network alterations predispose to seizures and may be relevant to cognitive deficits in patients with polymicrogyria.
Postictal immobility and generalized EEG suppression are associated with the severity of respiratory dysfunction
The pathophysiology of sudden unexpected death in epilepsy (SUDEP) remains undetermined. Seizures are accompanied by respiratory dysfunction (RD). Postictal generalized electroencephalography (EEG) suppression (PGES) may follow generalized tonic–clonic seizures (GTCS). Following GTCS patients have impaired arousal and may be motionless. Patients with SUDEP are usually prone. Postictal immobility (PI) may contribute to SUDEP by not permitting repositioning of the head to allow unimpeded ventilation. To determine whether RD and/or ictal characteristics are associated with PI, we analyzed patients with GTCS in the epilepsy monitoring unit.Method
We investigated for associations between PI duration and PGES, ictal/postictal oxygen saturation (SpO2), end-tidal CO2 (ETCO2), seizure localization, duration, and tonic and total convulsive phase duration. We investigated for linkage between PGES and these measures.Results
Seventy patients with 181 GTCS and available SpO2 and/or ETCO2 data were studied. Simple linear regression analysis by seizures showed that PI duration was associated with peak periictal ETCO2 (p = 0.03), duration of oxygen desaturation (p = 0.005) and with SpO2 nadir (p = 0.02). PI duration was not associated with tonic, convulsive phase or total seizure duration. Analysis by patients also showed significant association of PI with RD. Duration of PI was longer following seizures with PGES (p < 0.001). PGES was not associated with the tonic, convulsive phase or total seizure duration. SpO2 nadir was lower in seizures with PGES (p = 0.046), ETCO2 peak change (p = 0.003) was higher, and duration of ETCO2 elevation (p = 0.03) was longer. Multivariable regression analysis showed that PGES and severe RD were associated with PI duration.Significance
The duration of PI and presence of PGES are associated with periictal RD. The duration of PI is also associated with the presence of PGES. Seizure duration or duration of the convulsive phase is not associated with PI or PGES. Interventions aimed at reversing impaired arousal and PI may reduce SUDEP risk.
What factors contribute to the risk of depression in epilepsy?—Tasmanian Epilepsy Register Mood Study (TERMS)
To model the factors associated with depression in a community sample of people with epilepsy. The factors investigated were derived from proposed risk factors for depression from patients with epilepsy, other chronic illness, and the general population.Methods
Multivariate analysis using general linear regression models of factors associated with depression in the Tasmanian Epilepsy Register Mood Study (TERMS), a cross-sectional community sample of 440 patients with epilepsy.Results
A model with acceptable fit was created that explained 66% of the variance of depression. Associated factors included in this model were neuroticism, physical functioning, social support, past history of depression, and stressful life events.Significance
In this cross-sectional study designed specifically to investigate depression in epilepsy, we showed that general risk factors for depression in other illness and in the general population are also important in patients with epilepsy, with little support for disease-related risk factors.
PCDH19 gene mutations have been recently associated with an epileptic syndrome characterized by focal and generalized seizures. The PCDH19 gene (Xq22.1) has an unusual X-linked inheritance with a selective involvement for female subjects. A cellular interference mechanism has been hypothesized and male patients can manifest epilepsy only in the case of a mosaicism. So far about 100 female patients, and only one symptomatic male have been described. Using targeted next generation sequencing (NGS) approach we found a PCDH19 point mutation in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. The system allowed us to verify that the two c.1352 C>T; p.(Pro451Leu) and c.918C>G; p.(Tyr306*) variants occurred in mosaic status. Mutations were confirmed by Sanger sequencing and quantified by real-time polymerase chain reaction (PCR). Up to now, the traditional molecular screening for PCDH19-related epilepsy has been targeted to all females with early onset epilepsy with or without cognitive impairment. Male patients were generally excluded. We describe for the first time two mosaic PCDH19 point mutations in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. This finding opens new opportunities for the molecular diagnoses in patients with a peculiar type of epilepsy that remains undiagnosed in male patients.
Health and economic benefits of public financing of epilepsy treatment in India: An agent-based simulation model
An estimated 6–10 million people in India live with active epilepsy, and less than half are treated. We analyze the health and economic benefits of three scenarios of publicly financed national epilepsy programs that provide: (1) first-line antiepilepsy drugs (AEDs), (2) first- and second-line AEDs, and (3) first- and second-line AEDs and surgery.Methods
We model the prevalence and distribution of epilepsy in India using IndiaSim, an agent-based, simulation model of the Indian population. Agents in the model are disease-free or in one of three disease states: untreated with seizures, treated with seizures, and treated without seizures. Outcome measures include the proportion of the population that has epilepsy and is untreated, disability-adjusted life years (DALYs) averted, and cost per DALY averted. Economic benefit measures estimated include out-of-pocket (OOP) expenditure averted and money-metric value of insurance.Results
All three scenarios represent a cost-effective use of resources and would avert 800,000–1 million DALYs per year in India relative to the current scenario. However, especially in poor regions and populations, scenario 1 (which publicly finances only first-line therapy) does not decrease the OOP expenditure or provide financial risk protection if we include care-seeking costs. The OOP expenditure averted increases from scenarios 1 through 3, and the money-metric value of insurance follows a similar trend between scenarios and typically decreases with wealth. In the first 10 years of scenarios 2 and 3, households avert on average over US$80 million per year in medical expenditure.Significance
Expanding and publicly financing epilepsy treatment in India averts substantial disease burden. A universal public finance policy that covers only first-line AEDs may not provide significant financial risk protection. Covering costs for both first- and second-line therapy and other medical costs alleviates the financial burden from epilepsy and is cost-effective across wealth quintiles and in all Indian states.
Long-term safety and seizure outcome in Japanese patients with Lennox–Gastaut syndrome receiving adjunctive rufinamide therapy: an open-label study following a randomized clinical trial
Measurement equivalence of the newly developed Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55)
The aim of this study was to examine measurement equivalence of the newly developed Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) across age, sex, and time in a representative sample of children with newly diagnosed epilepsy.Methods
Data come from 373 children enrolled in the Health-related Quality of Life in Children with Epilepsy Study (HERQULES), a multisite prospective cohort study. Measurement equivalence was examined using a multiple-group confirmatory factor analysis framework, whereby increasingly stringent parameter constraints are imposed on the model. Comparison groups were stratified based on age (4–7 years vs. 8–12 years), sex (male vs. female), and time (measurement of health-related quality of life at diagnosis vs. 24 months later).Results
The QOLCE-55 demonstrated measurement equivalence at the level of strict invariance for each model tested—age: χ2 (3,123) = 4,097.3, p < 0.001; Comparative Fit Index (CFI) = 0.968; Root Mean Square Error of Approximation (RMSEA) = 0.042 (0.038, 0.045); sex: χ2 (3,124) = 4,188.3, p < 0.001; CFI = 0.964; RMSEA = 0.044 (0.040, 0.047); and time: χ2 (3,121) = 5,185.0, p < 0.001; CFI = 0.965; RMSEA = 0.046 (0.043, 0.048).Significance
These findings suggest that items comprising the QOLCE-55 are perceived similarly among groups stratified by age, sex, and time and provide further evidence supporting the validity of the scale in children with epilepsy. Health professionals and researchers should be confident that group comparisons made using the QOLCE-55 are unbiased and that any group differences detected are meaningful; that is, not related to differences in the interpretation of items by informants. Future research replicating these findings is encouraged.