Do vaccines cause epilepsy? Review of cases in the National Vaccine Injury Compensation Program.

OBJECTIVE: The National Childhood Vaccine Injury Act of 1986 created the National Vaccine Injury Compensation Program (VICP), a no-fault alternative to the traditional tort system. Since 1988, the total compensation paid exceeds $5 billion. Although epilepsy is one of the leading reasons for filing a claim, there has been no review of the process and validity of the legal outcomes given current medical information. The objectives were to review the evolution of the VICP program in regard to vaccine-related epilepsy and assess the rationale behind decisions made by the court. METHODS: Publicly available cases involving epilepsy claims in the VICP were searched through Westlaw and the US Court of Federal Claims websites. All published reports were reviewed for petitioner's theories supporting vaccine-induced epilepsy, respondent's counterarguments, the final decision regarding compensation, and the rationale underlying these decisions. The primary goal was to determine which factors went into decisions regarding whether vaccines caused epilepsy. RESULTS: Since the first epilepsy case in 1989, there have been many changes in the program, including the removal of residual seizure disorder as a vaccine-related injury, publication of the Althen prongs, release of the acellular form of pertussis, and recognition that in genetic conditions the underlying genetic abnormality rather than the immunization causes epilepsy. We identified 532 unique cases with epilepsy: 105 with infantile spasms and 427 with epilepsy without infantile spasms. The petitioners' experts often espoused outdated, erroneous causation theories that lacked an acceptable medical or scientific foundation and were frequently criticized by the court. SIGNIFICANCE: Despite the lack of epidemiological or mechanistic evidence indicating that childhood vaccines covered by the VICP result in or aggravate epilepsy, these cases continue to be adjudicated. After 35 years of intense litigation, it is time to reconsider whether epilepsy should continue to be a compensable vaccine-induced injury.

Sex differences in cholinergic signaling affect functional outcomes for theta-gamma coordination in hippocampal subcircuits following experimental febrile status epilepticus.

OBJECTIVE: Sex determines cognitive outcome in animal models of early life seizure, where males exhibit impaired hippocampal-dependent learning and memory compared with females. The physiological underpinnings of this sex effect are unclear. Cholinergic signaling is essential for the generation of hippocampal oscillations, and supplementation of cholinergic precursors prior to status epilepticus in immature male rats prevents subsequent memory deficits. We hypothesized that there are sex differences in acetylcholine circuits and their response to experimental febrile status epilepticus (eFSE). METHODS: eFSE was induced in male and female rat pups. We transversed the hippocampus of postnatal day >60 control (CTL) and eFSE rats with a 64-channel laminar silicon probe to assay cholinergic-dependent theta oscillations under urethane anesthesia. Local field potential properties were compared during (1) baseline sensory stimulation, (2) pharmacological stimulation via acetylcholine reuptake blockade, and (3) sensory stimulation after muscarinic acetylcholine receptor block (atropine). RESULTS: In all groups, a baseline tail pinch could elicit theta oscillations via corticohippocampal synaptic input. Following atropine, a tail pinch response could no longer be elicited in CTL male, CTL female, or eFSE female rats. In contrast, induced slow theta power in eFSE males after atropine was not decreased to spontaneous levels. Analysis of oscillation bandwidths revealed sex differences in acetylcholine modulation of theta frequency and slow gamma frequency and power. This study also identified significant effects of both sex and eFSE on baseline theta-gamma comodulation, indicating a loss of coupling in eFSE males and a potential gain of function in eFSE females. SIGNIFICANCE: There are differences in cholinergic modulation of theta and gamma signal coordination between male and female rats. These differences may underlie worse cognitive outcomes in males following eFSE. Promoting the efficacy of muscarinic acetylcholine signaling prior to or following early life seizures could elucidate a mechanism for the temporal discoordination of neural signals within and between hippocampus and neocortex and provide a novel therapeutic approach for improving cognitive outcomes.

CBD treatment following early life seizures alters orbitofrontal-striatal signaling during adulthood.

Obsessive compulsive disorder (OCD) is a comorbid condition of epilepsy and often adds to the burden of epilepsy. Both OCD and epilepsy are disorders of hyperexcitable circuits. Fronto-striatal circuit dysfunction is implicated in OCD. Prior work in our laboratory has shown that in rat pups following a series of flurothyl-induced early life seizures (ELS) exhibit frontal-lobe dysfunction along with alterations in electrographic temporal coordination between the orbitofrontal cortex (OFC) and dorsomedial striatum (DMS), circuits implicated in OCD. Here, we studied the effects of ELS in male and female rat pups on OCD-like behaviors as adults using the marble burying test (MBT). Because cannabidiol (CBD) is an effective antiseizure medication and has shown efficacy in the treatment of individuals with OCD, we also randomized rats to CBD or vehicle treatment following ELS to determine if CBD had any effect on OCD-like behaviors. While the flurothyl model of ELS did not induce OCD-like behaviors, as measured in the MBT, ELS did alter neural signaling in structures implicated in OCD and CBD had sex-dependent effects of temporal coordination in a way which suggests it may have a beneficial effect on epilepsy-related OCD.

Optogenetic modulation of hippocampal oscillations ameliorates spatial cognition and hippocampal dysrhythmia following early-life seizures.

There is increasing human and animal evidence that brain oscillations play a critical role in the development of spatial cognition. In rat pups, disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition. Early-life seizures are associated with long-term deficits in spatial cognition and aberrant hippocampal oscillatory activity. Here we asked whether modulation of hippocampal rhythms following early-life seizures can reverse or improve hippocampal connectivity and spatial cognition. We used optogenetic stimulation of the medial septum to induce physiological 7 Hz theta oscillations in the hippocampus during the critical period of spatial cognition following early-life seizures. Optogenetic stimulation of the medial septum in control and rats subjected to early-life seizures resulted in precisely regulated frequency-matched hippocampal oscillations. Rat pups receiving active blue light stimulation performed better than the rats receiving inert yellow light in a test of spatial cognition. The improvement in spatial cognition in these rats was associated with a faster theta frequency and higher theta power, coherence and phase locking value in the hippocampus than rats with early-life seizures receiving inert yellow light. These findings indicate that following early life seizures, modification of hippocampal rhythms may be a potential novel therapeutic modality.

Spatial learning impairments and discoordination of entorhinal-hippocampal circuit coding following prolonged febrile seizures.

How the development and function of neural circuits governing learning and memory are affected by insults in early life remains poorly understood. The goal of this study was to identify putative changes in cortico-hippocampal signaling mechanisms that could lead to learning and memory deficits in a clinically relevant developmental pathophysiological rodent model, Febrile status epilepticus (FSE). FSE in both pediatric cases and the experimental animal model, is associated with enduring physiological alterations of the hippocampal circuit and cognitive impairment. Here, we deconstruct hippocampal circuit throughput by inducing slow theta oscillations in rats under urethane anesthesia and isolating the dendritic compartments of CA1 and dentate gyrus subfields, their reception of medial and lateral entorhinal cortex inputs, and the efficacy of signal propagation to each somatic cell layer. We identify FSE-induced theta-gamma decoupling at cortical synaptic input pathways and altered signal phase coherence along the CA1 and dentate gyrus somatodendritic axes. Moreover, increased DG synaptic activity levels are predictive of poor cognitive outcomes. We propose that these alterations in cortico-hippocampal coordination interfere with the ability of hippocampal dendrites to receive, decode and propagate neocortical inputs. If this frequency-specific syntax is necessary for cortico-hippocampal coordination and spatial learning and memory, its loss could be a mechanism for FSE cognitive comorbidities.

Early-life seizures alter habit behavior formation and fronto-striatal circuit dynamics.

Obsessive compulsive disorder (OCD) can occur comorbidly with epilepsy; both are complex, disruptive disorders that lower quality of life. Both OCD and epilepsy are disorders of hyperexcitable circuits, but it is unclear whether common circuit pathology may underlie the co-occurrence of these two neuropsychiatric disorders. Here, we induced early-life seizures (ELS) in rats to examine habit formation as a model for compulsive behaviors. Compulsive, repetitive behaviors in OCD utilize the same circuitry as habit formation. We hypothesized that rats with ELS could be more susceptible to habit formation than littermate controls, and that altered behavior would correspond to altered signaling in fronto-striatal circuits that underlie decision-making and action initiation. Here, we show instead that rats with ELS were significantly less likely to form habit behaviors compared with control rats. This behavioral difference corresponded with significant alterations to temporal coordination within and between brain regions that underpin the action to habit transition: 1) phase coherence between the lateral orbitofrontal cortex and dorsomedial striatum (DMS) and 2) theta-gamma coupling within DMS. Finally, we used cortical electrical stimulation as a model of transcranial magnetic stimulation (TMS) to show that temporal coordination of fronto-striatal circuits in control and ELS rats are differentially susceptible to potentiating and suppressive stimulation, suggesting that altered underlying circuit physiology may lead to altered response to therapeutic interventions such as TMS.

Cognitive impairment following experimental febrile seizures is determined by sex and seizure duration.

BACKGROUND: Febrile seizures are the most common type of seizures in children. While in most children the outcome is favorable, children with febrile status epilepticus may exhibit modest cognitive impairment. Whether children with other forms of complex febrile seizure, such as repetitive febrile seizures within the same illness are at risk of cognitive deficits is not known. In this study, we used a well-established model of experimental febrile seizures in rat pups to compare the effects of febrile status epilepticus and recurrent febrile seizures on subsequent spatial cognition and anxiety. METHODS: Male and female rat pups were subjected to hyperthermic seizures at postnatal day 10 and were divided into groups of rats with continuous seizures for ≥40 min or recurrent febrile seizures. They were then tested as adults in the active avoidance and spatial accuracy tests to assess spatial learning and memory and the elevated plus maze to measure anxiety. RESULTS: Febrile status epilepticus rats demonstrated impaired spatial cognition in active avoidance and spatial accuracy and exhibited reduced anxiety-like behavior in the elevated plus maze. Rats with recurrent febrile seizures did not differ significantly from the controls on any measures. There were also significant sex-related differences with females with FSE performing far better than males with FSE in active avoidance but demonstrating a navigational learning impairment relative to CTL females in spatial accuracy. However, once learned, females with FSE performed the spatial accuracy task as well as CTL females. CONCLUSION: There is a duration-dependent effect of febrile seizures on subsequent cognitive and behavioral outcomes. Febrile status epilepticus resulted in spatial cognitive deficits and reduced anxiety-related behaviors whereas rats with recurrent febrile seizures did not differ from controls. Sex had a remarkable effect on spatial cognitive outcome where males with FSE fared worse than females with FSE. The results demonstrate that sex should be considered as a biological variable in studies evaluating the effects of seizures on the developing brain.

Effects of early life seizures on coordination of hippocampal-prefrontal networks: Influence of sex and dynamic brain states.

OBJECTIVE: Early life seizures (ELSs) alter activity-dependent maturation of neuronal circuits underlying learning and memory. The pathophysiological mechanisms underpinning seizure-induced cognitive impairment are not fully understood, and critical variables such as sex and dynamic brain states with regard to cognitive outcomes have not been explored. We hypothesized that in comparison to control (CTL) rats, ELS rats would exhibit deficits in spatial cognition correlating with impaired dynamic neural signal coordination between the hippocampus and medial prefrontal cortex (mPFC). METHODS: Male and female rat pups were given 50 flurothyl-induced seizures over 10 days starting at postnatal Day 15. As adults, spatial cognition was tested through active avoidance on a rotating arena. Microwire tetrodes were implanted in the mPFC and CA1 subfield. Single cells and local field potentials were recorded and analyzed in each region during active avoidance and sleep. RESULTS: ELS males exhibited avoidance impairments, whereas female rats were unaffected. During avoidance, hippocampus-mPFC coherence was higher in CTL females than CTL males across bandwidths. In comparison to CTL males, ELS male learners exhibit increased coherence within theta bandwidth as well as altered burst-timing in mPFC cell activity. Hippocampus-mPFC coherence levels are predictive of cognitive outcome in the active avoidance spatial task. SIGNIFICANCE: Spatial cognitive outcome post-ELS is sex-dependent, as females fare better than males. ELS males that learn the task exhibit increased mPFC coherence levels at low-theta frequency, which may compensate for ELS effects on mPFC cell timing. These results suggest that coherence may serve as a biomarker for spatial cognitive outcome post-ELS and emphasize the significance of analyzing sex and dynamic cognition as variables in understanding seizure effects on the developing brain.

Recurrent febrile seizures alter intrahippocampal temporal coordination but do not cause spatial learning impairments.

OBJECTIVE: Febrile seizures (FSs) are the most common form of seizures in children. Single short FSs are benign, but FSs lasting longer than 30 min, termed febrile status epilepticus, may result in neurological sequelae. However, there is little information about an intermediary condition, brief recurrent FSs (RFSs). The goal of this study was to determine the role of RFSs on spatial learning and memory and the properties of spontaneous hippocampal signals. METHODS: A hippocampus-dependent active avoidance task was used to assess spatial learning and memory in adult rats that underwent experimental RFSs (eRFSs) in early life compared with their littermate controls. Following completion of the task, we utilized high-density laminar probes to measure spontaneous hippocampal CA1 circuit activity under urethane anesthesia, which allowed for the simultaneous recording of input regions in CA1 associated with both CA3 and entorhinal cortex. RESULTS: RFSs did not result in deficits in the active avoidance spatial test, a hippocampus-dependent test of spatial learning and memory. However, in vivo high-density laminar electrode recordings from eRFS rats had significantly altered power and frequency expression of theta and gamma bandwidths as well as signaling efficacy along the CA1 somatodendritic axis. Thus, although eRFS modified CA1 neuronal input/output dynamics, these alterations were not sufficient to impair active avoidance spatial behavior. SIGNIFICANCE: These findings indicate that although eRFSs do not result in spatial cognitive deficits in the active avoidance task, recurrent seizures do alter the brain and result in longstanding changes in the temporal organization of the hippocampus.

Electroencephalographic assessment of infant spinal anesthesia: A pilot prospective observational study.

INTRODUCTION: Spinal anesthesia is utilized as an alternative to general anesthesia in infants for some surgeries. After spinal anesthesia, infants often become less conscious without administration of sedative medications. The aim of this study was to assess electroencephalographic (EEG) correlates after spinal anesthesia in a cohort of infants. PATIENTS AND METHODS: This pilot study included 12 infants who underwent spinal anesthesia. Unprocessed electroencephalography was recorded. The electroencephalogram was interpreted by four neurologists. Processed analyses compared electroencephalogram changes 30 min after spinal anesthesia to baseline. RESULTS: Following spinal anesthesia, all 12 infants became sedated. Electroencephalography in all 12 demonstrated Stage 2 sleep with the appearance of sleep spindles (12-14 Hz) in the frontal and central leads in 8/12 (67%) of subjects. The median time to onset of sleep spindles was 24.7 interquartile range (21.2, 29.9) min. The duration of sleep spindles was 25.1 interquartile range (5.8, 99.8) min. Voltage attenuation and background slowing were the most common initial changes. Compared to baseline, the electroencephalogram 30 min after spinal anesthesia showed significantly increased absolute delta power (p = 0.02) and gamma power (p < 0.0001); decreases in beta (p = 0.0006) and higher beta (p < 0.0001) were also observed. The Fast Fourier Transform power ratio difference for delta/beta was increased (p = 0.03). Increased coherence was noted in the delta (p = 0.02) and theta (p = 0.04) bandwidths. DISCUSSION: Spinal anesthesia in infants is associated with increased electroencephalographic slow wave activity and decreased beta activity compared to the awake state, with appearance of sleep spindles suggestive of normal sleep. The etiology and significance of the observed voltage attenuation and background slowing remains unclear. CONCLUSIONS: The EEG signature of infant spinal anesthesia is distinct from that seen with general anesthesia and is consistent with normal sleep. Further investigation is required to better understand the etiology of these findings. Our preliminary findings contribute to the understanding of the brain effects of spinal anesthesia in early development.

Optogenetic "low-theta" pacing of the septohippocampal circuit is sufficient for spatial goal finding and is influenced by behavioral state and cognitive demand.

Hippocampal theta oscillations show prominent changes in frequency and amplitude depending on behavioral state or cognitive demands. How these dynamic changes in theta oscillations contribute to the spatial and temporal organization of hippocampal cells, and ultimately behavior, remain unclear. We used low-theta frequency optogenetic stimulation to pace coordination of cellular and network activity between the medial septum (MS) and hippocampus during baseline and MS stimulation while rats were at rest or performing a spatial accuracy task with a visible or hidden goal zone. Hippocampal receptivity to pan-neuronal septal stimulation at low-theta frequency was primarily determined by speed and secondarily by task demands. Competition between artificial and endogenous field potentials at theta frequency attenuated hippocampal phase preference relative to local theta, but the spike-timing activity of hippocampal pyramidal cells was effectively driven by artificial septal output, particularly during the hidden goal task. Notwithstanding temporal reorganization by artificial theta stimulation, place field properties were unchanged and alterations to spatial behavior were limited to goal zone approximation. Our results indicate that even a low-theta frequency timing signal in the septohippocampal circuit is sufficient for spatial goal finding behavior. The results also advance a mechanistic understanding of how endogenous or artificial somatodendritic timing signals relate to displacement computations during navigation and spatial memory.

Lacosamide in patients with epilepsy of cerebrovascular etiology.

OBJECTIVES: To assess tolerability and efficacy of lacosamide in adults with cerebrovascular epilepsy etiology (CVEE). MATERIALS AND METHODS: Exploratory post hoc analyses of a double-blind, initial monotherapy trial of lacosamide vs carbamazepine-controlled release (carbamazepine-CR) (SP0993; NCT01243177); a double-blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741); and an observational study of adjunctive lacosamide added to one antiepileptic drug (SP0973 VITOBA; NCT01098162). Patients with CVEE were identified based on epilepsy etiology recorded at baseline. RESULTS: In the initial monotherapy trial, 61 patients had CVEE (lacosamide: 27; carbamazepine-CR: 34). 20 (74.1%) patients on lacosamide (27 [79.4%] on carbamazepine-CR) reported treatment-emergent adverse events (TEAEs), most commonly (≥10%) headache, dizziness, and fatigue (carbamazepine-CR: headache, dizziness). A numerically higher proportion of patients on lacosamide than carbamazepine-CR completed 6 months (22 [81.5%]; 20 [58.8%]) and 12 months (18 [66.7%]; 17 [50.0%]) treatment without seizure at last evaluated dose. In the conversion to monotherapy trial, 26/30 (86.7%) patients with CVEE reported TEAEs, most commonly (≥4 patients) dizziness, convulsion, fatigue, headache, somnolence, and cognitive disorder. During lacosamide monotherapy, 17 (56.7%) patients were 50% responders and six (20.0%) were seizure-free. In the observational study, 36/83 (43.4%) patients with CVEE reported TEAEs, most commonly (≥5%) fatigue and dizziness. Effectiveness was assessed for 75 patients. During the last 3 months, 60 (80%) were 50% responders and 42 (56.0%) were seizure-free. CONCLUSIONS: These exploratory post hoc analyses suggested lacosamide was generally well tolerated and effective in patients with CVEE, with data from the initial monotherapy trial suggesting numerically better efficacy than carbamazepine-CR.

Long-term safety and tolerability of adjunctive eslicarbazepine acetate in children with focal seizures.

OBJECTIVE: The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive eslicarbazepine acetate (ESL) in children with focal seizures. METHODS: Safety data from patients aged 4-17 years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1-2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5 years total duration). The OLEs evaluated the safety and tolerability of ESL (10-30 mg/kg/day; maximum 1200 mg/day). RESULTS: The 1-year OLE and post-1-year OLE safety populations comprised 337 and 177 ESL-treated patients, respectively. The overall incidence of treatment-emergent adverse events (TEAEs) with ESL was 64.1% during the 1-year OLE and 52.5% during the post-1-year OLE. Nasopharyngitis, partial seizures, vomiting, pyrexia, headache, somnolence, and respiratory tract infection were the most frequently reported TEAEs during the 1-year OLE. The overall incidence of serious adverse events (AEs) was 8.9% during the 1-year OLE and 10.2% during the post-1-year OLE. Partial seizures (1.2%) and pneumonia (1.2%) were the most frequently reported serious AEs during the 1-year OLE. The overall incidence of TEAEs leading to discontinuation was 4.2% during the 1-year OLE and 0.6% during the post-1-year OLE. Partial seizures (1.5%) was the most frequently reported TEAE leading to discontinuation during the 1-year OLE. CONCLUSIONS: Overall, long-term treatment with ESL was generally well tolerated in pediatric patients aged 4-17 years with focal seizures. TEAEs were comparable to those observed in adults with no new events of concern.

Emergence of Coordinated Activity in the Developing Entorhinal-Hippocampal Network.

Correlated activity in the entorhinal-hippocampal neuronal networks, supported by oscillatory and intermittent population activity patterns is critical for learning and memory. However, when and how correlated activity emerges in these networks during development remains largely unknown. Here, we found that during the first postnatal week in non-anaesthetized head-restrained rats, activity in the superficial layers of the medial entorhinal cortex (MEC) and hippocampus was highly correlated, with intermittent population bursts in the MEC followed by early sharp waves (eSPWs) in the hippocampus. Neurons in the superficial MEC layers fired before neurons in the dentate gyrus, CA3 and CA1. eSPW current-source density profiles indicated that perforant/temporoammonic entorhinal inputs and intrinsic hippocampal connections are co-activated during entorhinal-hippocampal activity bursts. Finally, a majority of the entorhinal-hippocampal bursts were triggered by spontaneous myoclonic body movements, characteristic of the neonatal period. Thus, during the neonatal period, activity in the entorhinal cortex (EC) and hippocampus is highly synchronous, with the EC leading hippocampal activation. We propose that such correlated activity is embedded into a large-scale bottom-up circuit that processes somatosensory feedback resulting from neonatal movements, and that it is likely to instruct the development of connections between neocortex and hippocampus.

Construction and disruption of spatial memory networks during development.

Spatial memory, the aspect of memory involving encoding and retrieval of information regarding one's environment and spatial orientation, is a complex biological function incorporating multiple neuronal networks. Hippocampus-dependent spatial memory is not innate and emerges during development in both humans and rodents. In children, nonhippocampal dependent egocentric (self-to-object) memory develops before hippocampal-dependent allocentric (object-to-object) memory. The onset of allocentric spatial memory abilities in children around 22 mo of age occurs at an age-equivalent time in rodents when spatially tuned grid and place cells arise from patterned activity propagating through the entorhinal-hippocampal circuit. Neuronal activity, often driven by specific sensory signals, is critical for the normal maturation of brain circuits This patterned activity fine-tunes synaptic connectivity of the network and drives the emergence of specific firing necessary for spatial memory. Whereas normal activity patterns are required for circuit maturation, aberrant neuronal activity during development can have major adverse consequences, disrupting the development of spatial memory. Seizures during infancy, involving massive bursts of synchronized network activity, result in impaired spatial memory when animals are tested as adolescents or adults. This impaired spatial memory is accompanied by alterations in spatial and temporal coding of place cells. The molecular mechanisms by which early-life seizures lead to disruptions at the cellular and network levels are now becoming better understood, and provide a target for intervention, potentially leading to improved cognitive outcome in individuals experiencing early-life seizures.

Segregation of seizures and spreading depolarization across cortical layers.

OBJECTIVE: Cortical spreading depolarization (SD) and seizures are often co-occurring electrophysiological phenomena. However, the cross-layer dynamics of SD during seizures and the effect of SD on epileptic activity across cortical layers remain largely unknown. METHODS: We explored the spatial-temporal dynamics of SD and epileptic activity across layers of the rat barrel cortex using direct current silicone probe recordings during flurothyl-induced seizures. RESULTS: SD occurred in half of the flurothyl-evoked seizures. SD always started from the superficial layers and spread downward either through all cortical layers or stopping at the L4/L5 border. In cases without SD, seizures were characterized by synchronized population firing across all cortical layers throughout the entire seizure. However, when SD occurred, epileptic activity was transiently silenced in layers involved with SD but persisted in deeper layers. During partial SD, epileptiform activity persisted in deep layers throughout the entire seizure, with positive signals at the cortical surface reflecting passive sources of population spikes generated in deeper cortical layers. During full SD, the initial phase of SD propagation through the superficial layers was similar to partial SD, with suppression of activity at the superficial layers and segregation of seizures to deep layers. Further propagation of SD to deep layers resulted in a wave of transient suppression of epileptic activity through the entire cortical column. Thus, vertical propagation of SD through the cortical column creates dynamic network states during which epileptiform activity is restricted to layers without SD. SIGNIFICANCE: Our results point to the importance of vertical SD spread in the SD-related depression of epileptiform activity across cortical layers.

Functional brain connectivity in a rodent seizure model of autistic-like behavior.

OBJECTIVE: There is increasing evidence that Autism Spectrum Disorder (ASD) is a disorder of functional connectivity with both human and rodent studies demonstrating alterations in connectivity. Here, we hypothesized that early-life seizures (ELS) in rats would interrupt normal brain connectivity and result in autistic-like behavior (ALB). METHODS: Following 50 seizures, adult rats were tested in the social interaction and social novelty tests and then underwent qualitative and quantitative intracranial electroencephalography (EEG) monitoring in the medial prefrontal cortex (PFC) and the hippocampal subfields, CA3 and CA1. RESULTS: Rats with ELS showed deficits in social interaction and novelty, and compared with control, rats had marked increases in coherence within the hippocampus (CA3-CA1) and between the hippocampus and PFC during the awake and sleep states indicating hyperconnectivity. In addition, sleep spindle density was significantly reduced in rats with ELS. There were no differences in voltage correlations and power spectral densities between the ELS and control rats in any bandwidths. CONCLUSION: Taken together, these findings indicate that ELS can result in ALB and alter functional connectivity as measured by coherence and sleep spindle density. These findings implicate altered connectivity as a robust neural signature for ALB following ELS.

Enduring Memory Impairments Provoked by Developmental Febrile Seizures Are Mediated by Functional and Structural Effects of Neuronal Restrictive Silencing Factor.

In a subset of children experiencing prolonged febrile seizures (FSs), the most common type of childhood seizures, cognitive outcomes are compromised. However, the underlying mechanisms are unknown. Here we identified significant, enduring spatial memory problems in male rats following experimental prolonged FS (febrile status epilepticus; eFSE). Remarkably, these deficits were abolished by transient, post hoc interference with the chromatin binding of the transcriptional repressor neuron restrictive silencing factor (NRSF or REST). This transcriptional regulator is known to contribute to neuronal differentiation during development and to programmed gene expression in mature neurons. The mechanisms of the eFSE-provoked memory problems involved complex disruption of memory-related hippocampal oscillations recorded from CA1, likely resulting in part from impairments of dendritic filtering of cortical inputs as well as abnormal synaptic function. Accordingly, eFSE provoked region-specific dendritic loss in the hippocampus, and aberrant generation of excitatory synapses in dentate gyrus granule cells. Blocking NRSF transiently after eFSE prevented granule cell dysmaturation, restored a functional balance of γ-band network oscillations, and allowed treated eFSE rats to encode and retrieve spatial memories. Together, these studies provide novel insights into developing networks that underlie memory, the mechanisms by which early-life seizures influence them, and the means to abrogate the ensuing cognitive problems.SIGNIFICANCE STATEMENT Whereas seizures have been the central focus of epilepsy research, they are commonly accompanied by cognitive problems, including memory impairments that contribute to poor quality of life. These deficits often arise before the onset of spontaneous seizures, or independent from them, yet the mechanisms involved are unclear. Here, using a rodent model of common developmental seizures that provoke epilepsy in a subset of individuals, we identify serious consequent memory problems. We uncover molecular, cellular, and circuit-level mechanisms that underlie these deficits and successfully abolish them by targeted therapeutic interventions. These findings may be important for understanding and preventing cognitive problems in individuals suffering long febrile seizures.

Inhibition of blood-brain barrier efflux transporters promotes seizure in pregnant rats: Role of circulating factors.

Seizure-provoking factors circulate late in gestation during normal pregnancy, but do not readily gain access to the brain due to the protective nature of the blood-brain barrier. In particular, efflux transporters are powerful ATP-driven pumps that actively prevent unwanted compounds from entering the brain. We hypothesized that acute inhibition of efflux transporters at the blood-brain barrier would result in spontaneous seizures in pregnant rats. We further hypothesized that the blood-brain barrier protects the maternal brain from seizure by increasing expression and/or activity of p-glycoprotein (P-gp), a major efflux transporter. Main blood-brain barrier efflux transporters were inhibited in-vivo in nonpregnant (Nonpreg) and pregnant (Preg; d19) Sprague Dawley rats (n=8/group). Seizures were monitored in conscious animals for 8h via chronically implanted electroencephalography (EEG) electrodes in the hippocampus and motor cortex and time-synced video. P-gp activity was measured via a calcein accumulation assay in freshly isolated cortical and hippocampal capillaries from Preg (d20) and Nonpreg rats (n=8-16/group), to assess regional susceptibility to transporter inhibition. P-gp expression, capillary density, and microglial activation as a measure of neuroinflammation were quantified using immunohistochemistry (n=4-6/group). Efflux transporter inhibition elicited hippocampal seizures within 1h in 100% of Preg rats that was not associated with neuroinflammation or elevated tumor necrosis factor alpha (TNFα) or vascular endothelial growth factor (VEGF), but negatively correlated with levels of estradiol. Hippocampal seizures were considerably less prevalent in Nonpreg rats. However, behavioral seizures in the motor cortex developed of similar severity in both groups of rats, demonstrating regional heterogeneity in response to efflux transporter inhibition. Basal P-gp activity was similar between groups, however, exposure to serum from Preg rats significantly decreased P-gp activity in the hippocampus, but not cortex, compared to serum from Nonpreg rats (0.29±0.1units/s in Preg vs. 0.06±0.02units/s in Nonpreg rats; p<0.05) that was not associated with elevated TNFα or VEGF. Thus, pregnancy differentially increased the susceptibility of the hippocampus to seizures in response to blood-brain barrier efflux transporter inhibition that may be due to the inhibitory effect of circulating factors in pregnancy on P-gp activity in the hippocampus.

Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥2 years of age with focal seizures: The case for disease similarity.

Expediting pediatric access to new antiseizure drugs is particularly compelling, because epileptic seizures are the most common serious neurological symptom in children. Analysis of antiepileptic drug (AED) efficacy outcomes of randomized controlled trials, conducted during the past 20 years in different populations and a broad range of study sites and countries, has shown considerable consistency for each drug between adult and pediatric populations. Historically, the majority of regulatory approvals for AEDs have been for seizure types and not for specific epilepsy syndromes. Available data, both anatomical and neurophysiological, support a similar pathophysiology of focal seizures in adults and young children, and suggest that by age 2 years the structural and physiological milieu upon which seizures develop is similar. Although the distribution of specific etiologies and epilepsy syndromes is different in children from in adults, this should not impact approvals of efficacy based on seizure type, because the pathophysiology of focal seizures and the drug responsiveness of these seizure types are quite similar. Safety and pharmacokinetics cannot be extrapolated from adults to children. The scientific rationale, clinical consensus, and published data support a future approach accepting efficacy data from adult trials and focusing exclusively on prospective pharmacokinetic, tolerability, and safety studies and long-term follow-up in children. Whereas tolerability studies can be compared easily in children and adults, safety studies require large numbers of patients followed for many years.