Acquired epilepsy (i.e., after an insult to the brain) is often considered to be a progressive disorder, and the nature of this hypothetical progression remains controversial. Antiepileptic drug treatment necessarily confounds analyses of progressive changes in human patients with acquired epilepsy. Here, we describe experiments testing the hypothesis that development of acquired epilepsy begins as a continuous process of increased seizure frequency (i.e., proportional to probability of a spontaneous seizure) that ultimately plateaus. Using nearly continuous surface cortical and bilateral hippocampal recordings with radiotelemetry and semiautomated seizure detection, the frequency of electrographically recorded seizures (both convulsive and nonconvulsive) was analyzed quantitatively for ϳ100 d after kainate-induced status epilepticus in adult rats. The frequency of spontaneous recurrent seizures was not a step function of time (as implied by the "latent period"); rather, seizure frequency increased as a sigmoid function of time. The distribution of interseizure intervals was nonrandom, suggesting that seizure clusters (i.e., short interseizure intervals) obscured the early stages of progression, and may have contributed to the increase in seizure frequency. These data suggest that (1) the latent period is the first of many long interseizure intervals and a poor measure of the time frame of epileptogenesis, (2) epileptogenesis is a continuous process that extends much beyond the first spontaneous recurrent seizure, (3) uneven seizure clustering contributes to the variability in occurrence of epileptic seizures, and (4) the window for antiepileptogenic therapies aimed at suppressing acquired epilepsy probably extends well past the first clinical seizure.

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In organotypic hippocampal slice cultures, principal neurons form aberrant excitatory connections with other principal cells in response to slicing-induced deafferentation, similar to mechanisms underlying epileptogenesis in post-traumatic epilepsy. To investigate the consequences of this synaptogenesis, we recorded field potential activity from area CA3 during perfusion with the complete growth medium used during incubation. At 7 days in vitro (DIV), slice cultures only displayed multi-unit activity. At 14 DIV the majority displayed population bursts reminiscent of interictal-like spikes, but sustained synchronous activity was rare. Bandpass filtering of interictal discharges revealed fast ripple-like complexes, similar to in vivo recordings. Spontaneous ictal-like activity became progressively more prevalent with age: at 21 DIV 50% of organotypic hippocampal slice cultures displayed long lasting, ictal-like discharges that could be suppressed by phenytoin, whereas interictal-activity was not suppressed. The fraction of cultures displaying ictal events continually increased with incubation time. Quantification of population spike activity throughout epileptogenesis using automatic detection and clustering algorithms confirmed the appearance of interictal-like activity before ictal-like discharges, and also revealed high frequency pathological multi-unit activity in slice cultures at 14–17 DIV. These experiments indicate that interictal-like spikes precede the appearance of ictal-like activity in a reduced in vitro preparation. Epileptiform activity in cultures resembled in vivo epilepsy, including sensitivity to anticonvulsants and steadily increasing seizure incidence over time, although seizure frequency and rate of epileptogenesis were higher in vitro. Organotypic hippocampal slice cultures comprise a useful model system for investigating mechanisms of epileptogenesis as well as developing anti-epileptic and anti-epileptogenic drugs.

Synchronous activation of neural networks is an important physiological mechanism, and dysregulation of synchrony forms the basis of epilepsy. We analyzed the propagation of synchronous activity through chronically epileptic neural networks. Electrocortigraphic recordings from epileptic patients demonstrate remarkable variance in the pathways of propagation between sequential interictal spikes (IIS). Calcium imaging in chronically epileptic slice cultures demonstrates that pathway variance depends on the presence of GABAergic inhibition and that spike propagation becomes stereotyped following GABA-R blockade. Computer modeling suggests that GABAergic quenching of local network activations leaves behind regions of refractory neurons, whose late recruitment forms the anatomical basis of variability during subsequent network activation. Targeted path scanning of slice cultures confirmed local activations, while ex vivo recordings of human epileptic tissue confirmed the dependence of interspike variance on GABA-mediated inhibition. These data support the hypothesis that the paths by which synchronous activity spread through an epileptic network change with each activation, based on the recent history of localized activity that has been successfully inhibited.

Background: Computer analysis of high-resolution CT (HRCT) scans may improve the assessment of structural lung injury in children with cystic fi brosis (CF). The goal of this cross-sectional pilot study was to validate automated, observer-independent image analysis software to establish objective, simple criteria for bronchiectasis and air trapping.