Semiology, clustering, periodicity and natural history of seizures in an experimental visual cortical epilepsy model

Abstract

Objective:To characterize a rat model of focal neocortical epilepsy for use in developing novel therapeutic strategies in a type of epilepsy that represents a significant unmet need.Methods: Intracortical tetanus toxin (TeNT) injection was used to induce epilepsy in rats.Seizures and their behavioural manifestations were evaluated with continuous videoelectrocorticography telemetry. Results:TeNT injection into rat primary visual cortex induced focal neocortical epilepsy without preceding status epilepticus. The latency to first seizure ranged from 3 to 7 days.Seizure duration was bimodal, with both short (approximately 30s) and long-lasting (>100s) seizures occurring in the same animals. Seizures were accompanied by non-motor features such as behavioural arrest, or motor seizures with or without evolution to generalized tonicclonic seizures. Seizures were commoner during the sleep phase of a light-dark cycle.Seizure occurrence was not random, and tended to cluster with significantly higher probability of recurrence within 24 hours of a previous seizure. Across animals, the number of seizures in the first week could be used to predict the number of seizures in the following 22 days.Significance: The TeNT model of visual cortical epilepsy is a robust model of acquired focal neocortical epilepsy, and is well suited for preclinical evaluation of novel anti-epileptic strategies. We provide here a detailed analysis of the epilepsy phenotype, seizure activity, electrographic features, and the semiology. In addition we provide a predictive framework that can be used to reduce variation and consequently animal use in pre-clinical studies of potential treatments.3 Key Points Tetanus toxin injection into rat visual cortex induces focal cortical epilepsy. Electrographic seizures were associated with non-motor and motor features with or without evolution to generalized tonic-clonic seizures. Seizures could not be provoked by intermittent photic stimulation.  Seizures were clustered in time and exhibited a circadian variation in frequency. The number of seizures in first week after seizure onset could be used to predict the total number of seizures in the following 3 weeks.

Epilepsy gene therapy using non-integrating lentiviral delivery of an engineered potassium channel gene

“…proposing that seizure initiation is rapidly accompanied by propagation to other brain areas, beyond 216 the lentivector-treated region, consistent with the convulsions seen in the majority of seizures in the 217 visual cortex TeNT model (Chang et al, 2018). The difference, which parallels that seen with occipital lobe seizures and EPC in human patients, may 222 be a consequence of different connectivity in the occipital and motor cortices.…”

“…1C). As is 129 typical of this model (Chang et al, 2018), the total number of seizures experienced by each animal 130 over the 6 weeks of recording was highly variable (Fig. 1D).…”

“…In vitro studies showed that Kv1.1 overexpression 82 reduced both intrinsic neuronal excitability and glutamate release from transduced pyramidal 83 neurons (Heeroma et al, 2009;Wykes et al, 2012 To bring potassium channel gene therapy closer to the clinic, we have developed an optimized 102 lentiviral vector designed to boost Kv1.1 expression and reduce its inactivation with an engineered 103 KCNA1 gene (EKC), and improve safety with a cell type specific (CAMK2A) promoter and non-104 integrating delivery vector (Rahim et al, 2009;Yáñez-Muñoz et al, 2006). The lentivector was tested 105 for efficacy in a rat model of FNE characterised by long-lasting, discrete occipital cortex seizures 106 (Chang et al, 2018). In a blinded, randomized, placebo-controlled pre-clinical trial, EKC gene therapy 107 rapidly and persistently suppressed spontaneous seizures relative to a control lentivector without 108 EKC.…”