Single injection of a low dose of pentylenetetrazole leads to epileptogenesis in an animal model of cortical dysplasia.

Purpose: Cortical dysplasia (CD) is one of themost frequent causes of pharmacoresistent focalepilepsy. Despite signiﬁcant advances in variousdiagnostic and therapeutic methods, the basicmechanisms of higher susceptibility for seizures inpatients with CD are unknown. Animal models ofCD present with a lower threshold for seizureinduction. The purpose of this study is to furthercharacterize the animal model of in utero radia-tion-induced CD and to illustrate the effect of alate postnatal second hit (low dose of pentylen-etetrazole,PTZ)onthedevelopmentofspontane-ousseizures.Methods: Pregnant Sprague–Dawley rats wereirradiated on E17 (145 cGy; control group was leftuntreated). Litters were implanted with bifrontalepidural and hippocampal depth electrodes. Afterbaseline electroencephalography (EEG) record-ing, animals received 30 mg/kg PTZ and werechronically monitored. Histopathology of thebrainswasveriﬁed.Results:Noseizuresweredetectedinanimalsthatdid not receive PTZ. PTZ-injected irradiated(XRT) rats showed severe prolonged, repetitiveseizures during the acute period. During thechronic period, XRT rats had recurrent seizuresand epileptiform spikes. PTZ-injected control ani-mals exhibited milder and fewer acute seizuresand did not show seizures during the chronicperiod. Histology was consistent with cortical andhippocampaldysplasia.Conclusions: This study shows that a single treat-ment with a low dose of PTZ renders XRT rats(but not age-matched controls) epileptic, exhibit-ing spontaneous epileptiform spikes and seizureson EEG. These results might mirror the naturalhistory of patients with CD thought to be causedbyprenatal/congenitalorperinatalinsults.KEY WORDS: Cortical dysplasia, In utero radia-tion,Animalmodel,Secondhit,Epilepsy.Cortical dysplasia (CD) is a confirmed histopathologicfinding in many cases of medically intractable epilepsy(Taylor et al., 1971; Corsellis et al., 1973). Many reportsfrom epilepsy surgery centers describe a high correlationbetween different types of cortical dysplasia and epilep-togenicityinpatientswithintractableepilepsy.Retrospectively,alargepercentage ofpatientswithepi-lepsy have been diagnosed with malformations of corticaldevelopment (MCD). As witnessed in clinical practice,thesepatientpopulationswithcongenitalorattimespossi-bly perinatal lesions develop seizures at different ages,starting during the neonatal period all the way to adult-hood (Widdess-Walsh et al., 2005). Several mechanismsmay play a role in triggering the onset of seizures inpatients who are at particularly high risk, such as thosewith preexisting cortical dysplasia. In fact, patients withan underlying MCD substrate may have a higher risk ofdeveloping epilepsy (Porter et al., 2003). Triggers for thedevelopment of epilepsy in susceptible patients includefebrile seizures in children, trauma, infection involvingthe brain or meninges,stroke, hypoglycemia or other met-abolic disturbances, and a variety of other insults causingdamage to the brain or surrounding structures (Widdess-Walshetal.,2005).Thestudyofsuchconditionsislimitedby the availability of surgically resected tissue from epi-leptic patients, as well as the technical and ethical issuesinvolvedindealingwithhumansubjects.Anotherconcern