Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers.
Whether long febrile seizures (FSs) can cause epilepsy in the absence of genetic or acquired predisposing factors is unclear. Having established causality between long FSs and limbic epilepsy in an animal model, we studied here if the duration of the inciting FSs influenced the probability of developing subsequent epilepsy and the severity of the spontaneous seizures. We evaluated if interictal epileptifom activity and/or elevation of hippocampal T2 signal on magnetic resonance image (MRI) provided predictive biomarkers for epileptogenesis, and if the inflammatory mediator interleukin-1beta (IL-1beta), an intrinsic element of FS generation, contributed also to subsequent epileptogenesis. We found that febrile status epilepticus, lasting an average of 64 min, increased the severity and duration of subsequent spontaneous seizures compared with FSs averaging 24 min. Interictal activity in rats sustaining febrile status epilepticus was also significantly longer and more robust, and correlated with the presence of hippocampal T2 changes in individual rats. Neither T2 changes nor interictal activity predicted epileptogenesis. Hippocampal levels of IL-1beta were significantly higher for >24 h after prolonged FSs. Chronically, IL-1beta levels were elevated only in rats developing spontaneous limbic seizures after febrile status epilepticus, consistent with a role for this inflammatory mediator in epileptogenesis. Establishing seizure duration as an important determinant in epileptogenesis and defining the predictive roles of interictal activity, MRI, and inflammatory processes are of paramount importance to the clinical understanding of the outcome of FSs, the most common neurological insult in infants and children.
Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, USA.
Céline M
CM
Dubé
Teresa
T
Ravizza
Mark
M
Hamamura
Qinqin
Q
Zha
Andrew
A
Keebaugh
Kimberly
K
Fok
Adrienne L
AL
Andres
Orhan
O
Nalcioglu
Andre
A
Obenaus
Annamaria
A
Vezzani
Tallie Z
TZ
Baram
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000009:adverse effects; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000209:etiology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D003294:Seizures, Febrile / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors; D053675:Versicans; D014741:Video Recording / Q000379:methods
D015415:Biomarkers; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D053583:Interleukin-1beta; D037102:Lectins; C508324:Vcan protein, rat; D053675:Versicans