Abstracts

Rationale: Febrile status epilepticus (SE) accounts for 25-30% of pediatric SE episodes. The preoptic hypothalamus (POA) regulates the body’s thermal homeostasis; however, its activation during febrile seizures remains unexplored. We mapped activation of the temperature-sensing and respiratory control nuclei of the hypothalamus in a mouse model of febrile status epilepticus (fSE).

Methods: C57Bl6 pups (12-30 day-old, P12-30) of either sex were exposed to an elevated external temperature. Provoked seizures were monitored by continuous video-EEG. Brain temperature was monitored via a thermal probe placed in the secondary somatosensory cortex. Respiration rate (RR) was determined using whole-body plethysmography, and respiratory alkalosis was evaluated by measuring the blood pH. Immunohistochemistry was used to map cFos expression resulting from activation of the POA.

Results: Hyperthermia triggered fSE in P12-P30 animals. The highest incidence of fSE (90%) and the longest seizure duration (46 ± 12 min, n=10) was at P16/17. Mortality was low at P12-19, but 100% at P21 and P30. The brain temperature required to trigger seizures was 43-44°C. To reach this temperature a higher external temperature was required at P21 and P30. Hyperventilation and blood alkalosis preceded the onset of seizures at P16/17 and P21 but not at P30. The RR increased by 50-100% increased at P16/17 (n=6) and this was accompanied by a blood CO2 level of 17 ± 2 mm Hg (n= 4), which was lower than that of normothermic animals (blood CO2 level of 26 ± 2, n=4, p=0.014, t-test), and an alkaline blood pH of 7.56 ± 0.02, which was higher than that of the normothermic animals (pH of 7.43 ± 0.02, n= 4, p= 0.0072, t-test). The RR increased by 20-50% at P21 and P30 (n= 4 each). At P21, a reduction in pCO2 (fSE: 16 ± 5 vs normothermic: 33 ± 1; n=4 each group; p=0.019, t-test) and increase in blood pH (fSE 7.6 ± 0.06 vs normothermic: 7.4 ±0.02; n=4 each group: p=0.04, t-test) occurred. A similar change was not observed at P30 in either pCO2 (fSE 24 ± 3 mm Hg vs normothermic: 24 ± 4; n=4 each group) or pH (fSE 7.4 ± 0.04 vs normothermic 7.4 ± 0.02; n=4 each group).

cFos expression was observed in the thermoregulatory hypothalamus; this included median preoptic nucleus, medial preoptic nucleus, and lateral and ventrolateral preoptic areas. In contrast, cFos expression in the medial preoptic area did not change. Dorsomedial hypothalamus (DMH) and caudal lateral hypothalamus (LH), which regulate breathing were also activated in fSE animals (Figure 1).

Conclusions: We report a mouse model of fSE which replicated the developmental window of heightened susceptibility to febrile seizures seen in young children. The induction of seizures was associated with increased RR and blood alkalosis in the younger animals, but not in the P30 animals. The activation of thermosensitive hypothalamic nuclei could trigger fSE via direct connections to the cortex and limbic structures or indirectly via a hyperventilation response resulting from its activation of the DMH and caudal LH.

Funding: Please list any funding that was received in support of this abstract.: None.