Temperature homeostasis disruption and hypothalamic alterations in experimental drug-resistant epilepsy

Elevated body temperature may increase seizure risk, yet the relationship between thermoregulation and seizures, as well as the underlying mechanisms, remains poorly understood. We investigated whether thermoregulatory control is altered in experimental temporal lobe epilepsy (TLE), as such impairment could reduce the ability of affected individuals to adapt to environmental temperature changes.

Using an adult mouse model of temporal lobe epilepsy (TLE), we longitudinally measured brain temperature before and after epilepsy onset using 7 T ¹H-magnetic resonance spectroscopy thermometry. The temporal relationship between spontaneous seizures and body temperature fluctuations was assessed using electroencephalographic recordings combined with implanted temperature probes under controlled environmental conditions. Neuronal density, glial reactivity, and transcriptomic profiles were examined in hypothalamic temperature-sensing regions (ventromedial preoptic nucleus [VMPO] and dorsomedial nucleus [DMD]) in epileptic mice and sham mice. Hypothalamic volume was assessed by magnetic resonance imaging (MRI) in both mice and people with epilepsy (PWE). Serum thyroid-stimulating hormone (TSH), T3, and T4 concentrations were measured as indices of hypothalamic-pituitary-thyroid (HPT) axis activity and metabolic thermogenesis.

Hippocampal temperature increased by ~.5-1.5°C prior to epilepsy onset (3 days postkainate) and remained elevated during chronic epilepsy (1.5 months postkainate). Acutely, body temperature rose from 15 min before to 15 min after spontaneous seizures. Serum T3 and T4 levels were reduced by ~50% without compensatory TSH elevation, indicating HPT axis dysregulation in epileptic mice. Neuronal density in VMPO and DMD decreased by ~20% in chronic epileptic mice versus sham mice (p < .05), accompanied by induction of FosB, immune/inflammatory pathways, and glia reactivity. MRI revealed reduced hypothalamic volume in epileptic mice (p < .05), paralleling findings in PWE.

Thermoregulatory control is impaired in experimental TLE and is associated with neuronal loss and inflammation in hypothalamic temperature-sensing regions. These findings reveal a link between thermoregulatory dysfunction and epilepsy and highlight that alterations in temperature homeostasis may interact with mechanisms underlying seizure generation.