The Kcna1 model of SUDEP exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death.

SummaryObjective: Chronic sleep deficiency is associated with early mortality. In the epileptic population, there is a higher prevalence of sleep disorders, and individuals with severe refractory epilepsy are at greater risk of premature mortality than the general population. Sudden unexpected death in epilepsy affects 1:1000 cases of epilepsy each year. Ketogenic diet (KD) treatment is one of the few effective options for refractory seizures. Despite KD reducing seizures and increasing longevity in Kv1.1 knockout (KO) mice, they still succumb to sudden death. This study aims to determine whether (1) the rest profiles of KO and KD-treated KO (KOKD) mice resemble each other as a function of either age or proximity to death and (2) the timing of death correlates with acute or chronic changes in rest. Methods: Noninvasive actimetry was used to monitor rest throughout the lives of KO and wild-type (WT) littermates administered standard diet or KD. Results: As KO mice age, rest is reduced (P < .0001). Rest is significantly improved in KDKO mice (P < .0001), resembling WT values at several ages. When age is removed as a variable and data are realigned to the day of death, the rest profiles of KO and KOKD groups worsen to similar degrees as a function of proximity to death. The amount of rest acutely is not sensitive to the timing of death, whereas chronic rest deficiency profiles (10-15 days prior to death) of both groups were indistinguishable. Chronic accumulation of rest deficiency over the final 15 days was associated with 75% of deaths. Significance: Our data suggest that the accumulated rest deficiency is associated with sudden death in Kv1.1 KO mice. These data (1) support the proposed clinical hypothesis that chronic sleep deficiency may be associated with early mortality in epileptic patients and (2) warrant future preclinical and clinical studies on sleep monitoring in epileptic patients. K E Y W O R D Sepilepsy, ketogenic diet, Kv1.1 knockout, sleep disorders, sudden unexpected death in epilepsy,

Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic‐clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2) in low‐risk and high‐risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high‐risk KO mice. Methods Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Results Intermittent bradycardia was more prevalent in high‐risk KO mice, an effect that may be the result of increased parasympathetic drive. High‐risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild‐type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea‐apnea. Blocking orexin receptors prevented the methacholine (MCh)–induced increase in breathing frequency in KO mice and reduced MCh‐induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high‐risk KO mice increased longevity. Significance High‐risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.

The present study attempts to chronicle the series of changes starting from the consumption of high fat diet till reproductive activity in male mice. A marginal increase in body weight was observed in male mice fed with high fat diet with 3-fold increase in total body fat and 1.4-fold increase in adipose tissue. A significant reduction in number and diameter of seminiferous tubules were observed in high fat diet fed mice compared to control mice. FACS analysis of testicular germ cells revealed very high percentage of apoptotic cells (84%) compared to control animals (2-3 %) indicative of reduced spermatogenic activity. In addition, a significant decrease in litter size (11.6%-Control to 3.66%-HFD) indicates that reproductive efficiency in high fat diet fed mice reduced to a great extent. The present study revealed high fat diet alters the fertility in male mice significantly and the first in this process appears to be apoptosis of testicular cells due to increase in ROS.