Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death, likely stemming from seizure activity disrupting vital brain centers controlling heart and breathing function. However, understanding of SUDEP's anatomical basis and mechanisms remains limited, hampering risk evaluation and prevention strategies. Prior studies using a neuron-specific Kcna1 conditional knockout mouse model of SUDEP identified the primary importance of brain-driven mechanisms contributing to sudden death and cardiorespiratory dysregulation; yet, the underlying neurocircuits have not been identified. Using the Emx1-Cre driver, we generated a new conditional knockout mouse model lacking Kcna1 in excitatory neurons of the cortex, hippocampus, amygdala, and select vagal afferents. To test whether the absence of Kv1.1 in forebrain corticolimbic circuits is sufficient to induce spontaneous seizures, premature mortality and cardiorespiratory dysfunction, we performed survival studies and electroencephalogram, electrocardiogram, and plethysmography (EEG-ECG-Pleth) recordings. We demonstrate premature death and epilepsy in corticolimbic conditional knockout mice. During monitoring, we fortuitously captured one SUDEP event, which showed a generalized tonic-clonic seizure that initiated respiratory dysfunction culminating in cardiorespiratory failure. In addition, we observed that cardiorespiratory abnormalities are common during nonfatal seizures in conditional knockout mice, but mostly absent during interictal periods, implying ictal, not interictal, cardiorespiratory impairment as a more reliable indicator of SUDEP risk. These results point to corticolimbic excitatory neurons as critical neural substrates in SUDEP and affirm seizure-related respiratory and cardiac failure as a likely cause of death.
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Paulhus and colleagues also instrumented a subset of the Kcna1 cKO mice for cardiac and respiratory measurement during seizures and found that some seizures caused cardiac arrhythmias and respiratory dysfunction. Cardiac dysfunction was rare, occurring in less than 27% of seizures, and included conduction block, tachycardia, and bradycardia. Using chronic whole-body plethysmography recordings, a much greater proportion (up to 70%) of seizures were found to produce respiratory dysfunction. The most common respiratory phenotype was tachypnea or increased respiratory rate. Considering the energetic demands of seizures, an increased breathing rate may not be unexpected; however, suppressed breathing in the form of hypopnea, bradypnea, and apnea was also observed in many seizures. The authors also point out that cardiac dysfunction never preceded, and usually (about 80%) followed, respiratory dysfunction. This finding is significant as it suggests that cardiac anomalies may result from prior dysfunctional breathing, as was observed in all SUDEP cases in the MORTEMUS study.
The authors were fortunate to catch a single fatal seizure with adequate cardiorespiratory monitoring. The fatal seizure was a GTCS with an extended tonic phase at the end that coincided with bradycardia and apnea. This is similar to observations in germline KO of Kcna1 and other models.5,6,10 Prior to the fatal seizure, this mouse had experienced 15 GTCS-equivalent seizures in the preceding 24 h. In addition, this mouse had the longest seizure durations of any mouse recorded in the study. Taken together, the mouse that died from SUDEP had a significant seizure burden that may have led to the fatality.
As mentioned above, a dichotomy exists in SUDEP occurrence. On the one hand, the number of GTCSs is a clear predictor of SUDEP likelihood. On the other hand, numerous cases of SUDEP where few seizures have been observed and/or seizures are well controlled are reported. The current preclinical study provides a model of the former situation. The single observed fatality was in a mouse that had a high seizure burden. A question going forward: “Is seizure burden a correlation or a cause?” That is, did the repetitive seizures in the Kcna1 cKO mouse cause lasting changes (ie, plasticity) that enabled production of the eventual terminal seizure? Or is a more severe seizure phenotype also results in fatality? Perhaps, based on the clinical data, the circumstances of a fatal seizure are somewhat stochastic and a larger sample set of seizures simply increases the odds. More work is needed, but a role for the cortical and limbic system cannot be ignored when trying to understand the neural circuitry of SUDEP.
We still know so little about SUDEP. Identifying biomarkers and therapeutically relevant mechanisms will be critical in the development of treatment strategies. It may be that patients with prolonged and frequent seizures, and possibly co-occurring cardiorespiratory dysfunction, are most at risk and would benefit from intervention. Having a diverse range of animal models that explore different pathways to the same outcome will help us identify other risk factors and lead to better outcomes for patients with epilepsy.
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