Baseline respiratory abnormalities as a predictor of SUDEP

Heidi L. Grabenstatter (2016) Irregular Respiratory Rhythm: A Physiological Biomarker of SUDEP Risk in Patients With Nocturnal Seizures?. Epilepsy Currents: September/October, Vol. 16, No. 5, pp. 327-329.

A subset of patients with temporal lobe epilepsy (TLE) have been identified as at greater risk for sudden unexpected/unexplained death in epilepsy (SUDEP), specifically, those with generalized tonic-clonic seizures, nocturnal seizures, early onset epilepsy, and long duration of epilepsy that is refractory to antiseizure drugs (ASDs). A few prototypical ASDs (e.g., carbamazepine) have also been associated with SUDEP risk. Over 30% of patients with TLE have seizures that are refractory to commonly used ASDs and 9 in 1000 of these intractable patients will die yearly from SUDEP. Given these contributing factors, there is a need for the 1) identification of reversible indicators (i.e., physiological biomarkers) of SUDEP risk in animal models of epilepsy and most importantly, 2) development of novel therapies to modify SUDEP biomarkers to prevent fatalities in this relatively large patient population…

Animal models and patients with TLE demonstrate more frequent seizures during non–rapid eye movement (NREM) sleep, and relatively infrequent seizures during REM. However, Hajek and Buchanan demonstrate that mice have 100% mortality following MES-induced seizures induced in REM sleep. Furthermore, mice that died following a seizure during any state had increased baseline respiratory rate variability. The added insult of an evoked seizure to an underlying predisposition to cardiorespiratory instability may overwhelm the system causing death. These results suggest respiratory rate variability is a valid biomarker of SUDEP risk and that regular monitoring of epileptic patients for baseline changes to determine increased risk is a reasonable clinical addition to the treatment of refractory epilepsy patients…

Seizures induced during sleep were more likely to be associated with respiratory suppression and death. Additionally, seizures induced during sleep were more severe and longer. All seizures were associated with respiratory arrest regardless of sleep state. However, postictal apnea was longer in mice that survived induced seizures in NREM compared with those occurring in wakefulness, and breathing (i.e., breaths/minute, ventilation, and tidal volume) was impaired upon recovery. In contrast, HRV (a common measure of intact cardiac function) was not significantly different comparing the different sleep states postictally. This may be attributed to the lack of assessment of the REM state due to 100% mortality following MES-induced seizures in REM sleep…

Interestingly, mice that died following a seizure had increased respiratory rhythm irregularity and a nonsignificant trend toward a reduced HRV (i.e., cardiac dysfunction) relative to those that survived. This was an insightful use of the data that could have easily been overlooked and points to future experiments that should be conducted in “at risk” epileptic animals with cardiorespiratory susceptibility at baseline. As animal and human studies have now demonstrated that impaired breathing, cardiac function, and arousal during and after seizures can be attributed to SUDEP, the next step may be to study these in subjects who do not die…

These studies provide the basic science community with an empirically tested result that validates the parental reports to clinicians that their child wakes gasping for breath following nocturnal GTCS that surely span decades. More importantly, the physiological marker of risk that Hajek and Buchanan have identified is not only easily monitored in at risk patients, but there are clinically-approved modes of intervention for patients identified as having irregular respiratory rates. Thus, studies by Hajek and Buchanan have set the stage for a potential means for the prevention of SUDEP-related fatalities. Important directions for future studies (some already in process by the Buchanan group and others) include the role of adenosine, serotonin, acetylcholine, and norepinephrine on autonomic control of the cardiorespiratory system and arousal changes occurring during spontaneous seizures. Additionally, trials should be conducted evaluating the effect of clinically used ASDs on respiratory rate, HRV, and sleep in spontaneously seizing animals.

Hajek MA, Buchanan GF. Influence of Vigilance State on Physiological Consequences of Seizures and Seizure-Induced Death in Mice.  J Neurophysiol 2016;115:2286–2293.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP occurs more commonly during nighttime sleep. The details of why SUDEP occurs at night are not well understood. Understanding why SUDEP occurs at night during sleep might help to better understand why SUDEP occurs at all and hasten development of preventive strategies. Here we aimed to understand circumstances causing seizures that occur during sleep to result in death. Groups of 12 adult male mice were instrumented for EEG, EMG, and EKG recording and subjected to seizure induction via maximal electroshock (MES) during wakefulness, nonrapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Seizure inductions were performed with concomitant EEG, EMG, and EKG recording and breathing assessment via whole body plethysmography. Seizures induced via MES during sleep were associated with more profound respiratory suppression and were more likely to result in death. Despite REM sleep being a time when seizures do not typically occur spontaneously, when seizures were forced to occur during REM sleep, they were invariably fatal in this model. An examination of baseline breathing revealed that mice that died following a seizure had increased baseline respiratory rate variability compared with those that did not die. These data demonstrate that sleep, especially REM sleep, can be a dangerous time for a seizure to occur. These data also demonstrate that there may be baseline respiratory abnormalities that can predict which individuals have higher risk for seizure-induced death.

See:  http://childnervoussystem.blogspot.com/2015/05/respiration-and-sudep.html