This study did not monitor the vigilance state of the animal at the time of the fatal seizure, so it is impossible to determine whether this is an effect of sleep, circadian time, or both. Figure 2. Temporal distribution of spontaneous seizure induced death in Kv1.
Seizures induced by MES during the day, the rodent inactive phase, are similar to seizures induced during the night in terms of duration and severity; however, MES seizures induced in the day during sleep resulted in a greater degree of postictal respiratory suppression Figure 3 , Seizures induced during this time also resulted in prolonged EEG suppression. This effect was even greater when seizures were also induced during sleep Two caveats to this data are that only two time points were compared, and these experiments were conducted with the animals in a light-dark cycle environment.
A broader sampling of time points throughout the 24 h day and conducting experiments in constant darkness, i.
Figure 3. Quantification of seizure induced suppression of breathing RR; respiratory rate, V T ; tidal volume, V E ; minute ventilation following maximal electroshock seizures induced during wakefulness or non-rapid eye movement sleep NREM at different times of day [redrawn with permission from Purnell et al.
SUDEP victims are more likely to have a nocturnal pattern of seizures 12 , Presently, it is impossible to determine whether this effect is driven by circadian rhythms or homeostatic sleep processes. SUDEP is not uniformly distributed throughout the 24 h day SUDEP presumed to have happened during sleep most commonly occurred between and SUDEP which is presumed to have happened during wakefulness most commonly occurred between the and The increased risk of seizures between and 1, is interesting as it suggests that there may be a circadian component to SUDEP which occurs independent of sleep state.
If the nocturnality of SUDEP was attributable to sleep factors alone it would be expected that SUDEP frequency would decrease dramatically after when most people are no longer sleeping. In the central nervous system, serotonergic neurons are found in the raphe nuclei along the midline of the brainstem Serotonergic neurotransmission modulates breathing, sleep-wake regulation, circadian rhythmicity, and seizures — Neuronal activity in the raphe nuclei is highest during wakefulness, reduced during NREM sleep, and almost entirely silent during REM sleep Serotonin levels vary depending on circadian phase in areas such as the dorsal raphe, locus coeruleus, and hippocampus [Figure 4 , , , , ].
Seizures suppress serotonergic neurotransmission in the ictal and the postictal period Increases in serotonergic neurotransmission is a critical component of the arousal response to inspired CO 2 — Stable breathing requires serotonergic neurotransmission Seizure induced disruption of normal serotonergic arousal mechanisms may prevent the normal arousal response to CO 2 in the postictal period and facilitate death Figure 4.
In epilepsy patients, selective serotonin reuptake inhibitors SSRI reduce seizure associated hypoxemia Larger seizure induced changes in serum serotonin are associated with a reduction in the tonic phase of a convulsive seizure Furthermore, interictal serum serotonin levels are associated with shorter PGES The likelihood of seizure induced respiratory arrest is also reduced by administration of 5-hydroxytryptophan, a molecule required in serotonin synthesis Conversely, serotonin antagonism increases the likelihood of seizure induced respiratory arrest consequent to audiogenic seizures Times in which serotonergic activity is lower, such as the during the night, may lower seizure threshold and make seizures which do occur more dangerous , , Adenosine is a purinergic transmitter which is found in many brain areas and known for its role in sleep-wake regulation, breathing, epilepsy, and a variety of other diseases — Adenosine accumulation and clearance is regulated in a circadian fashion in a variety of brain areas [Figure 4 , — , ].
Adenosine levels increase during wakefulness and are depleted during sleep , The sleep disturbances often associated with epilepsy may be explained by alterations in adenosine signaling Adenosine is an endogenous anticonvulsant and adenosine levels increase during seizures , Furthermore, manipulations to adenosine or its clearance modulate epileptogenesis — Having recurrent seizures may, in turn, decrease, or increase adenosine levels in different brain areas Adenosine analogs applied to the brainstem of rats cause prolonged suppression of breathing , Adenosine analogs administered intracerebroventricularly decrease respiration and elicits apnea in cats Inhibition of adenosine clearance initially prevents the escalating severity of motor seizures following kainate injection; however, the adenosine kinase inhibited animals quickly progress to more severe motor seizures and invariably die, whereas animals not subjected to adenosine kinase inhibition do not die.
Treating with caffeine following seizure onset prolongs survival in mice subjected to inhibition of adenosine clearance prior to seizure induction with kainate These results suggest that an unchecked surge in adenosine consequent to a seizure may result in precariously increased levels of neuronal inhibition and thereby facilitate death Norepinephrine, a catecholaminergic neurotransmitter found in the rostral brainstem including in the locus coeruleus, modulates seizure activity, breathing, , and is subject to circadian regulation in an array of different brain areas [Figure 4 , , — ].
Like serotonin, norepinephrine promotes wakefulness and is an important part of the ascending arousal system In light of this evidence, times at which noradrenergic tone is low might make seizure induced respiratory arrest more likely. The reason that SUDEP happens more during the night is likely multifactorial involving both situational factors, such as being unattended, and physiological changes due to the influence of sleep and circadian rhythms.
Human studies suggest that being without a witness and prone following a seizure, which is more likely during the night, might increase risk for nocturnal SUDEP. At the same time, experimentation in animal models and observation of human seizures indicate that both sleep and circadian phase may adversely affect postictal cardiovascular recovery.
Sleep and circadian phase have additive effects on breathing which may compound in some way to produce a hazardous postictal state. Similarly, it may be that sleep, and circadian phase have additive effects on vulnerability to seizure induced respiratory arrest. When the factors associated with being without a witness and prone are added to the mix along with the potential effects of sleep and circadian phase SUDEP might be more likely Figure 5. Figure 5. A schematic representation of how different factors relevant to the night might alter the likelihood that a seizure results in SUDEP.
Altering the circumstances in which a seizure occurs is currently the best way for reducing the probability of nocturnal SUDEP, but it is not enough. Patients who do not sleep alone or are being monitored by the use of a device seem to be somewhat protected against SUDEP; however, numerous SUDEP cases have occurred in the direct presence of medical professionals and none of their interventions were sufficient to prevent death. Families and caregivers should be educated about SUDEP and given instruction in basic seizure first aid; however, it should be made abundantly clear that such interventions might be sufficient to prevent death, but it might not and those who have lost someone due to SUDEP are in no way at fault.
The risk of SUDEP, nocturnal and otherwise, should be taken into account by patients considering any choice which might alter their likelihood of having a seizure such as adherence, titrating off their medications, switching medication, or pursuing surgical interventions or other non-pharmacological measures.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Opeskin K, Berkovic SF. Risk factors for sudden unexpected death in epilepsy: a controlled prospective study based on coroners cases. Seizure — Neurology —3. Jehi L, Najm IM. Sudden unexpected death in epilepsy: impact, mechanisms, and prevention. Cleve Clin J Med 75 Suppl. Sudden unexpected death in epilepsy: assessing the public health burden.
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