Sudden unexpected death in epilepsy (SUDEP) is a common cause of epilepsy-related
mortality, with an incidence of 1.2 per 1,000 persons (1). SUDEP causes 15–17% of
all epilepsy-related deaths and carries a lifetime risk of 4–8% (1, 2). Reliable biomarkers
and predictors are still lacking, but the most important risk factors are nocturnal
and frequent tonic-clonic seizures. Mechanisms include tachycardia and tachypnea followed
by bradycardia, asystole, and apnea in SUDEP cases documented in epilepsy monitoring
units (3). The underlying neuronal and molecular pathomechanisms that turn non-fatal
into fatal seizures remain to be elucidated, but brainstem dysfunction and spreading
depression as well as defects in serotonin-related signaling appear to be involved.
Comprehensive information about SUDEP is recommended and desired by most patients,
relatives, and caregivers. Improved seizure control by pharmacotherapy, epilepsy surgery,
and neuromodulatory devices is key to SUDEP prevention. Nocturnal supervision is associated
with reduced SUDEP risk, and clinically tested seizure detection systems are available.
Postictal breathing disturbances are a hallmark of monitored SUDEP cases (3). In this
Research Topic, Vilella et al. investigated the occurrence and influencing factors
of seizure-related central apnea in a prospective multicenter study. They found that
postictal central apnea occurred in about 20% of tonic-clonic seizures (generalized
convulsive seizures) in 20% of the patients, its recurrence risk amounted to about
50% in a given individual. Postictal central apnea was less frequent than ictal central
apnea and seen in all epilepsy types, possibly indicating different pathomechanisms.
In addition to respiratory dysfunction, recent studies described profound alterations
of systemic arterial blood pressure and its regulation in association with seizures
[e.g., (4, 5)], suggesting a possible role in SUDEP (6). Nass et al. summarize the
current knowledge on control of blood pressure in epilepsy, describe the relevant
cerebral mechanisms and pathways and discuss how epilepsy- and seizure-related blood
pressure alterations may contribute to premature mortality and SUDEP.
Risk Factor “Nocturnal Seizures” and Nutrition
Seizures arising from sleep or occurring during nighttime were identified as a risk
factor for SUDEP (7). To date, it is still unresolved whether this is predominantly
due to the fact that people are more often unsupervised or to distinct neuronal mechanisms
and networks properties related to sleep. Purnell et al. review the possible factors
contributing to the relationship between sleep and SUDEP and explain potential molecular
and neuronal mechanisms. In a mouse model of Dravet syndrome with high mortality,
Teran et al. observed that SUDEP rates and seizure frequency were higher in the early
evening and nighttime, suggesting that specific circadian or sleep-related neuronal
mechanisms increase the risk of SUDEP. They also noted that placing mice on a ketogenic
diet led to a considerable reduction in mortality. Importantly, the mice fed with
ketogenic diet did not have fewer seizures than control mice, indicating that nutritional
effects on mortality and the SUDEP rate were independent of seizure frequency. In
another experimental study of this Research Topic, Taha et al. tested the effects
of dietary measures on seizure thresholds in rat models of kindling and acute seizures.
They found that chronic dietary omega-3 polyunsaturated fatty acid deficiency did
not alter seizure thresholds, but impaired the effects of acutely applied omega-3
docosahexaenoic acid (Taha et al.) Altogether, the results of these two experimental
studies confirm that nutrition has an impact on brain excitability and underscore
that more research should be performed on diet in the context of epilepsy and maybe
Biomarkers, Risk Identification, and Prevention
The search for reliable biomarkers and predictors of an elevated SUDEP risk is of
great importance for designing appropriate safety measures and interventional studies
to prevent SUDEP. An increasing number of studies deals with the question whether
brain regions involved in the regulation of autonomic function display functional
and structural alterations that are linked to the SUDEP risk. If present, these alterations
could serve as neuroimaging markers that would help to identify people at higher risk.
In this Research Topic, Allen et al. have compiled recent findings on resting-state
functional and structural MRI studies, strengthening the view that disturbed central
autonomic and respiratory control contributes to the pathophysiology of SUDEP. For
instance, studies on morphometry and cortical thickness revealed reduced volume and
cortical thinning in the thalamus, frontal cortex and at brainstem sites in patients
with SUDEP and in those with tonic-clonic seizures. Importantly, the authors point
out that the MRI-based prediction of the individual SUDEP risk requires further studies.
A personalized estimation of the danger, however, would be very helpful when counseling
people with epilepsy and their relatives or caregivers. In this context, Shankar et
al. ask if “the time has come to stratify and score SUDEP risk to inform people with
epilepsy of their changes in safety”. The authors present work which identifies the
need to improve communication at a primary care level. They suggest that regular reviews
using a structured risk factor checklist as a screening tool would help in earlier
identification of people whose health is worsening and to justify referrals to specialists.
This Research Topic compiles recent findings on seizure-related breathing disturbances
and blood pressure regulation, reviews the impact of sleep and nutrition on brain
excitability and SUDEP and summarizes our current knowledge on neuroimaging markers.
The variety of the contributions illustrates that an increasing number of clinicians
and researchers are committed to understand SUDEP, identify biomarkers and develop
strategies and interventions to mitigate the SUDEP risk. These worldwide efforts are
also the success of tireless activities of patients, families and bereaved to promote
awareness for premature mortality in epilepsy and SUDEP (8).
RS drafted the editorial. MS and CD critically revised the draft.
Conflict of Interest
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.