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Review
. 2014 May;10(5):271-82.
doi: 10.1038/nrneurol.2014.64. Epub 2014 Apr 22.

Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention

Cory A Massey  1 , Levi P Sowers  1 , Brian J Dlouhy  2 , George B Richerson  1
Affiliations
Review

Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention

Cory A Massey et al. Nat Rev Neurol. 2014 May.

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, with an estimated 35% lifetime risk in this patient population. There is a surprising lack of awareness among patients and physicians of this increased risk of sudden death: in a recent survey, only 33% of Canadian paediatricians who treated patients with epilepsy knew the term SUDEP. Controversy prevails over whether cardiac arrhythmia or respiratory arrest is more important as the primary cause of death. Effective preventive strategies in high-risk patients will rely on definition of the mechanisms that lead from seizures to death. Here, we summarize evidence for the mechanisms that cause cardiac, respiratory and arousal abnormalities during the ictal and postictal period. We highlight potential cellular mechanisms underlying these abnormalities, such as a defect in the serotonergic system, ictal adenosine release, and changes in autonomic output. We discuss genetic mutations that cause Dravet and long QT syndromes, both of which are linked with increased risk of sudden death. We then highlight possible preventive interventions that are likely to decrease SUDEP incidence, including respiratory monitoring in epilepsy monitoring units and overnight supervision. Finally, we discuss treatments, such as selective serotonin reuptake inhibitors, that might be personalized to a specific genetic or pathological defect.

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Figures

Figure 1
Figure 1. Distribution of SUDEP cases by age
The peak age of SUDEP incidence occurs at 30 years old.
Figure 2
Figure 2. Cardiac and respiratory abnormalities commonly occur following seizure activity in mice and humans
A) EEG (black) and EKG (blue) traces from Dravet syndrome mice that died prematurely illustrating bradycardia following a seizure. Modified with permissions from Kalume et al., 2013. B) Oxygen saturation drops below 40% during a partial seizure in a 19-year-old male patient. Patient was awake and sitting in bed during the hypoxic event. Seizure duration is marked by bottom arrows. Heart rate is marked by the upper arrows and beats per minute are given. Modified with permission from Bateman et al., 2008.
Figure 3
Figure 3. Anatomical distribution of arousal networks and brain stem nuclei that could be affected by seizure
A) Seizure in forebrain activates anatomical connections leading to dysfunction of brainstem nuclei critical for cardiorespiratory control. PreBotC: Pre-Botzinger complex, BotC: Botzinger complex, NTS: Nucleus tractus solitaries, NA: Nucleus ambiguous. B) Seizure spread into the midbrain disrupts both ascending and descending arousal systems. TMN : tuberomammillary nucleus, LDT: Laterodorsal tegmental nucleus, PPT: pedunculopontine tegmental nucleus, LC: Locus coeruleus.
Figure 4
Figure 4. Hypothesized model for SUDEP
A patient with epilepsy has a seizure which spreads to both the midbrain and medulla. Spread to the midbrain causes acute dysfunction of the ascending arousal system, including 5-HT neurons, which leads to PGES and arousal failure. When combined with the face in pillows or bedding, the arousal failure leads to hypoventilation. Seizure spread into the medulla causes disruption of descending arousal system. This, along with increased extracellular adenosine, precipitates dyfunction in both respiratory nuclei and autonomic and cardiovascular control. Hypoventilation, apnea, and arrhythmias develop and lead to severe hypercapnia, hypoxia, and death.
Figure 5
Figure 5. Proposed sequence of events surrounding a respiratory death
Normal vitals and EEG during the pre-ictal state. Seizure begins as a focal seizure and tachycardia quickly follows. Upon seizure generalization, ictal apnea occurs and pO2 begins to fall. Tachycardia continues until the end of the seizure while the pO2 continues to drop and the pCO2 begins to rise during the seizure. In the post-ictal state, PGES occurs and there is bradycardia which worsens over the course of several minutes. Tachypnea occurs due to decreased pO2 and increased pCO2 but respiratory activity decreases and apnea occurs again. pO2 drops to dangerously low levels and the patient becomes severely hypoxic and hypercapnic. Terminal gasps occur, but auto-resuscitation fails. Finally, the patient's heart stops and death quickly follows.
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References

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